Neuropsychiatric Disorders

Neuropsychiatric Disorders
Koho Miyoshi Yasushi Morimura

●
Kiyoshi Maeda
Editors
Neuropsychiatric Disorders
Editors
Koho Miyoshi, M.D., Ph.D. Yasushi Morimura, M.D, Ph.D.
Director Chief Executive Officer
Jinmeikai Research Institute for Mental Jinmeikai Foundation and Hospital
Health 53-20 Kabutoyama-cho, Nishinomiya
53-20 Kabutoyama-cho, Nishinomiya Hyogo 662-0001, Japan
Hyogo 662-0001, Japan
Ohmura Hospital
The former Professor 200 Kitayama-Ohmura, Miki
Department of Neuropsychiatry Hyogo 673-0404, Japan
Kyoto University Graduate School
of Medicine
Kyoto, Japan
Kiyoshi Maeda, M.D., Ph.D.

Professor
Department of Occupational Therapy
Kobe Gakuin University School of
Rehabilitation
518 Ikawadani-cho, Nishi-ku
Kobe 651-2180, Japan
ISBN 978-4-431-53870-7 e-ISBN 978-4-431-53871-4

DOI 10.1007/978-4-431-53871-4
Springer Tokyo Dordrecht Heidelberg London New York
Library of Congress Control Number: 2010924621
© Springer 2010
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,
reproduction on microfilm or in any other way, and storage in data banks.
The use of general descriptive names, registered names, trademarks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant protective
laws and regulations and therefore free for general use.
Product liability: The publishers cannot guarantee the accuracy of any information about dosage and
application contained in this book. In every individual case the user must check such information by
consulting the relevant literature.
Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)

Preface
Neuropsychiatry is an integrating neuroscience of neurology and psychiatry that

aims to investigate the psychiatric symptoms of neurological disorders as well as
the neurobiological bases of psychiatric disorders, including organic mental disor-
ders and endogenous psychoses. Additionally, neuropsychiatry aims to prevent or
reduce the suffering of individuals with the psychiatric symptoms of cerebral
disorders. The International Organization of Neuropsychiatry (ION), the forerunner
of the current association, was established in Seville in 1996 and was reorganized as
the International Neuropsychiatric Association (INA) in Toronto in 1998. Since then,
it has continued to provide a forum for exchanging knowledge acquired by scientific
activities in the field to accomplish the purposes of the association. Toward that end,
international congresses have been held every 2 years in cities around the world:
Seville (1996), Toronto (1998), Kyoto (2000), Buenos Aires (2002), Athens (2004),
Sydney (2006), and Cancun (2008). In addition to the international congresses,
regional congresses of neuropsychiatry have been organized regularly in Europe and
Latin America. All the meetings have been successful and fruitful in stimulating
progress in neuropsychiatry. As one of the results of the meetings, the monograph
Contemporary Neuropsychiatry was published by Springer Japan in 2001.
This present monograph consists of papers from the Kobe Conference of the
International Neuropsychiatric Association, which was held by the International
Neuropsychiatric Association in collaboration with the Jinmeikai Foundation and
the Japan Neuropsychiatric Association in Kobe, September 12–13, 2009. The
meeting was originally planned to be a semi-closed workshop for the publication
of this monograph in neuropsychiatry. Because the meeting was organized to be
held between two international congresses of neuropsychiatry – the 7th INA
Congress in Cancun (2008) and the 8th INA Congress in Chennai (2011) – it was
planned so as to concentrate on rather limited areas of neuropsychiatry, namely, the
clinical aspects of neuropsychiatric disorders.
As the editors, we are confident that this publication will stimulate further progress
and research in neuropsychiatry in all parts of the world. We express our heartfelt
gratitude for the contributions by all the authors who attended the meeting and sub-
mitted papers. We are very pleased to have received their excellent work in neurop-
sychiatry for this publication. We express our special appreciation to Dr. Perminder
Sachdev, who allowed us to publish “The Core Curriculum of Neuropsychiatry,”
v
vi Preface
which originally appeared on the website of the International Neuropsychiatric

Association in 2004, for standardizing the guidelines of training in neuropsychiatry.
We would like to acknowledge the support for the Kobe Conference of the
International Neuropsychiatric Association by the Jinmeikai Foundation, Ohmura
Hospital, the Federation of Pharmaceutical Manufacturers Association of Japan,
the Osaka Pharmaceutical Manufacturers Association, Kaiseikai (Japan Psychiatric
Association for Partnership), the Kobe Convention and Visitors Association, the
Tsutomu-Nakauchi Foundation, Japan Eisai Pharmaceutical Company, Japan Pfizer
Pharmaceutical Company, Japan Janssen Pharmaceutical Company, and Japan Eli
Lilly Pharmaceutical Company.
Koho Miyoshi, M.D., Ph.D.
Yasushi Morimura, M.D., Ph.D.
Kiyoshi Maeda, M.D., Ph.D.
Editors
Contents
Part I Introduction
Clinical Manifestations of Neuropsychiatric Disorders .............................. 3

Koho Miyoshi and Yasushi Morimura
Part II Neuropsychiatric Syndromes
Thyroid–Brain Interactions in Neuropsychiatric Disorders ....................... 19

Robertas Bunevičius and Arthur J. Prange, Jr.
Lack of Insight and Awareness in Schizophrenia

and Neuropsychiatric Disorders .................................................................... 33
James Gilleen, Kathryn Greenwood, and Anthony S. David
Visual Hallucinations in Neurodegenerative Disorders............................... 51

Spyridon Papapetropoulos and Blake K. Scanlon
Organic Delusional Syndrome: Tentative Neuropsychological

Mechanism of Delusions ................................................................................. 65
Yoshitaka Ohigashi and Makiko Yamada
Neurological and Psychological Forms of Amnesia ..................................... 77

Michael D. Kopelman
Part III Seizure Disorders
The Neuropsychological Aspect of Epilepsy ................................................. 95

Yoshio Morita
The Interictal Dysphoric Disorder of Epilepsy ............................................ 103

Marco Mula
vii
viii Contents
Neuropsychiatric Symptoms of Seizure Disorders

with Special Reference to the Amygdala....................................................... 113
Michael Trimble
Part IV Traumatic Brain Injury
Neuropsychiatric Assessment of Traumatic Brain Injury

During Acute Neurorehabilitation ................................................................ 125
David B. Arciniegas
Part V Vascular and Inflammatory Disorders
Neuropsychiatric Aspects of Vascular Cognitive Impairment.................... 149

Ingmar Skoog
Neuropsychiatric Complications of Cerebrovascular Disease .................... 163

Moises Gaviria and Rhonda DePaul Verzal
Systemic Inflammation and Cognition in the Elderly ................................. 177

Julian Trollor and Emmeline Agars
Part VI Neurodegenerative Disorders
Diagnosis and Clinical Relevance of Depression and Apathy

in Alzheimer’s Disease .................................................................................... 201
Sergio E. Starkstein and Simone Brockman
Cognitive Decline and Treatment of Alzheimer’s Disease ........................... 213

Luis Ignacio Brusco
Alzheimer’s Disease in Japan: Current Situation

and Issues of the Care for Persons with Dementia....................................... 227
Akira Homma
AD-FTLD Spectrum: New Understanding

of the Neurodegenerative Process from the Study of Risk Genes............... 235
Masatoshi Takeda, Takashi Kudo, Toshihisa Tanaka,
Masayasu Okochi, Ryota Hashimoto, Takashi Morihara,
and Shinji Tagami
Dementia with Lewy Bodies ........................................................................... 247

Ian Grant McKeith
Dementia with Lewy Bodies and Parkinson Disease

with Dementia Within the Spectrum of Lewy Body Disease ...................... 255
Kenji Kosaka
Contents ix
Clinicopathological Characterization of Frontotemporal

Lobar Degeneration ........................................................................................ 261
Yoshio Mitsuyama
Diffuse Neurofibrillary Tangles with Calcification ...................................... 271

Shigetoshi Kuroda, Hideki Ishizu, Seishi Terada, Osamu Yokota,
Yasuyuki Tanabe, and Takashi Haraguchi
Part VII Topics of Neuropsychiatric Disorders
Ayahuasca: Current Interest in an Ancient Ritual ...................................... 281

Eduardo Gastelumendi
The Molecular Genetics of Suicide ................................................................ 287

Kiyoshi Maeda, Osamu Shirakawa, Naoki Nishiguchi,
and Masaaki Fukutake
Part VIII International Neuropsychiatric Association
Brief History and Current Status of the International

Neuropsychiatric Association......................................................................... 301
Koho Miyoshi
Core Curriculum in Neuropsychiatry of the International

Neuropsychiatric Association......................................................................... 317
Perminder Sachdev and The Curriculum Committee
of the International Neuropsychiatric Association
Index ................................................................................................................. 347

Contributors
Emmeline Agars
Brain and Ageing Program, School of Psychiatry, University of New South Wales,
Sydney, NSW, Australia
David B. Arciniegas
Brain Injury Rehabilitation Unit, HealthONE Spalding Rehabilitation Hospital,
Aurora, CO, USA;
Department of Psychiatry, University of Colorado School of Medicine,
Aurora, CO, USA
Simone Brockman
School of Psychiatry and Clinical Neurosciences, University of Western Australia,
Perth, WA, Australia;
Fremantle Hospital, Fremantle, WA, Australia
Luis Ignacio Brusco
Alzheimer Center, School of Medicine, Buenos Aires University,
Buenos Aires, Argentina
Robertas Bunevičius
Institute of Psychophysiology and Rehabilitation, Kaunas University of Medicine,
Palanga, Lithuania
Anthony S. David
Department of Psychiatry, Section of Cognitive Neuropsychiatry,
Institute of Psychiatry, King’s College London, London, UK
Masaaki Fukutake
Department of Psychiatry, Kobe University School of Medicine, Kobe, Japan
Peruvian Psychiatric Society; Peruvian Psychoanalytic Society, Lima, Perú
Moises Gaviria
Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA;
Advocate Christ Medical Center, Oak Lawn, IL, USA
xi
xii Contributors
James Gilleen
Kathryn Greenwood
Takashi Haraguchi
Department of Neurology, South Okayama Medical Center, Okayama, Japan
Ryota Hashimoto
Department of Psychiatry, Osaka University Medical School, Suita, Japan
Akira Homma
Department of Psychiatry, Center for Dementia Care Research and Training
in Tokyo, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
Hideki Ishizu
Zikei Hospital, Okayama, Japan
Michael D. Kopelman
Institute of Psychiatry, King’s College London, London, UK;
Academic Unit of Neuropsychiatry, Adamson Centre, London, UK
Kenji Kosaka
Yokohama Houyuu Hospital, Yokohama, Japan
Takashi Kudo
Shigetoshi Kuroda
Zikei Hospital, Okayama, Japan;
Department of Neuropsychiatry, Okayama University Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Kiyoshi Maeda
Department of Occupational Therapy, Kobe Gakuin University
School of Rehabilitation, Kobe, Japan
Ian Grant McKeith
Wolfson Research Centre, Institute for Ageing and Health, Newcastle
University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
Yoshio Mitsuyama
Psychogeriatric Center of Daigo Hospital, Miyazaki, Japan
Koho Miyoshi
Jinmeikai Research Institute for Mental Health, Nishinomiya, Hyogo, Japan;
The former Professor, Department of Neuropsychiatry, Kyoto University
Graduate School of Medicine, Kyoto, Japan
Contributors xiii
Takashi Morihara
Yasushi Morimura
Jinmeikai Foundation and Hospital, Nishinomiya, Japan
Yoshio Morita
Department of Neuropsychiatry, Hyogo College of Medicine, Nishinomiya, Japan
Marco Mula
Division of Neurology, Maggiore Hospital, Amedeo Avogadro University,
Novara, Italy
Naoki Nishiguchi
Department of Neuropsychiatry, Kinki University School of Medicine,
Osakasayama, Japan
Yoshitaka Ohigashi
International Center, Graduate School of Human and Environmental Studies,
Kyoto University, Kyoto, Japan
Masayasu Okochi
Spyridon Papapetropoulos
Department of Neurology, Miller School of Medicine, University of Miami,
Miami, FL, USA;
Biogen Idec, Cambridge, MA, USA
Arthur J. Prange, Jr.
Department of Psychiatry, University of North Carolina at Chapel Hill, NC, USA
Perminder Sachdev
School of Psychiatry, University of New South Wales, Sydney, NSW, Australia;
Neuropsychiatric Institute, Prince of Wales Hospital, Euroa Centre, Randwick,
NSW, Australia
Blake K. Scanlon
Department of Neurology, Miller School of Medicine, University of Miami,
Miami, FL, USA;
Department of Psychology, University of Miami, Coral Gables, FL, USA
Osamu Shirakawa
Department of Neuropsychiatry, Kinki University School of Medicine,
Osakasayama, Japan
Ingmar Skoog
Neuropsychiatric Epidemiology Unite, Department of Psychiatry,
Institute of Neuroscience and Physiology, Sahlgrenska Academy at Göteborg
University, Göteborg, Sweden
xiv Contributors
Sergio E. Starkstein
School of Psychiatry and Clinical Neurosciences, University of Western Australia,
WA, Australia
Fremantle Hospital, Fremantle, WA, Australia
Shinji Tagami
Masatoshi Takeda
Yasuyuki Tanabe
Department of Neurology, South Okayama Medical Center, Okayama, Japan
Toshihisa Tanaka
Seishi Terada
Michael Trimble
Department of Neuropsychiatry, Institute of Neurology, London, UK
Julian Trollor
Brain and Ageing Program, School of Psychiatry, University of New South Wales,
Sydney, NSW, Australia;
Department of Developmental Disability Neuropsychiatry, School of Psychiatry,
University of New South Wales, Sydney, NSW, Australia
Rhonda DePaul Verzal
Director of Neuropsychiatry, Advocate Christ Medical Center,
University of Illinois at Chicago, Chicago, IL, USA
Makiko Yamada
Molecular Imaging Center, National Institute of Radiological Sciences,
Chiba, Japan
Osamu Yokota
Clinical Manifestations
of Neuropsychiatric Disorders
Koho Miyoshi and Yasushi Morimura
Abstract Cerebral disorders commonly cause psychiatric symptoms. It is

recommended to call psychiatric symptoms or syndromes that are caused by organic
cerebral disorders “neuropsychiatric symptoms” or “neuropsychiatric syndromes.”
And, in this context, cerebral disorders, which cause psychiatric symptoms, are called
neuropsychiatric disorders. The main characteristics of neuropsychiatric symptoms
are (1) concurrent occurrence of the various psychiatric symptoms, (2) cognitive
impairment as a core symptom, (3) the possibility of early cerebral symptoms, and
(4) occasional resemblance to endogenous psychiatric disorders. The characteristics
of neuropsychiatric symptoms, namely, anxiety, neurotic complaint, apathy, mood
disorder, hallucinations, delusions, behavioral and personality changes, delirium,
and cognitive impairment (dementia), are discussed briefly.
Keywords Cognitive impairment • Dementia • Neuropsychiatric disorders

• Neuropsychiatry • Organic psychosis
Introduction
Almost all brain disorders may cause psychiatric symptoms [1]. Psychiatric symp-
toms caused by organic brain disorders could be called “neuropsychiatric” symp-
toms. Psychiatric manifestations caused by organic brain disease have been
traditionally called organic mental disorders. In DSM-IV-TR, however, the term
“organic psychosis” is not applied to the psychosis caused by organic cerebral dis-
orders. Because the “organic” or neurobiological bases of psychoses, including
K. Miyoshi (*) and Y. Morimura

Jinmeikai Research Institute for Mental Health,
Nishinomiya, Hyogo, Japan
e-mail: [email protected]
K. Miyoshi et al. (eds.), Neuropsychiatric Disorders, 3

DOI 10.1007/978-4-431-53871-4_1, © Springer 2010
4 K. Miyoshi and Y. Morimura
endogenous psychiatric disorders, have been revealed by recent investigations, it

would be recommended not to use the poorly defined term “organic” to avoid
implying that mental disorders other than “organic” mental disorders do not have a
neurobiological component. Alternatively, the use of the term “neuropsychiatric
symptoms” would be recommended to indicate psychiatric symptoms caused by
organic cerebral disorders. In this context, organic cerebral disorders or neuro-
logical disorders that cause psychiatric symptoms could be called “neuropsychi-
atric disorders.”
Neuropsychiatric disorder commonly occurs in elderly patients and occasionally
mimics endogenous psychoses. Therefore, the organic factors should be carefully
evaluated in diagnostic procedures in patients with psychiatric symptoms among
the elderly. The clinical manifestations and characteristics of neuropsychiatric
symptoms, especially in elderly patients, are briefly discussed in this chapter.
Neuropsychiatric Symptoms and Neuropsychiatric Disorders
Neuropsychiatric symptoms could be defined as psychiatric manifestations of

cerebral (neuropsychiatric) disorders. Cerebral disorders cause various psychiatric
symptoms.
Some of these symptoms occasionally mimic the psychiatric manifestation of
endogenous psychiatric disorders. In ICD-10 [2], psychiatric symptoms caused by
organic cerebral disorders are classified as organic (including symptomatic) mental
disorders. The psychiatric symptoms described in this classification are as follows:
dementia in Alzheimer’s disease, vascular dementia, dementia in other diseases
classified elsewhere, unspecific dementia, organic amnestic syndrome, not induced
by alcohol and other psychoactive substances, other mental disorders caused by
brain damage and dysfunction and by physical illness, including organic hallucino-
sis, organic catatonic disorder, organic delusional disorder, organic mood disorder,
organic anxiety disorder, organic dissociative disorder, organic emotionally labile
disorder, mild cognitive disorder, other specific mental disorders, and personality
and behavioral disorders resulting from brain disease, damage, and dysfunction.
In the core curriculum of the International Neuropsychiatric Association,
neuropsychiatric symptoms and syndromes are also classified as follows: cognitive
disorders (dementias and predementia syndromes, nondementing cognitive disorders),
seizure disorders, movement disorders, traumatic brain injury, secondary psychiatric
disorders (psychosis, depression, mania and anxiety disorders secondary to
“organic” brain disease), substance-induced psychiatric disorders, attentional
disorders, and sleep disorders.
The core curriculum of the American Neuropsychiatric Association also defines
the major neuropsychiatric syndromes as delirium, the dementias, and the major
primary psychiatric disorders, including those of learning and communication, and
motor skill disorders. Also, neuropsychiatric disorders are defined as neurological
disorders with cognitive, emotional, behavioral features; neurodegenerative disorders
Clinical Manifestations of Neuropsychiatric Disorders 5
(dementias), movement disorders, stroke, epilepsy, multiple sclerosis, traumatic

brain injury, infections, neuroendocrine disorders, metabolic disorders, intoxica-
tion, etc. [3].
The term “neuropsychiatric disorders” should be applied to brain diseases that
cause psychiatric symptoms. Therefore, organic cerebral disorders, including
neurodegenerative diseases (Alzheimer’s disease, frontotemporal lobar degeneration,
progressive supranuclear palsy, corticobasal degeneration, Huntington’s disease, and
Lewy body disease), Creutzfeldt–Jakob disease, cerebrovascular disorders, subdural
hematoma, encephalitis, traumatic brain injury, brain tumor, metabolic encephalopathy,
intoxication, and normal pressure hydrocephalus, could be called neuropsychiatric
disorders.
Characteristics of Clinical Manifestations of Neuropsychiatric

Disorders
Multiple Neuropsychiatric Symptoms Occur Simultaneously
Brain diseases commonly cause neurological, neuropsychological, and psychiatric

symptoms concurrently in the course of illness (Fig. 1). Therefore, clinical mani-
festations of the cerebral disorders usually are composed of these three components.
Neurological symptoms, such as motor and sensory disturbances, are commonly
encountered in neurological disorders. Neuropsychological symptoms, such as
aphasia, apraxia, and agnosia, caused by the circumscribed lesion of the cerebrum,
commonly occur in cerebral disorders. Also, diffuse lesions of the cerebrum usually
cause neuropsychiatric symptoms such as cognitive impairment, mood disorder,
Neuropsychiatric Symptoms
Neuropsychological Neurological Symptoms

Symptoms
Fig. 1 Structures of the clinical manifestations of cerebral disorders

Fig. 2 Structures of the neuropsychiatric symptoms of cerebral disorders
apathy, hallucination, delusion, and behavioral disorders. These three components form
complex clinical manifestations of neuropsychiatric disorders.
Multiple neuropsychiatric symptoms, such as cognitive impairment, disturbance
of consciousness, anxiety, mood disorders, hallucination, delusion, behavioral
change, and apathy, commonly occur concurrently in the course of cerebral
disorders (Fig. 2). The psychiatric symptoms are usually accompanied by other
psychiatric symptoms. Namely, depression, neurotic states, behavioral changes,
apathy, and cognitive impairment occur simultaneously in Alzheimer’s disease, and
mood change, apathy, visual hallucination, and cognitive impairment are encoun-
tered concurrently in patients with Parkinson’s disease. Any of the neuropsychiatric
symptoms rarely occur independently in the course of illness. Clinical manifesta-
tions of neuropsychiatric disorders usually consist of the multiple components of
psychiatric symptoms.
Probable and Possible Symptoms of Neuropsychiatric Disorders
Cognitive impairment is a core symptom of neuropsychiatric disorders. Almost

all neuropsychiatric symptoms are intermingled with impairment of cognition,
if evaluated carefully. If distinct cognitive impairment is evaluated in psychiat-
ric patients, it could be a sign indicating the symptoms might be caused by
cerebral disease.
Disturbance of consciousness, on the other hand, could be a clue for diagnosis
of cerebral disorders, if the possibility of physical illness can be ruled out. In the
diagnostic procedure, these two symptoms, namely, cognitive impairment and
disturbance of consciousness, indicate that the psychiatric symptoms are probably
caused by brain disease. Therefore, these symptoms could be called “probable”
neuropsychiatric symptoms (Fig. 3).
Probable and Possible Neuropsychiatric Symptoms
1. Probable Neuropsychiatric Symptoms

–Cognitive impairment
–Disturbance of consciousness
2. Possible Neuropsychiatric Symptoms

–Neurotic complaints, anxiety
–Mood changes
–Psychotic States: Hallucination & delusion
–Behavioral and personality changes
Fig. 3 Probable and possible neuropsychiatric symptoms
On the other hand, psychiatric symptoms such as neurotic complaints, mood

changes, hallucination, delusion, and behavioral and personality changes could
possibly be caused by cerebral disorders. Therefore, these symptoms could be
called “possible” neuropsychiatric symptoms (Fig. 3).
Neuropsychiatric Symptoms Could Be the Earliest Symptoms

in Cerebral Disorders
Mild neuropsychiatric symptoms, such as anxiety, depression, apathy, and person-

ality changes, occasionally precede dementia in cerebral disorders (Fig. 4). Mild
psychiatric symptoms could be the earliest manifestations of the neuropsychiatric
disorders. Occasionally these symptoms are composed of vague somatic complaints.
Patients with neuropsychiatric disorders commonly complain of subjective work
difficulties, forgetting the location of objects, decreased functioning in demanding
employment settings, and difficulty in traveling to new locations in the early stage
of their illness. Hypochondria, anxiety, irritability, dysphoria, dysthymia, depressive
mood, agitation, euphoria, hypomanic mood, flattening of affects, sleep disorder,
apathy, and psychomotor retardation may occur, preceding dementia, in the initial
stage of brain disease.
Mild Neuropsychiatric Symptoms, precede Dementia
1) Neurotic Symptoms: Headache, vertigo, dizziness, fatigueability, listlessness,

pain, weakness, hypochondria, anxiety, irritability,
2) Mood Disoders: dysphoria, dysthymia, depressive mood, agitation, euphoria,

hypomanic mood, flattening of affect, sleep disorders,
3) Behaviors: apathy, psychomotor retardation, subjective work difficulties,
4) Cognitive Impairment: forgetting location of objects, decreased functioning in

demanding employment settings, and difficulty in traveling to new locations.
Fig. 4 Mild neuropsychiatric symptoms that precede dementia

Cognitive impairment preceding dementia is called mild cognitive impairment

(MCI) [4]. It is reported that MCI is commonly accompanied by neuropsychiatric
symptoms such as depression, dysphoria, apathy, irritability, anxiety, agitation,
aberrant motor behavior, and parkinsonian-like signs. Neuropsychiatric symptoms
in the MCI stage could be the predictors of conversion to dementia [5].
Neuropsychiatric Symptoms Are Not Pathognomonic to a Certain

Cerebral Disorder
Psychiatric symptoms are nonspecific to certain neurological diseases. Therefore,

it usually is not possible to indicate what kind of disease causes the psychiatric
symptoms in the patients. Almost all neuropsychiatric symptoms may occur in
any of the cerebral disorders. For example, depressive mood and agitation occa-
sionally occur in Alzheimer’s disease, cerebrovascular disorders, and Parkinson’s
disease. Neurotic symptoms are commonly encountered in patients with
Alzheimer’s disease, traumatic brain injury, and seizure disorders, which means
that no type of neuropsychiatric symptom is pathognomonic to a specific cere-
bral disorder.
Neuropsychiatric Symptoms May Mimic Endogenous Psychoses
Cerebral disorders may mimic endogenous psychoses. Paranoid-hallucinatory state

and mood disorders could be caused by cerebral diseases. Visual hallucination,
especially, commonly occurs in cerebral disorders. Delusions of persecution and
infidelity are occasionally seen in patients with organic brain disorders. Less
frequently, delusional misidentification occurs in neuropsychiatric disorders.
Therefore, endogenous psychosis should be diagnosed carefully by excluding the
possibility of cerebral disorders.
The neurobiological basis of the endogenous psychoses, such as schizophrenia
and mood disorder, is still unknown. However, the pathophysiology of the
endogenous psychoses could be revealed by neurobiological investigations of
neuropsychiatric disorders in the future.
Neuropsychiatric Symptoms and Syndromes
Various neuropsychiatric symptoms and syndromes, such as anxiety, neurotic com-

plaints, apathy, mood disorder, hallucination, delusion, behavioral change, personality
alteration, and delirium, occur in patients with cerebral disorders and cause dementia
in the advanced stages of illness (Fig. 5).
Diseases MCI Type Disturbance of Mood Disorders Volition Neurotic Other Non-cognitive Other
Cognitive Functions State Symptoms Neuropsychiatric Symptoms
Vascular Cognitive Multiple or Executive Function Depression Apathy Somatic Personality Delirium
Impairment Nonmemory Emotional complaints Change Neurological Signs
Domains MCI Incontinence Anxiety
Alzheimer’s Amnestic MCI Memory Depression Apathy Somatic Personality

Disease Depressive complaints Change
Pseudo-dementia Anxiety Delusion
Frontotemporal Nonmemory Language Depression Apathy Personality Change
Dementia Domains MCI Executive Function Hyperthymia
Parkinson’s Nonmemory Subcortical Dementia Depression Apathy Somatic Parkinsonism
Clinical Manifestations of Neuropsychiatric Disorders
Disease Domains MCI PDD (DLB) Brady- Complaints

phrenia Anxiety
Dementia with Memory Memory or Depression Apathy Visual Hallucination, Delirium, Parkinsonism
Lewy Bodies Domains MCI Nonmemory Delusion
Progressive Nonmemory Subcortical Dementia Depression Apathy Personality Nuchal Rigidity

Supranulear Palsy Domains Change Stiffness
MCI
Fig. 5 Neuropsychiatric symptoms in cerebral disorders

9
Anxiety and Neurotic Complaints
Anxiety commonly occurs in the initial stage of a neuropsychiatric disorder [6, 7].
However, it usually becomes less obvious as the progress of cognitive decline
continues. Anxiety, intermingled with depressive mood or dysphoria, is one of the
most common neuropsychiatric symptoms in Alzheimer’s disease and vascular
dementia. Somatic distress, such as headache, vertigo, dizziness, fatigability, list-
lessness, and feeling of weakness are occasional complaints. Excessive anxiety is
usually accompanied by restlessness, irritability, muscle tension, fears, and respiratory
symptoms of anxiety.
Apathy
Apathy, a syndrome of decreased initiation and motivation, is a common neuropsy-

chiatric symptom in demented patients. The prevalence of apathy is reported to be
almost 65% of patients with dementia and 70% in Alzheimer’s disease patients.
Although there is some overlap between apathy and depression, these two condi-
tions are independent in the course of illness [8]. Apathy is significantly associated
with more severe cognitive deficit and has been reported to reflect the interaction
between cholinergic deficiency and neuropathological changes in the frontal brain
regions. Increased apathy is associated with poor quality of life.
Mood Disorder
The prevalence of depression in cerebral diseases is strikingly high, particularly in

Alzheimer’s disease, Parkinson’s disease, and cerebral stroke. Depression is one of
the most common neuropsychiatric symptoms in patients with Alzheimer’s disease.
Depressive symptoms that most strongly discriminate between Alzheimer’s disease
patients with (major depression) and without (minor depression) sad moods are
guilty ideation, suicidal ideation, loss of energy, insomnia, weight loss, psychomotor
retardation /agitation, poor concentration, and loss of interest [8].
Patients with Alzheimer’s disease are more likely to report a diminished ability
to concentrate or indecisiveness and are less likely to experience sleep disturbances
and feelings of worthlessness or excessive guilt during their major depressive
episodes [9]. Among the various neuropsychiatric symptoms, depression frequently
occurs in the preclinical phase of Alzheimer’s disease and is considered to be one
of the predictors of conversion to dementia in the stage of MCI [5].
Depressive patients with Parkinson’s disease develop depressive mood change,
loss of interest, and feelings of hopelessness [10]. Diminished ability to concentrate
is also seen in parkinsonian patients with depression. Psychiatric features of guilt,
self-reproach, or feelings of guilt and punishment are occasionally manifested

in depression in Parkinson’s disease. Anxiety, irritability, suicidal ideation, and
depressive delusions are less frequent in Parkinson’s patients with depression when
compared to endogenous depressives. In addition, circadian rhythm of mood and
manic state are exceptional. Somatic complaints such as fatigue, constipation,
headache, insomnia, loss of appetite, dizziness, and abnormal sweating are frequent
in patients with Parkinson’s disease and depression.
The concept of vascular depression was proposed because of the comorbidity of
depression and vascular disease [11]. Therefore, the diagnostic criteria for vascular
depression require a major depression associated with evidence of confluent or
diffuse vascular lesions in the subcortical regions seen on neuroimaging.
Disruptions of the prefrontal systems or their modulating pathway are hypothesized
to cause depressive mood in cerebrovascular disorders. Clinical symptoms of vas-
cular depression are characterized by greater disability and higher risk for poorer
outcomes, which may be related in part to executive dysfunction and consequent
disability. Patients with late-life depression have significant impairment in executive
functioning.
Poststroke depression (PSD) is a complication that occurs in patients with cere-
bral stroke. It has been reported that stroke in the left hemisphere causes depression
more frequently than that in the right hemisphere [12]. Magnetic resonance imaging
(MRI)-defined vascular depression is late-onset depression with mild infarction and
rather intense white matter abnormalities in MRI [13].
Hallucinations and Delusions
Visual hallucination is usually one of the symptoms of delirium, caused by acute

cerebral dysfunctions or physical illnesses. Hallucinosis could be caused by a local-
ized brain lesion, especially in the brainstem or occipital lobe. Visual hallucination
is the most common type of hallucinations in cerebral disorders. Organic hallucina-
tions are frequently accompanied by illusions and delusional misidentifications.
Delusional elaboration of hallucination also may occur in elderly patients. Charles
Bonnet syndrome is nonorganic hallucination in the elderly, characterized by visual
impairment, vivid visual hallucination, and illusion without any other psychotic
symptoms. A special type of auditory hallucination, namely, musical hallucination,
may occur in geriatric patients with auditory disturbance.
Psychiatric symptoms develop usually in the advanced stage of Parkinson’s
disease during long-term treatment with dopaminergic drugs. Recurrent episodes of
visual hallucination and illusion are characteristic features of drug-induced psychi-
atric symptoms of Parkinson’s disease. In approximately half the parkinsonian
patients, hallucinations are accompanied by cognitive impairments [10].
Recently, visual hallucinations and delusions are considered to be characteristic
clinical features of “dementia with Lewy bodies.” Visual hallucination and other
perceptual disorders, including misidentification syndrome and visual agnosia, are
common symptoms in this disorder. Characteristic delusions, such as Capgras

syndrome and “phantom boarders,” occasionally occur in patients in their old age.
Delusions of persecution, especially delusion of theft, are frequently encountered
in the early stage of Alzheimer’s disease. Delusions caused by cerebral diseases are
usually poorly systematized and are occasionally accompanied by confabulation.
Behavioral and Personality Changes
Behavioral and personality changes characterized by disturbances of mood,

volition, and cognition could be caused by chronic brain disorders [14]. Agitation,
psychomotor retardation, apathy, and stereotyped behavior are common types of
behavioral changes in chronic neuropsychiatric disorders. Aggression, screaming,
restlessness, wandering, culturally inappropriate behavior, sexual disinhibition,
hoarding, cursing, and shadowing are common behavioral disturbances in patients
with dementia. Current pharmacologic treatments or sociopsychological interven-
tions may ameliorate behavioral symptoms significantly.
Personality change is characterized by significant alterations of habitual patterns
of behavior. It is usually accompanied by impairment of cognition and volition and
by change of mood in cerebral disorders. Irritability, apathy, and exaggerated
emotionality are common behavioral changes in various neurological disorders.
Personality disorder frequently occurs, especially in the advanced stages of neuro-
degenerative disorders or vascular dementia.
Delirium
Delirium is a psychiatric state that is characterized clinically by transient disturbances

of consciousness and attention, perception, memory, thinking, psychomotor behavior,
and emotion. Visual hallucination and disturbance of sleep–wake rhythms occur
frequently [15]. Acute cerebral damage, physical illnesses, and withdrawal of psycho-
active substances of abuse, including alcohol, cause delirium. Complete recovery could
be expected if the causal disorders or dysfunction diminished. During recovery from
delirium, mild neuropsychiatric symptoms, such as disturbance of memory and
attention, may continue for a long period, even for several months.
Persistent Cognitive Impairment (Dementia)
Persistent cognitive impairment is a core symptom of cerebral disorders. Brain

diseases, for the most part, cause cognitive decline in the advanced stage. Therefore,
persistent cognitive impairment could be a clue for the diagnosis of cerebral disorders.
As well as impairment of memory, disturbances of attention, abstract thinking,

judgment, calculation, language, and executive function are common clinical
features of dementia.
Dementia of the Alzheimer Type
Dementia in Alzheimer’s disease is clinically characterized by amnestic syndrome and

neuropsychological symptoms, including aphasia, apraxia, and agnosia. Impairment of
episodic memory is one of the most important criteria for the diagnosis of Alzheimer’s
disease [16]. It is characterized clinically by slowly progressive impairment of cognitive
functions, occasionally accompanied by disturbance of mood, behavior, and psychi-
atric symptoms, such as hallucination and delusion. The Mini-Mental State Examination
reveals the disturbance of attention, impairment of recent memory, and disorientation
in the earliest stage of Alzheimer’s disease. Language abilities, such as naming and
reading, are relatively spared until the advanced stages of the illness.
Neurodegenerative Dementias of Non-Alzheimer Type
Personality changes and language disturbances with less marked memory impair-
ment are the main characteristics of cortical dementia in frontotemporal dementia.
The early clinical features of frontotemporal dementia are changes of character
and social behavior rather than impairment of memory and intellect. With the
progression of the disease, impairment of cognitive functions, including memory,
becomes obvious and slowly increases in severity. Stereotyped speech with a promi-
nent reduction of vocabulary is conspicuous in the advanced stage of illness.
Semantic dementia, as well as progressive nonfluent aphasia, is the characteristic
clinical symptom of this type of dementia. Frontotemporal dementia with motor
neuron disease is clinically characterized by the complication with motor neuron
disease.
Subcortical dementia in progressive supranuclear palsy, corticobasal degenera-
tion, Parkinson’s disease, and Huntington’s disease are characterized by peculiar
“forgetfulness,” psychomotor retardation, and mood changes. Progression of
cognitive impairment with visual disturbance is a characteristic clinical feature of
Creutzfeldt–Jakob disease, which causes a diffuse cortical degeneration with
accentuation of occipital change. Progressive supranuclear palsy is clinically char-
acterized by dementia, supranuclear ophthalmoplegia, and pseudobulbar palsy.
Clinical characteristics of “subcortical dementia,” namely, forgetfulness with
psychomotor retardation, difficulty with complex problem solving and concept
formation, and a relative absence of “cortical” features, including aphasia, apraxia,
and agnosia, was originally described in this disorder.
Corticobasal degeneration is characterized clinically by cognitive impairment,
rigidity, clumsiness, and “alien limb” phenomena.
Clinical features of dementia with Lewy bodies (DLB) are characterized by

persistent cognitive impairment with fluctuation, recurrent visual hallucination, and
parkinsonism [17]. It is still obscure what kind of factor causes the fluctuations of
cognitive impairment and disturbance of consciousness.
Recently, it has been thought that the “dementia in Parkinson’s disease (Parkinson
disease dementia, PDD)” and DLB is essentially the same a-synucleinopathy in the
spectrum of Lewy body disease [17, 18].
Vascular Cognitive Impairment
Cerebrovascular disorders may cause persistent cognitive impairment. After

Alzheimer’s disease, vascular dementia is the second most common disorder in the
dementias of the elderly [19, 20]. Multiinfarction, and diffuse degeneration of the
subcortical white matter, are the two main characteristic neuropathologies. Because
hippocampal formation and adjacent structures are usually spared at the early stage
of multiple cerebral infarctions, impairment of recent memory is not conspicuous
in vascular cognitive impairment or vascular dementia until the advanced stage of
illness. Executive dysfunction is conspicuous in comparison to memory impairment
in the early stage of vascular dementia. Delirium occasionally intermingles with
cognitive impairment in vascular dementia.
Conclusions
In general, almost all organic cerebral diseases cause psychiatric symptoms.

Psychiatric symptoms caused by organic cerebral disorders are neuropsychiatric
symptoms. Needless to say, neuropsychiatric symptoms and syndromes are the
main target of neuropsychiatric studies. The main components of neuropsychiatric
symptoms are cognitive impairment and disturbance of consciousness. Other
neuropsychiatric symptoms, such as depression, anxiety, paranoid-hallucinatory
states, and behavioral and personality changes, also commonly occur in the course
of organic cerebral disorders. Mild neuropsychiatric symptoms could be the earliest
manifestations of cerebral disorders. Cerebral diseases commonly cause neurologi-
cal, neuropsychological, and psychiatric symptoms concurrently in the course of
illness. Multiple neuropsychiatric symptoms commonly occur concurrently in the
course of cerebral disorders. The organic factors should be carefully evaluated in
the psychoses, especially in patients of older age. Clinicians who engage in the
treatment of cerebral disorders or psychiatric disorders should have enough experience
in the integrating neuroscience, that is, neuropsychiatry.
References
1. Lyketsos C (2006) Lessons from neuropsychiatry. J Neuropsychiatry Clin Neurosci

18:445–449
2. World Health Organization (1992) The ICD-10 classification of mental and behavioural
disorders. Clinical descriptions and diagnostic guidelines. WHO, Geneva
3. Arciniegas DB, Kaufer DI et al (2006) Core curriculum for training in behavioral neurology
and neuropsychiatry. J Neuropsychiatry Clin Neurosci 18:6–13
4. Petersen RC, Doody R, Kurz A et al (2001) Current concepts in mild cognitive impairment.
Arch Neurol 58:1985–1992
5. Palmer K, Berger AK, Monastero R, Winblad B et al (2007) Predictors of progression from
mild cognitive impairment to Alzheimer’s disease. Neurology 68:1596–1602
6. Lyketsos CG, Lopez O, Jones B, Fitzpatrick A et al (2002) Prevalence of neuropsychiatric
symptoms in dementia and mild cognitive impairment results from the cardiovascular health
study. JAMA 288:1475–1483
7. Seignourel PJ, Kunik ME, Snow L et al (2008) Anxiety in dementia. A critical review. Clin
Psychol Rev 28:1071–1082
8. Starkstein SE, Ingram L, Garau ML et al (2005) The overlap between apathy and depression
in dementia. J Neurol Neurosurg Psychiatry 76:1070–1074
9. Zubenko G, Moosy J (1993) Major depression in primary dementia. Clinical and neuropatho-
logic correlates. Arch Neurol 45:1182–1186
10. Miyoshi K, Ueki A, Nagano O (1996) Management of psychiatric symptoms of Parkinson’s
disease. Eur Neurol 36(Suppl 1):49–54
11. Alexopoulos GS, Meyers BS, Young RC et al (1997) Vascular depression hypothesis. Arch
Gen Psychiatry 54:915–922
12. Robinson RG (2001) The neuropsychiatry of stroke. In: Miyoshi K, Shapiro C, Gaviria M,
Morita Y (eds) Contemporary neuropsychiatry. Springer, Tokyo, pp 116–127
13. Krishnan KR, Hays JC, Blazer DG (1997) MRI-defined vascular depression. Am J Psychiatry
154:497–501
14. Finkel SI (1996) New focus on behavioral and psychological signs and symptoms of dementia.
Int Psychogeriatr 8(Suppl 3):215–216
15. Trzepacz PT, Baker RW, Greenhouse J (1988) A symptom rating scale for delirium. Psychiatry
Res 23:89–97
16. Dubois B, Feldman HH, Jacova C et al (2007) Research criteria for the diagnosis of
Alzheimer’s disease. Revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746
17. McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with
Lewy bodies. Third report of the DLB consortium. Neurology 65:1863–1872
18. Kosaka K (1990) Diffuse Lewy body disease in Japan. J Neurol 237:197–207
19. O’Brien JT, Erkinjuntti T, Reisberg B et al (2003) Vascular cognitive impairment. Lancet
Neurol 2:89–98
20. Román GC, Tatemichi TK, Erkinjuntti T et al (1993) Vascular dementia. Diagnostic criteria
for research studies. Report of NINDS-AIREN international workshop. Neurology
43:250–260
Thyroid–Brain Interactions
in Neuropsychiatric Disorders
Robertas Bunevičius and Arthur J. Prange, Jr.
Abstract Thyroid hormones are important for the development and maturation of
the brain as well as for the functioning of the mature brain. Most thyroid hormone-
responsive genes are sensitive to thyroid hormones only during distinct periods of
brain development, but some are also sensitive in the mature brain. A variety of factors
influence the effects of thyroid hormones in the brain: availability of iodine; thyroid
diseases and dysfunction; genetic variations that affect thyroid axis-related proteins,
such as deiodinases, thyroid hormone transporters, and receptors; and timing of events.
Interaction of these factors contributes to the development of the brain as well as to
presentation of psychiatric symptoms and disorders in the mature brain. Clinical and
subclinical thyroid dysfunction, thyroid autoimmunity, as well as individual genetic
variations and mutations of thyroid axis-related proteins, may contribute not only to the
presentation of psychiatric symptoms and disorders but also to response to psychiatric
treatments. Better understanding of genomic and nongenomic mechanisms related to
thyroid hormone metabolism in the brain opens new venues for finding new markers,
new targets, and new agents for the treatment of mental disorders.
Keywords Brain development • Neuropsychiatric disorders • Thyroid hormones

• Thyroid physiology
R. Bunevičius (*)
Institute of Psychophysiology and Rehabilitation,
Kaunas University of Medicine, Vyduno 4, 00135 Palanga, Lithuania
A.J. Prange, Jr.
Department of Psychiatry, University of North Carolina at Chapel Hill,
Campus Box #7160, Chapel Hill, NC 27599-7160, USA

DOI 10.1007/978-4-431-53871-4_2, © Springer 2010
20 R. Bunevičius and A.J. Prange, Jr.
Introduction
Thyroid hormones are important for the development and maturation of the brain
as well as for functioning of the mature brain. Thyroid hormones influence brain
gene expression. The majority of these genes are sensitive to thyroid hormones only
during distinct periods of brain development, but some of them are also sensitive in
the mature brain. Thyroid hormone deficiency during fetal and early postnatal life
results in severe mental retardation and cretinism, while thyroid dysfunction in
adult life results in mental symptoms, such as mood disorders and cognitive dys-
function. Although most psychiatric patients do not display overt thyroid dysfunc-
tion, many patients display lesser abnormalities. A variety of factors influence the
effects of thyroid hormones in the brain: availability of iodine; thyroid diseases and
dysfunction; genetic variations that affect proteins, such as deiodinases, thyroid
hormone transporters, and receptors; and timing of events. Consideration of inter-
action of these factors contributes to better understanding of the presentation of
psychiatric disorders as well as of the response to psychiatric treatments [1].
Thyroid Axis Hormone Secretion and Metabolism
Thyroid hormone secretion is controlled by pituitary thyrotropin, which is stimu-

lated by hypothalamic thyrotropin-releasing hormone (TRH) and suppressed by
negative feedback from serum thyroid hormones. In serum, more than 99% of thy-
roid hormones are bound to specific proteins and only free hormones are active. The
thyroid gland secretes several hormones, including thyroxine (T4), triiodothyronine
(T3), and metabolically inactive reverse T3 (rT3). The main secretion of the thyroid
gland is T4, and the thyroid gland is the only source of this hormone. In contrast, no
more than 20% of the more biologically active hormone T3 is secreted by the thyroid
gland. The remainder of T3 is produced in other tissues by removal of iodine from
the T4 molecule by enzymes called deiodinases, which exist in several forms and are
located intracellularly. Type I deiodinase (D1) is located primarily in liver and kid-
ney and is responsible for producing as much as 80% of T3. Type II deiodinase (D2)
is located primarily in brain glial cells, including astrocytes, and in muscles and
mainly accounts for T3 tissue concentrations. Type III deiodinase (D3) converts T4
to inactive rT3 and also degrades T3. In the brain, D3 is located in neurons [1].
The major cause of disturbed thyroid hormone secretion is autoimmune thyroid
disease (AITD), when autoantibodies against the normal elements of the thyroid
axis are produced. Results of biopsy as well as autopsy show that up to 40% of
women have AITD [2].There are two major forms of AITD: Graves’ disease, a
common cause of hyperthyroidism, and autoimmune thyroiditis, a common cause
of hypothyroidism [3]. Other major causes of hyperthyroidism are toxic nodular
goiters and adenomas; other major causes of hypothyroidism are treatments of
thyroid disorders (radiation, thyroidectomy), thyroid dysgenesis, and iodine
Thyroid–Brain Interactions 21
deficiency. In overt hyperthyroidism, thyroid hormone secretion is increased and

thyrotropin secretion is suppressed. In overt hypothyroidism, thyroid hormone
secretion is decreased and thyrotropin secretion is augmented. In subclinical
thyroid dysfunction, only thyrotropin secretion, but not thyroid hormone secretion,
is altered.
Circulating thyroid axis hormone concentrations in subjects with an unaffected
thyroid gland show substantial interindividual variability, in which genetic varia-
tions play a major role. Genetic variation in deiodinase enzymes and thyrotropin
receptors causes alteration in the balance of circulating thyroid hormones and their
tissue concentrations, affecting thyroid hormone-related endpoints [4], including
physiological consequences.
Thyroid Hormone Transport to the Brain
Thyroid hormones penetrate cell membranes and are responsible for the majority
of genomic and nongenomic effects of thyroid hormones. Until recently it was
presumed that cellular entry by free thyroid hormones was mediated via passive
diffusion because of their lipophylic nature. Now it is recognized that thyroid hor-
mones enter target cells using an energy-dependent transport mechanism that is
mediated by the monocarboxylate transporter-8 (MCT8) and by other transporters
such as the organic anion transporter protein 1c1 (OATP1c1). To enter the brain, thyroid
hormones must cross the blood–brain barrier or the choroid-plexus–cerebrospinal
fluid (CSF) barrier. OATP1c1 is a T4-specific transporter; MCT8 may transport T3
as well as T4. In the brain, T4 enters astrocytes, where it is converted to T3 by local
D2. T3 generated in the astrocytes as well as T3 from the general circulation is
transported into neurons via MCT8, where, after completion of its action, it is
degraded by D3 [5, 6] (Fig. 1).
Thyroid Hormone Receptors and Homeostasis in the Brain
The genomic action of T3 is mediated via nuclear thyroid hormone receptors (TRs),
which are members of the steroid/thyroid family. Human TRs are encoded by two
genes and have alpha- and beta-receptor isoforms. TRs bind T3 and, as ligand-
inducible transcription factors, regulate expression of T3-responsive target genes.
TR alpha-1, beta-1, and beta-2 isoforms can be occupied by T3, but the TR alpha-2
isoform cannot be occupied by T3. TRs, whether or not occupied by T3, bind to the
DNA response elements, producing different effects on gene expression. Binding
of T3-occupied TRs leads to activation of the responsive gene; binding of T3-
unocupied TRs leads to suppression [7].
TRs are expressed in the brain before fetal thyroid hormone secretion.
TR alpha-1 is the major isoform expressed in the brain during fetal development.
Neuron
Glial Cell
Tanycyte
DNA
CSF
TR
Nucleus
mRNA
Protein
T3 T4 MCT8 D2 ? MCT8 T3 D3 T2
? T4 T3
?
OATP1c1
OATP1c1
MCT8
ChP Endothelium BBB

?
T4 T3 T4 T3 Circulation
Fig. 1 Thyroid hormone delivery and metabolism in the brain. Thyroxine (T4) is transported across
the blood–brain barrier (BBB) via organic anion transporter protein 1c1 (OATP1c1) located in
endothelium cells. Triiodothyronine (T3) is transported via an unknown mechanism. From the cere-
brospinal fluid (CSF), thyroid hormones are transported via monocarboxylate transporter-8 (MCT8)
located in tanycytes. Choroid plexus (ChP) expresses both transporters OATP1c1 and MCT8. T4
enters the glial cell via an unknown mechanism and is converted to T3 by type II deiodinase (D2).
T3 exits the glial cell via an unknown mechanism and enters the neuron via MCT8. In the neuron,
T3 binds to nuclear thyroid receptor (TR) and acts as a transcription factor initiating protein synthe-
sis, or is converted to inactive diiodothyronine (T2) by type III deiodinase (D3)
Later, together with TR beta-1, it demonstrates different temporal and spatial

distribution in the postnatal and mature brain, suggesting different expression
of thyroid hormone-responsive genes in the developing versus the mature
brain [3]. In the mature brain, thyroid hormones regulate expression of sev-
eral genes that may affect mood and cognition, including genes for neurotro-
phins, such as nerve growth factor and brain-derived neurotrophic factor. By
genomic and possibly nongenomic mechanisms, T3 interacts with several
important neurotransmitters such as serotonin and norepinephrine, which are
crucial for mood regulation, and with acetylcholine, which is crucial for
cognition [8].
A mutation in the TR beta gene that eliminates ligand binding is associated
with thyroid hormone resistance syndrome, clinically presenting as a type of hypo-
thyroidism with goiter, elevated serum thyroid hormone concentrations, and non-
suppressed thyrotropin concentrations [9]. Most affected children show
attention-deficit disorder [10].
Regulation of thyroid hormone homeostasis in specific regions of the brain

is achieved by temporal and spatial regulation of the deiodinase system.
Expression of D3 in early gestation suppresses thyroid hormone activity in fetal
tissues, maintaining proliferation and inhibiting differentiation. Later, expression
of D2 activity initiates tissue differentiation. Deiodinase activity is different in
specific regions of the brain. It also maintains brain thyroid hormone homeo-
stasis in hyperthyroidism by increasing expression of D3 and suppressing
expression of D2 and in hypothyroidism by increasing expression of D2 [5].
Fetal Thyroid Economy and Development of the Brain
During pregnancy, maternal thyroid hormone requirements increase by 50%. In the

developing brain thyroid hormones regulate the process of differentiation such as
axonal and dendrite proliferation, synapse formation, neural migration, and
myelination [11]. In humans, thyroid hormone-dependent neurological development
can be separated into several stages [5, 11, 12].
1. From conception to 16–20 weeks of pregnancy, before the onset of fetal thyroid
hormone production, thyroid hormones are entirely derived from the mother.
At this stage thyroid hormones influence neuronal proliferation and migration
in the cerebral cortex, hippocampus, and medial ganglionic eminence.
2. From 16–20 weeks of gestation to birth, thyroid hormones are supplied from
both the fetal and the maternal thyroid gland. At this stage, thyroid hormones
influence neurogenesis, axonal and dendritic proliferation, synapse formation,
glial cell differentiation, and the onset of myelination.
3. From birth, thyroid hormones are entirely derived from the infant’s thyroid gland
and still play an important role for the development of the brain. At this stage
thyroid hormones influence gliogenesis, glial cell migration in the hippocampus,
cerebellum, and cortex, as well as myelination.
4. After the second year of postnatal life, the effects of thyroid hormones are more
related to physiological brain functioning than to brain development.
If thyroid hormone deficiency occurs, its timing is critical; this may be illus-
trated by the differences in neurological symptoms in endemic cretinism and in
congenital hypothyroidism [5]. In endemic cretinism, maternal iodine deficiency
causes both maternal hypothyroxinemia and fetal hypothyroidism, including
fetal brain hypothyroidism, during the entire gestation. For the fetus, hypothy-
roidism is most severe early in gestation, before the fetal thyroid gland becomes
active. This early hypothyroidism results in profound and irreversible mental
retardation, deaf-mutism, spasticity, and ataxia, although thyroid function may
be normal after birth.
In congenital hypothyroidism, fetal thyroid gland hypoplasia or aplasia is
compensated by the maternal thyroid hormone secretion. Hypothyroidism occurs after
birth. Neonates with congenital hypothyroidism in whom thyroid hormone replacement
has not been started demonstrate symptoms of hypothyroidism and growth retardation
together with mental retardation, spasticity, and speech and language deficits.
Neurological deficits are less severe than in endemic cretinism [13]. Immediate thyroid
hormone replacement prevents most neurological symptoms in neonatal hypothyroid-
ism, although mild deficits in cognitive functioning persist [13].
Endemic cretinism may be prevented if administration of iodine is started in the
first trimester. Despite knowledge of this simple remedy, iodine deficiency remains
the most prevalent preventable cause of mental retardation worldwide [11].
Findings in iodine-deficient areas in China revealed a positive association of D2
polymorphisms with mental retardation [14]. This finding suggests an important
interaction between environmental iodine deficiency and genetic variation,
diminishing the enzymatic conversion of T4 to T3 in the brain.
In most parts of the world, dietary iodine is sufficient. Nevertheless, maternal
hypothyroidism [15] or hypothyroxinemia [16], especially in early pregnancy, is
associated with delay in infant neurodevelopment. Women who are unable to
increase their production of T4 early in pregnancy may constitute a population at
risk for producing children with neurological disabilities [17]. On the other hand,
maternal hyperthyroidism [18] may affect reactivity to stress in offspring [19].
MCT-8 Mutations and Neurodevelopment
It has been recognized recently that mutations in MCT8 affect T3 transport into the
neuron, causing isolated brain hypothyroidism with elevated serum T3 concentra-
tions [5, 6]. Clinical features of MCT8 mutations include severe mental retardation,
axial hypotonia, absence of speech, and resemblance to patients with Allan–
Herndon–Dudley syndrome (AHDS). In fact, MCT8 mutations were found in all
families with AHDS, providing a molecular basis for this syndrome [20].
Apparently, when hypothyroidism is confined to the brain, the effects on brain
development resemble those caused by systematic hypothyroidism. Although there
are no effective treatments for patients with MCT8 mutation, the detection of this
mutation is important for genetic counseling.
Hypothyroidism and Mental Function in Adults
In adults, hypothyroidism is frequently accompanied by symptoms such as

diminished cognition, slow thought process, slow motor function, and drowsiness.
Depression seems to be especially related to hypothyroidism; even subclinical
hypothyroidism may affect mood [21]. Thyroid deficits are frequently observed in
bipolar patients, especially in women with the rapid-cycling form of the disease
[22]. In elderly patients, overt hypothyroidism may cause cognitive deficits that
respond to thyroid hormone replacement. Both subclinical hypothyroidism and

subclinical hyperthyroidism increase the risk for Alzheimer’s disease, especially in
women [23].
Treatment of Hypothyroidism
In hypothyroidism, replacement therapy with T4 remains the treatment of choice

and resolves most physical and psychological signs and symptoms in most patients.
However, some patients do not feel entirely well despite adequate dosage of T4 [24].
In T4-treated patients it was found that reduced psychological well-being is associ-
ated with occurrence of polymorphism in the D2 encoding gene [25], as well as in
the OATP1c1 encoding gene [26].
Thyroid hormone replacement with a combination of T4 and T3 in comparison
to T4 monotherapy differentially improves mental functioning in some but not all
hypothyroid patients [27], and the majority of patients subjectively prefer com-
bined treatment with T4 and T3 [28]. Two studies have evaluated whether D2
encoding gene polymorphism is associated with changes in psychological well-
being after combined T4 and T3 treatment. One study reported only a trend toward
improvement [29]. In a second study involving a very large sample, D2 encoding
gene polymorphism was associated with improvement in psychological well-
being after T4 and T3 treatment [25].
Hyperthyroidism and Mental Symptoms in Adults
The symptoms and signs of hyperthyroidism resemble those of primary mental

disorders such as mania, depression, or anxiety. Overactivity of the adrenergic sys-
tem caused by hyperthyroidism may explain the similarity between the clinical
presentations of hyperthyroidism and mania or anxiety, as well as the precipitating
role of hyperthyroidism in the development of mania or anxiety [30]. It also may
explain the increased sense of well-being in persons in early stages of hyperthyroid-
ism [31, 32].
The relationship between hyperthyroidism and depression is less clear. As
already discussed, depression is usually linked to hypothyroidism, not hyperthy-
roidism. However, prolonged hyperthyroidism might exhaust noradrenergic trans-
mission and thus contribute to depression. Noradrenergic exhaustion might well
occur in patients with hyperthyroidism who have bipolar disorder. In the initial
phase of hyperthyroidism, thyroid hormone stimulation of the noradrenergic
system may cause mania; later, when noradrenergic neurotransmission is exhausted,
it may contribute to depression [33].
Treatment of Hyperthyroidism
Mental symptoms and disorders secondary to hyperthyroidism should be treated in

the first instance by restoring euthyroidism. Treatment with a beta-adrenergic
antagonist drug in combination with antithyroid therapy remains the treatment of
choice for the entire spectrum of mental symptoms caused by hyperthyroidism
[34]. The majority of mental disorders and mental symptoms usually resolve once
euthyroidism has been regained.
The use of beta-adrenergic antagonist drugs is part of the standard treatment of
hyperthyroidism. These drugs quickly relieve many symptoms, including mental
symptoms, and they do not interfere with endocrine diagnostic tests. Among these
drugs, propranolol and metoprolol have the highest lipid solubility and cross the
blood–brain barrier most readily [35].
Low T3 Syndrome in Mental Disorders
A decrease in serum T3 concentration and a parallel increase in rT3 concentration are

common findings in many illnesses, in trauma, in starvation, and after surgical opera-
tions. These changes in thyroid axis function, taken together, are referred to as the low
T3 syndrome. Low T3 syndrome has also been called euthyroid sick syndrome, tend-
ing to minimize its clinical significance. An alternative designation, which does not
presume metabolic significance, is nonthyroidal illness syndrome [36].
A principal mechanism underlying low serum concentration of T3 in patients with
nonthyroidal illness syndrome is reduced activity of the D1 enzyme in liver. Increased
concentration of cytokines, such as interleukin-6 and tumor necrosis factor-alpha, are
responsible for the impaired expression of hepatic D1. Other mechanisms involved in
the pathogenesis of the syndrome include a decrease in concentration of thyroid
hormone-binding proteins and decreased secretion of TRH [36].
Low T3 syndrome can play a significant role in development of cognitive
dysfunction, e.g., delirium, in patients with Alzheimer’s disease after surgical inter-
ventions [37]. It also has been described in other mental disorders such as major
depression [38] and schizophrenia [39].
Thyroid Autoimmunity and Mood Disorders
AITD is frequently related to thyroid dysfunction, and even marginal thyroid

dysfunction may be associated with mood and anxiety disorders. However, a large
epidemiological study found no association between overt or subclinical thyroid
gland dysfunction and the presence of depression or anxiety disorders [40]. An
association between AITD and depression was reported in primary care patients
[41] and in pregnant women [42].
It may be that it is not thyroid gland dysfunction per se, but rather thyroid
autoimmune processes, that frequently cause thyroid gland dysfunction [43], is
responsible for comorbidity with mood disorders. Involvement of AIT in brain
functioning was found in several neuroimaging studies. Euthyroid patients with
autoimmune thyroiditis were compared to euthyroid patients without autoimmune
thyroiditis. The former group showed more brain perfusion abnormalities, anxiety,
and depression [44]. Neuroimaging abnormalities were similar to those observed in
Hashimoto’s encephalopathy, an infrequent but life-threatening acute brain syn-
drome caused by AITD. These findings suggest a higher than expected involvement
of the brain in AITD [45].
Thyroid Function in Mood Disorders
Although most overtly hypothyroid or hyperthyroid patients show mental deficits,

predominantly depression, most depressed patients are euthyroid; however, some
show transient hyperthyroxinemia [46], which may indicate involvement of the
thyroid axis in a restorative effort. A small proportion of patients with recognized
major depression demonstrate subclinical hypothyroidism, of which an exaggerated
thyrotropin response to TRH injection is a most sensitive characteristic. At the
same time, a quarter to a third of depressed patients demonstrate a blunted thyrotropin
response to TRH [43], which is believed to be a biological marker of depression
and may indicate exhaustion of a compensatory effort in euthyroid patients and
early stages of the low T3 syndrome. Basal thyrotropin levels in major depression
are usually normal or low normal. Recovery from depression, similar to recovery
from other nonthyroid illness, results in normalization of thyrotropin secretion as
well as in normalization of thyroid hormone concentration in serum and in the
cerebrospinal fluid (CSF) [46]. Thyroid hormone metabolism in brain undergoes a
specific change in depressed patients during recovery, and increasing T3 concentrations
may be a precondition for the recovery process [47].
Thyroid Abnormalities and Schizophrenia
An increased prevalence of thyroid function abnormalities was reported in families

of patients with schizophrenia [48], suggesting a possible genetic linkage of the two
disorders. It was reported that polymorphism of the human opposite paired (HOPA)
gene, which is located on chromosome X, is linked to both hypothyroidism and
schizophrenia [49].
Elevated T4 concentrations [50] or low T3 concentrations [39] are found in
schizophrenia. Higher thyroid hormone concentrations predict better response to
treatment. Clinical response to treatment usually correlates with normalization of
thyroid hormone concentrations [50].
Thyroid Axis Hormones in Treatment of Mental Disorders
Thyroid Hormones
A significant proportion of depressed patients do not respond to standard drug treatment.

Even patients who do respond need weeks to achieve full remission. This delay
pertains to both groups of standard antidepressants, tricyclics (TCAs) and selective
serotonin reuptake inhibitors (SSRIs). The delay prolongs both the morbidity of
symptoms and the risk of mortality through suicide [51].
Thyroid hormones may provide an ancillary treatment because many connec-
tions between the thyroid axis and depression are known. Both TCAs and SSRIs
increase brain D2 activity, which is responsible for local production of T3 [47]. As
an ancillary treatment, T3 has been used in two ways: to accelerate the antidepres-
sant drug from the beginning of treatment; and later to convert to responders
patients whose response to drug has been inadequate. There is conclusive evidence
that T3 can accelerate the effects of TCAs [52]. There is also conclusive evidence
that T3 can convert TCA nonresponders to responders [53].
SSRIs have mainly replaced TCAs as the first-line treatment of depression.
The ancillary use of T3 with SSRIs is controversial. Recent meta-analyses found
that differences in response and remission rates were insignificant in T3 versus
placebo supplementation. However, the authors concluded that SSRI and T3
therapy may be effective in some subgroups of depressed patients, including
patients with atypical depression and patients with functional D1 encoding gene
polymorphism [54]. Depressed patients who have lower genetically determined
T4 conversion to T3 may be more likely to benefit from T3 supplementation [55].
The antidepressant effect of T3 augmentation of SSRIs correlates with signifi-
cant changes in the brain bioenergetic metabolism [56], suggesting that T3 is an
important factor regulating bioenergetic processes in the brain and that these
processes are related to the manifestation and treatment of depressive disorders.
Direct comparison of two treatment approaches augmenting the antidepressive
effects of TCA showed that addition of T3 is more beneficial than addition
of T4 [57].
Thyrotropin-Releasing Hormone
Thyrotropin-releasing hormone (TRH) was the first hormone described as a product

of brain tissue. It is suggested [58] that TRH neurons compose a homeostatic sys-
tem organized into four anatomical components: (1) the hypothalamic–pituitary–
endocrine system; (2) the brainstem–midbrain–spinal cord system; (3) the
limbic–cortical system; and (4) the chronobiological system. Later an even broader
concept proposed “the TRH-immune system homeostatic hypothesis” [59].
Emphasis was given to the state-dependent and normalizing effects of TRH.
Some clinical reports, although not all, show that a single intravenous injection
of TRH produces a prompt, albeit partial and brief, relief of symptoms in depressed
patients. Consistent with the state-dependent concept is the finding that TRH also
may cause improvement in manic patients [60]. TRH has yet to find broad accep-
tance as a treatment modality. However, one TRH congener, taltirelin, is available
in Japan for the treatment of spinocerebellar degeneration. Also in Japan an intra-
venous formulation of TRH is available for the treatment of head injury and distur-
bances of consciousness. The recent finding that there are at least two types of TRH
receptors [59] may give added impetus to the search for other TRH-related drugs.
Conclusion
Thyroid hormone action in the brain is determined by a complex of factors, including

circulating concentrations of thyroid hormones; availability of free hormone; activity
of thyroid hormone transporters, deiodinase enzymes, and TRs; thyroid autoim-
munity; and, finally, timing of hormone action and the availability of iodine in the
diet. Individual genetic variations and mutations of thyroid axis-related proteins
may also contribute to presentation of psychiatric disorders, as well as to response
to psychiatric treatments. Better understanding of genomic and nongenomic mech-
anisms related to thyroid hormone metabolism in the brain opens new venues for
finding new markers, new targets, and new compounds for the treatment of mental
symptoms and disorders.
Acknowledgments The authors thank the Hope for Depression Research Foundation (HDRF)
and the Institute of the Study of Affective Neuroscience (ISAN) for research support.
References
1. Bunevicius R (2009) Thyroid disorders in mental patients. Curr Opin Psychiatry 22:391–395
2. Weetman AP (2004) Autoimmune thyroid disease. Autoimmunity 37:337–340
3. Pedersen IB, Knudsen N, Jorgensen T et al (2003) Thyroid peroxidase and thyroglobulin
autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clin
Endocrinol (Oxf) 58:36–42
4. Peeters RP, van der Deure WM et al (2006) Genetic variation in thyroid hormone pathway
genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases. Eur J Endocrinol
155:655–662
5. Williams GR (2008) Neurodevelopmental and neurophysiological actions of thyroid hormone.
J Neuroendocrinol 20:784–794
6. Suzuki T, Abe T (2008) Thyroid hormone transporters in the brain. Cerebellum 7:75–83
7. Yen PM (2005) Genomic and nongenomic actions of thyroid hormones. In: Braverman
LE, Utiger RD (eds) Warner and Ingbar’s the thyroid: a fundamental and clinical text, 9th edn.
Lippincott Williams & Wilkins, Philadelphia
8. Lifschytz T, Segman R, Shalom G et al (2006) Basic mechanisms of augmentation of
antidepressant effects with thyroid hormone. Curr Drug Targets 7:203–210
9. Refetoff S, Dumitrescu AM (2007) Syndromes of reduced sensitivity to thyroid hormone:

genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin
Endocrinol Metab 21:277–305
10. Hauser P, Zametkin AJ, Martinez P et al (1993) Attention deficit-hyperactivity disorder in
people with generalized resistance to thyroid hormone. N Engl J Med 328:997–1001
11. de Escobar GM, Obregon MJ (2004) del Rey FE (2004) Maternal thyroid hormones early
in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metab
18:225–248
12. Bernal J, Guadano-Ferraz A, Morte B (2003) Perspectives in the study of thyroid hormone
action on brain development and function. Thyroid 13:1005–1012
13. Zoeller RT, Rovet J (2004) Timing of thyroid hormone action in the developing brain: clinical
observations and experimental findings. J Neuroendocrinol 16:809–818
14. Guo TW, Zhang FC, Yang MS et al (2004) Positive association of the DIO2 (deiodinase type
2) gene with mental retardation in the iodine-deficient areas of China. J Med Genet
2004(41):585–590
15. Haddow JE, Palomaki GE, Allan WC et al (1999) Maternal thyroid deficiency during preg-
nancy and subsequent neuropsychological development of the child. N Engl J Med
341:549–555
16. Pop VJ, Brouwers EP, Vader HL et al (2003) Maternal hypothyroxinaemia during early preg-
nancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf)
59:280–281
17. de Escobar GM, Obregón MJ, del Rey FE (2007) Iodine deficiency and brain development in
the first half of pregnancy. Public Health Nutr 10:1554–1570
18. Bunevicius R, Kusminskas L, Mickuviene N et al (2009) Depressive disorder and thyroid axis
functioning during pregnancy. World J Biol Psychiatry 10(4):324–329
19. Zhang L, Hernandez VS, Medina-Pizarro M et al (2008) Maternal hyperthyroidism in rats
impairs stress coping of adult offspring. Neurosci Res 86:1306–1315
20. Visser WE, Friesema EC, Jansen J et al (2008) Thyroid hormone transport in and out of cells.
Trends Endocrinol Metab 19:50–56
21. Haggerty JJ Jr, Prange AJ Jr (1995) Borderline hypothyroidism and depression. Annu Rev
Med 46:37–46
22. Bauer M, Goetz T, Glenn T et al (2008) The thyroid–brain interaction in thyroid disorders and
mood disorders. J Neuroendocrinol 20:1101–1114
23. Tan ZS, Beiser A, Vasan RS et al (2008) Thyroid function and the risk of Alzheimer disease:
the Framingham study. Arch Intern Med 168:1514–1520
24. Saravanan P, Chau WF, Roberts N et al (2002) Psychological well-being in patients on
‘adequate’ doses of l-thyroxine: results of a large, controlled community-based questionnaire
study. Clin Endocrinol (Oxf) 57:577–585
25. Panicker V, Saravanan P, Vaidya B et al (2009) Common variation in the DIO2 gene predicts
baseline psychological well-being and response to combination thyroxine plus triiodothyro-
nine therapy in hypothyroid patients. J Clin Endocrinol Metab 94:1623–1629
26. van der Deure WM, Appelhof BC, Peeters RP et al (2008) Polymorphisms in the brain-spe-
cific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in
hypothyroid patients. Clin Endocrinol (Oxf) 69:804–811
27. Bunevicius R, Kazanavicius G, Zalinkevicius R et al (1999) Effects of thyroxine as compared
with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med
340:424–429
28. Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F et al (2005) Review: Treatment
of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol
Metab 90:4946–4954
29. Appelhof BC, Peeters RP, Wiersinga WM et al (2005) Polymorphisms in type 2 deiodinase
are not associated with wellbeing, neurocognitive functioning and preference for combined
T4/T3 therapy. J Clin Endocrinol Metab 90:6296–6299
30. Mason GA, Bondy SC, Nemeroff CB et al (1987) The effects of thyroid state on beta-adrenergic
and serotonergic receptors in rat brain. Psychoneuroendocrinology 12:261–270
31. Grabe HJ, Volzke H, Ludemann J et al (2005) Mental and physical complaints in thyroid
disorders in the general population. Acta Psychiatr Scand 112:286–293
32. Samuels MH, Schuff KG, Carlson NE et al (2008) Health status, mood, and cognition in
experimentally induced subclinical thyrotoxicosis. J Clin Endocrinol Metab 93:1730–1736
33. Bunevicius R, Velickiene D, Prange AJ Jr (2005) Mood and anxiety disorders in women with
treated hyperthyroidism and ophthalmopathy caused by Graves’ disease. Gen Hosp Psychiatry
27:133–139
34. Trzepacz PT, McCue M, Klein I et al (1988) Psychiatric and neuropsychological response to
propranolol in Graves’ disease. Biol Psychiatry 23:678–688
35. Bunevicius R, Prange AJ Jr (2006) Psychiatric manifestations of Graves’ hyperthyroidism:
pathophysiology and treatment options. CNS Drugs 20:897–909
36. Bunevicius R (2009) Low triiodothyronine syndrome and depression in patients with chronic
heart failure. In: Iervasi G, Pingitore A (eds) Thyroid and heart failure: from pathophysiology
to clinics. Springer, Milan
37. Mafrica F, Fodale V (2008) Thyroid function, Alzheimer’s disease and postoperative cognitive
dysfunction: a tale of dangerous liaisons? J Alzheimers Dis 14:95–105
38. Premachandra BN, Kabir MA, Williams IK (2006) Low T3 syndrome in psychiatric depression.
J Endocrinol Invest 29:568–572
39. Yazici K, Yazici AE, Taneli B (2002) Different neuroendocrine profiles of remitted and non-
remitted schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 26:579–584
40. Engum A, Bjoro T, Mykletun A et al (2002) An association between depression, anxiety and
thyroid function: a clinical fact or an artefact? Acta Psychiatr Scand 106:27–34
41. Bunevicius R, Peceliuniene J, Mickuviene N et al (2007) Mood and thyroid immunity
assessed by ultrasonographic imaging in a primary health care. J Affect Disord 97:85–90
42. Pop VJ, Wijnen HA, Lapkiene L et al (2006) The relation between gestational thyroid parameters
and depression: a reflection of the downregulation of the immune system during pregnancy?
Thyroid 16:485–492
43. Bunevicius R, Lasas L, Kazanavicius G et al (1996) Pituitary responses to thyrotropin releasing
hormone stimulation in depressed women with thyroid gland disorders. Psychoneuroendo-
crinology 21:631–639
44. Zettinig G, Asenbaum S, Fueger BJ et al (2003) Increased prevalence of subclinical brain
perfusion abnormalities in patients with autoimmune thyroiditis: evidence of Hashimoto’s
encephalitis? Clin Endocrinol (Oxf) 59:637–643
45. Chong JY, Rowland LP, Utiger RD (2003) Hashimoto encephalopathy: syndrome or myth?
Arch Neurol 60:164–171
46. Kirkegaard C, Faber J (1991) Free thyroxine and 3, 3’, 5’-triiodothyronine levels in cerebrospinal
fluid in patients with endogenous depression. Acta Endocrinol (Copenh) 124:166–172
47. Baumgartner A (2000) Thyroxine and the treatment of affective disorders: an overview of the
results of basic and clinical research. Int J Neuropsychopharmacol 3:149–165
48. DeLisi LE, Boccio AM, Riordan H et al (1991) Familial thyroid disease and delayed language
development in first admission patients with schizophrenia. Psychiatry Res 38:39–50
49. Philibert RA, Sandhu HK, Hutton AM et al (2001) Population-based association analyses of
the HOPA12bp polymorphism for schizophrenia and hypothyroidism. Am J Med Genet
105:130–134
50. Baumgartner A, Pietzcker A, Gaebel W (2000) The hypothalamic-pituitary-thyroid axis in
patients with schizophrenia. Schizophr Res 44:233–243
51. Jick H, Kaye JA, Jick SS (2004) Antidepressants and the risk of suicidal behaviors. JAMA
292:338–343
52. Altshuler LL, Bauer M, Frye MA et al (2001) Does thyroid supplementation accelerate tricyclic
antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry
158:1617–1622
53. Aronson R, Offman HJ, Joffe RT et al (1996) Triiodothyronine augmentation in the treatment
of refractory depression. A meta-analysis Arch Gen Psychiatry 53:842–848
54. Papakostas GI, Cooper-Kazaz R, Appelhof BC et al (2009) Simultaneous initiation (coinitiation)
of pharmacotherapy with triiodothyronine and a selective serotonin reuptake inhibitor for
major depressive disorder: a quantitative synthesis of double-blind studies. Int Clin
Psychopharmacol 24:19–25
55. Cooper-Kazaz R, van der Deure WM, Medici M et al (2009) Preliminary evidence that a
functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the
antidepressant effect of sertraline by triiodothyronine. J Affect Disord 116:113–116
56. Iosifescu DV, Bolo NR, Nierenberg AA et al (2008) Brain bioenergetics and response to
triiodothyronine augmentation in major depressive disorder. Biol Psychiatry 63:1127–1134
57. Joffe RT, Singer W (1990) A comparison of triiodothyronine and thyroxine in the potentiation
of tricyclic antidepressants. Psychiatry Res 32:241–251
58. Gary KA, Sevarino KA, Yarbrough GG et al (2003) The thyrotropin-releasing hormone
(TRH) hypothesis of homeostatic regulation: Implications for TRH-based therapeutics.
J Pharmacol Exp Ther 305:410–416
59. Kamath J, Yarbrough GG, Prange AJ Jr et al (2009) The thyrotropin-releasing hormone
(TRH)-immune system homeostatic hypothesis. Pharmacol Ther 121:20–28
60. Yarbrough GG, Kamath J, Winokur A et al (2007) Thyrotropin-releasing hormone (TRH) in
the neuroaxis: therapeutic effects reflect physiological functions and molecular actions. Med
Hypotheses 69:1249–1256
Lack of Insight and Awareness in Schizophrenia
and Neuropsychiatric Disorders
James Gilleen, Kathryn Greenwood, and Anthony S. David
Abstract Lack of insight or awareness of illness is a major problem in the

management of patients with a range of neuropsychiatric disorders. Insight in
schizophrenia has been extensively studied over the past 20 years, and much is
known about its clinical associations. In this chapter, we review the literature
on insight in schizophrenia and go on to describe the results of a study in which
awareness of illness and impairment was compared in three clinical groups
matched for premorbid IQ: patients with schizophrenia, Alzheimer’s disease,
and brain injury. We considered performance and awareness across a number of
domains: social behavior, psychopathology, and executive function. Awareness was
measured by different methods including clinician ratings and discrepancy scores
between patients’ own ratings and their relatives’ ratings using the Dysexecutive
Questionnaire. All groups showed varying levels of deficit in each domain as well
as varying levels of awareness. The Alzheimer group showed the most severe lack
of awareness of cognitive and behavioral problems, followed by the brain-injured
and schizophrenia patients. Low mood was associated with better insight in all
groups. We conclude that insight is multidimensional and domain specific but that
it also has associations which are common across domains and disorders.
Keywords Alzheimer’s disease • Awareness • Brain injury • Insight

• Schizophrenia
J. Gilleen, K. Greenwood, and A.S. David (*)

Institute of Psychiatry, King’s College London,
PO Box 68, London SE5 8AF, UK

DOI 10.1007/978-4-431-53871-4_3, © Springer 2010
34 J. Gilleen et al.
Introduction
The terms “anosognosia,” “insight,” “lack of awareness,” and even “denial” are often
used synonymously to describe a collection of attitudes and behaviors directed at
one’s illness. Anosognosia is generally used to convey lack of awareness of
specific functions seen after brain injury, such as hemiplegia. In contrast, insight
and lack of awareness are typically used to describe the phenomena in psychiatric
disorders, such as schizophrenia, and in neurological conditions, such as
Alzheimer’s disease (AD), where the awareness in question refers to that
of being ill in general and, more specifically, the capacity to judge impairment of
memory, or finally, the content of symptoms, such as delusions and hallucinations,
as not being real [1, 2]. These terms, therefore, differ regarding the object(s) of
insight to which they refer [3]. This distinction is crucial because awareness of an
objective obvious deficit such as hemiplegia would seem to be different in kind
from that of an objectively verifiable but invisible deficit such as amnesia, which
is different again from a subjective experience such as a hallucination.
Within the schizophrenia field there has been an attempt to fractionate insight
into different components or dimensions of awareness, which may, to some degree,
be independent (e.g. [1, 4–6]). David [1] proposed three dimensions: recognition of
having a mental illness, compliance with treatment, and the ability to label unusual
events as pathological. Amador et al. [6] split insight into five components: four
relate to (un)awareness of having a mental disorder, of the effects of medication, of
consequences of illness, and of specific symptoms, and the fifth or final component
is the attribution of symptoms to illness. Popular measures of insight include the
Schedule for the Assessment of Insight – Expanded Version (SAI-E) [7, 8]; the
semistructured interview: Scale to Assess Unawareness of Mental Disorder
(SUMD) [6]; the simple clinician-rated Insight and Treatment Attitudes
Questionnaire (ITAQ) [9]; and the Birchwood self-report Insight Scale (IS) [10].
All these scales have reasonably good intercorrelation [8]. Many authors have used
a single item from general psychopathology schedules, and others, particularly in
the dementia and brain injury fields, have made use of patient–carer discrepancy
questionnaires such as the Patient Competency Rating Scale (PCRS) [11] and the
Dysexecutive Questionnaire (DEX) [12].
Insight into Psychiatric Disorders

(Schizophrenia)
Theories seeking to explain awareness in neuropsychiatric conditions broadly fall

into three categories. Lack of awareness is conceptualized as a direct manifestation
of psychiatric symptomatology (or a symptom in itself), a function of general or
specific neuropsychological (e.g., executive) impairment, or a motivated response
to a mental disorder to preserve self-esteem and protect against low mood.
Lack of Insight and Awareness in Schizophrenia and Neuropsychiatric Disorders 35
Awareness and Symptomatology
Before the early nineteenth century, it would have been seen as a logical contradiction
in terms to talk of “insight” into psychiatric symptoms such as delusions, yet at
around this time, early French “alienists” began to acknowledge the concept of
“partial” insanity, wherein “madness” could be accompanied by lucidity, indicating
that some aspects of mental function could be “deranged” while others were
preserved [3, 13]. It seems intuitive that awareness would be associated with severity
of psychopathology, such that increased severity of delusions and hallucinations
would necessarily by their very nature leave the sufferer unaware that their experi-
ences were not real. Several studies have shown a relationship between awareness
and global psychopathology in schizophrenia [4, 14–20], whereas others have
found associations only with positive symptoms [21–27], or only with negative
symptoms [28–31], or with both positive and negative symptoms (e.g., [32]). Other
studies find awareness to be associated with specific symptoms such as “formal
thought disorder” [33, 34], “degree of grandiosity” [35], or with degree of “unusual
thought content” (equivalent to delusions), as measured by the Brief Psychiatric
Rating Scale [20, 36].
In an effort to clarify the relationship of awareness and psychopathology, Mintz
et al. [32] conducted a meta-analysis of 40 relevant studies and found small nega-
tive associations between awareness and global, positive, and negative symptoms,
accounting for 7.2%, 6.3%, and 5.2% of the variance in awareness, respectively.
This finding would strongly suggest that symptomatology plays only a small part
in the degree of awareness displayed by schizophrenia patients. It must therefore be
concluded that insight is related to psychopathology: as one increases, the other
tends to decrease. Nevertheless the association is weak cross sectionally and variable
longitudinally. In other words, lack of awareness or poor insight is more than “just
psychopathology” [37].
Several studies have shown that schizophrenia patients present with less aware-
ness than patients with other diagnoses such as bipolar disorder and major
depressive disorder [17, 38] and schizo-affective disorder and mood disorder with
and without psychosis ([39]; but see [40, 41]), or with similar levels of awareness
as bipolar patients but less awareness than patients with unipolar affective disorder
[42, 43]. However, others have found no significant differences between different
patient groups [4, 30, 34, 44, 45].
Clinical and Demographic Factors
There is little consistency across studies regarding reliable sociodemographic

predictors of awareness in schizophrenia (see [3]). For example, age and gender do
not appear to be associated with level of awareness, nor does awareness appear to be
related to level of education [6]. Studies that report positive findings have occasionally
done so in opposite directions, for example, duration of illness and awareness [46, 47].
Age has been found to associate with awareness in only a few studies [6, 22, 23, 42].
A meta-analysis reported that age at onset of the disorder moderated the relation-
ship between awareness and symptom clusters [32], such that acute patient status
was also found to act as a moderator variable between awareness and positive
symptoms; acutely ill patients were least aware.
Awareness and Neurocognition
Several studies have suggested a relationship between intelligence (IQ) and

awareness in schizophrenia [48], whereas others claim a more specific association
with executive functioning [15, 18], particularly as assessed using the Wisconsin
Card Sorting Test (WCST). The WCST is generally thought to be a measure of
set-shifting ability, where impairment has been hypothesized to be analogous to
patients’ inability to shift from an previously established “set” (that of being
well) to a more accurate, postmorbid “set” (of being ill). Cooke et al. [49] exam-
ined 29 studies that included a measure of WCST performance and awareness and
found 11 studies reported no association between any WCST measure and
awareness; 9 studies found all WCST measures correlated with awareness; and 9
found some but not all WCST measures correlated with awareness. All findings
were in the anticipated direction, with lower awareness being associated with
poorer WCST performance. In total, 12 of the 29 studies reported a correlation
between “perseverative errors” and awareness and 9 between “sets achieved” and
awareness. It has been suggested that cognitive perseveration may underlie
patients “perseverating in denial of illness despite evidence to the contrary”
[50], but the evidence remains contradictory [51]. The most comprehensive and
quantitative systematic review and meta-analysis of work in this area [52], how-
ever, suggests that WCST performance has more in common with awareness than
other measures such as IQ, or memory, with 13 studies creating a pooled effect
size of r = 0.23.
Neuroimaging
As interest in awareness has grown, so has the use of magnetic resonance imaging
(MRI) as an investigative tool. The findings to date suggest an association between
poor insight and reduced total brain volume [53, 54], frontal lobe atrophy [31],
reduced frontal lobe volume [55, 56], reduced cingulate gyrus and temporal lobe
grey matter volume [56], and ventricular enlargement [14]. There is, however, some
inconsistency in these findings, much study variation in the location of brain–
insight correlates, and in some instances a failure to identify any brain abnormalities
associated with poor insight [57]. One explanation for this inconsistency could
be measurements or voxel-based morphometry (VBM) methods of analysis.

In some studies, a single insight assessment item has been used [44, 58], while in
others insight schedules were employed [19, 59]. Shad et al. [59] investigated
SUMD scores and brain volume in 14 patients with schizophrenia and found lower
awareness of current symptoms to be associated with lower right dorsolateral pre-
frontal cortex volume, although misattribution of current symptoms was associ-
ated with higher right medial orbitofrontal cortex volume. Cooke et al. [60] used
VBM in a different but overlapping sample reported earlier [56] and found tem-
poral and parietal grey matter reductions to be correlated with various insight
dimensions. Finally, Morgan et al. [109] also used VBM methods in a large sample
of first-episode psychosis patients and found deficits, particularly with respect to
attribution of symptoms in the cingulate cortex, perhaps related to the midline cere-
bral system for self-processing [61], as well as right posterior deficits, reminiscent
of regions implicated in neurological cases of anosognosia of hemiplegia and
neglect [62]. Damage to any of these putative systems could potentially account
for impaired self-awareness. Research in other psychiatric disorders is needed
before we can say whether these findings are disorder specific.
Mood
One of the more reliable findings in the literature is the positive correlation
between awareness and low mood or depression (and between elevated mood
and lack of awareness [41]), which has been shown across different patient
groups [3, 63]. Although findings are variable, many studies have reported that
increased awareness in schizophrenia is associated with greater depressive
symptoms [25, 34, 47, 64–69], including a meta-analysis [32]. In this way, low
awareness of symptoms and illness is conceptualized as a form of denial to main-
tain self-esteem and preclude the psychological consequences of acknowledging
one has a mental illness.
A critical question is this: Does a depressive mood ensue from awareness of
illness, or does a depressive mood foster a more self-critical attitude? The frame-
work of “depressive realism” may help explain this association (see [70]). On the
other hand, Rathod et al. [71] reported that patients undergoing cognitive-behavioral
therapy (CBT) intervention to improve awareness became depressed subsequent to
gaining awareness, but this result was not found in an earlier study [72].
Insight and Awareness in Alzheimer’s Disease
Alzheimer’s disease (AD) can be characterized by a deterioration in memory and

self-care as well as behavioral and mood disturbance. Despite the severity of their impair-
ments, Alzheimer’s patients often show profound unawareness of their deficits [73],
even at the earliest stages [74]. Understanding awareness in dementia has important
implications [63, 75], as it has been found to be associated with greater perceived
burden of care by their carers [76], delayed diagnosis [77], and poorer outcome after
rehabilitative treatment [78].
Awareness has been shown to worsen with disease progression [79] and has
been found to be associated more frequently with damage to certain anatomical
sites, for example, right frontal and parietal lobes [80–82], which are also often
found to be associated with anosognosia following brain injury (see [80]). Other
studies have found awareness to worsen with disease severity [83], although
some have not [84, 85]. Similarly, although some studies have found an association
between “frontal”/executive performance and awareness [86, 87], others have
not [88, 89].
Less commonly, unawareness is conceived as being a defense mechanism against
the knowledge and consequences of illness. As already noted with respect to schizo-
phrenia, defensive denial is proposed to serve to defend Alzheimer’s patients from
depression, and indeed patients with less insight show less depressive symptomatology
[82, 83, 90, 91], but again other studies have not shown this [77, 84, 92], and the
direction of causality of this effect is debatable.
Insight and Awareness in Brain Injury
Disturbances to awareness of functional impairments are common sequelae of

brain injury [93] and have been suggested to be present, to some level, in
between 76% and 97% of postacute patients with brain injury and up to 45% of
individuals with moderate to severe brain injury [94]. Such individuals may have
multiple medical, physical, and cognitive limitations of which they are often
unaware. Brain injury patients may exhibit global deficits in awareness of mental
disorder or more circumscribed lack of awareness of specific deficits such as
hemiparesis, object agnosia [80], and hemispatial neglect [62]. Paradoxically,
patients are often unaware of even the grossest impairments in functioning but
may be aware of more minor impairments; and just as seen with delusions in
schizophrenia, false beliefs of unimpaired functioning can persist despite over-
whelming contradictory evidence.
As a consequence of lack of awareness, patients with brain injury may not be
capable of monitoring their own behavior or comprehending the impact of the
consequences of their deficits on day-to-day life. Moreover, unawareness has
been shown to greatly impede rehabilitation [94] and is associated with lower
vocational and residential status [95, 96] (see also [97] for a review of studies
pertaining to employment outcome), “less favorable outcome” [98], and perpetu-
ation of socially inappropriate behaviors [99], and has been shown to be associated
with increased burden for the respective carer [84]. Therefore, understanding the
nature of awareness could have profound benefits for patient prognosis and carer
quality of life.
Direct Comparison of Insight and Awareness

in Patients with Schizophrenia, AD, and Brain Injury
Most studies of awareness investigate a single patient population. Is there a case for
comparing different patient groups on the same measures [100, 101]? As well as
perhaps revealing more about the nature of awareness per se, doing so also allows
us to observe how awareness may differ in these different groups where pathology
is a known factor. By contrasting different patient groups, it may be possible to better
elucidate which mechanisms subserve awareness, or alternatively it may reveal that
patients from different clinical groups show lack of awareness for different reasons.
Just as patients with schizophrenia have, in addition to their core symptoms, cognitive
impairments and behavioral and social deficits, so patients with AD and brain injury
may have a range of psychopathologies about which they may or may not have
degrees of awareness. Comparison within – as well as between – groups may have
important theoretical implications. For example, if patient groups with widely divergent
pathologies (e.g., Alzheimer and schizophrenia patients) both have memory deficits,
then we can ask whether the same factors associated with awareness of these are
consistent across the groups (e.g., [102, 103] for awareness of cognitive deficits in
schizophrenia). If the answer is broadly affirmative, it suggests that a common cognitive
structure of awareness pertains, and this in turn can prompt overarching cognitive
models that need not be overly concerned with diagnosis. Furthermore, if, say, awareness
of psychopathology is relatively independent of awareness into cognitive deficits (the
correlation was nonsignificant in one recent study [102], regardless of diagnosis), it
points to modularity in awareness. Modularity of “awarenesses” is perhaps the most
likely pattern from the neurological literature [79] (Fig. 1). Such modularity has seldom
Social Cognitive Psychiatric Physical

Poor ADLs
difficulties problems symptoms disabilities
� � �
Insight into… Insight into… Insight into… Insight into… Insight into…
modulation
Mood +/–
Fig. 1 Model of multiple, modality-specific awareness systems (modularity), each of which may
or may not be impaired, but with general modulation by factors such as mood. In this theoretical
example, insight is preserved into social difficulties, psychiatric symptoms, and physical disability
but not cognitive problems and poor activities of daily living (ADLs)
been tested using broad domains such as psychopathology and behavioral problems
(alongside neuropsychological impairments). Where it has, as in the large
pan-European brain injury study [104], considerable within-diagnosis heterogeneity
was found. Similarly, in the dementia field different levels of awareness have been
noted by contrasting behavior with cognition [63, 73, 75, 105].
Participants
We recently conducted a study in which we compared different aspects of aware-

ness in three different neuropsychiatric populations: schizophrenia, brain injury,
and probable AD (Table 1). The former were mostly subacute, chronic, and
treated outpatients plus some inpatients at the Maudsley Hospital, London; the
Alzheimer group were locally dwelling subjects identified as part of a larger
cohort study. The brain injury patients were a heterogeneous group with a mixture
of traumatic, hypoxic, and vascular etiologies and with behavioral problems.
We were keen to address to what extent awareness in the same domain differed
between neuropsychiatric patient groups and whether differences could be
measured using standard scales.
Naturally, the patients were not matched on factors such as age and length of
illness. We contend that for the purposes of making inferences about the pattern
of awareness deficits in different pathological groups and contrasting profiles of
awareness within groups, this distinction is not critical. We acknowledge,
however, that there may be subtle period- and age-related effects regarding social
influences in accepting illness that require further study.
Table 1 Demographic and insight data on clinical groups

Variable Schizophrenia Brain injury Alzheimer’s
Mean (SD) n = 31 n = 26 n = 27
Age, years 38.3 (10.4) 40.0 (12.1) 82.4 (4.3)
Sex, M/F 16/15 22/4 14/13
Premorbid IQ (NART) 102.3 (12.8) 102.2 (13.8) 109.1 (12.8)
SAI-E 11.2 (7.15) 15.4 (5.7) 7.0 (6.4)
SUMD awareness of mental 3.37 (1.6) 1.92 (1.43) 4.04 (1.4)
illness
DEX discrepancy scoresa 2.48 –14.76 –25.96
(mean and range) (–33 to 31) (–55 to 15) (–62 to 13)
NART National Adult Reading Test (estimate of premorbid IQ); SAI-E Schedule for the
Assessment of Insight–Expanded; SUMD Scale to Assess Unawareness of Mental Disorder
a
Self-rating of difficulties minus informant rating of difficulties yielding a negative score. The
more negative, the greater the discrepancy (greater patient unawareness)
Methods
The groups were compared on measures of estimated premorbid IQ (NART) and

clinician-rated and patient–carer-rated awareness scales. All were rated on the
SAI-E, and the SUMD (it was found that the awareness of mental illness was the
most useful item from the scale; many Alzheimer patients were on no medication),
and the DEX (see Table 1).
The DEX from the Behavioural Assessment of the Dysexecutive Syndrome
(BADS) [106] was originally designed for use with brain injury populations;
however, questions concerning functioning apply equally well to dementia and
schizophrenia patients. It is a 20-item measure of functioning that addresses
problems such as impulsivity, apathy, distractibility, unconcern for social rules,
and difficulties with abstract thinking. Informants rate patient functioning, and
the patient rates him/herself on the scales, and the difference between patient
and informant scores creates a discrepancy score; the greater and more negative
the discrepancy between the scores, the greater the unawareness of the patient.
Items are scored on a 5-point scale from 0 (never) to 4 (very often). Hence,
DEX discrepancy scores can range from –80 to +80. A score of 0 indicates
perfect awareness in that the patient agrees with the level of impairment scored
by the respective informant.
The validity of the discrepancy index to measure insight and awareness may be
questioned because it assumes that the informant is the “gold standard.” Informants
may overestimate deficits (e.g., because of their own frustration or inability to cope)
or underestimate them (e.g., because they are hidden, or because the informant
wishes to protect the person they care for). Correlation with clinician ratings may
be poor (see [63, 75]). Nevertheless, the methodology has been found to be valuable
and consistently shows underestimation of deficits by patients in relationship to
informal caregivers.
Results
Between-Group Contrasts
Across the groups, patient and informant ratings of behavioral problems, as mea-
sured by the total DEX score, were highly discrepant in the brain injury and AD
groups (see Table 1; Fig. 2), representing low awareness of behavioral impairments,
but this was much less so in the schizophrenia group, suggesting that patients
exhibit different levels of unawareness of behavioral deficits. Importantly, ratings
made by either patients or informants in any patient group were not grossly at
ceiling or floor, but varied somewhat, suggesting that these scales provided
sensitivity in measuring behavioral impairment and, in turn, awareness.
Fig. 2 Graphs show mean Dysexecutive Questionnaire (DEX) self and informant subfactor
scores (per individual item) paneled according to patient group. Zero scores reflect the absence of
problems. The lower panel shows the resultant DEX discrepancy scores for the three groups. For
ease of presentation, the sign of the discrepancy score has been reversed so that a more positive
value indicates greater discrepancy (i.e., less patient awareness). BI brain injury; ALZ Alzheimer’s;
SCZ schizophrenia
It was also of interest to see in what dimensions awareness between behavioral

domains may differ, and whether there is an extant hierarchy of awareness (i.e., more
awareness of motor/sensory versus executive and social cognitive deficits). Comparison
of subfactor scores between groups can also reveal whether there are different
“profiles” of awareness in different patient groups. From Fig. 2 it can be seen that
both the brain injury and Alzheimer groups rated themselves as having few problems
with executive functioning including inhibition, intentionality, social interactions, and
abstract reasoning. The two groups differed in that the informants in the Alzheimer
group rated these patients as having particular problems in intentional behavior, that
is, apathy. Comparatively, the schizophrenia group rated themselves as lower
functioning, but their ratings were concordant with the informants’ view across all
subdomains; this reflects good awareness of behavioral problems. The lower panel
shows that this results in lowest awareness for the Alzheimer group, and greatest
awareness for the schizophrenia group, but also that there is no consistent profile
across patients, failing to support the notion of a hierarchy of awareness.
Pooled Patient Analysis
The entire patient sample was pooled (n = 84), and Pearson correlational analyses
were performed between the awareness and other clinical and symptoms ratings.
The DEX discrepancy score correlated with clinician-rated insight (SAI-E) at 0.321
(P < 0.001) and self-rated depression on the Beck Depression Inventory at r = 0.562
(P < 0.001) (Fig. 3); SAI-E also correlated with BDI at r = 0.239 (P < 0.05). That is
to say, as the discrepancy score became closer to zero or positive, indicating good
awareness, so did depression scores increase. DEX scores were correlated signifi-
cantly negatively with overall psychopathology as measured by the BPRS
(r = –0.570, P < 0.001); that is, as the discrepancy became smaller (i.e., awareness
increased), so depressive symptoms became worse.
Fig. 3 Scatterplot shows the correlation between DEX discrepancy scores (DEX-D) and total
Beck Depression scores (BDtot) for the three patient groups: schizophrenia (SCZ), Alzheimer’s
(ALZ), and brain injury (BI). The regression line shows that increasing awareness is associated
with increasing depression scores
Summary and Conclusions
In summary, insight or awareness in psychiatric disorders such as schizophrenia

and neuropsychiatric conditions may be multiply determined, although broadly
speaking there is converging evidence for key etiological factors, such as executive
function and positive psychopathology, with mood playing a mediating role. Insight
is an important indicator of prognosis and outcome. In the data we present here,
patients with chronic schizophrenia show good awareness of their functional and
executive problems compared to patients with brain injury and AD, despite being
mostly unaware of their mental illness and being mostly unable to reattribute their
symptoms to mental illness. Pooling the neuropsychiatric patients together showed
that overall awareness, as measured by the DEX discrepancy, correlated inversely
with symptom severity and positively with mood (worse symptoms, worse aware-
ness; lower mood, better awareness). These results are generally in favor of modu-
larity of awareness with a degree of consistency regardless of diagnosis [107, 108].
We propose, tentatively, that the pattern is consistent with the existence of a
common cognitive architecture for awareness of psychopathologies that may be
disrupted following varied neurophysiological and neuroanatomical dysfunction –
as in brain injury, schizophrenia, and AD. This concept would go against focal
localization of such an architecture but instead points to a somewhat distributed, or
multiple, function-specific system or systems. However, such a system (or systems)
appears to rely on general support systems, such as executive processing, and may
be modulated by generalized factors such as mood.
Acknowledgments James Gilleen was supported by an MRC Ph.D. Studentship. We are grateful
to Prof. Simon Lovestone for facilitating access to his Alzheimer cohort; Laura Bach helped with
recruitment of brain injury patients, and Sandra Randell provided secretarial support. We are
grateful to all the patients and carers who generously took part in our studies.
References
1. David AS (1990) Insight and psychosis. Br J Psychiatry 156:798–808

2. Amador XF, David AS (eds) (2004) Insight and psychosis: awareness of illness in schizophre-
nia and related disorders, 2nd edn. Oxford University Press, Oxford
3. Markova IS (2005) Insight in psychiatry. Cambridge University Press, Cambridge
4. David A, Buchanan A, Reed A et al (1992) The assessment of insight in psychosis. Br
J Psychiatry 161:599
5. Amador XF, Strauss DH, Yale SA et al (1991) Awareness of illness in schizophrenia.
Schizophr Bull 17:113–132
6. Amador XF, Strauss DH, Yale SA et al (1993) Assessment of insight in psychosis. Am
J Psychiatry 150:873–879
7. Kemp R, David AS (1997) Insight and compliance. In: Blackwell B (ed) Treatment compliance
and the therapeutic alliance. Harwood, Amsterdam
8. Sanz M, Constable G, Lopez-Ibor I et al (1998) A comparative study of insight scales and
their relationship to psychopathological and clinical variables. Psychol Med 28:437–446
9. McEvoy JP, Apperson LJ, Appelbaum PS et al (1989) Insight in schizophrenia. Its relationship
to acute psychopathology. J Nerv Ment Dis 177:43–47
10. Birchwood M et al (1994) A self-report Insight Scale for psychosis: reliability, validity and
sensitivity to change. Acta Psychiatr Scand 89:62–67
11. Prigatano GP, Fordyce DJ (1986) Cognitive dysfunction and psychosocial adjustment after
brain injury. In: Prigatano GP, Fordyce DJ (eds) Neuropsychological rehabilitation after brain
injury. John Hopkins University Press, Baltimore, pp 96–118
12. Burgess PW, Alderman N, Evans J et al (1998) The ecological validity of tests of executive
function. J Int Neuropsychol Soc 4:547–558
13. Berrios GE (2004) Insight: a conceptual history. In: Amador XF, David AS (eds) Insight and
psychosis: awareness of illness in schizophrenia and related disorders, 2nd edn. Oxford
University Press, Oxford
14. Takai A, Uematsu M, Ueki H et al (1992) Insight and its related factors in chronic schizo-
phrenic patients: a preliminary study. Eur J Psychiatry 6:159–170
15. Young DA, Davila R, Scher H (1993) Unawareness of illness and neuropsychological
performance in chronic schizophrenia. Schizophr Res 10:117–124
16. Kemp RA, Lambert TJ (1995) Insight in schizophrenia and its relationship to psychopathology.
Schizophr Res 18:21–28
17. Fennig S, Everett E, Bromet EJ et al (1996) Insight in first-admission psychotic patients.
18. Young DA, Zakzanis KK, Bailey C et al (1998) Further parameters of insight and neuropsy-
chological deficit in schizophrenia and other chronic mental disease. J Nerv Ment Dis
186:44–50
19. Rossell SL, Coakes J, Shapleske J et al (2003) Insight: its relationship with cognitive function,
brain volume and symptoms in schizophrenia. Psychol Med 33:111–119
20. Keshavan MS, Rabinowitz J, DeSmedt G et al (2004) Correlates of insight in first episode
psychosis. Schizophr Res 70:187–194
21. Almeida OP, Levy R, Howard RJ et al (1996) Insight and paranoid disorders in late life (late
paraphrenia). Int J Geriatr Psychiatry 11:653–658
22. Kim Y, Sakamoto K, Kamo T et al (1997) Insight and clinical correlates in schizophrenia.
Compr Psychiatry 38:117–123
23. Lysaker PH, Bell MD, Bryson G et al (1998) Neurocognitive function and insight in schizo-
phrenia: support for an association with impairments in executive function but not with
impairments in global function. Acta Psychiatr Scand 97:297–301
24. Schwartz RC (1998) Symptomatology and insight in schizophrenia. Psychol Rep
82:227–233
25. Carroll A, Fattah S, Clyde Z et al (1999) Correlates of insight and insight change in schizo-
phrenia. Schizophr Res 35:247–253
26. McCabe R, Quayle E, Beirne AD et al (2002) Insight, global neuropsychological functioning,
and symptomatology in chronic schizophrenia. J Nerv Ment Dis 190:519–525
27. Olfson M, Marcus SC, Wilk J et al (2006) Awareness of illness and nonadherence to
antipsychotic medications among persons with schizophrenia. Psychiatr Serv 57:205–211
28. Macpherson R, Jerrom B, Hughes A (1996) Relationship between insight, educational
background and cognition in schizophrenia. Br J Psychiatry 168:718
29. Collins AA, Remington GJ, Coulter K et al (1997) Insight, neurocognitive function and symp-
tom clusters in chronic schizophrenia. Schizophr Res 27:37–44
30. Cuesta MJ, Peralta V, Zarzuela A (2000) Reappraising insight in psychosis. Multi-scale
longitudinal study. Br J Psychiatry 177:233–240
31. Laroi F, Fannemel M, Ronneberg U et al (2000) Unawareness of illness in chronic schizophre-
nia and its relationship to structural brain measures and neuropsychological tests. Psychiatry
Res 100:49–58
32. Mintz AR, Dobson KS, Romney DM (2003) Insight in schizophrenia: a meta-analysis.
33. Baier M, DeShay E, Owens K et al (2000) The relationship between insight and clinical fac-
tors for persons with schizophrenia. Arch Psychiatr Nurs 14:259–265
34. Smith TE, Hull JW, Israel LM et al (2000) Insight, symptoms, and neurocognition in schizo-
phrenia and schizoaffective disorder. Schizophr Bull 26:193–200
35. Heinrichs DW, Cohen BP, Carpenter WT Jr (1985) Early insight and the management of
schizophrenic decompensation. J Nerv Ment Dis 173:133–138
36. Overall JE, Gorham D (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10:799–812
37. David AS (2004) The clinical importance of insight. In: Amador XF, David AS (eds) Insight
and psychosis: awareness of illness in schizophrenia and related disorders. Oxford University
Press, Oxford
38. Michalakeas A, Skoutas C, Charalambous A et al (1994) Insight in schizophrenia and mood
disorders and its relation to psychopathology. Acta Psychiatr Scand 90:46–49
39. Amador XF et al (1994) Awareness of illness in schizophrenia and schizoaffective and mood
disorders. Arch Gen Psychiatry 51:826–836
40. Varga M, Magnusson A, Flekkoy K et al (2007) Clinical and neuropsychological correlates of
insight in schizophrenia and bipolar I disorder: does diagnosis matter? Compr Psychiatry
28:583–591
41. Ghaemi SN, Rosenquist KJ (2004) Is insight in mania state-dependent?: a meta-analysis.
J Nerv Ment Dis 192:771–775
42. Weiler MA, Fleisher MH, Arthur-Campbell D (2000) Insight and symptom change in schizo-
phrenia and other disorders. Schizophr Res 45:29–36
43. Pini S, Cassano GB, Dell’Osso L et al (2001) Insight into illness in schizophrenia, schizoaf-
fective disorder, and mood disorders with psychotic features. Am J Psychiatry 158:122–125
44. David A, van Os J, Jones P et al (1995) Insight and psychotic illness. Cross-sectional and
longitudinal associations. Br J Psychiatry 167:621–628
45. Arduini L, Kalyvoka A, Stratta P et al (2003) Insight and neuropsychological function in
patients with schizophrenia and bipolar disorder with psychotic features. Can J Psychiatry
48:338–341
46. Marks KA, Fastenau PS, Lysaker PH et al (2000) Self-Appraisal of Illness Questionnaire
(SAIQ): relationship to researcher-rated insight and neuropsychological function in schizo-
phrenia. Schizophr Res 45:203–211
47. Pyne JM, Bean D, Sullivan G (2001) Characteristics of patients with schizophrenia who do
not believe they are mentally ill. J Nerv Ment Dis 189:146–153
48. David AS (1999) To see ourselves as others see us. Aubrey Lewis’s insight. Br J Psychiatry
174:210–216
49. Cooke MA, Peters ER, Kuipers E et al (2005) Disease, deficit or denial? Models of poor
insight in psychosis. Acta Psychiatr Scand 112:4–17
50. Lysaker P, Bell M (1994) Insight and cognitive impairment in schizophrenia. Performance
on repeated administrations of the Wisconsin Card Sorting Test. J Nerv Ment Dis
182:656–660
51. Morgan KD, David AS (2004) Neuropsychological studies of insight in patients with psy-
chotic disorders. In: Insight and psychosis: awareness of illness in schizophrenia and related
disorders. Oxford University Press, Oxford
52. Aleman A, Agrawal N, Morgan KD et al (2006) Insight in psychosis and neuropsychological
function: meta-analysis. Br J Psychiatry 189:204–212
53. Flashman LA, McAllister TW, Andreasen NC et al (2000) Smaller brain size associated with
unawareness of illness in patients with schizophrenia. Am J Psychiatry 157:1167–1169
54. McEvoy JP, Johnson J, Perkins D et al (2006) Insight in first-episode psychosis. Psychol Med
36:1385–1393
55. Flashman LA, McAllister TW, Johnson SC et al (2001) Specific frontal lobe subregions cor-
related with unawareness of illness in schizophrenia: a preliminary study. J Neuropsychiatry
Clin Neurosci 13:255–257
56. Sapara A, Cooke M, Fannon D et al (2007) Prefrontal cortex and insight in schizophrenia: a
volumetric MRI study. Schizophr Res 89:22–34
57. Bassitt DP, Neto MRL, de Castro CC et al (2007) Insight and regional brain volumes in
schizophrenia. Eur Arch Psychiatry Clin Neurosci 257:58–62
58. Ha TH, Youna T, Ha K et al (2004) Grey matter abnormalities in paranoid schizophrenia and
their clinical correlations. Psychiatry Res Neuroimaging 132:251–260
59. Shad MU, Muddasani S, Keshavan MS (2006) Prefrontal subregions and dimensions of
insight in first-episode schizophrenia: a pilot study. Psychiatry Res 146:35–42
60. Cooke MA, Fannon D, Kuipers E et al (2008) Neurological basis of poor insight in psychosis:
a voxel-based MRI study. Schizophr Res 103:40–51
61. Schmitz TW, Johnson SC (2007) Relevance to self: a brief review and framework of neural
systems underlying appraisal. Neurosci Biobehav Rev 31:585–596
62. Berti A, Bottini G, Gandola M et al (2005) Shared cortical anatomy for motor awareness and
motor control. Science 309:488–491
63. Clare L (2004) Awareness in early-stage Alzheimer’s disease: a review of methods and evi-
dence. Br J Clin Psychol 43:177–196
64. Smith TE, Hull JW, Santos L (1998) The relationship between symptoms and insight in
schizophrenia: a longitudinal perspective. Schizophr Res 33:63–67
65. Moore O, Cassidy E, Carr A et al (1999) Unawareness of illness and its relationship with
depression and self-deception in schizophrenia. Eur Psychiatry 14:264–269
66. Iqbal Z, Birchwood M, Chadwick P et al (2000) Cognitive approach to depression and suicidal
thinking in psychosis. 2. Testing the validity of a social ranking model. Br J Psychiatry
177:522–528
67. White R, Bebbington P, Pearson J et al (2000) The social context of insight in schizophrenia.
Soc Psychiatry Psychiatr Epidemiol 35:500–507
68. Schwartz RC (2001) Self-awareness in schizophrenia: its relationship to depressive
symptomatology and broad psychiatric impairments. J Nerv Ment Dis 189:401–403
69. Mutsatsa SH, Joyce EM, Hutton SB et al (2006) Relationship between insight, cognitive func-
tion, social function and symptomatology in schizophrenia: the West London first episode
study. Eur Arch Psychiatry Clin Neurosci 256:356–363
70. Ghaemi SN (2007) Feeling and time: the phenomenology of mood disorders, depressive
realism, and existential psychotherapy. Schizophr Bull 33:122–130
71. Rathod S, Kingdon D, Smith P et al (2005) Insight into schizophrenia: the effects of cognitive
behavioural therapy on the components of insight and association with sociodemographics:
data on a previously published randomised controlled trial. Schizophr Res 74:211–219
72. Kemp R, Kirov G, Everitt B et al (1998) Randomised controlled trial of compliance therapy:
18-month follow-up. Br J Psychiatry 172:413–419
73. Vasterling JJ, Seltzer B, Foss JW et al (1995) Unawareness of deficit in Alzheimer’s disease.
Domain-specific differences and disease correlates. Neuropsychiatry Neuropsychol Behav
Neurol 8:26–32
74. Starkstein SE, Chemerinski E, Sabe L et al (1997) Prospective longitudinal study of depression
and anosognosia in Alzheimer’s disease. Br J Psychiatry 171:47–52
75. Clare L (2004) The construction of awareness in early-stage Alzheimer’s disease: a review of
concepts and models. Br J Clin Psychol 43:155–175
76. Seltzer B, Vasterling JJ, Hale MA et al (1995) Unawareness of memory deficit in Alzheimer’s
disease relation to mood and other disease variables. Neuropsychiatry Neuropsychol Behav
Neurol 8:176–181
77. Derouesne C, Thibault S, Lagha-Pierucci S et al (1999) Decreased awareness of cognitive deficits
in patients with mild dementia of the Alzheimer type. Int J Geriatr Psychiatry 14:1019–1030
78. Koltai DC, Welsh-Bohmer KA, Schmechel DE (2001) Influence of anosognosia on treatment
outcome among dementia patients. Cogn Rehabil Dement 3:455–475
79. McGlynn SM, Schacter DL (1989) Unawareness of deficits in neuropsychological syndromes.
J Clin Exp Neuropsychol 11:143–205
80. Laroi F, Barr WB, Keefe RSE (2004) The neuropsychology of insight in psychiatric and neu-
rological disorders. In: Amador X, David A (eds) Insight and psychosis: awareness of illness
in schizophrenia and related disorders. Oxford University Press, Oxford
81. Vogel A, Hasselbalch SG, Gade A et al (2005) Cognitive and functional neuroimaging
correlate for anosognosia in mild cognitive impairment and Alzheimer’s disease. Int J
Geriatr Psychiatry 20:238–246
82. Harwood DG, Sultzer DL, Wheatley MV (2000) Impaired insight in Alzheimer disease:
association with cognitive deficits, psychiatric symptoms, and behavioral disturbances.
Neuropsychiatry Neuropsychol Behav Neurol 13:83–88
83. Feher EP, Mahurin RK, Inbody SB et al (1991) Anosognosia in Alzheimer’s disease.
Neuropsychiatry Neuropsychol Behav Neurol 4:136–146
84. DeBettignies BH, Mahurin RK, Pirozzolo FJ (1990) Insight for impairment in independent liv-
ing skills in Alzheimer’s disease and multi-infarct dementia. J Clin Exp Neuropsychol
12:355–363
85. Michon A, Deweer B, Pillon B et al (1994) Relation of anosognosia to frontal lobe dysfunc-
tion in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 57:805–809
86. Auchus AP, Goldstein FC, Green J et al (1994) Unawareness of cognitive impairments in
Alzheimer’s disease. Neuropsychiatry Neuropsychol Behav Neurol 7:25–29
87. Lopez OL, Becker JT, Somsak D et al (1994) Awareness of cognitive deficits and anosognosia
in probable Alzheimer’s disease. Eur Neurol 34:277–282
88. Dalla Barba G, Parlato V, Iavarone A et al (1995) Anosognosia, intrusions and frontal functions
in Alzheimer’s disease and depression. Neuropsychologia 33:247–259
89. Migliorelli R, Teson A, Sabe L et al (1995) Prevalence and correlates of dysthymia and major
depression among patients with Alzheimer’s disease. Am J Psychiatry 152:37–44
90. Sevush S (1999) Relationship between denial of memory deficit and dementia severity in
Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol 12:88–94
91. Feher EP, Larrabee GJ, Sudilovsky A et al (1994) Memory self-report in Alzheimer’s disease
and in age-associated memory impairment. J Geriatr Psychiatry Neurol 7:58–65
92. Zanetti O, Vallotti B, Frisoni GB et al (1999) Insight in dementia: when does it occur?
Evidence for a nonlinear relationship between insight and cognitive status. J Gerontol B
Psychol Sci Soc Sci 54:100–106
93. Prigatano GP, Altman IM (1990) Impaired awareness of behavioral limitations after trau-
matic brain injury. Arch Phys Med Rehabil 71:1058–1064
94. Sherer M, Boake C, Levin E (1998) Characteristics of impaired awareness after traumatic
brain injury. J Int Neuropsychol Soc 4:380–387
95. Trudel TM, Tryon WW, Purdum CM (1998) Awareness of disability and long-term outcome
after traumatic brain injury. Rehabil Psychol 43:267–281
96. Sherer M, Hart T, Nick TG et al (2003) Early impaired self-awareness after traumatic brain
injury. Arch Phys Med Rehabil 84:168–176
97. Wise K, Ownsworth T, Fleming J (2005) Convergent validity of self-awareness measures and
their association with employment outcome in adults following acquired brain injury. Brain
Inj 19:765–775
98. Bergquist TF, Jacket MP (1993) Awareness and goal setting with the traumatically -brain
injured. Brain Inj 7:275–282
99. Prigatano GP (2005) Disturbances of self-awareness and rehabilitation of patients with trau-
matic brain injury: a 20-year perspective. J Head Trauma Rehabil 20:19–29
100. Banks SJ, Weintraub S (2009) Generalized and symptom-specific insight in behavioral variant
frontotemporal dementia and primary progressive aphasia. J Neuropsychiatry Clin Neurosci
21:299–306
101. O’Keeffe FM, Murray B, Coen RF et al (2007) Loss of insight in frontotemporal dementia,
corticobasal degeneration and progressive supranuclear palsy. Brain 130:753–764
102. Medalia A, Lim RW (2004) Self-awareness of cognitive functioning in schizophrenia.
103. Kircher TTJ, Koch K, Stottmeister F et al (2007) Metacognition and reflexivity in patients
with schizophrenia. Psychopathology 40:254–260
104. Teasdale TW, Christensen AL, Willmes K et al (1997) Subjective experience in brain injured
patients and their close relatives: a European Brain Injury Questionnaire study. Brain Inj
11:543–564
105. Vasterling JJ, Seltzer B, Watrous WE (1997) Longitudinal assessment of deficit unawareness
in Alzheimer’s disease. Neuropsychiatry Neuropsychol Behav Neurol 10:197–202
106. Burgess PW, Alderman N, Emslie H, Evans JJ, Wilson BA (1996) The dysexecutive
questionnaire. In: Wilson BA, Alderman N, Burgess PW, Emslie H, Evans JJ (eds)
Behavioural assessment of the Dysexecutive Syndrome. Thames Valley Test Company, Bury
St. Edmunds, UK
107. Bayard S, Capdevielle D, Boulenger JP et al (2009) Dissociating self-reported cognitive
complaint from clinical insight in schizophrenia. Eur Psychiatry 24:251–258
108. Flashman LA, Roth RM, McAllister TW et al (2007) Dissociation of awareness of different
components of illness in schizophrenia. J Neuropsychiatry Clin Neurosci 19:221–222
109. Morgan KD, Dazzan P, Morgan C et al (2010). Insight, grey matter and cognitive function
in first-onset psychosis, Brit J Psychiat (in press).
Visual Hallucinations in Neurodegenerative
Disorders
Spyridon Papapetropoulos and Blake K. Scanlon
Abstract Neuropsychiatric symptoms, such as hallucinations, are common in

neurodegenerative disorders and primarily in Parkinson’s disease, where they
contribute significantly to disease morbidity and caregiver burden, eventually leading
to early nursing home placement. As the average life expectancy in developed nations
continues on an upward trend, the incidence of neurodegenerative disease and their
neuropsychiatric complications follows in parallel. This review provides an overview
of synucleinopathies, tauopathies, prion diseases, and heredodegenerative disorders in
which visual hallucinations (VH) are present. Epidemiological information along with
factors associated with symptom presentation is outlined. The clinical characteristics
of visual disturbances and their impact on disease management are discussed. Relevant
treatment options for VH in each neurodegenerative syndrome are also reviewed.
Keywords Alzheimer’s disease • Dementia with Lewy bodies • Neurodegenerative

disorders • Parkinson’s disease • Visual hallucinations
Introduction
Neurodegenerative diseases are characterized by progressive decline in the
structure, activity, and function of the central nervous system. Neuronal dropout
usually results in disruption of multiple pathways, regional neurotransmitter
S. Papapetropoulos (*) and B.K. Scanlon

Department of Neurology, University of Miami Miller School of Medicine,
1536 9th Avenue, Miami, FL 33136, USA
S. Papapetropoulos
Biogen Idec, 14 Cambridge Center, Bio 6A, 6th Floor,
Cambridge, MA 02142, USA
B.K. Scanlon
Department of Psychology, University of Miami,
5665 Ponce de Leon Blvd., Coral Gables, FL 33146, USA

DOI 10.1007/978-4-431-53871-4_4, © Springer 2010
52 S. Papapetropoulos and B.K. Scanlon
deficits, and neurochemical imbalance. As a result, distinctive phenotypic

expressions are grouped into disease clinicopathological entities [Alzheimer’s dis-
ease (AD), Parkinson’s disease (PD), etc.]. Clinicians recognize this distinctive set
of progressive signs and symptoms and, on pathological examination, the patholo-
gist reports lesions in brain regions that underpin these signs and symptoms.
Neuropsychiatric manifestations are very prevalent and an integral part of the
symptom/sign pattern of neurodegenerative diseases. Most importantly, they sig-
nificantly add to disease morbidity, caregiver burden, and deteriorating health-
related quality of life. Although the mechanism remains unknown, it is hypothesized
that neuropsychiatric symptoms may be primary and an integral part of the neuro-
degenerative process, secondary to medication or comorbid conditions affecting the
dysregulated and susceptible system, or simply reactive phenomena.
The pattern recognition approach to disease has been palliative, and there has been
no knowledge of the causes of the damage. Advances in molecular genetics and
immune-based histopathology techniques have allowed a classification system of neuro-
degenerative diseases based on protein accumulation. Microtubule-associated tau is
one protein that has important functions in healthy neurons but which forms insoluble
deposits in diseases now known collectively as tauopathies. Tauopathies encompass
more than 20 clinicopathological entities, including AD, the most common tauopathy,
progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), corticobasal
degeneration, and postencephalitic parkinsonism. The term synucleinopathies refers to
a certain subset of neurodegenerative diseases with a similar pathological lesion pat-
tern consisting of insoluble alpha-synuclein in selected neuronal and glial cells.
Accumulation of alpha-synuclein is seen in dementia with Lewy bodies (DLB), PD,
and multiple systems atrophy (MSA). A smaller subset of neurodegenerative diseases
is genetically determined and can be collectively grouped into the heredodegenerative
category. This review focuses on one of the most common neuropsychiatric symptoms
in neurodegenerative disorders: the characteristics, etiology, and treatment of visual
hallucinations (VH) are discussed in the most common neurodegenerative disorders.
Visual Hallucinations in Synucleinopathies
Dementia with Lewy Bodies
Epidemiology
Dementia with Lewy bodies (DLB) is frequently recognized as the second most
common degenerative dementia [1]. Although extensive epidemiological literature
is lacking, a recent review indicates that prevalence estimates for DLB range from
0.1% to 5.0% in the general population and from 1.7% and 30.5% in dementia cases
[1]. In accordance with current consensus criteria, recurrent VH are among the core
Visual Hallucinations in Neurodegenerative Disorders 53
features indicative of DLB [2]. Approximately two-thirds of patients with DLB present
with VH [3, 4]. Patients with DLB commonly present with hallucinations, and
nearly half have hallucinations within 2 years after the first clinical symptom [5].
Factors Associated with VH in DLB
A recent community-based autopsy study found that cases with VH were more
likely than cases without VH to have Lewy-related pathology (78% versus 45%)
[6]. Overall cortical Lewy body (LB) burden is greater in cases with early VH (at
onset or within the first 2 years of the disease course), which relates to more LBs
in the inferior temporal cortices [5]. Additional neuropathological evidence indi-
cates that VH are associated with more LB pathology in the parahippocampus and
amygdala [5].
Neuroimaging technologies are also used to elucidate factors associated with VH.
Although most effort focuses on identifying imaging markers that differentiate DLB
from other dementing disorders, some investigations examine potential mechanisms
related specifically to VH in DLB. 18F-Fluorodeoxyglucose-positron emission
tomography (18F-FDG-PET) evaluations show that people living with DLB and VH
have relative metabolic reductions in the right temporo-occipital junction and the
right middle frontal gyrus compared to those with DLB without VH [7].
Certain clinical characteristics are also associated with VH in DLB. The
Consortium on DLB [8] reports that VH may particularly present during periods of
diminished consciousness. Visual impairment exacerbates VH; this is likely a con-
sequence of selective sensory deprivation, and an increase in environmental stimu-
lation may provide temporary relief [8]. People living with DLB and VH perform
worse on overlapping figure identification compared to those without VH [9].
Additional evidence shows that DLB and demented PD patients with recurrent VH
are significantly more impaired in visual discrimination, space-motion perception,
and object-form perception than patients without VH [10].
Clinical Characteristics of VH in DLB
While people living with DLB have hallucinatory experiences that encompass a
variety of modalities, VH are most common [4]. These VH are frequently complex,
occur at least once a day, last for minutes, and consist of a single, colored, station-
ary object in the central visual field [11]. The experiences are often benign and not
perceived as threatening. However, there are exceptions. These characteristics are
largely similar to those evidenced in PD dementia. Specific phenomenological
characteristics of VH in DLB include anonymous people/soldiers; body parts;
animals; friends and family; children/babies; and machines [11]. VH in DLB tend
to persist and are stable over time [12].
Clinical Impact and Treatment of VH in DLB
VH are considered one of the most important neuropsychiatric targets for

intervention in DLB [13]. Several pharmacological intervention strategies show
some success in the treatment of hallucinations in DLB. Deficits in cortical
acetylcholine are associated with VH [14] and thus, unsurprisingly, VH are often
responsive to pharmacotherapies with anticholinesterase properties. DLB patients
with VH who are cognitive responders to acetylcholinesterase inhibitors such as
donepezil, galantamine, and rivastigmine show greater improvement than respond-
ers without VH [15]. Furthermore, cognitive nonresponders with VH show less
cognitive decline at follow-up than do cognitive nonresponders without VH [15].
Although these medications were originally created to treat AD, evidence shows a
better response in the treatment of DLB than AD [16]. Because of the potential for
severe adverse reactions to neuroleptics [2, 17], the use of antipsychotics in the
treatment of DLB should only be initiated after careful consideration.
Parkinson’s Disease
Epidemiology
Worldwide prevalence rates of Parkinson’s disease (PD) tend to vary widely [18].
Estimates of the number of people living with PD in the world’s ten most populous
nations, along with Western Europe’s five most populous nations, range between
4.1 and 4.6 million [19]. This number is expected to double to somewhere between
8.7 and 9.3 million by 2030. Annual incidence ranges between 4.9 and 26 per
100,000 [20]. Hallucinations occur in 20% to 40% of PD patients receiving
symptomatic therapy [21], although as many as 75% of patients develop
hallucinatory phenomena of a visual nature [22]. VH in PD are often considered
treatment related because prevalence rates in the pre-levodopa era were as low as
5% [23, 24].
Factors Associated with the Presentation of Hallucinations in PD
Longer PD disease duration, higher unified PD rating scale (UPDRS) total

score, and dementia show independent associations with the occurrence of medica-
tion-induced VH in PD [25]. All dopaminergic therapies (direct, through receptor
stimulation, or indirect, through metabolic enzyme inhibition), and especially dop-
amine agonist therapy, can elicit hallucinations and psychosis [26]. Additionally,
numerous studies find greater prevalence of hallucinations and other psychotic
symptoms in demented versus nondemented patients with PD [27]. VH are present
in 70% of PD patients with dementia [28]. Approximately 45% of nondemented PD
patients with VH go on to develop dementia within a year [29]. Additional evidence
suggests that deficient performance on cognitive tasks, such as verbal fluency,

predicts the development of hallucinations in people living with PD [30].
Furthermore, REM (rapid eye movement) sleep behavior disorder comorbidity is
associated with increased VH risk in PD.
Clinical Characteristics of VH in PD
The VH most often reported in PD are drug induced, complex, and consist of ani-
mate or inanimate objects or persons [31]. However, perceptual phenomena that are
more transient and less clear can also occur [28]. VH typically appear several years
after disease onset and usually contain five or fewer images, which are sometimes
meaningful to the patient. The typical “hallucinator’s experience” [32] occurs while
alert and with eyes open, in dim surroundings. The hallucination is present for a few
seconds and then suddenly vanishes. Initially, hallucinations are “friendly.” Patients
often see fragmented figures of beloved familiar persons or animals. As reality test-
ing and insight further decrease, the content of the hallucinations may change to
frightening images (e.g., insects, rats), inducing anxiety and panic attacks [33].
Hallucinations may become malignant, disabling, and intermingled with paranoid
patterns, including suspiciousness, negativism, and sexual accusations. Ideas of
persecution, fearfulness, agitation, aggression, confusion, and delirium become
commonplace. It is at this point that the situation at home often becomes unbear-
able, and the patient is frequently placed in a nursing home [34]. Although VH are
predominant, auditory hallucinations (mixed with visual) are reported to affect
about 10% of patients [28].
Clinical Impact and Treatment of VH in PD
Without intervention, hallucinations with retained insight can evolve to malignant

hallucinations without insight [35]. Presence of hallucinations can predict nursing
home placement [36] and may predict mortality in PD [37]. When hallucinations
first present, a systematic evaluation for potential causes should ensue. Once factors
such as secondary illness or medication overdose are ruled out, the physician
should revisit the diagnosis of PD to ensure premorbid psychosis or other neuro-
degenerative diseases do not explain the VH.
As a first-line treatment, visual, cognitive, and interactional coping strategies
[38], along with appropriate sleep hygiene, should be encouraged. If these strategies
do not effectively resolve the VH, removal or taper of medications with the lowest
antiparkinsonian effect may be useful. Adjustment of dopaminergic therapy to bal-
ance the treatment of motor and nonmotor symptoms such as VH is perhaps the most
effective treatment strategy. Although some evidence suggests that treatment with
antipsychotics may delay psychiatric deterioration [39], the U.S. Food and Drug
Administration (FDA) has determined that atypical antipsychotic use may contribute
to increased mortality in elderly dementia patients [40]. Additional evidence linking
antipsychotic use to increased risk of pneumonia is particularly relevant to treatment

considerations, as pneumonia is the most commonly reported cause of death in PD
[41]. Although clozapine is considered “probably effective” and quetiapine is con-
sidered “possibly effective” in the treatment of psychosis in PD [42], caution must
be used when using antipsychotics “off-label” to treat hallucinations and other psy-
chotic symptoms in PD. Pimavanserin tartrate, a selective 5-HT2A inverse agonist,
has shown encouraging efficacy against psychotic symptoms in PD in phase II and
is currently being tested in phase III pivotal trials [43]. Acetylcholinesterase inhibi-
tors may also have potential utility in the treatment of VH in PD. A case report
indicates donepezil may decrease VH in PD [44], and PD patients with VH may
show greater benefit from rivastigmine than those without VH [45]. However, no
large, controlled trials have been conducted to determine the efficacy of acetylcho-
linesterase inhibitors in the treatment of VH in PD.
Multiple System Atrophy
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder with a

diverse clinical presentation that can include parkinsonism, autonomic failure, uro-
genital dysfunction, cerebellar ataxia, and corticospinal disorders [46]. Prevalence
estimates range from 1.9/100,000 to 4.9/100,000 per year, with an estimated inci-
dence of 0.6/100,000 per year [47]. Nonmedication-induced hallucinations are
considered nonsupportive of MSA diagnosis [46]. Nonetheless, evidence from case
reports suggests that VH occur in up to 9.5% of pathologically confirmed MSA
cases [48]. VH reported in a study by Papapetropoulos and colleagues consisted of
small and friendly animals in one case not receiving dopaminergic therapy and
fragmented friendly faces in dimly lit surroundings related to levodopa in another
case. Neither case required treatment with antipsychotics [48].
VH in Tauopathies
Alzheimer’s Disease
Epidemiology
AD is the most common degenerative dementia. There were 4.5 million people
living with AD in the United States in 2000; this number is expected to nearly triple
by 2050 [49]. A population-based European study estimates the age-standardized
prevalence of AD to be 4.4%, with prevalence increasing with age [50]. Nearly
19% of patients with AD experience VH [51]. Data on persistence of psychotic
symptoms, including VH, in AD are mixed, and methodological differences likely
contribute to disparate findings.
Factors Associated with the Presentation of Hallucinations in AD
The severity of cognitive impairment in AD often relates to prevalence of halluci-

nations, with more impaired patients being at higher risk for hallucinations [51].
Several studies show that African Americans have a higher risk of developing hallu-
cinations than Caucasians; however, this relationship appears to be more relevant in
advanced disease stages. Data on other clinicodemographic factors are either mixed
or equivocal and are discussed more fully by Ropacki and Jeste [51]. Additional
evidence indicates that patients with dementia (including, but not limited to AD) and
hallucinations are more likely to present with agitation, delusions, and apathy than
those without hallucinations [6]. This cohort of hallucinators was also more likely
to have Lewy-related pathology upon autopsy.
Clinical Characteristics of VH in AD
Assessing VH in people living with AD and other cognitive disorders is frequently

challenging. Some studies rely on caregiver reports to identify patients experiencing
VH, whereas others do not often report characteristics of the hallucinations other
than prevalence or Neuropsychiatric Inventory score. Some work shows that VH in
AD include images of familiar people, dead relatives, animals, and machinery [52].
Other work shows that 54% of AD patients with VH also experience an auditory
component [53]. Because of the clinical presentation of AD, VH may not be adequately
captured with common methodologies.
Clinical Impact and Treatment of VH in AD
Hallucinations in AD have been associated with aggressive behavior, verbal out-

bursts, asocial behavior, and falls; however, other studies have failed to show
these relationships [54]. The presence of hallucinations predicts increased risk for
cognitive/functional decline, institutionalization, and mortality in AD [55]. At
present, regulatory authorities including the FDA have yet to approve any
pharmacotherapeutic agent for the treatment of dementia-related psychosis.
Consequently, as with previously mentioned disorders, nonpharmacological manage-
ment is the recommended first-line treatment. Although some atypical
antipsychotics may be modestly effective treatments for psychosis in AD, adverse
event and mortality risk may significantly outweigh the treatment benefits in this
population [17, 40, 56].
Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is a phenotypically heterogeneous, progres-

sive neurodegenerative disorder consisting of parkinsonism, mild dementia,
supranuclear gaze palsy, and postural instability [57]. Prevalence estimates range
from 1.39/100,000 to 6.5/100,000 [58–60], and incidence is estimated to be 5.3
new cases per 100,000 person-years in people 50 to 99 years of age [61].
Estimates of VH prevalence in PSP range from 9.1% to 13.4% [62, 63]. Several
studies report phenomenological characteristics of VH in PSP [62, 64–66]. VH
are frequently whole people, animals, or fragmented faces. They are familiar
sights and occur during twilight or nighttime more often than not. VH can present
with an auditory component and may become frightening as complexity increases
and disease progresses. The relationship between VH in PSP and antiparkinso-
nian treatment appears to be equivocal. Nonpharmacological interventions are the
first-line treatment, and pharmacotherapy may be useful if the VH become threat-
ening and severely impair quality of life. Antipsychotics show limited utility in
treating VH in PSP. However, before implementation, the risk of severe adverse
events must be strongly considered [62].
Frontotemporal Dementia
Frontotemporal dementia (FTD) is a term used to define a grouping of pathologi-

cally and clinically heterogeneous disorders that demonstrate degeneration of the
frontal and temporal lobes. Prevalence estimates range from 4/100,000 to
15/100,000 for those aged 45 to 64 years [67, 68]. Incidence for the same age range
is estimated to be 3.5 cases per 100,000 person-years [69]. Studies published after
the initial frontotemporal lobar degeneration consensus diagnostic criteria [70]
have examined hallucinations, without differentiating sensory types, and report
prevalence of hallucinations ranging from 2% to 13% [71–73]. However, per recent
review by the Committee on Research of the American Neuropsychiatric
Association, there are several reports of psychotic symptoms in FTD with only one
case [74] truly showing an association between possible FTD and bizarre VH [75].
Nonpharmacological interventions are the first-line treatment for hallucinations
that may arise in people living with FTD. Pharmaceutical management decisions
should be made on a case-by-case basis with particular caution given to potential
neuroleptic hypersensitivity [76] and other adverse events.
VH in Heredodegenerative and Other Neurodegenerative Diseases
Huntington’s disease (HD) is a progressive, heredodegenerative disorder that

presents with neuropsychiatric, cognitive, and motor symptoms. Prevalence of
psychosis in HD ranges from 3% to 11% [77], with approximately 2% presenting
with hallucinations [78]. Studies of hallucinations in HD often group hallucinations
with delusions and examine them collectively rather than individually. Psychiatric
symptoms that occur in people living with HD are not related to cognitive or motor
presentation [78, 79]. However, they may be related to mood disorders. Once mood
disorders, intoxication, and delirium are taken into consideration, antipsychotics
may be useful. Assuming neuroleptics are not needed for the control of involuntary
movements, newer agents such as risperidone, olanzepine, or quetiapine may be best
as these have less chance of extrapyramidal side effects [80]. Systematic review
deems risperidone “possibly useful” for the treatment of psychosis in HD [81].
Creutzfeldt–Jakob disease (CJD), although quite rare, is the most common prion
disease affecting humans. Several forms of the disease are currently recognized,
including sporadic, familial, iatrogenic, and variant. Rapidly progressive dementia
and myoclonus are the cardinal features of sporadic CJD (sCJD). One study
describing VH in CJD reports patients hallucinate birds, people, and other visual
phenomena [82]. Cases of sCJD are frequently referred to as the Heidenhain variant
if visual disturbances, including VH, occur within the first week after onset [83].
VH are present in approximately 13% of Heidenhain variant cases and 2.3% of all
sCJD cases [83]. However, other studies show hallucinations of unspecified modal-
ity occur in nearly 25% of cases [84].
Although VH occur in other neurodegenerative disorders, this review is unable
to address them all. As the neuropsychiatric features of neurodegenerative disorders
receive more attention in the literature, a more developed understanding of symp-
tom presentation and treatment options will likely ensue.
Conclusions
Visual hallucinations (VH) are a common feature of neurodegenerative disease.

Alpha-synuclein pathology may predispose individuals to develop VH. In PD, VH
are frequently treatment related, and may lead to nursing home placement and
increased mortality. In DLB, VH are very common, primary, and one of the core
diagnostic features. Clinical treatment of VH in neurodegenerative disorders is
complex. Neuroleptics should be considered with caution, particularly in disorders
with dopamine deficit.
References
1. Zaccai J, McCracken C, Brayne C (2005) A systematic review of prevalence and incidence

studies of dementia with Lewy bodies. Age Ageing 34(6):561–566
Lewy bodies: third report of the DLB Consortium. Neurology 65(12):1863–1872
3. Ballard C, Holmes C, McKeith I et al (1999) Psychiatric morbidity in dementia with Lewy
bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s
disease. Am J Psychiatry 156(7):1039–1045
4. Aarsland D, Ballard C, Larsen JP et al (2001) A comparative study of psychiatric symptoms
in dementia with Lewy bodies and Parkinson’s disease with and without dementia. Int J
Geriatr Psychiatry 16(5):528–536
5. Harding AJ, Broe GA, Halliday GM (2002) Visual hallucinations in Lewy body disease relate
to Lewy bodies in the temporal lobe. Brain 125(Pt 2):391–403
6. Tsuang D, Larson EB, Bolen E et al (2009) Visual hallucinations in dementia: a prospective

community-based study with autopsy. Am J Geriatr Psychiatry 17(4):317–323
7. Perneczky R, Drzezga A, Boecker H et al (2008) Cerebral metabolic dysfunction in patients
with dementia with Lewy bodies and visual hallucinations. Dement Geriatr Cogn Disord
25(6):531–538
8. McKeith IG, Galasko D, Kosaka K et al (1996) Consensus guidelines for the clinical and
pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB
international workshop. Neurology 47(5):1113–1124
9. Mori E, Shimomura T, Fujimori M et al (2000) Visuoperceptual impairment in dementia with
Lewy bodies. Arch Neurol 57(4):489–493
10. Mosimann UP, Mather G, Wesnes KA et al (2004) Visual perception in Parkinson disease
dementia and dementia with Lewy bodies. Neurology 63(11):2091–2096
11. Mosimann UP, Rowan EN, Partington CE et al (2006) Characteristics of visual hallucinations
in Parkinson disease dementia and dementia with Lewy bodies. Am J Geriatr Psychiatry
14(2):153–160
12. Ballard CG, O’Brien JT, Swann AG et al (2001) The natural history of psychosis and depres-
sion in dementia with Lewy bodies and Alzheimer’s disease: persistence and new cases over
1 year of follow-up. J Clin Psychiatry 62(1):46–49
13. McKeith I, Mintzer J, Aarsland D et al (2004) Dementia with Lewy bodies. Lancet Neurol
3(1):19–28
14. Perry EK, McKeith I, Thompson P et al (1991) Topography, extent, and clinical relevance of
neurochemical deficits in dementia of Lewy body type, Parkinson’s disease, and Alzheimer’s
disease. Ann N Y Acad Sci 640:197–202
15. Pakrasi S, Mukaetova-Ladinska EB, McKeith IG et al (2003) Clinical predictors of response
to Acetyl Cholinesterase Inhibitors: experience from routine clinical use in Newcastle. Int J
Geriatr Psychiatry 18(10):879–886
16. Samuel W, Caligiuri M, Galasko D et al (2000) Better cognitive and psychopathologic
response to donepezil in patients prospectively diagnosed as dementia with Lewy bodies: a
preliminary study. Int J Geriatr Psychiatry 15(9):794–802
17. Schneider LS, Dagerman KS, Insel P (2005) Risk of death with atypical antipsychotic drug
treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA
294(15):1934–1943
18. Zhang ZX, Roman GC (1993) Worldwide occurrence of Parkinson’s disease: an updated
review. Neuroepidemiology 12(4):195–208
19. Dorsey ER, Constantinescu R, Thompson JP et al (2007) Projected number of people with
Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68(5):384–386
20. Schrag A (2007) Epidemiology of movement disorders. In: Jankovic J, Tolosa E (eds)
Parkinson’s disease and movement disorders. Lippincott Williams & Wilkins, Philadelphia
21. Papapetropoulos S, Mash DC (2005) Psychotic symptoms in Parkinson’s disease. From
description to etiology. J Neurol 252(7):753–764
22. Diederich NJ, Fenelon G, Stebbins G et al (2009) Hallucinations in Parkinson disease. Nat
Rev Neurol 5(6):331–342
23. Lewy F (1923) Die Lehre vom Tonus und der Bewegung. Springer, Berlin
24. Schwab RS, Fabing HD, Prichard JS (1951) Psychiatric symptoms and syndromes in
Parkinson’s disease. Am J Psychiatry 107(12):901–907
25. Papapetropoulos S, Argyriou AA, Ellul J (2005) Factors associated with drug-induced visual
hallucinations in Parkinson’s disease. J Neurol 252(10):1223–1228
26. Tolosa E, Katzenschlager R (2007) Pharmacological management of Parkinson’s disease. In:
Jankovic J, Tolosa E (eds) Parkinson’s disease and movement disorders. Lippincott Williams
& Wilkins, Philadelphia
27. Papapetropoulos S, Gonzalez J, Lieberman A et al (2005) Dementia in Parkinson’s disease: a
post-mortem study in a population of brain donors. Int J Geriatr Psychiatry 20(5):418–422
28. Fenelon G, Mahieux F, Huon R et al (2000) Hallucinations in Parkinson’s disease: prevalence,
phenomenology and risk factors. Brain 123(Pt 4):733–745
29. Ramirez-Ruiz B, Junque C, Marti MJ et al (2007) Cognitive changes in Parkinson’s disease

patients with visual hallucinations. Dement Geriatr Cogn Disord 23(5):281–288
30. Santangelo G, Trojano L, Vitale C et al (2007) A neuropsychological longitudinal study in
Parkinson’s patients with and without hallucinations. Mov Disord 22(16):2418–2425
31. Haeske-Dewick HC (1995) Hallucinations in Parkinson’s disease: characteristics and associ-
ated clinical features. Int J Geriatr Psychiatry 10(6):487–495
32. Barnes J, David AS (2001) Visual hallucinations in Parkinson’s disease: a review and phe-
nomenological survey. J Neurol Neurosurg Psychiatry 70(6):727–733
33. Wolters EC (2001) Intrinsic and extrinsic psychosis in Parkinson’s disease. J Neurol
248(suppl 3):III22–III27
34. Baker MG (1999) Depression, psychosis and dementia in Parkinson’s disease. Neurology
52(7 suppl 3):S1
35. Goetz CG, Fan W, Leurgans S et al (2006) The malignant course of “benign hallucinations”
in Parkinson disease. Arch Neurol 63(5):713–716
36. Goetz CG, Stebbins GT (1993) Risk factors for nursing home placement in advanced
Parkinson’s disease. Neurology 43(11):2227–2229
37. Sinforiani E, Pacchetti C, Zangaglia R et al (2008) REM behavior disorder, hallucinations and
cognitive impairment in Parkinson’s disease: a two-year follow up. Mov Disord
23(10):1441–1445
38. Diederich NJ, Pieri V, Goetz CG (2003) Coping strategies for visual hallucinations in
Parkinson’s disease. Mov Disord 18(7):831–832
39. Goetz CG, Fan W, Leurgans S (2008) Antipsychotic medication treatment for mild hallucina-
tions in Parkinson’s disease: positive impact on long-term worsening. Mov Disord
23(11):1541–1545
40. U.S. Food and Drug Administration (2009) Deaths with antipsychotics in elderly patients with
behavioral disturbances. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/
ucm053171.htm. Accessed 15 Aug 2009
41. Knol W, van Marum RJ, Jansen PA et al (2008) Antipsychotic drug use and risk of pneumonia
in elderly people. J Am Geriatr Soc 56(4):661–666
42. Miyasaki JM, Shannon K, Voon V et al (2006) Practice parameter: evaluation and treatment
of depression, psychosis, and dementia in Parkinson disease (an evidence-based review).
Report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology 66(7):996–1002
43. Abbas A, Roth BL (2008) Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for
treating various neuropsychiatric disorders. Expert Opin Pharmacother 9(18):3251–3259
44. Kurita A, Ochiai Y, Kono Y et al (2003) The beneficial effect of donepezil on visual hallucina-
tions in three patients with Parkinson’s disease. J Geriatr Psychiatry Neurol 16(3):184–188
45. Burn D, Emre M, McKeith I et al (2006) Effects of rivastigmine in patients with and without
visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord
21(11):1899–1907
46. Gilman S, Wenning GK, Low PA et al (2008) Second consensus statement on the diagnosis
of multiple system atrophy. Neurology 71(9):670–676
47. Wenning GK, Colosimo C, Geser F et al (2004) Multiple system atrophy. Lancet Neurol
3(2):93–103
48. Papapetropoulos S, Tuchman A, Laufer D et al (2007) Hallucinations in multiple system
atrophy. Parkinsonism Relat Disord 13(3):193–194
49. Hebert LE, Scherr PA, Bienias JL et al (2003) Alzheimer disease in the US population: preva-
lence estimates using the 2000 census. Arch Neurol 60(8):1119–1122
50. Lobo A, Launer LJ, Fratiglioni L et al (2000) Prevalence of dementia and major subtypes in
Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly
Research Group. Neurology 54(11 Suppl 5):S4–S9
51. Ropacki SA, Jeste DV (2005) Epidemiology of and risk factors for psychosis of Alzheimer’s
disease: a review of 55 studies published from 1990 to 2003. Am J Psychiatry
162(11):2022–2030
52. Lin SH, Yu CY, Pai MC (2006) The occipital white matter lesions in Alzheimer’s disease
patients with visual hallucinations. Clin Imaging 30(6):388–393
53. Wilson RS, Krueger KR, Kamenetsky JM et al (2005) Hallucinations and mortality in
Alzheimer disease. Am J Geriatr Psychiatry 13(11):984–990
54. Bassiony MM, Lyketsos CG (2003) Delusions and hallucinations in Alzheimer’s disease:
review of the brain decade. Psychosomatics 44(5):388–401
55. Scarmeas N, Brandt J, Albert M et al (2005) Delusions and hallucinations are associated with
worse outcome in Alzheimer disease. Arch Neurol 62(10):1601–1608
56. Ballard C, Waite J (2006) The effectiveness of atypical antipsychotics for the treatment of
aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev 1:CD003476
57. Williams DR, Lees AJ (2009) Progressive supranuclear palsy: clinicopathological concepts
and diagnostic challenges. Lancet Neurol 8(3):270–279
58. Golbe LI, Davis PH, Schoenberg BS et al (1988) Prevalence and natural history of progressive
supranuclear palsy. Neurology 38(7):1031–1034
59. Schrag A, Ben-Shlomo Y, Quinn NP (1999) Prevalence of progressive supranuclear palsy and
multiple system atrophy: a cross-sectional study. Lancet 354(9192):1771–1775
60. Nath U, Ben-Shlomo Y, Thomson RG et al (2001) The prevalence of progressive supranuclear
palsy (Steele-Richardson-Olszewski syndrome) in the UK. Brain 124(Pt 7):1438–1449
61. Bower JH, Maraganore DM, McDonnell SK et al (1997) Incidence of progressive supranu-
clear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990.
Neurology 49(5):1284–1288
62. Papapetropoulos S, Mash DC (2005) Visual hallucinations in progressive supranuclear palsy.
Eur Neurol 54(4):217–219
63. Williams DR, Warren JD, Lees AJ (2008) Using the presence of visual hallucinations to dif-
ferentiate Parkinson’s disease from atypical parkinsonism. J Neurol Neurosurg Psychiatry
79(6):652–655
64. Compta Y, Marti MJ, Rey MJ et al (2009) Parkinsonism, dysautonomia, REM behaviour
disorder and visual hallucinations mimicking synucleinopathy in a patient with progressive
supranuclear palsy. J Neurol Neurosurg Psychiatry 80(5):578–579
65. Cooper AD, Josephs KA (2009) Photophobia, visual hallucinations, and REM sleep behavior
disorder in progressive supranuclear palsy and corticobasal degeneration: a prospective study.
Parkinsonism Relat Disord 15(1):59–61
66. Diederich NJ, Leurgans S, Fan W et al (2008) Visual hallucinations and symptoms of REM
sleep behavior disorder in Parkinsonian tauopathies. Int J Geriatr Psychiatry 23(6):598–603
67. Rosso SM, Donker Kaat L, Baks T et al (2003) Frontotemporal dementia in The Netherlands:
patient characteristics and prevalence estimates from a population-based study. Brain 126(Pt
9):2016–2022
68. Ratnavalli E, Brayne C, Dawson K et al (2002) The prevalence of frontotemporal dementia.
Neurology 58(11):1615–1621
69. Mercy L, Hodges JR, Dawson K et al (2008) Incidence of early-onset dementias in
Cambridgeshire, United Kingdom. Neurology 71(19):1496–1499
70. Neary D, Snowden JS, Gustafson L et al (1998) Frontotemporal lobar degeneration: a consen-
sus on clinical diagnostic criteria. Neurology 51(6):1546–1554
71. Le Ber I, Guedj E, Gabelle A et al (2006) Demographic, neurological and behavioural char-
acteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia. Brain
129(Pt 11):3051–3065
72. Mourik JC, Rosso SM, Niermeijer MF et al (2004) Frontotemporal dementia: behavioral
symptoms and caregiver distress. Dement Geriatr Cogn Disord 18(3–4):299–306
73. Liu W, Miller BL, Kramer JH et al (2004) Behavioral disorders in the frontal and temporal
variants of frontotemporal dementia. Neurology 62(5):742–748
74. Reischle E, Sturm K, Schuierer G et al (2003) A case of schizophreniform disorder in fronto-
temporal dementia (FTD). Psychiatr Prax 30(suppl 2):S78–S82
75. Mendez MF, Lauterbach EC, Sampson SM et al (2008) An evidence-based review of the
psychopathology of frontotemporal dementia: a report of the ANPA Committee on Research.
J Neuropsychiatry Clin Neurosci 20(2):130–149
76. Mendez MF, Lipton A (2001) Emergent neuroleptic hypersensitivity as a herald of presenile
dementia. J Neuropsychiatry Clin Neurosci 13(3):347–356
77. van Duijn E, Kingma EM, van der Mast RC (2007) Psychopathology in verified Huntington’s
disease gene carriers. J Neuropsychiatry Clin Neurosci 19(4):441–448
78. Paulsen JS, Ready RE, Hamilton JM et al (2001) Neuropsychiatric aspects of Huntington’s
disease. J Neurol Neurosurg Psychiatry 71(3):310–314
79. Zappacosta B, Monza D, Meoni C et al (1996) Psychiatric symptoms do not correlate with
cognitive decline, motor symptoms, or CAG repeat length in Huntington’s disease. Arch
Neurol 53(6):493–497
80. Rosenblatt A, Ranen N, Nance M, et al (1999) A physician’s guide to the management of
Huntington’s disease. http://www.hdsa.org/images/content/1/1/11289.pdf. Accessed 1 Sept
2009
81. Bonelli RM, Wenning GK (2006) Pharmacological management of Huntington’s disease: an
evidence-based review. Curr Pharm Des 12(21):2701–2720
82. Proulx AA, Strong MJ, Nicolle DA (2008) Creutzfeldt-Jakob disease presenting with visual
manifestations. Can J Ophthalmol 43(5):591–595
83. Appleby BS, Appleby KK, Crain BJ et al (2009) Characteristics of established and proposed
sporadic Creutzfeldt-Jakob disease variants. Arch Neurol 66(2):208–215
84. Lundberg PO (1998) Creutzfeldt-Jakob disease in Sweden. J Neurol Neurosurg Psychiatry
65(6):836–841
Organic Delusional Syndrome: Tentative
Neuropsychological Mechanism of Delusions
Yoshitaka Ohigashi and Makiko Yamada
Abstract Three organic delusions, namely, “persecutory delusions in psychotic

disorder following traumatic brain injury (PDFTBI),” “Capgras syndrome, a
major form of delusional misidentification syndrome,” and “anosognosia for
left hemiplegia or somatoparaphrenia,” are discussed in this chapter. Concerning
persecutory delusions in PDFTBI, we underscore the role of the temporal pole
lesion that may segregate the function of the amygdala from visual information
processed in the temporal lobe. The isolated function of the amygdala is speculated
to cause an undiscerning oversensitive response to any incoming emotional stimuli.
With regard to Capgras delusion, the most conventional neuropsychological account
of “the mirror-image model of prosopagnosia” is reevaluated, and several important
critiques are mentioned. Last, we have attempted to provide a novel explanation
of anosognosia for left hemiplegia and somatoparaphrenia by refining definitions
of “body consciousness” and “body schema” and by taking account of Edelman’s
reentry hypothesis for the genesis of consciousness. In the end, it is concluded that
ingenious neuropsychological approaches are indispensable for the understanding
of organic delusional syndromes.
Keywords Anosognosia฀ •฀ Capgras฀ syndrome฀ •฀ Neuropsychology฀ •฀ Persecutory฀

delusion฀•฀Somatoparaphrenia
Y. Ohigashi
International Center, Graduate School of Human and Environmental Studies,
Kyoto University, Kyoto, Japan
M. Yamada (*)
Molecular Imaging Center,
National฀Institute฀of฀Radiological฀Sciences,฀Chiba,฀Japan

DOI 10.1007/978-4-431-53871-4_5, © Springer 2010
66 Y. Ohigashi and M. Yamada
Introduction
Various types of organic delusions can be observed in neurological patients, yet

their mechanisms are still to be determined. In this chapter, three major organic
delusions are discussed, and we attempt to provide the neuropsychological
mechanisms of each delusion. The first topic is the “persecutory delusion” that is
observed in psychotic disorders following traumatic brain injury (PDFTBI). The sec-
ond is the “delusional misidentification syndrome” (DMS), represented mainly by
Capgras syndrome. The third is “anosognosia for left hemiplegia” [1] and
“somatoparaphrenia” [2], both of which are generally observed following large
right hemispheric lesions.
Given that the persecutory delusion and delusional misidentification can occur
independently in neurological settings, these delusions are based on the distinct
neurolopsychological mechanisms. Although the lesion in the temporal pole seems
to be responsible for persecutory delusion in PDFTBI, abnormal functions in the
limbic structures together with the right frontal lobe could be related to Capgras
syndrome. The third type of delusion, anosognosia for left hemiplegia and
somatoparaphrenia, is of special interest. Body schema and body consciousness are
distinctive in nature. As the former is supposed to possess symbolic or semiotic
features, it must be represented mainly in the left hemisphere. In contrast, the latter
can be represented in the bilateral hemisphere in such a way that the right hemi-
sphere represents whole-body consciousness while the left hemisphere supports
only the contralateral, that is, the right side of body consciousness. As a consequence
of a large right hemisphere lesion, a patient’s bilateral body consciousness might be
reduced, producing a residual consciousness of only the right side of his/her body.
We consider that this is the fundamental feature of anosognosia for left hemiplegia
and the phenomenon of somatoparaphrenia.
Persecutory Delusion and Delusional Perception in PDFTBI
Psychotic disorder following traumatic brain injury (PDFTBI), originally reported

by Fujii and Ahmed [3, 4], is the psychotic state that consists predominantly of
persecutory delusions and auditory hallucinations with an absence of negative
symptoms. Abnormalities in the temporal and frontal areas are often associated
with PDFTBI. The latency between traumatic brain injury and the onset of
psychotic symptoms varies between patients, but the recent consensus falls around
4 to 5 years.
Our major interest here is whether delusional perception in PDFTBI is related to
the patient’s biased-emotion evaluations of others, which may provide insight
regarding the neuropsychological mechanisms of persecutory delusion. In the
following, we present two PDFTBI patients with temporal lobe lesions. Based on
our examination of their ability to estimate emotion intensity from facial expressions,
the critical role of the temporal pole for delusional perception is suggested.
Organic฀Delusional฀Syndrome:฀Tentative฀Neuropsychological฀Mechanism฀of฀Delusions 67
Fig. 1 Computed tomography (CT) findings of case SA
Case SA was a 23-year-old female ambidextrous college student. She had a traffic
accident at age 16 years and had been unconscious for about 10 days. She received
a craniotomy to remove a left parietal hematoma. Her lesions were detected in the
right temporal pole and the left parietal lobe (Fig. 1). When she was discharged from
hospital after 3 months, she showed mildly impaired memory retention, reduced
calculation ability, articulation disorder, and mild right hemiparesis. After the acci-
dent, she was noticed by her family and friends to behave and talk like a child. She
complained of her difficulty in memory retention and concentration; however, she
had spent a quasi-normal daily life without many serious problems.
About 4 years later she began to experience hallucinations and delusions. She
complained: “my father looks like a different person,” “I feel as if TV is speaking
of me,” and “I’m very scared and always feel as if I’m chased by someone.” She
also experienced functional auditory hallucinations, such as “I hear the sound of
typing computer keyboard as human voice.”
Case DR was a 36-year-old right-handed woman. She received a college educa-
tion. A traffic accident at age 14 resulted in skull fracture and intracranial hemorrhage
with a loss of consciousness for 3 days. Her major complaint was headache, insom-
nia, and irritability. After 5 years after the accident, she began to develop persecutory
delusion, such as “I hear some noise that speaks evil of me” and “my vulgar idea is
detected by other people.” She was first diagnosed as “schizophrenia” in a psychiatric
department but was now rediagnosed as PDFTBI. Computed tomography (CT) and
single-photon emission computerized tomography (SPECT) indicated apparent
lesions in the left anterior temporal lobe and the left posterior frontal cortex (Fig. 2).
The ability of both patients to evaluate emotional intensity from others’ faces was
investigated using the Emotional Intensity Scale (EIS [5]) and compared with that of
healthy subjects. In this task, subjects were asked to rate the perceived intensity of a
given emotion word (six basic emotions in total) for each facial expression of six basic
emotions (see [5]฀for฀detailed฀procedure).฀Results฀indicated฀that฀case฀SA฀perceived฀a฀
sad facial expressions not only as “sadness” itself but also as high intensities of
Fig. 2 CT฀findings฀of฀case฀DR
5 5
**
Happiness intensity
Surprise intensity
Mean Rating of
Mean Rating of
4 4
3 3
*
2 2
**
1 1
0 0
happiness surprise fear anger disgust sadness happiness surprise fear anger disgust sadness
Facial Expression Facial Expression
5 5
** **
4 4
**
Mean Rating of
Mean Rating of
Anger intensity
Fear intensity
3 3
2 2
1 1
0 0
5 5
4 4
Sadness intensity
Mean Rating of
Disgust intensity
Mean Rating of
3 3
2 2
1 1
0 0
Comparison subjects Case SA * P < 0.05 ** P < 0.01
Fig. 3 Results฀ of฀ Emotional฀ Intensity฀ Scale฀ in฀ case฀ SA.฀ Horizonta axis, evaluated facial
expressions; vertical axis, intensity of an emotion word
“surprise” and “fear” (Fig. 3). This patient showed a tendency to perceive facial expressions
in heightened emotions of “surprise,” “disgust,” and “happiness” compared to
normal฀subjects.฀Case฀DR฀perceived฀emotions฀of฀fear,฀anger,฀and฀sadness฀in฀almost฀all฀
facial expressions except for happiness (Fig. 4).
Happiness intensity 5 5 **
Surprise intensity
** 4
Mean Rating of
4
Mean Rating of
3 3
**
2 2
1 1
0 0
5 5
** ** **
4 ** ** 4 **
Mean Rating of
Mean Rating of
Anger intensity
**
Fear intensity
3 3
2 2
1 1
0 0
5 5
** ** ** **
**
Sadness intensity
4 ** 4
Disgust intensity
Mean Rating of
Mean Rating of
3 3
2 2
1 1
0 0
Comparison subjects Case DR ** P < 0.01
Fig. 4 Results฀of฀Emotional฀Intensity฀Scale฀(EIS)฀in฀case฀DR
Several common features between the two cases can be pointed out. (1) Their
common lesion site was the temporal pole. (2) Psychotic states appeared 4 to 5 years
after head injuries. (3) Persecutory delusion with hallucination was the predominant
clinical฀picture฀in฀both฀cases.฀(4)฀Results฀of฀EIS฀suggested฀the฀confused฀judgments฀of฀
facial expressions, characterized by a negatively biased-emotion estimation.
The temporal pole is known to play a crucial role in high-level recognition
because it is anatomically located at the endpoint of the auditory and visual “what”
stream. A general function of the temporal pole is supposed to be to couple emotional
responses to highly processed sensory stimuli through a tight connection with the
amygdala [6]. Thus, the temporal pole is regarded as a relay point that links the
final “what” perception to emotional responses in the amygdala. The lesion sites
in our cases suggest that the route from the temporal pole to the amygdala could be
disrupted, and that the functions between these two sites might be isolated. As
indicated by EIS results, the patients overestimated negative emotions regardless of
the actual emotional signals of the facial expression. This overestimation of negative
emotion has been observed in the case of ictal fear [7], which implied that the
amygdala was not dysfunctional but rather hypersensitive. Consistent with this
amygdala hypersensitivity account, a negatively biased perception in our cases
could have persisted through limbic kindling, which might have created a trait-like
misinterpretation of others’ minds, or persecutory delusions.
In sum, the temporal pole lesions in patients with PDFTBI may segregate the function
of the amygdala from visual information processing. This isolation may cause the
amygdala to respond to emotional stimuli overly intensively and unselectively. We regard
this as one possible cause of delusional perception and persecutory delusion in PDFTBI.
Delusional Misidentification Syndrome: Capgras Syndrome
Capgras syndrome is the most common form of delusional misidentification, origi-

nally฀described฀by฀Capgras฀and฀Reboul-Lachaux฀[8]. This disorder is characterized
as the delusional belief that familiar persons have been replaced by identical impos-
tors. This condition was once (or is still now) explained by the psychoanalytical
view that posits this disorder as a defense mechanism against unconscious
prohibited desires. However, accumulating neurological and neuropsychological
evidence suggests that organic factors are important in the pathogenesis of Capgras
syndrome [9].
One most conventional neuropsychological account is “the mirror-image model
of prosopagnosia” [10], based on the dual-route theory of facial recognition (Fig. 5).
According to this model, two anatomically independent routes to face recognition,
namely, overt and covert recognition pathways (Fig. 5a, b, respectively), are damaged
in a mirror-reversed manner between prosopagnosia and Capgras syndrome. As
Fig. 5 illustrates, although the overt route interruption causes prosopagnosia, the
covert route disconnection yields Capgras syndrome. This claim is derived exclusively
from฀ undifferentiated฀ skin฀ conductance฀ responses฀ (SCRs)฀ toward฀ known฀ and฀
unknown฀ faces฀ in฀ Capgras฀ patients,฀ in฀ contrast฀ to฀ normal฀ SCRs฀ toward฀ unrecog-
nized-yet-known faces in prosopagnostic patients. Disconnection between the
face-processing areas and the amygdala has been considered to represent a lack of
affection/familiar feeling toward known faces in Capgras syndrome. This discon-
nectionist account has been favored by several researchers ([12], etc.); however, it
seems that quite a few serious objections impede upholding this idea.
Major criticisms include the following. (1) Although this model claims that the
SCR฀is฀a฀measure฀of฀covert฀recognition,฀the฀relationship฀between฀SCRs฀and฀the฀true฀
experience of patients is far less clear [13, 14].฀(2)฀SCRs฀usually฀index฀a฀generalized฀฀
arousal state following an unexpected external stimulus that is often threat- or fear
related;฀this฀contradicts฀the฀assumption฀that฀SCRs฀signify฀a฀“familiar฀feeling”฀in฀the฀
mirror-image model. (3) Correspondingly, although this model regards the amygdala
functions as a “familiar feeling,” the widely accepted view of this region is mainly
to detect threat-related information. (4) The disconnection in the covert route is
assumed in Capgras syndrome, but the actual anatomical disconnection has not
Visual Input
Structural encoding
Expression Speech Visual

analysis Codes Codes
Face recognition units Arousal, orienting

response
A B
C
Name Name Person identity Affect response Skin conductance
production Retrieval nodes To familiar stimuli response
Semantic Integrative Attribution

Information units device processes
Fig. 5 Model of face recognition and Capgras delusion, formulated by Ellis and Young [10]
(figure is a reprint from [11], modified for this publication). Disconnection in the overt recognition
route (a) yields prosopagnosia, whereas that in the covert recognition route (b) produces Capgras
syndrome
been identified. (5) The model explains the face recognition processing but ignores
the occasional coexistence of misidentification of objects or places. (6) The model
does not account for patients’ resistance to modify their delusional belief in the
presence of very strong evidence against it.
Among different explanations for DMS provided by other researchers, a two-
factor model, proposed by Coltheart and his colleagues [15], takes into consider-
ation the foregoing issue (see “6,” above). In their model, although the first factor
is composed of the failure of autonomic responsiveness to familiar faces, the second
abnormal factor is the patient’s resistance to revise the delusional belief, which is
speculated to arise from a disrupted belief evaluation system associated with the
right frontal cortex. In accord with their idea, neuroimaging studies revealed that
the right prefrontal cortex was involved in mediating the ability to detect or resolve
conflicts in thinking [16, 17]. In this sense, we also hypothesize that the delusion
in Capgras syndrome as well as other DMSs might represent a dysfunction of the
cognitive-conflict resolution mechanism, which is supported by the right frontal
lobe. Further support for this view is observed from evidence that right frontotemporal
lesions are predominant in patients with Capgras syndrome in the setting of focal
brain damage [18–20].฀The฀reduction฀in฀event-related฀potential฀(ERP)฀in฀the฀right฀

frontal lobe was also reported in deluded patients [21].
Alghough Ellis &Young’s original one-stage account was recently incorporated
into two-factor model, called “an interactionist model” [11], the puzzle still remains
as to what special mechanisms create the delusional misidentification. The exami-
nation of neurological patients suggests the involvement of the limbic structure, yet
its functional relationship with the misidentification phenomenon must be deter-
mined in future research. Considering that the amygdala is an alarm system that
deals with not only threat-related stimuli but also anything ambiguous for an organ-
ism, we dare advocate a new proposal of misidentification in Capgras syndrome. If
the same argument that we made for delusional perception in PDFTBI can be
applied to Capgras syndrome, we speculate that regardless of known or unknown
persons (or objects), the maladaptive function of the hypersensitive amygdala cre-
ates a feeling too strongly suspicious to be rejected; that is, “a deluded misidentifi-
cation in Capgras syndrome.”
Anosognosia and Somatoparaphrenia
Anosognosia for left hemiplegia was first described by Babinski [1] as the denial
of left hemiplegia. Somatoparaphrenia was reported by Gerstmann [2] as delu-
sional beliefs concerning a contralesional side of body (the left side in most
cases), which is characterized by a pathological alteration of the ownership of the
limbs. In a famous monograph, The Parietal Lobes [23], Critchley classified the
content of distortion of the body image as follows: (1) unilateral neglect, (2) lack
of concern (anosodiaphoria), (3) unawareness of hemiparesis (anosognosia), (4)
defective appreciation of the existence of hemiparesis, (5) denial of hemiparesis,
(6) denial of hemiparesis with confabulation, (7) loss of awareness of one body-
half (asomatognosia), (8) undue heaviness, deadness, or lifelessness of one half,
(9) phantom third limb, (10) personification of paralyzed limb, and (11) misople-
gia (the last two categories were included in 1955 and 1974, respectively). In his
categorization, anosognosia and various somatoparaphrenia were not sharply
demarcated but closely related. In 1972, Hécaen [24] distinguished hemi-
somatognosic disorder into three categories: (1) anosognosia for the left hemiple-
gia, (2) hemi-asomatognosia raging from simple neglect to amnesia, unawareness
of one side of the body, and (3) feeling of absence of one’s body part or one side
of the body, including disownership and phantom limbs. Apparently, these disor-
ders still lie on a continuum.
Here we attempt to provide a neuropsychological mechanism of anosognosia
(unawareness of left hemiparesis) and a feeling of disownership of the left side of
the body, based on a novel framework of consciousness proposed by Edelman
[25] and on our refined definitions of “body schema” and “body consciousness.”
Body schema represents a symbolic semiotic or linguistic body concept, possibly
SELF NONSELF
Internal homeostatic systems World signals
and proprioception
Brainstem, Primary and

Hypothalamus, Secondary cortex in
Autonomic centers Each modality
Current neural registration Current perceptual
Of Internal Sates categorization
Correlation in septum, Broca’s and

Amygdala, Wernicke’s PRIMARY
Hippocampus,etc. Areas CONSCIOUNESS
Conceptual
categorization
Reentrant loop
Connection value-category
HIGHER- ORDER memory to current

CONSCIOUNSESS perceptual categorization
Special
Value-category
Memory in frontal, temporal.
Parietal areas
Fig. 6 Reentry฀genetic฀theory฀of฀consciousness฀by฀Edelman฀[25] (modified for this publication)
supported by the left parietal lobe. Phylogenetically, new “body schema,” which
would have coincided with the genesis of language, could be attributed to the
higher-order consciousness within Edelman’s reentry hypothesis for the genesis
of consciousness [25] (Fig. 6). The close relationship between body schema and
language is supported by the evidence that impaired body schema can provoke,
for instance, bilateral finger agnosia or autotopagnosia. In contrast, body con-
sciousness represents a basic and immediate body feeling that would be phyloge-
netically older than body schema. We would attribute body consciousness to the
primary consciousness in Edelman’s model, which may be supported predomi-
nantly by the right hemisphere.
We further speculate that body consciousness, which was originally distributed

bilaterally and symmetrically, that is, the right body was in the left hemisphere
and vice versa, gradually shifted to the right hemisphere as a consequent of a
“body schema” lateralization in the left hemisphere. If so, it can be hypothe-
sized that the right hemisphere represents the bilateral body consciousness,
whereas the left hemisphere represents only a residual consciousness of the
right฀side฀of฀the฀body.฀Recent฀lesion฀studies฀indicated฀that฀body฀consciousness฀
would be represented by a neural circuitry of right hemisphere regions, includ-
ing the temporo-parietal junction, posterior insula, and subcortical structures,
such as basal ganglia [26–29]. Thus, damage to this neural circuitry in the
right hemisphere may yield a loss of bilateral body consciousness whereas the
right-body consciousness may survive without damage to the left hemisphere.
Therefore, patients are aware of only the right side of the body, and the “ano-
sognosia” and the “somatoparaphrenia” appear exclusively on the left side of
the body.
In the patients’ consciousness, the left body is no longer their own body. The
conviction that they can move their own left arm would not work for them
because the left arm no longer exists in their consciousness. In turn, they would
say they can move it by showing their moving right arm, or would talk about their
own left arm as if it did not belong to their body. These delusions are not false
but quite real in their consciousness. We propose that this is the fundamental
feature of “anosognosia for left hemiplegia” and the phenomenon of the
“somatoparaphrenia.”
Conclusion
In this chapter, we took a neuropsychological approach to understand organic

delusional syndromes. One possible account for persecutory delusions in PDFTBI
was the segregation of amygdala function caused by temporal pole lesions. The
isolated amygdala may respond to any emotional stimuli because of inadequate
visual information or rundown visual processing areas in the amygdala; this may
create an overly reactive amygdala and shape the delusional perception in these
patients. The pathogenesis of Capgras syndrome could be related to the abnormal
functioning in the right hemisphere and the limbic areas; however, the most
accepted neuropsychological account of “the mirror-image model of prosopagno-
sia” faces several critical problems, and the advanced theory warrants future
research. Our novel explanation of anosognosia for left hemiplegia and somatopara-
phrenia was provided within Edelman’s reentry hypothesis for the genesis of
consciousness, together with the refined definitions of “body consciousness” and
“body schema.”
References
1. Babinski MJ (1914) Contribution a l’értude des troubles mentaux dans l’hemiplegie organique
cérébrale.฀Rev฀Neurol฀1:845–848
2. Gerstmann J (1942) Problem of imperception of disease and of impaired body territories with
organic฀lesions.฀Relation฀to฀body฀scheme฀and฀its฀disorders.฀Arch฀Neurol฀Psychiatry฀48:890–913
3. Fujii DE, Ahmed I (2002) Psychotic disorder following traumatic brain injury: a conceptual
framework.฀Cogn฀Neuropsychiatry฀7:41–62
4. Fujii DE, Ahmed I, Hishimura E (2004) A neuropsychological comparison of psychotic
disorder following traumatic brain injury, traumatic brain injury without psychotic disorder,
and฀schizophrenia.฀J฀Neuropsychiatry฀Clin฀Neurosci฀16:306–314
฀ 5.฀ Adolphs฀ R,฀ Tranel฀ D,฀ Damasio฀ H฀ et฀ al฀ (1994)฀ Impaired฀ recognition฀ of฀ emotion฀ in฀ facial฀
expressions฀following฀bilateral฀damage฀to฀the฀human฀amygdala.฀Nature฀(Lond)฀372:669–672
฀ 6.฀ Olson฀IR,฀Plotzker฀A,฀Ezzyatb฀Y฀(2007)฀The฀enigmatic฀temporal฀pole:฀a฀review฀of฀findings฀on฀
social and emotional processing. Brain 130:1718–1731
7. Yamada M, Murai T, Sato W et al (2005) Emotion recognition from facial expressions in a
temporal฀lobe฀epileptic฀patient฀with฀ictal฀fear.฀Neuropsychologia฀43:434–441
฀ 8.฀ Capgras฀ J,฀ Reboul-Lachaux฀ J฀ (1923)฀ L’illusion฀ des฀ ‘soises’฀ dans฀ un฀ délire฀ systématisé฀
chronique. Bull Soc Clin Med Ment 11:6–16. In: Enoch MD, Trethowan WH (eds)
Uncommon psychiatric syndromes. Wright and Sons, Bristol, 1979
9. Forstl H, Almeida OP, Owen AM et al (1991) Psychiatric, neurological and medical aspects
of misidentification syndromes: a review of 260 cases. Psychol Med 21:905–910
10. Ellis HD, Young AW (1990) Accounting for delusional misidentification. Br J Psychiatry 157:239–248
11. Ellis HD (2007) Delusions: a suitable case for imaging? Int J Psychophysiol 62:146–151
฀12.฀ Hirstein฀W,฀Ramachandran฀VS฀(1997)฀Capgras฀syndrome:฀a฀novel฀probe฀for฀understanding฀the฀
neural representation of the identity and familiarity of persons. Proc Biol Sci 264:437–444
฀13.฀ Breen฀N,฀Caine฀D,฀Coltheart฀M฀(2000)฀Models฀of฀face฀recognition฀and฀delusional฀misidenti-
fication:฀a฀critical฀review.฀Cogn฀Neuropsychol฀17:55–71
14. Hohwy J (2004) Top-down and bottom-up in delusion formation. Philos Psychiatr Psychol
11:65–70
฀15.฀ Coltheart฀ M,฀ Langdon฀ R,฀ McKay฀ R฀ (2007)฀ Schizophrenia฀ and฀ monothematic฀ delusions.฀
Schizophr Bull 33:642–647
฀16.฀ Fink฀GR,฀Marshall฀JC,฀Halligan฀PW฀et฀al฀(1999)฀The฀neural฀consequences฀of฀conflict฀between฀
intention and the senses. Brain 122:497–512
17. Goel V, Buchel C, Frith C et al (2000) Dissociation of mechanisms underlying syllogistic
reasoning.฀Neuroimage฀12:504–514
18. Alexander MP, Stuss DT, Benson DF (1979) Capgras syndrome: a reduplicative phenomenon.
Neurology฀29:334–339
฀19.฀ Staton฀ RD,฀ Brumback฀ RA,฀ Wilson฀ H฀ (1982)฀ Reduplicative฀ paramnesia:฀ a฀ disconnection฀
syndrome of memory. Cortex 18:23–35
฀20.฀ Moser฀ DJ,฀ Cohen฀ RA,฀ Malloy฀ PF฀ et฀ al฀ (1998)฀ Reduplicative฀ paramnesia:฀ longitudinal฀
neurobehavioral฀and฀neuroimaging฀analysis.฀J฀Geriatr฀Psychiatry฀Neurol฀11:174–180
21. Papageorgiou P, Ventouras E, Lykouras L et al (2003) Psychophysiological evidence for
altered฀information฀in฀delusional฀misidentification฀syndromes.฀Prog฀Neuropsychopharmacol฀
Biol Psychiatry 27:365–372
22. Young G (2008) Capgras delusion: an interactionist model. Conscious Cogn 17:863–876
฀23.฀ Critchley฀M฀(1953)฀The฀parietal฀lobes.฀Hafner,฀New฀York
24. Hécaen H (1972) Introduction à la neuropsychologie. Larousse, Paris
25. Edelman GM (2004) Wider than the sky: the phenomenal gift of consciousness. Yale
University฀Press,฀New฀Haven
฀26.฀ Cereda฀C,฀Ghika฀J,฀Maeder฀P฀et฀al฀(2002)฀Strokes฀restricted฀to฀the฀insular฀cortex.฀Neurology฀
59:1950–1955
฀27.฀ Karnath฀ HO,฀ Baier฀ B,฀ Nagele฀ T฀ (2005)฀ Awareness฀ of฀ the฀ functioning฀ of฀ one’s฀ own฀ limbs฀
mediated฀by฀the฀insular฀cortex?฀J฀Neurosci฀25:7134–7138
28. Baier B, Karnath H-O (2008) Tight link between our sense of limb ownership and self-
awareness of actions. Stroke 39:486–488
29. Halligan PW, Marshall JC (1995) Supernumerary phantom limb after right hemispheric
stroke.฀J฀Neurol฀Neurosurg฀Psychiatry฀59:341–342
Neurological and Psychological Forms
of Amnesia
Michael D. Kopelman
Abstract Amnesic disorders can be transient (a discrete episode of memory loss)

or persisting. They can have a neurological or a psychological basis. Furthermore,
neurological memory disorders can affect primarily episodic or semantic memory
or both. Implicit (procedural) and working memory are commonly preserved.
Psychogenic amnesia may be “global” or “situation specific.” The global form
affects the whole of a person’s previous life and is commonly accompanied by a
loss of the sense of personal identity. Situation-specific amnesia involves a discrete
gap in a person’s memory, usually related to a traumatic episode. Examples of these
various forms of memory loss are given and discussed in relationship to our current
concepts of memory and the underlying pathophysiology.
Keywords Amnesia • Anterograde • Neurological • Psychogenic • Retrograde
Introduction
Memory disorders have either a neurological or a psychological basis. Moreover,

both these types may involve either a discrete (transient) episode of memory loss or
a more persisting memory disorder. Figure 1 shows specific conditions giving rise
to transient or persistent neurological or psychogenic memory disorders. Examples
from each quadrant are discussed below. It should, of course, be acknowledged that
admixtures of neurological and psychological factors are very common.
Anterograde amnesia (AA) consists of an impairment in new learning, that is,
recall and recognition memory for episodes and facts that have arisen after the
M.D. Kopelman (*)

and
Academic Unit of Neuropsychiatry, 3rd Floor, Adamson Centre, South Wing,
St. Thomas’s Hospital, Westminster Bridge Road, London SE1 7EH, UK

DOI 10.1007/978-4-431-53871-4_6, © Springer 2010
78 M.D. Kopelman
onset of an illness or injury. Retrograde amnesia (RA) involves the loss of memory
for episodes or facts that occurred before the onset of an illness or injury.
Primary or working memory (“short-term memory” in psychological parlance)
consists of memories lasting a few seconds or as long as they are actively rehearsed
and held in consciousness – what Williams James called the “specious present” [1].
This type of memory is characteristically preserved in the amnesic syndrome.
Autobiographical memory involves a person’s recollection of past incidents or
events, which occurred at a specific time and place, such that the person can “travel
back mentally in time.” The term autobiographical memory is sometimes used
interchangeably with “episodic memory,” although the latter also includes a person’s
performance on standard learning tasks that may have a differing neurobiological
basis [2]. By definition, autobiographical or episodic memory is severely impaired in
amnesia. Semantic memory refers to a person’s knowledge of language, concepts, and
facts that do not have a specific location in time or place; this is variably affected in
amnesia. Implicit memory refers to learning without awareness, and this incorporates
both procedural (perceptuo-motor) skill learning and the response to priming. Implicit
memory is characteristically spared in amnesia, as is discussed below. In principle,
episodic, semantic, and implicit memory can each have an anterograde and a retro-
grade component. Figure 1 shows that they can be differentially affected in memory
disorders: the amnesic syndrome principally affects episodic (autobiographical)
memory, sometimes exclusively so; semantic dementia principally involves semantic
AMNESIC STATES
Discrete Episode: Persistent:

NEURO- Toxic confusional state Continuing drug toxicity
LOGICAL: Head Injury Amnesic syndrome - episodic
Epilepsy Semantic dementia -semantic
Alcoholic ‘black-out’ Alzheimer dementia - global
Cerebral hypoxia
Transient Global Amnesia (TGA)
Post-ECT (electro-convulsive therapy)
PSYCHOGENIC: Situation – specific (e.g. offence, Depressive Pseudodementia

PTSD )
Fugue states ‘Focal retrograde amnesia ’
Fig. 1 Specific conditions giving rise to transient or persistent, neurological or psychogenic

memory disorders. PTSD posttraumatic stress disorder, ECT. (Modified from British Journal of
Psychiatry (1987) 150:428–442)
Neurological and Psychological Forms of Amnesia 79
memory; and Alzheimer dementia usually affects both the episodic and semantic
components of memory, and eventually implicit skills may also be affected.
Transient Neurological Amnesias
Transient Global Amnesia
Transient global amnesia (TGA) occurs most commonly in the middle-aged or

elderly, more frequently in men. It results in a period of amnesia usually lasting
several hours.
TGA is characterized by repetitive questioning; there may be some confusion,
but patients do not report any loss of the sense of personal identity; that is, they
know who they are. Hodges and Ward found that in 114 cases of TGA the mean
duration of amnesia was 4 h and that the maximum was 12 h [3]. Sometimes, the
episode had been preceded by headache or nausea, a stressful life event, a medical
procedure, or vigorous exercise. In 25% of their sample, there was a past history of
migraine, which was considered to have a possible etiological role. In a further 7%
of the sample, the patients subsequently developed epilepsy, usually complex
partial seizures, although there had not been any past history of epilepsy or overt
features of epilepsy evident during the original attack. In these latter cases, the
memory loss was attributed in retrospect to epilepsy (see following). In this
investigation, as in previous ones [4], TGA was not statistically associated with a
past history of vascular disease, clinical signs suggestive of vascular pathology, or
known risk factors for vascular disease. In particular, there was no specific associa-
tion with transient ischemic attacks. Moreover, in 60–70% of this TGA sample, the
underlying etiology was unclear.
More recently, Quinette et al. reviewed findings in 1,353 patients reported in the
clinical literature since 1956 and their own data from 142 patients seen between
1994 and 2004 [5]. In general, the findings were consistent across the two sources.
In these series, most of the attacks occurred between the ages of 50 and 80
(mean = 60.3), and they occurred equally among men and women. Most patients
had a single attack, and the annual rate of recurrence ranged from 2.9% to 26.3%
across different studies, being 6.3% in Quinette et al.’s own series. Moreover, in
their own series, the duration of attacks ranged from 30 min to 16 h (mean = 5.6 h).
These authors also investigated putative predisposing and precipitating factors in
great detail, concluding that TGA may encompass at least three groups of patients:
(1) younger patients with a history of migraine, in whom spreading neurochemical
depression may be implicated; (2) women who have experienced acute emotional
or physical stress, and who often have a history of anxiety or depression; and (3)
men who, following physical exertion, develop venous congestion in the context of
insufficient jugular vein valves and a precipitating Valsalva maneuver.
In those cases of TGA where neuropsychological tests have been administered
to patients during the acute episode of memory loss [3, 6], the patients have shown
80 M.D. Kopelman
a profound AA on tests of verbal and nonverbal memory, as would be expected.

However, performance on tests of retrograde memory has been very variable, some
patients showing no retrograde memory loss, others showing a brief retrograde loss,
occasional others showing an extensive RA. Follow-up investigations have usually
shown either complete or almost complete recovery of memories several weeks to
months after the acute attack. In general, RA recovers before AA.
There is general agreement that the amnesic disorder in TGA results from tran-
sient dysfunction in limbic-hippocampal circuits, crucial to memory formation.
Medial temporal abnormalities have been reported bilaterally on single-photon
emission tomography (SPECT), positron emission tomography (PET), and diffu-
sion-weighted imaging (DWI), and small hippocampal cavities have been seen on T2
reversed magnetic resonance imaging (MRI) [7, 8]. Moreover, venous duplex
sonography has shown jugular vein valve insufficiency in a proportion of cases [8].
Transient Epileptic Amnesia
Transient epileptic amnesia (TEA) refers to the minority of patients with TGA in
whom epilepsy appears to be the underlying cause of the syndrome [3]. The term was
originally coined by Kapur [9]. The main predictive factors for an underlying epileptic
etiology in TGA are brief episodes of memory loss, lasting an hour or less, and a
multiplicity of attacks [3]. It is important to note that standard electroencephalography
(EEG) and computed tomography (CT) findings are often normal. However, an epilep-
tic basis to the disorder may be revealed on a sleep-deprived EEG recording [3, 10].
TEA patients may show residual memory deficits between their attacks, pre-
sumably related to their underlying neuropathology. Kopelman et al. found a
moderate degree of residual anterograde memory impairment, which was probably
related to small foci of MRI signal alteration and bilateral medial temporal hypo-
metabolism on PET in the medial temporal lobes bilaterally [10]. Such patients
quite commonly also report “gaps” in their past personal memories [11]. Manes
et al. and Butler and Zeman have reported abnormal long-term forgetting of newly
learned material, which they attributed to hippocampal dysfunction [11, 12].
However, forgetting rates are extremely difficult to measure across long intervals,
and these studies have been confounded by “ceiling” and “floor” effects, such that
the apparently fast forgetting may have reflected impaired initial acquisition of the
material. Similarly, disproportionate RA has been claimed, but whether a patient’s
reported gaps in past memories result from faulty initial encoding of those memo-
ries (because of subclinical ictal activity), impaired memory consolidation, or defi-
cits in memory retrieval remains highly controversial and difficult to disentangle.
Epilepsy can, of course, give rise to automatisms or postictal confusional states.
Such automatisms appear always to be associated with bilateral involvement of those
medial temporal brain structures involved in memory formation. Hence, amnesia for
the period of automatic behavior is always present and is usually complete; claims
of automatism in the absence of significant amnesia should be rejected.
Persistent Neurological Memory Disorders
The amnesic syndrome can be defined as “an abnormal mental state in which
memory and learning are affected out of all proportion to other cognitive functions
in an otherwise alert and responsive patient” [13]. Please note that there is no
reference to short-term memory in this definition and no reference to confabulation.
Moreover, many patients may suffer from variable degrees of specific memory
impairment (in the absence of generalized cognitive impairment), but not so
severely as to constitute an amnesic syndrome; such patients are poorly categorized
within the International Classification of Diseases.
The critical lesions that give rise to AA involve pathology in the medial temporal
lobes (hippocampi, parahippocampal gyri), thalami, mammillary bodies, the mam-
millo-thalamic tract, the retrosplenium, and the fornix. Through their interconnections
with these limbic circuits, pathology in the basal forebrain (particularly the septal
nucleus) and elsewhere within the frontal lobes can also give rise to anterograde
memory impairment. The neuropathological basis of RA is much more controversial,
some theorists arguing that damage to the hippocampi (and their connections) is
critical [14, 15], whereas others have argued that it is damage beyond the medial
temporal lobes which is critical for RA [16, 17].
The diseases or disorders that give rise to an amnesic syndrome are those which
implicate these critical brain structures. Hence, bilateral medial temporal lobec-
tomy in the patient HM gave rise to profound amnesia [18], and bilateral damage
is now a well-recognized reason for avoiding temporal lobe surgery in epilepsy.
Herpes encephalitis or voltage-gated potassium channel pathology gives rise to
structural damage in the medial temporal lobes and resulting memory disorder [19];
and profound hypoxia or hypoxic/ischemic insufficiency can also give rise to hip-
pocampal damage and amnesia [20]. By contrast, thiamine deficiency (for example,
in the alcoholic Korsakoff syndrome) particularly affects the thalami, the mammillary
bodies, and the mammillo-thalamic tract. Vascular infarction in branches of the pos-
terior cerebral artery can affect either the thalami, the hippocampi, or both, and
subarachnoid hemorrhage sometimes produces profound amnesia by damage to the
septal nucleus. Head injury, deep midline tumors, and TB meningitis can all
produce amnesia by effects upon the medial temporal, diencephalic, or frontal
structures of the brain.
The Korsakoff Syndrome
The term Korsakoff syndrome should nowadays be reserved for cases of the
amnesic syndrome resulting from thiamine deficiency. These cases are almost
invariably a consequence of alcohol misuse [21].
There is a profound AA, and a RA that extends back at least 20–25 years and
involves autographical, personal semantic, and more general knowledge of public
82 M.D. Kopelman
information [22]. Korsakoff noted these patients had severe disorientation in time,
in particular, difficulty in remembering the temporal sequence of events [23]. He also
noted his patients’ preserved reasoning and other skills. Confabulation is not
necessarily present, and it often consists of the inappropriate retrieval of fragments
of real memory, jumbled up and confused in temporal context, as various others
have also noted [13].
Many cases of the Korsakoff syndrome are diagnosed following an acute
Wernicke encephalopathy, involving confusion, ataxia, nystagmus, and opthal-
moplegia. Usually, not all these features are present, and the opthalmoplegia in
particular responds rapidly to treatment with high-dose vitamins. These features
are often also associated with a peripheral neuropathy. However, the Korsakoff
syndrome can alternatively have an insidious onset, and such slower-onset
cases are more likely to come to the attention of psychiatrists or clinical
psychologists. In such cases, there may be either no known history of Wernicke
features, or only a transient history of such signs. Moreover, reports from
Scandinavia and Australia indicate that the characteristic Wernicke–Korsakoff
neuropathology (see following) is found much more commonly at autopsy in
alcoholics than the diagnosis is made in life, implying that many cases are
missed [24, 25].
Victor et al. reported that 25% of patients with the Korsakoff’s syndrome
“recover,” 50% show improvement through time, and 25% remain unchanged [13].
Although it is unlikely that any established patient shows complete recovery, the
present author’s experience is that a substantial improvement does occur over a
matter of years if the patient remains abstinent. In such cases, it is probably correct
to say that 75% of these patients show a variable degree of improvement while 25%
show no change [21].
The characteristic neuropathology in the Wernicke–Korsakoff syndrome consists
of neuronal loss, microhemorrhages, and gliosis in the paraventricular and the
periaqueductal grey matter [13]. There has been considerable debate concerning
which particular lesions are critical for the presence of chronic memory disorder
(Korsakoff syndrome). Victor et al. argued that damage in the medial dorsal nucleus
of the thalamus was critical in that patients who lacked pathology within this
specific site showed only a transient Wernicke state [13]. However, Mair et al. and
Mayes et al. argued that it was pathology within the mammillary bodies, the
midline and anterior portions of the thalamus, but not the medial-dorsal nuclei,
which was critical for memory disorder, and they based this observation on careful
ante mortem neuropsychological and post mortem neuropathological assessments
[26, 27]. More recently, Harding et al. compared eight patients who had suffered a
persistent Korsakoff syndrome with five patients who experienced only a transient
Wernicke episode: they argued that pathology in the anterior principal thalamic
nuclei was the critical difference between these two groups of patients [28]. Taken
together, these various findings suggest that the connections between the mammillary
bodies, the mammillo-thalamic tract, and the anterior thalamus may be more
important to memory dysfunction than pathology within the medial dorsal nucleus
of the thalamus.
There are now a substantial number of neuroimaging studies in the Korsakoff

syndrome, using CT, MRI, or PET. Atrophy of the thalami and mammillary bodies
is found, but also a variable degree of accompanying cortical atrophy, particularly
within the frontal lobes [29, 30]. Very commonly, there is also cerebellar atrophy
with involvement of the vermis and pons, contributing to the ataxia. PET
investigations show variable findings, but hypometabolism has been reported in the
thalamic, orbital-medial frontal, and retrospleenial regions [31].
Herpes Encephalitis
Herpes encephalitis (HSE) can give rise to a particularly severe form of the amnesic
syndrome as a result of devastating damage to the medial aspects of the temporal
lobes [32, 33].
Many cases are said to be primary infections, although others may involve a
reactivation of the virus after it has lain dormant in neural tissue. Characteristically,
the disorder commences with a fairly abrupt onset of acute fever, headache, and
nausea. There may be accompanying behavioral changes, and seizures can occur.
Later, there is neck rigidity, vomiting, and motor and sensory deficits. However,
some cases commence more insidiously with behavioral change or psychiatric
phenomena, the confusion and neurological features becoming evident only much
later. These latter cases are those most likely to be missed, which is now important
because antiviral agents, such as acyclovir, are most effective when administered
within the first 48 h of symptoms [34, 35]. Diagnosis is by polymerase chain reac-
tion (PCR) test or a raised titer of antibodies in the cerebrospinal fluid (CSF), but a
presumptive diagnosis sometimes has to be made on the basis of the clinical picture
as well as severe signal alteration and subsequent atrophy in the medial temporal
lobes on MRI.
Neuropathological and neuroimaging studies usually show extensive bilateral
temporal lobe damage (signal alteration, volume loss, and hemorrhage), although
occasionally the changes are surprisingly unilateral [29, 36]. There may be frontal
changes, often in the orbitofrontal regions, and there may be focal changes else-
where as well as a variable degree of general cortical atrophy. The medial temporal
lobes are usually particularly severely affected, resulting in a profound AA, usually
accompanied by an extensive retrograde memory loss. Autobiographical and epi-
sodic memory are particularly severely affected. Widespread damage to the left
temporal lobes characteristically affects aspects of semantic memory, the patients
often showing severe impairment in naming and word-finding, reading (a so-called
surface dyslexia, in which the reading of irregularly spelled words is particularly
affected), and impairments in comprehension. Right temporal lobe damage can
result in particularly severe impairment in face recognition memory knowledge of
people and/or remote autobiographical memory loss [37].
Wilson et al. have described a particularly severe case of amnesia following
herpes encephalitis [33]. In this case, there was a long delay before the prescription
84 M.D. Kopelman
of an antiviral agent, resulting in extensive left temporal lobe and right medial
temporal lobe damage, evident on a quantified, structural MRI brain scan. An
interesting feature of this patient was his relatively preserved skill as a musician
(procedural/implicit memory). Despite this, he lacked any memory of having used
his musical skills recently (episodic memory); when he was shown a video of him-
self playing the piano, he stated that he had not been “conscious” at the time that
the video-clip was recorded. Indeed, for many years, he stated several times a day
that he had “just woken up,” and he also wrote this frequently in his diary.
Confabulation
Confabulation can be subdivided into “spontaneous” confabulation, in which there

is a persistent, unprovoked outpouring of erroneous memories, and “momentary”
or “provoked” confabulation, in which fleeting intrusion errors or distortions are
seen in response to a challenge to memory, such as a memory test [37, 39].
Confabulation is widely believed to be particularly associated with the Korsakoff
syndrome, but this is incorrect. Spontaneous confabulation arises in confusional
states and in frontal lobe pathology, particularly where there is ventromedial or
orbitofrontal damage [40–42]. Spontaneous confabulation is often seen in the confu-
sional state of a Wernicke encephalopathy, but it is rare in the more chronic phases of
the Korsakoff syndrome. On the other hand, fleeting intrusion errors or distortions
(“momentary confabulation”) do occur in the chronic phase of a Korsakoff syndrome,
as well as other amnesic disorders or dementia, when a memory is challenged.
However, such intrusion errors are also seen in healthy subjects when memory is
“weak” for any reason, such as a prolonged delay until recall, and they are certainly
not specific to the Korsakoff syndrome [39].
There has been considerable controversy concerning the underlying nature of
spontaneous confabulation, which can extend across episodic, personal semantic,
and more general semantic memories [43]. Korsakoff himself emphasized problems
in the temporal ordering of memories, and the inappropriate retrieval of memory
fragments, as discussed previously [23]. In a particularly elegant study, Schnider
et al. found that spontaneous confabulators could be differentiated from other amne-
sic patients and healthy participants on the basis of their errors on a temporal context
memory test, but not on other memory or executive tasks, and Schnider has more
recently interpreted this as a failure in “reality monitoring” [39, 43]. By contrast,
Gilboa et al. have argued that a failure in the strategic retrieval and postretrieval
monitoring of memories, related to ventromedial and orbitofrontal pathology, is
critical for confabulation to arise, and somewhat similar hypotheses have been pro-
posed by others [41, 45, 46]. A third view, postulated by Fotopoulou and colleagues
[46, 47], is that the content of confabulations is heavily influenced by motivational
factors, and that confabulating patients tend to retrieve memories from a happier
time or to manifest some degree of wish fulfilment [47, 48]. By contrast, Dalla Barba
[48, 49] has argued that confabulating patients tend to retrieve the most stable ele-
ments from their long-term memories, often from earlier time periods [49, 50].
Transient Psychogenic Amnesia
Transient psychogenic amnesias (“dissociative amnesia”) can be either global or

situation specific. In global psychogenic amnesia, patients lose all memories of
their earlier life, and this is often accompanied by a loss of the sense of personal
identity or self: this occurs in a psychogenic fugue state. In situation-specific
amnesia, there is a gap in memory for a particularly traumatic incident, which may
be an accident or catastrophe, as in posttraumatic stress disorder; or being the victim
of a crime, as in rape or child sexual abuse; and it also occurs in certain instances
in the perpetrators of crime, particularly in violent offenses (see below).
Psychogenic Fugue
A fugue state is a syndrome consisting of the sudden loss of all autobiographical

memories and knowledge of personal identity, usually associated with a period
of wandering, for which there is a subsequent amnesic gap on recovery. Characte-
ristically, fugue states last only a few hours or days – up to 3 or 4 weeks. If the state
lasts longer than this, the question of simulation must always be considered, and if
that is excluded, the diagnosis of “psychogenic focal RA” is probably the more
appropriate (see following).
In clinical practice, fugue states can easily be differentiated from TGA or TEA,
although these can also be precipitated by an emotional or traumatic event (see above)
and may show no abnormalities on either brain imaging or a standard EEG. Although
patients in TGA or TEA characteristically show repetitive questioning, this is not true
of a fugue episode. Moreover, TGA/TEA patients virtually never lose their sense of
personal identity, whereas this is characteristic in fugues. There are also differences
in the pattern of retrograde memory loss: those with a neurological etiology charac-
teristically show relative sparing of earlier memories, whereas those with a psycho-
genic etiology may show relative preservation of more recent memories [6, 10].
Fugue states are virtually always preceded by a severe precipitating stress, such
as a marital crisis, financial crisis, or being charged with an offense, and they are
more common in wartime (particularly in soldiers having to return to the front).
Second, depressed mood is an extremely common antecedent to a psychogenic
fugue state [51], and this may be associated with suicidal ideas evident just before
the episode or following recovery from the fugue [52]. Various authors have noted
that there is often a past history in such patients of a previous transient neurological
amnesia, such as epilepsy, a head injury, or an alcoholic blackout, which may act
as a kind of “learning experience” or ”substrate” to the occurrence of the fugue at
the time of depression and severe precipitating stress.
Schacter et al. described a patient who lost all his memories after attending the
funeral of his grandfather [52]. He showed a severe amnesia for autobiographical
memories with semantic memories and new learning relatively preserved. When
constrained to recall memories from earlier time periods, he could do so mainly
86 M.D. Kopelman
from just one particularly happy period of his life. This patient recovered his
memories after watching a funeral on television a few days after the onset. Glisky
et al. described a German who lost his memories in Tucson, Arizona, following
offenses in Germany and being thrown out of accommodation in Tucson [53]. He
appeared not to retain any memory of his past, or of the German language. However,
he did show implicit knowledge of German on a paired-associate test, and he also
manifested increased galvanic skin responses to personal information of which he
denied “explicit” knowledge. A functional MRI (fMRI) task involving German
words indicated relatively diminished frontal lobe activation.
Situation-Specific Amnesia
Situation-specific amnesia occurs in victims of crime such as rape [54] and,

although controversial in some quarters, in cases of child sexual abuse [55, 56]. It
can also occur in the perpetrators of crime, and it is claimed in 25–45% of offenders
of homicide, approximately 8% of perpetrators of other violent crimes, and a small
percentage of nonviolent offenders [57–59]. Although a few of these instances
result from automatisms in epilepsy, parasomnias, hypoglycemia, or head injury,
and many cases result from severe intoxication with alcohol or substances, more
purely psychogenic cases of amnesia occur in so-called crimes of passion.
In these “crimes of passion,” there has commonly been extreme emotional
arousal and pretraumatic depression, the offense is unplanned and unpremeditated,
and the victim is usually a lover, wife, or family member. Such amnesias remain
controversial [60], but it should be noted that many offenders claiming amnesia
report their own offense or, at least, fail to take measures to avoid capture. There
are consistencies across their reports that are striking, and their descriptions do
indeed bear resemblances to other patients’ accounts of psychological forms of
amnesia in other clinical circumstances. Moreover, victims sometimes report similar
amnesias, and memory errors are common in eye-witnesses: nobody disputes the
motives of these parties. In addition, amnesia itself only rarely has legal implica-
tions (as in automatisms), and it may actually be damaging to the conduct of a
person’s defense.
Gudjonsson and MacKeith described a 67-year-old man who had apparently
battered his wife to death without any obvious motive [60]. He then telephoned the
police and gave himself up. On their arrival, he reported that he had no memory of
the actual attack, but that he recalled standing over the body, realizing that he had
been responsible for his wife’s death. His amnesia persisted until trial. (Other cases
are described by Kopelman [57].)
Pyszora et al. examined the psychiatric reports of all offenders given a life
sentence in England and Wales in 1994 [58]. They found that 29% of these
offenders claimed amnesia and 31% of the homicide offenders reported amnesia.
Detailed follow-up reports were available 3 years after conviction, and these were
also examined. At this follow-up, only about 2% of the cases were thought to have
been malingering their amnesia. Of the other cases who had claimed amnesia, 33%
reported complete return of their memories at 3 years post conviction, 26% had
partial recovery of their memories, and 41% reported no change in their amnesia.
Persistent Psychogenic Amnesia
Persistent psychogenic amnesia occurs in so-called psychogenic focal RA (FRA).

Again, this is a controversial topic [61, 62]. Kapur coined the term focal RA (FRA)
to describe patients who appeared to show their RA in the absence of any anterograde
memory loss [63]. There have been various reports of such cases in the neuropsy-
chological literature. Sometimes these cases have been initially accompanied by loss
of the sense of personal identity, but this is usually transient and not characteristi-
cally accompanied by a period of wandering. Moreover, unlike a fugue state, the
memory disorder persists. Often (but not always) the amnesia follows a mild concus-
sion or other minor cerebral event that is insufficient to account for the severity or
disproportionate nature of the retrograde memory loss. Moreover, brain imaging is
almost invariably normal. In a detailed critique of such cases, Kopelman argued that
many, if not all, such cases have a psychogenic basis [61].
Kopelman described a 55-year-old man who collapsed at work during early
1998 with a transient left-sided weakness and complete loss of autobiographical
memory and personal identity [61]. At initial admission, this patient was disorien-
tated in time and place as well as person, and there was a mild loss of power in the
left arm and left leg with an equivocal left plantar response. A CT scan was normal,
but an MRI brain scan showed evidence of a few pinpoint regions of altered signal
bilaterally, consistent with a history of previously diagnosed hypercholesteremia
and diabetes. However, the physicians attending this man felt confident that his
memory loss was entirely disproportionate to his neurological signs, which resolved
rapidly. The man did not recognize his wife, and he could not remember the names
and ages of his wife or children. He claimed to have “relearned” language and
mental calculation, and stated that each day he remembered more about the day
before. On formal tests, he showed severe and extensive autobiographical and
remote memory loss with intact anterograde memory. When first seen, he and his
family were extremely angry at any suggestion that there might be a psychological
component to his memory loss. However, during the succeeding weeks, his wife
informed the clinical team about an emotionally deprived childhood and sub-
sequent psychological problems. The initial onset had occurred following dismissal
from two jobs that he had been carrying out simultaneously. After being seen on a
regular basis for several weeks, the patient was more willing to accept a
psychological contribution to his RA. At that point, following an interview under
sedation, virtually all of this man’s memories were recovered.
There are now psychological models for such amnesias. For example, Anderson
and Green have demonstrated that the deliberate suppression of associative
memories can result in subsequent forgetting [64]. Moreover, in a functional MRI
88 M.D. Kopelman
investigation [65], they demonstrated that this suppression of memories is

associated with bilateral dorsolateral prefrontal activation as well as with frontopolar
and bilateral hippocampal deactivation [65]. However, there have also been a
number of neuroimaging studies of patients reporting psychogenic amnesias,
usually of FRA type; these have produced rather conflicting findings, and the
neurophysiological correlates of psychogenic amnesia remain to be fully
elucidated.
Conclusions
In summary, memory disorders can be either neurological or psychogenic, and

sometimes there is a complex admixture of contributory factors. In this chapter, I
have focused on severe disorders of autobiographical or episodic memory, but there
are other disorders in which either semantic memory or procedural memory can be
particularly severely affected. There is now good understanding of the brain cir-
cuits that are critical for memory formation, damage to which gives rise to AA.
The nature of neurological RA is more controversial. Similarly, we now have a
fairly good understanding of the precipitating factors that can give rise to a psycho-
genic amnesia, which may often particularly affect aspects of retrograde memory.
However, the neurophysiological correlates of psychologically induced amnesias
remain to be properly elucidated.
References
1. James W (1890) The principles of psychology, vol 1. Holt, New York

2. Gilboa A (2004) Autobiographical and episodic memory – one and the same? Neuropsychologia
42:1336–1349
3. Hodges JR, Ward CD (1989) Observations during transient global amnesia: a behavioural and
neuropsychological study of five cases. Brain 112:595–620
4. Miller JW, Petersen RC, Metter EJ et al (1987) Transient global amnesia: clinical character-
istics and prognosis. Neurology 1987:733–737
5. Quinette P, Guillery-Girard B, Dayan V et al (2006) What does transient global amnesia really
mean? Review of the literature and thorough study of 142 cases. Brain 129:1640–1658
6. Kritchevsky M, Squire LR, Zouzounis JA (1988) Transient global amnesia: characterization
of anterograde and retrograde amnesia. Neurology 38:213–219
7. Nakada T, Kwee IL, Fujii Y et al (2005) High-field, T2 reversed MRI of the hippocampus in
transient global amnesia. Neurology 64:1170–1174
8. Sander K, Sander D (2005) New insights into transient global amnesia: recent imaging and
clinical findings. Lancet Neurol 4:437–444
9. Kapur N (1990) Transient epileptic amnesia: a clinically distinct form of neurological memory
disorder. In: Markowitsch H (ed) Transient global amnesia and related disorders. Hogrefe and
Huber, New York, pp 140–151
10. Kopelman MD, Panayiotopoulos CP, Lewis P (1994) Transient epileptic amnesia differenti-
ated from psychogenic ‘fugue’: neuropsychological, EEG and PET findings. J Neurol
Neurosurg Psychiatry 57:1002–1004
11. Butler CR, Zeman A (2008) Recent insights into the impairment of memory in epilepsy: a
systematic review of transient epileptic amnesia, accelerated long-term forgetting and remote
memory impairment. Brain 131:2243–2263
12. Manes F, Graham KS, Zeman A et al (2005) Autobiographical amnesia and accelerated for-
getting in transient epileptic amnesia. J Neurol Neurosurg Psychiatry 76:1387–1391
13. Victor M, Adams RD, Collins GH (1971) The Wernicke-Korsakoff syndrome. Davis,
Philadelphia
14. Nadel L, Moscovitch M (1997) Memory consolidation, retrograde amnesia and the hippocam-
pal complex. Curr Opin Neurobiol 7:217–227
15. Moscovitch M, Nadel L, Winocur G et al (2006) The cognitive neuroscience of remote epi-
sodic, semantic and spatial memory. Curr Opin Neurobiol 16:179–190
16. Bayley PJ, Gold JJ, Hopkins RO et al (2005) The neuroanatomy of remote memory. Neuron
46:799–810
17. Bright P, Buckman J, Fradera A et al (2006) Retrograde amnesia in patients with hippocam-
pal, medial temporal, temporal lobe, or frontal pathology. Learn Mem 13:545–557
18. Scoville WB, Milner B (1957) Loss of recent memory after bilateral hippocampal lesions. J
Neurol Neurosurg Psychiatry 20:11–21
19. Vincent A, Buckley C, Schott JM et al (2004) Potassium channel antibody-associated enceph-
alopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain
127:701–712
20. Caine D, Watson JD (2000) Neuropsychological and neuropathological sequelae of cerebral
anoxia: a critical review. J Int Neuropsychol Soc 6:86–99
21. Kopelman MD, Thomson A, Guerrini I et al (2009) The Korsakoff syndrome: clinical aspects,
psychology and treatment. Alcohol Alcohol 44:148–154
22. Kopelman MD (1989) Remote and autobiographical memory, temporal context memory, and
frontal atrophy in Korsakoff and Alzheimer patients. Neuropsychologia 27:437–460
23. Korsakoff SS (1889) Psychic disorder in conjunction with peripheral neuritis (translated and
republished: Victor M, Yakovlev PI (1955)) Neurology 5:394–406
24. Harper C (2009) The neuropathology of alcohol-related brain damage. Alcohol Alcohol
44:136–140
25. Torvik A, Lindboe C, Rogde S (1982) Brain lesions in alcoholics: a neuropathological study.
J Neurol Sci 56:233–248
26. Mair WGP, Warrington EK, Weiskrantz L (1979) Memory disorder in Korsakoff’s psychosis;
a neuropathological and neuropsychological investigation of two cases. Brain 102:749–783
27. Mayes AR, Meudell PR, Mann D et al (1988) Location of lesions in Korsakoff’s syndrome:
neuropsychological and neuropathological data on two patients. Cortex 24:367–388
28. Harding A, Halliday G, Caine D et al (2000) Degeneration of anterior thalamic nuclei dif-
ferentiates alcoholics with amnesia. Brain 123:141–154
29. Colchester A, Kingsley D, Lasserson D et al (2001) Structural MRI volumetric analysis in
patients with organic amnesia: 1. Methods and comparative findings across diagnostic groups.
J Neurol Neurosurg Psychiatry 71:13–22
30. Sullivan EV, Pfefferbaum A (2009) Neuroimaging of the Wernicke–Korsakoff syndrome.
Alcohol Alcohol 44:155–165
31. Reed LJ, Lasserson D, Marsden P et al (2003) 18FDG–PET findings in the Wernicke–Korsakoff
syndrome. Cortex 39:1027–1045
32. Hokkanen L, Launes J (2007) Neuropsychological sequelae of acute-onset sporadic viral
encephalitis. Neuropsychol Rehabil 17:429–449
33. Wilson BA, Kopelman M, Kapur N (2008) Prominent and persistent loss of past awareness in
amnesia: delusion, impaired consciousness or coping strategy? Neuropsychol Rehabil 18:527–540
34. McGrath N, Anderson NE, Croxson MC et al (1997) Herpes simplex encephalitis treated with
acyclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 63:321–326
35. Raschilas F, Wolff M, Delatour F et al (2002) Outcome of and prognostic factors for herpes
simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis
35:254–260
90 M.D. Kopelman
36. Reed LJ, Lasserson D, Marsden P et al (2005) Correlations of regional cerebral metabolism
with memory performance and executive function in patients with herpes encephalitis or
frontal lobe lesions. Neuropsychology 19:555–565
37. Kopelman MD (2002) Disorders of memory. Brain 125:2152–2190
38. Kopelman MD (1987) Two types of confabulation. J Neurol Neurosurg Psychiatry
50:1482–1487
39. Schnider A (2003) Spontaneous confabulation and the adaptation of thought to ongoing real-
ity. Nat Rev Neurosci 4:662–671
40. Gilboa A, Alain C, Stuss DT et al (2006) Mechanisms of spontaneous confabulations: a stra-
tegic retrieval account. Brain 129:1399–1414
41. Turner MS, Cipolotti T, Yousry TA et al (2008) Confabulation: damage to a specific interior
medial prefrontal system. Cortex 44:637–648
42. Kopelman MD, Ng N, Van den Brouke O (1997) Confabulation extending across episodic
memory, personal and general semantic memory. Cognit Neuropsychol 14:683–712
43. Schnider A, von Däniken C, Gutbrod K (1996) The mechanisms of spontaneous and provoked
confabulations. Brain 119:1365–1375
44. Burgess PW, Shallice T (1996) Confabulation and the control of recollection. Memory
4:359–411
45. Schacter DL, Norman KA, Koustaal W (1998) The cognitive neuroscience of constructive
memory. Annu Rev Psychol 49:289–318
46. Fotopoulou A, Solms M, Turnbull O (2004) Wishful reality distortions in confabulations: a
case study. Neuropsychologia 42:727–744
47. Fotopoulou A, Conway MA, Solms M et al (2008) Self-serving confabulation in prose recall.
Neuropsychologia 46:1429–1441
48. Dalla Barba G (1993) Confabulation: knowledge and recollective experience. Cognit
Neuropsychol 10:1–20
49. Dalla Barba G, Cappelletti YJ, Signorini M et al (1997) Confabulation: remembering
“another” past, planning “another” future. Neurocase 3:425–436
50. Berrington WP, Liddell DW, Foulds GA (1956) A re-evaluation of the fugue. J Ment Sci
102:280–286
51. Stengel E (1941) On the aetiology of the fugue states. J Ment Sci 87:572–599
52. Schacter DL, Wang PL, Tulving E et al (1982) Functional retrograde amnesia: a quantitative
case study. Neuropsychologia 5:523–532
53. Glisky EL, Ryan L, Reminger S et al (2004) A case of psychogenic fugue: I understand, aber
ich verstehe nichts. Neuropsychologia 42:1132–1147
54. Mechanic M, Resick PA, Griffin MG (1998) A comparison of normal forgetting, psychopa-
thology, and information-processing models of reported amnesia of recent sexual trauma.
J Consult Clin Psychol 66:948–957
55. Andrews B, Brewin CR, Rose S et al (2000) Predicting PTSD symptoms in victims of violent
crime: the role of shame, anger, and childhood abuse. J Abnorm Psychol 109:69–73
56. Taylor PJ, Kopelman MD (1984) Amnesia for criminal offences. Psychol Med 14:581–588
57. Kopelman MD (2002) Psychogenic amnesia. In: Baddeley AD, Kopelman MD, Wilson BA
(eds) The handbook of memory disorders, 2nd edn. Wiley, Chichester
58. Pyszora NM, Barker AF, Kopelman MD (2003) Amnesia for criminal offences: a study of life
sentence prisoners. J Forens Psychiatry Psychol 14:475–490
59. Christianson SA, Merckelbach H, Kopelman MD (2006) Crime-related amnesia. In: Heaton-
Armstrong A, Shepherd E, Gudjonsson G et al (eds) Witness testimony: psychological, inves-
tigative and evidential perspectives. Oxford University Press, Oxford, pp 105–126
60. Gudjonsson GH, MacKeith JAC (1983) A specific recognition deficit in case of homicide.
Med Sci Law 23:37–40
61. Kopelman MD (2000) Focal retrograde amnesia and the attribution of causality: an exception-
ally critical review. Cognit Neuropsychol 17:585–621
62. Kapur N (2000) Focal retrograde amnesia and the attribution of causality: an exceptionally
benign commentary. Cognit Neuropsychol 17:623–637
63. Kapur N (1993) Focal retrograde amnesia in neurological disease: a critical review. Cortex
29:217–234
64. Anderson MC, Green C (2001) Suppressing unwanted memories by executive control. Nature
(Lond) 410:366–369
65. Anderson MC, Ochsner KN, Kuhl B et al (2004) Neural systems underlying the suppression
of unwanted memories. Science 303:232–235
The Neuropsychological Aspect of Epilepsy
Yoshio Morita
Abstract A supplementary relationship is observed between clinical epileptology

and clinical neuropsychology with regard to the method of studying higher brain
functions in the human cortex. For example, ictal illusions and hallucinations asso-
ciated with localization-related epilepsy can contribute to the phenomenological
works dealing with both epilepsy and neuropsychology. We evaluated the content
and type of aura-sensations and determined the laterality of epileptic focus using
scalp EEG. Epigastric and visual auras ware the most frequently observed sensa-
tions. However, the laterality of the aura-sensations was not clarified in the EEG
recordings.
Keywords Aura-sensations฀ •฀ Epilepsy฀ •฀ Ictal฀ illusions฀ and฀ hallucinations฀

•฀Lateralization฀•฀Neuropsychology
Introduction
In฀studies฀of฀higher฀brain฀function,฀clinical฀neuropsychology฀and฀clinical฀epileptology฀
are closely related. Both sciences aim at the elucidation of local brain functions:
clinical neuropsychology presents syndromes of functional loss and stimulation
associated with local injuries of the human brain, whereas various syndromes of
human epileptic seizures are observed in clinical epileptology.
Studies attempt to elucidate the association between changes in brain function
induced in the cerebral disease process and the psychological process employing
methods supplementing each other. Clinical brain wave measurement including
evoked responses and psychological measurement are employed in this study.
Paroxysmal neuropsychological symptoms; visuo-spatial disorders and body-scheme
Y. Morita (*)
Department฀of฀Neuropsychiatry,฀Hyogo฀College฀of฀Medicine,฀
1-1,฀Mukogawa-cho,฀Nishinomiya,฀663-8501,฀Hyogo,฀Japan

DOI฀10.1007/978-4-431-53871-4_7,฀©฀Springer฀2010
96 Y. Morita
disorders (heautoscopy) in temporal lobe epilepsy will be mentioned in this chapter

for understanding the close relations between neuropsychology and epileptology.
Neuropsychological Symptoms in Epilepsy
According฀to฀W.G.฀Lennox,฀epilepsy฀is฀defined฀as฀recurrent฀self-sustained฀paroxys-
mal disorders of brain function.
Epilepsy encompasses paroxysmal disorders, and the international classification
categorizes epileptic seizures as follows [1]:
1.฀ Localization-related฀(focal,฀local,฀and฀partial)฀epilepsies฀and฀syndromes
(a)฀ Idiopathic฀(with฀age-related฀onset)
(b) Symptomatic
(c) Cryptogenic
2.฀ Generalized฀epilepsies฀and฀syndromes
3.฀ Epilepsies฀and฀syndromes฀undetermined฀as฀to฀whether฀focal฀or฀generalized
4.฀ Special฀syndromes
Temporal lobe epilepsy, one of the types of complex partial seizures, is classified as
symptomatic epilepsy in this classification [1]. The paroxysmal symptoms of this
type of epilepsy are closely related to anatomical localization of the lesion in the
temporal lobe.
In฀ addition฀ to฀ paroxysmal฀ symptoms,฀ accompanying฀ signs฀ and฀ symptoms฀ at฀
onset are important indices of the origin of paroxysmal discharge. On the other
hand, classical clinical neuropsychology searches for associations between func-
tional changes in brain disorders and psychological processes.
Neurological฀symptoms;฀essential฀sensation฀and฀movement฀disorders,฀as฀well฀as฀
neuropsychological symptoms; aphasia, apraxia, and agnosia, are common symp-
toms in epileptic patients. On the other hand, neuropsychiatric symptoms, such as
hallucination, disturbance of memory, spontaneity disorder, personality disorder
are less frequently noted in epilepsy.
Paroxysmal Visuo-Spatial Disorders
Fifty-seven฀episodes฀of฀aura฀sensations฀in฀18฀patients฀with฀temporal฀lobe฀epilepsy฀
are฀tabulated฀in฀Table฀1฀and฀2.
The main symptoms of temporal lobe syndrome in temporal lobe epilepsies
(TLEs)฀are฀simple฀and฀complex฀partial฀seizures,฀secondarily฀generalized฀seizures,฀
or a combination of these symptoms.
Complex฀ partial฀ seizure฀ can฀ be฀ categorized฀ into฀ P0–P4฀ based฀ on฀ the฀ phasal฀
development฀of฀seizures;฀P0฀aura-sensations,฀P1฀represents฀the฀tonic-lapse฀phase,฀
P2฀ oral฀ automatism,฀ P3฀ behavioral฀ automatism,฀ and฀ P4฀ secondarily฀ generalized฀
tonic-clonic seizures. Aura-sensations of visuo-spatial distortions were noted in the
P0฀stage฀of฀18฀patients฀with฀temporal฀lobe฀epilepsy.
The฀Neuropsychological฀Aspect฀of฀Epilepsy 97
Table 1 Classification of n Percent

aura-sensations
Cephalic 11 19.3
Visceral ฀8 14.0
Autonomic ฀3 5.3
Somatosensory ฀2 3.5
Emotional ฀7 12.3
Illusional 17 29.8
Hallucinatory ฀7 12.3
Ideational 2 3.5
57 100
(a) On interictal scalp-recorded EEG, paroxysmal abnormality was detected in

right฀anterotemporal฀lobe฀(15฀patients),฀left฀anterotemporal฀lobe฀(29฀patients)฀
and฀bilateral฀anterotemporal฀lobe฀(7฀patients).฀
฀ (b)฀ ฀Fifty-seven฀episodes฀of฀aura฀sensation฀occurred฀in฀the฀18฀patients,฀and฀24฀
(about฀42%)฀showed฀visuo-spatial฀distortion.
The anterotemporal spikes during the interictal period on scalp-recorded EEG
in฀ the฀ 18฀ patients฀ was฀ detected฀ in฀ right฀ anterotemporal฀ lobe฀ (7฀ patients),฀ left฀
anterotemporal฀lobe฀(7฀patients)฀and฀bilateral฀anterotemporal฀lobe฀(7฀patients).
The฀57฀episodes฀of฀aura-sensations฀are฀tabulated฀in฀Table฀2.
When foci of aT spikes on the left and right sides were counted on interictal
scalp-recorded EEG, no distinct difference of laterality was noted in the cases of
aura-sensations.
Visuo-spatial distortions are usually complaint by the patients with temporal
lobe epilepsy as distortion of the size, shape, distance and dimension of objects,
disorientation,฀ experiences฀ of฀ déjà฀ vu฀ and/or฀ jamais฀ vu,฀ distortion฀ of฀ scene฀ and฀
body฀schema฀[2–4].
Visceral auras, like epigastric distress, and changes of feeling of familiarity are
the common aura symptoms in the patients with temporal lobe epilepsy.
Aphasia฀is฀also฀reported฀as฀one฀of฀the฀symptoms฀of฀an฀aura-sensation฀[2]฀(Table฀3).
Taylor฀ and฀ Lochery฀ [4]฀ reported฀ the฀ idiosyncratic฀ auras฀ in฀ temporal฀ lobe฀ epi-
lepsy. Déjà vu with micropsia, sense of being enveloped by a “monster”, feeling of
inferiority, rerealization, and other peculiar feelings are reported in this category.
Illusions฀of฀recognition฀and฀illusional฀emotions,฀caused฀by฀experimental฀stimula-
tion of the brain, appeared to be similar to the illusions in visuo-spatial aura in
temporal lobe epilepsy [5] (Table 5).
Body Scheme Disorders (Heautoscopy)
Paroxysmal฀ heautoscopy฀ accompanied฀ by฀ visuo-spatial฀ disorder฀ occurred฀ in฀ 2฀ of฀

the 51 patients with temporal lobe epilepsy. Paroxysmal heautoscopy is rare in
epilepsy, but it well known in psychopathology. Penfield and Perot reported four
electrical stimulation-induced human cases of heautoscopy in an epilepsy study in
98 Y. Morita
Table 2 Ictal฀visual฀spatial฀ RaT LaT Bil

distortions and lateralization
Size 2 0 2
Shape 2 0 2
Distance 2 1 2
Dimension 3 4 2
Orientation 1 4 1
Deja฀ve/jamais฀vu 2 1 1
Scene 1 1 1
Body schema 2 1 0
n฀=฀38฀(19฀patients)
Table 3 Frequency of n Percent

different aura-sensations in
Epigastric ฀ 50 35
our patients (from Kanemoto
and฀Janz฀[2]) Familiarity ฀ 45 31
(Déjà vu) ฀ 28 19
Aphasia ฀ 24 17
Anxiety ฀ 23 16
Thought-disorder 19 13
“Es” ฀ 16 10
Visual ฀ 12 ฀8
Somatosensory ฀ 12 ฀8
Gustatory ฀ 12 ฀6
Porropia-porracousia ฀฀8 5
Olfactory ฀฀7 5
Auditory ฀฀7 ฀3
Dysarthria ฀฀4 ฀4
Others 5 22
No฀aura ฀ 31
Total N 143
which฀69฀patients฀underwent฀electric฀stimulation฀during฀brain฀surgery.฀It฀showed฀
another characteristic in that it concomitantly occurred with other visuo-spatial
distortions [4].
Penfield and Perot [5] reported the case of patient with heautoscopy. Their case
was฀a฀37-year-old฀housewife,฀who฀began฀to฀have฀seizures฀at฀the฀age฀of฀20,฀consist-
ing฀of฀the฀following฀pattern:฀(1)฀thoracic฀sensation฀and฀palpitation,฀(2)฀experiential฀
hallucination,฀visual฀type,฀and฀(3)฀occasional฀major฀seizures,฀mainly฀right฀sided.฀
At the beginning of an attack, she would mentally visualize scenes that she some-
times had difficulty recognizing or remembering, but they were often from her
own past. Frequently, the scene consisted of herself during childbirth and also in
a picture. Often, as soon as she recognized the scene it would disappear. On sur-
gery, the left temporal lobe was exposed, and an area of gliosis identified.
Stimulation฀at฀point฀N฀(Brodmann฀21)฀caused฀the฀patient฀to฀say฀that฀she฀suddenly฀
Table 4 Interpretive฀responses฀and฀illusions฀(from฀Penield฀and฀Perot฀[5])
Auditory illusions: Sounds heard seemed louder or clearer, fainter or more distinct, nearer or
farther
Visual illusions: Things seen seemed clearer or blurred; nearer or farther; larger or smaller;
fatter or thinner
Illusions฀of฀recognition:฀Present฀experience฀seemed฀familiar฀(déjà฀vu),฀strange,฀altered,฀or฀unreal
Illusional฀emotions:฀Feelings฀of฀fear,฀loneliness,฀sorrow,฀or฀disgust
Table 5 Ictal฀autoscopy฀hallucination฀[6]
Author Focus
1 Nouet 1923 r. temporal
฀2 Ehrenwald 1931 r. central
฀3 Lunn 1948 r. central
฀4 Lunn 1948 l. central
5 Hecaen and Ajuriaguerra 1952 l. centro-parieto occipital
฀6 Ionasescu 1960 l. temporal-occipital
฀7 Ionasescu 1960 r. temporal
฀8 Ohashi 1965 r. temporal
9 Hamanaka 1974 bil. diffuse
10 Morita 1978 r. temporal
11 Sengoku 1981 r. temporal
12 Kamiya and Okamoto 1982 r. temporal
13 Kamiya and Okamoto 1982 l. temporal
14 Kamiya and Okamoto 1982 r. temporal
saw herself in childbirth and she felt as if she were reliving the experience [5]
(Table 4).
Here the brief history of our patient with heautoscopy is presented.
The฀female฀patient฀of฀26฀years฀old฀who฀suffered฀with฀aura-sensation฀of฀complex฀
partial seizure of temporal lobe epilepsy complaint the frequent episodes of heau-
toscopic฀experiences฀and฀inverted฀vision.฀Inter-ictal฀scalp-record฀electroencepha-
logram showed the spike and slow wave complex at left anterior temporal lobe of
this฀patient฀[6]฀(Table฀5).
Ictal฀autoscopy฀hallucination฀is฀observed฀frequently฀in฀the฀patients฀with฀temporal฀
lobe epilepsy. This peculiar experience is considered one of the feeling of alteration of
body scheme and asomatognosia.
Discussion and Conclusion
Visuo-spatial and body-schema cognitions are firmly established brain functions in

humans and are rarely impaired. However, paroxysmal distortions of visuo-space
and body image frequently occur simultaneously in the patients with temporal lobe
100 Y. Morita
Table 6 Paroxysmal 1. Sentiment dábsence dune partie du corps

disorders of body image 2.฀ Illusion฀de฀transformation฀corporalle
(from Ohhashi et al. [8])
3.฀ Illusion฀de฀deplacement฀cofporel
4.฀ Membre฀fantome
5. Héautoscopie
epilepsy฀ [2,3].฀ And,฀ occasionally฀ the฀ symptoms฀ are฀ accompanied฀ by฀ the฀ state฀ of฀
double฀ consciousness฀ [7].฀ Neuropsychological฀ symptoms,฀ like฀ aphasia,฀ heautos-
copy฀[8],฀and฀inverted฀vision,฀distortion฀of฀the฀time฀sense฀[9]฀are฀also฀encountered฀
in the complex partial seizures.
Heautoscopy is regarded as one of the disorder of body scheme (asomatognosia)
[8]฀(Table฀6).฀Paroxysmal฀episodes฀of฀the฀peculiar฀experience฀of฀seeing฀one’s฀self฀
or “double” self (heautoscopy) may occur in the patients with temporal lobe epilepsy.
In฀ the฀ brain฀ stimulation฀ study฀ reported฀ by฀ Penfield฀ and฀ Perot฀ [5],฀ heautoscopy฀
was฀ reproduced฀in฀4฀of฀69฀cases,฀and฀the฀foci฀of฀the฀seizures฀were฀present฀in฀the฀
temporal lobe, similarly to our patients.
As we see in the present chapter, neuropsychological symptoms commonly occur
in paroxysmal seizures of the complex partial epilepsy, especially temporal lobe
epilepsy. Therefore, collaborative studies in the fields of epileptology and neuropsy-
chology are important to understand the complexity of the psychiatric symptoms in
temporal lobe epilepsy.
Although the complete understanding of human brain function might not be pos-
sible at this moment, it should be a goal of the clinical neurosciences in the future.
There is no doubt, however, neuropsychological studies of epileptic patients con-
tribute to understand the brain function, as the encourage words of Penfield and
Jackson:฀“He฀who฀is฀faithfully฀analyzing฀many฀different฀cases฀of฀epilepsy฀is฀doing฀
far฀more฀than฀studying฀epilepsy”฀(Wilder฀Penfield฀and฀Hughlinge฀Jackson).
References
1. Commission on classification and terminology of the international league against epilepsy

(1981)฀ Proposal฀ for฀ revised฀ clinical฀ and฀ electroencephalographic฀ classification฀ of฀ epileptic฀
seizures.฀Epilepsia฀22:489–501
2.฀ Kanemoto฀K,฀Janz฀D฀(1989)฀The฀temporal฀sequence฀of฀aurasensations฀in฀patients฀with฀complex฀
focal฀ seizures฀ with฀ particular฀ attention฀ to฀ ictal฀ aphasia.฀ J฀ Neurol฀ Neurosurg฀ Psychiatry฀
52:52–56
3.฀ Ionasescu฀ V฀ (1960)฀ Paroxymal฀ disorders฀ of฀ the฀ body฀ image฀ in฀ temporal฀ lobe฀ epilepsy.฀ Acta฀
Psychiatr฀Scand฀35:171–181
4.฀ Taylor฀ D,฀ Lochery฀ M฀ (1987)฀ Temporal฀ lobe฀ epilepsy:฀ origin฀ and฀ significance฀ of฀ simple฀ and฀
complex฀auras.฀J฀Neurol฀Neurosurg฀Psychiatry฀50:673–681
5.฀ Penfield฀ W,฀ Perot฀ P฀ (1963)฀ The฀ brain’s฀ record฀ of฀ auditory฀ and฀ visual฀ experience.฀ Brain฀
86:39–696
6.฀ Morita฀ Y฀ (1978)฀ Paroxysmal฀ disorders฀ of฀ body฀ image,฀ 2฀ cases.฀ Clin฀ Electroencephalogr฀
20:223–224
7.฀ Kamiya฀S,฀Okamoto฀S฀(1982)฀Double฀consciousness฀in฀epileptics:฀a฀clinical฀picture฀and฀minor฀
hemispheric฀specialization.฀Advances฀in฀epileptology.฀Raven,฀New฀York
8.฀ Ohhashi฀H,฀Kawai฀I,฀Hamanaka฀T฀(1969)฀A฀clinical฀and฀electroencephalographic฀study฀on฀the฀
paroxysmal฀disorders฀of฀body฀image.฀Psychiatr฀Neurol฀Jpn฀71:435–449
9.฀ Kawai฀I,฀Kawagoe฀T,฀Hatada฀K฀et฀al฀(1983)฀Ictal฀distortion฀of฀time฀sense฀in฀epileptic฀patients.฀
J฀Jpn฀Epilepsy฀Soc฀1:17–22
The Interictal Dysphoric Disorder of Epilepsy
Marco Mula
Abstract Depression represents a common psychiatric comorbidity in patients with

epilepsy, particularly among those with partial seizures of temporal lobe origin,
ranging between 24% and 74% according to the population investigated. However, a
number of authors have pointed out that the phenomenology of depression, especially
among patients with refractory epilepsy, frequently fails to meet widely standardized
criteria for psychiatric disorders such as DSM-IV. In this regard, it has been sug-
gested that, within the overall presentations of depression in epilepsy, a subgroup of
patients may develop an affective-somatoform syndrome also known as the interictal
dysphoric disorder of epilepsy. This chapter is aimed at reviewing, with historical
reference, the psychopathological and clinical features of such a controversial entity
in the light of recent studies pointing out the commonalities with a specific subset of
cyclothymic subjects in which depressive periods and labile–angry–irritable moods
dominate the clinical picture. It is, therefore, tempting to speculate that the interictal
dysphoric disorder may represent an interesting biological model to further clarify a
number of issues on the neurobiology of mood regulation.
Keywords Antiepileptic฀ drugs฀ •฀ Bipolar฀ disorder฀ •฀ Depression฀ •฀ Epilepsy฀

•฀Interictal฀dysphoric฀disorder
Epilepsy and Depression: An Overview
It has been known for a long time that there are some associations between epilepsy
and depression. The Greek physician Hippocrates, around 400 b.c., observed that
“melancholics ordinarily become epileptics, and epileptics, melancholics: what
M. Mula (*)
Division of Neurology, Maggiore Hospital, Amedeo Avogadro University,
C.so Mazzini 18, 28100, Novara, Italy

DOI 10.1007/978-4-431-53871-4_8, © Springer 2010
104 M. Mula
determines the preference is the direction the malady takes; if it bears upon the
body, epilepsy, if upon the intelligence, melancholy” [1].
There are several reasons why these two conditions may be closely linked, and
such฀reasons฀are฀both฀biological฀and฀psychosocial.฀Epilepsy฀is฀a฀chronic฀disorder,฀
which still brings about much social discrimination, and as with any chronic disor-
der, epilepsy might be expected to be linked to demoralization and a negative
perspective toward life. On the other hand, the biological contribution to the asso-
ciation, based on neuroanatomical and neurochemical principles, needs to be taken
into฀account.฀Epilepsy฀is฀frequently฀associated฀with฀damages฀in฀the฀limbic฀system,฀
which plays a key role in the processing of emotions. Also, patients with epilepsy
are chronically exposed to antiepileptic drugs that are potent psychoactive com-
pounds with a number of effects on mood and behavior. For all these reasons it is
expected that depression is more frequent among patients with epilepsy when com-
pared to the general population, and data coming from community studies support
such an impression. The General Practice UK study reported a 22% prevalence of
depression in unselected samples of patients with epilepsy [2]. A Canadian
Community Health Survey noted very similar lifetime prevalence rates for depression
(around 22%), much higher than those reported in the general population (around
12%) [3]. A U.S. survey pointed out that depression is more frequent in epilepsy
(36.5%) in comparison to people with asthma (27.8%) and healthy controls [4], sug-
gesting that depression is more frequently reported in epilepsy than in other chronic
medical conditions. Another relevant point relates to seizure control being such
comorbidity greater in those patients with higher seizure frequencies and with con-
tinuing seizures compared to seizure-free patients. In fact, several authors have
noted a correlation with seizure frequency that most likely reflects in a large part
on the intractability of the seizure disorders. Jacoby et al. [5] reported depression
in 4% of seizure-free patients, 10% in patients with less than one seizure per month,
and 21% in patients with higher seizure frequency. O’Donoghue et al. [6] pointed
out that patients with epilepsy with continuing seizures are significantly more likely
to suffer from depression than those in remission (33% vs. 6%).
The association between depression and epilepsy has relevant implications in
terms of prognosis and treatment; in fact, it seems quite established that depressive
symptoms are the most important predictor of quality of life of patients with epilepsy,
an even more powerful predictor than the actual seizure frequency [7–9].
An important finding that has been replicated by several studies is that the link
between depression and epilepsy is not necessarily unidirectional; that is, patients
with such a comorbidity always present with the seizure disorder before the emer-
gence of the depression, but it has been noted that having a prior mood disorder can
be associated with an increased risk of epilepsy [10, 11]. Although it is reasonable to
hypothesize that the development of the epilepsy may be related to suicidal attempts,
or to drug abuse, or follow some other kinds of trauma such as head trauma, it
tempting to speculate that such a finding may reflect an underlying common patho-
genesis, which may relate to some as yet unknown genetic factor, or some link with
neurotransmitter function (for example, related to transmitters that are known to play
a฀role฀in฀both฀epilepsy฀and฀depression฀such฀as฀serotonin฀or฀GABA)฀[12, 13].
The฀Interictal฀Dysphoric฀Disorder฀of฀Epilepsy 105
Is Depression Associated with Any Specific Epilepsy Syndrome?
There has been considerable debate, which is unresolved, as to the association

between depression and any particular epilepsy syndrome. It is well known that
people with lesional mesial temporal lobe epilepsy are likely to have intractable
seizures, and they are also likely to be on a polytherapy regimen. It has been sug-
gested that such patients are more prone to develop depression than other groups,
and this association seems to be strictly related to the degree of involvement of the
limbic structures [14]. However, other authors failed to show any difference
between temporal lobe and extratemporal lobe epilepsy in terms of mood disorders
[15]. In this regard, it is interesting to note that there are a number of studies outside
the field of epilepsy suggesting that hippocampal volume loss is associated with
depression [16, 17]. Thus, although further research in this area is needed, neuro-
imaging studies are revealing an underlying brain network of depression in psychi-
atric patients without a neurological disorder, which includes the hippocampus,
nicely in keeping with the findings in epilepsy patients.
Current literature on neurobiology of depression in epilepsy has also focused on
frontal lobe dysfunction, the latter having emerged from investigations using brain
imaging฀ techniques฀ [positron฀ emission฀ tomography฀ (PET)฀ or฀ single-photon฀ emis-
sion฀computed฀tomography฀(SPECT)]฀and฀neuropsychological฀testing.฀It฀has฀been฀
shown that patients with left-sided temporal lobe epilepsy and depression were more
likely to perform poorly on frontal lobe tasks [18]. Similar results have been reported
by neuroimaging studies [19, 20]. Although these findings, of necessity, were
derived from a limited number of patients, the concordance between the conclusions
does support an anatomical association between temporal lobe epilepsy, especially
left-sided epileptic activity, depression, and frontal lobe dysfunction.
Is There a Mood Disorder Specific of Epilepsy? The Interictal

Dysphoric Disorder
The issue of phenomenology of depression in epilepsy has been and still is very
much a matter of debate. Some authors have emphasized the endogenous features
[21] while others commented on the reactive nature of depression [22]. In general
terms, the spectrum of manifestations is likely to be large, and it is reasonable to
hypothesize that patients with epilepsy can experience forms of mood disorders
identical to those of patients without epilepsy. However, it is equally reasonable to
assume that the underlying brain pathology may influence the final phenomenology
of mood disorder symptoms, emphasizing some aspects or attenuating others.
Data favoring the existence of an epilepsy-specific mood disorder come from the
clinical observation that the psychopathology of patients with epilepsy often has
unique manifestations that are poorly reflected by conventional classification
systems such as Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV
106 M. Mula
and International Classification of Diseases (ICD)-10 [23]. Some authors observed

that up to 22% of patients consecutively assessed for the phenomenology of depres-
sion could be classified as having atypical features [24]. In fact, it is a common
observation that classic endogenous-type depressive symptoms, such as feelings of
guilt, lack of emotions or “Gefühl der Gefühllosigkeit,” and a circadian pattern of
symptom severity are rarely reported by patients with epilepsy. Kanner et al. [25]
reported that such atypical symptoms are much more frequent among subjects with
refractory epilepsy with percentages as high as 71%; moreover, it is important to
point out that 64% fail to meet any DSM-IV criteria using two structured clinical
interviews, namely, the Structured Clinical Interview for DSM-IV Axis I (SCID-I)
and the Mini International Neuropsychiatric Interview (MINI) [26]. Among differ-
ent potential causes for the atypical features of mood disorders in epilepsy, the peri-
ictal cluster of symptoms, to some degree, may account for such an atypicality [27],
but the possibility that the mood disorders of epilepsy may have unique characteris-
tics has plausibility.
In classic psychiatric writings, especially the German literature [28, 29], patients
with epilepsy were described as having a pleomorphic pattern of symptoms, includ-
ing affective symptoms with prominent irritability intermixed with euphoric moods,
fear, anxiety as well as anergia, pain, and insomnia. Such observations have been
confirmed by Gastaut [30],฀and฀later฀Blumer฀coined฀the฀term฀interictal฀dysphoric฀
disorder to refer to this type of depressive disorder seen in patients with epilepsy
[31].฀ Blumer฀ used฀ the฀ term฀ “dysphoria”฀ to฀ emphasize฀ the฀ periodicity฀ of฀ mood฀
changes and the presence of outbursts of irritability and aggressive behavior as key
symptoms. Other authors [25, 32, 33] highlighted the chronic course of this state of
moderate neurotic depression with symptom-free intervals typical of epilepsy,
referring to a dimension very close to dysthymia. It is obvious that the interictal
dysphoric disorder may present in our time with features that are different from
those described by premodern psychiatry. For example, depressed mood and aner-
gia may be much more evident than previously because modern antiepileptic medi-
cations may attenuate the dysphoric symptoms.
The phenomenology of this somatoform-affective disorder, as reported by
Blumer,฀ is฀ particularly฀ intriguing฀ [31, 34]. He described eight key symptoms
grouped in three major categories: labile depressive symptoms (depressive mood,
anergia, pain, and insomnia), labile affective symptoms (fear, anxiety), and supposedly
“specific” symptoms (paroxysmal irritability, and euphoric moods; Table 1). The
dysphoric episodes are described as occurring without external triggers and without
clouding of consciousness; beginning and ending rapidly and recurring fairly regu-
larly in a uniform manner (every few days to every few months and lasting for a
few hours up to 2 days). The concept of the interictal dysphoric disorder theorized
by฀Blumer฀goes฀beyond฀the฀mood฀disorder฀itself฀to฀encompass฀a฀spectrum฀of฀condi-
tions with transient psychotic features, to an even more debilitating disorder with
prolonged฀psychotic฀states.฀In฀fact,฀according฀to฀Blumer’s฀view,฀the฀schizophrenia-
like psychoses of epilepsy can be considered as a severe interictal dysphoric disor-
der with psychotic features or better a schizoaffective interictal dysphoric disorder
[31, 34]. Such a hypothesis is deeply influenced by classic German psychiatric
Table 1 Principal symptom groups of the interictal dysphoric disorder of

epilepsy฀according฀to฀Blumer’s฀deinition
Labile depressive symptoms Anergia
Depressed mood
Insomnia
Pain
Labile affective symptoms Anxiety
Fear
Specific symptoms Euphoric฀moods
Paroxysmal irritability
literature, especially Kraepelin’s view of the relationship between manic-depressive

illness and schizophrenia [28].
Recent studies from my group specifically investigated the clinical and
psychopathological features of the interictal dysphoric disorder [35, 36]. We observed
that such a syndrome represents a homogeneous construct with specific clinical
features and affects a relevant proportion of patients with epilepsy (about 17%).
However, it seems not to be specifically associated to the epilepsy itself, being
diagnosed also in subjects with migraine (about 18%) [35]. Therefore, it needs to be
clarified whether the so-called interictal dysphoric disorder is an organic affective
syndrome that occurs in patients with brain disturbances or whether it can be
diagnosed also in subjects with chronic medical conditions not affecting primarily the
central฀ nervous฀ system.฀ Theoretically,฀ this฀ issue฀ was฀ partly฀ addressed฀ by฀ Blumer฀
himself, stating that such a syndrome can occasionally occur in the absence of clinical
฀seizures,฀in฀patients฀with฀brain฀lesions฀(with฀or฀without฀an฀abnormal฀EEG)฀[37]. From
a psychopathological point of view, we speculated that some features of the interictal
dysphoric disorder, especially the co-occurrence of mood instability and irritability,
belong to the bipolar spectrum rather than to unipolar depression [38, 39]. This con-
cept seems to be further supported by the use of standardized clinical instruments for
manic and depressive symptoms. In fact, the Mood Disorder Questionnaire came out
to be more specific for a diagnosis of interictal dysphoric disorder (86.0%) then the
Beck฀Depression฀Inventory฀(65.9%)฀[35], the former being highly specific for manic
symptoms [40]. From a clinical point of view, patients with the interictal dysphoric
disorder have several features in common with a subset of cyclothymic subjects
where depressive periods and labile–angry–irritable moods dominate the clinical
picture, representing the more unstable form of bipolar II disorder [41]. In this regard,
it฀interesting฀to฀note฀that฀Blumer฀reported฀a฀combined฀therapy฀of฀antiepileptic฀and฀
antidepressant drugs as effective [34], a combination extensively used in bipolar
depression. In another study from my group, we looked at the prevalence and clinical
features of manic symptoms in patients with epilepsy observing that although they are
highly present (12–14%), in a large proportion of cases these symptoms are related
to the interictal dysphoric disorder and can be misleadingly interpreted as bipolar
symptoms [36], whereas the prevalence of a true manic-depressive illness in epilepsy
showed to be in line with that reported in the general population (about 2%) [42].
108 M. Mula
Fig. 1 Major DSM-IV Axis I diagnoses overlapping with the interictal dysphoric disorder
The features of the so-called interictal dysphoric disorder overlap with a variety
of affective disorders seen in clinical psychiatric practice (Fig. 1); however, data
presented suggest that such a syndrome represents a frequent comorbidity in
patients with epilepsy and its diagnosis can be challenging even for expert clini-
cians because of the pleomorphic phenomenology of the syndrome.
Diagnosing Mood Disorders in Patients with Epilepsy
As already discussed, a diagnosis of depression can be challenging in patients with

epilepsy because of the atypicality and pleomorphic nature of symptoms. Moreover,
a number of manifestations, which are recognized as diagnostic criteria for a
depressive episode by the ICD-10 and DSM-IV (e.g., loss of energy, insomnia or
hypersomnia, increase or decrease in appetite, loss of libido, psychomotor retarda-
tion, diminished ability to think or concentrate), may occur in epilepsy secondary
to seizure activity or the antiepileptic drug treatment. For all these reasons, clini-
cians need to fully explore the mental state of their patients, trying to identify key
symptoms that cannot be influenced by epilepsy-related variables. For example,
anhedonia has been suggested to be an excellent indicator of the presence of
depression [13]. This issue is strictly related to that of available clinical instruments
specifically validated in patients with epilepsy. In this regard, Krishnamoorthy
pointed out that the vast majority of studies use measures or cutoff scores that may
not be valid in the epilepsy population [43].
Mintzer and Lopez [44]฀ proposed฀ the฀ Epilepsy฀ Addendum฀ for฀ Psychiatric฀
Assessment฀(EAPA),฀an฀instrument฀expressly฀designed฀for฀use฀with฀the฀MINI,฀
and฀a฀version฀of฀the฀SCID-I฀adapted฀for฀patients฀with฀epilepsy,฀named฀SCID-E,฀
has been proposed [45]. However, the relative benefits of these various instruments,
in the assessment of generic psychopathology in community-based studies, are

the subject of considerable debate. Among well-known screening instruments,
the฀psychometric฀properties฀of฀the฀Beck฀Depression฀Inventory฀have฀been฀inves-
tigated in epilepsy, showing a good sensitivity (0.93), an acceptable specificity
(0.81), and an excellent negative predictive value (0.98), but a very low positive
predictive value (0.47) [46]. A six-item, self-report, screening instrument, the
Neurological฀Disorders฀Depression฀Inventory฀for฀Epilepsy฀(NDDI-E),฀was฀vali-
dated to screen for major depressive episodes in epilepsy [47]. It has the advan-
tage of being constructed specifically to minimize confounding factors, such as
adverse฀events฀related฀to฀AEDs฀or฀cognitive฀problems฀associated฀with฀epilepsy,฀
and showed an internal consistency of 0.85 and a test–retest reliability of 0.78.
A score of 15 or higher has a specificity of 0.90 and a sensitivity of 0.81 for a
diagnosis of major depressive episode. However, all these instruments relate to
a diagnosis of a mood disorder characterized by symptoms identical to those
referred by psychiatric populations without epilepsy. Therefore, a number of
atypical manifestations that can be seen in the epilepsy setting may remain unde-
tected.฀The฀Seizure฀Questionnaire฀developed฀by฀Blumer฀and฀collaborators฀con-
tains questions for the eight key symptoms of the interictal dysphoric disorder
[48]. Patient and caregiver answer them jointly, and the examiner then reviews
all answers for completeness and accuracy. We have developed a specific instru-
ment, named the Interictal Dysphoric Disorder Inventory (IDDI), a 38-item,
self-report questionnaire, to evaluate all symptoms of the interictal dysphoric
disorder in terms of presence, frequency, severity, and global impairment [35].
This questionnaire explores a time interval of 12 months. The diagnosis of inter-
ictal฀dysphoric฀disorder฀follows฀Blumer’s฀criteria฀[34], namely, the presence of
at least three symptoms of “moderate” or “severe” severity and causing “moder-
ate” or “severe” distress. It is possible to obtain a total score and three subscale
scores฀ that฀ mirror฀ the฀ three฀ major฀ symptom฀ categories฀ described฀ by฀ Blumer:฀
labile depressive symptoms, labile affective symptoms, and specific symptoms.
Furthermore, the IDDI allocates also “severeness” (IDDIsev) total and partial
scores that reflect the degree of interference or distress caused by symptoms.
The IDDI total and subscale scores showed strong or very strong correlations
among themselves (0.68–0.85), and the instrument displayed an acceptable sen-
sitivity and an excellent specificity when compared to a validated questionnaire
for฀the฀screening฀of฀major฀depression฀or฀bipolar฀disorder฀(i.e.,฀Beck฀Depression฀
Inventory and Mood Disorder Questionnaire) [35]. Finally, in the appendix to
the questionnaire, six questions investigate the time course of the disorder, dura-
tion of dysphoric symptoms, and their associations with seizures or antiepileptic
drug therapy. The entire questionnaire has been published and it is fully avail-
able [49].
It seems clear that the correct diagnosis of mood disorders in epilepsy is still
affected by unmet needs. However, some screening instruments shown to be valid
in฀ depression฀ (i.e.,฀ BDI฀ and฀ NDDI-E)฀ and฀ others฀ are฀ available฀ for฀ specific฀ syn-
dromes (i.e., IDDI). Nevertheless, clinical observation through a careful assessment
of the mental state of the patient still remains the gold standard.
110 M. Mula
Conclusions
Depression in epilepsy represents a frequently encountered psychiatric comorbidity

that is likely to be related to a number of variables which are both biological and
psychosocial. The arguments for whether the majority of the clinical presentations
could be explained by psychosocial factors have been variably prominent across
authors. However, whatever way one views this, the literature suggests that the link
between depression and epilepsy may not be unidirectional, further supporting the
hypothesis of common underlying biological mechanisms.
It does seem generally agreed that the clinical picture of depression in epilepsy
is not typical in all cases for a DSM categorization, and a number of authors have
noted the atypical nature of the clinical picture. Within the overall presentations of
depression in epilepsy, it appears that a subgroup of patients may have an affective
syndrome, which some have referred to as the interictal dysphoric disorder. Such a
condition seems to have overlapping features with the bipolar spectrum, with pos-
sible consequences in terms of prognosis and therapeutic strategies. It is, therefore,
essential that clinicians assess for these varied forms as well.
References
฀ 1.฀ Temkin฀O฀(1971)฀The฀falling฀sickness.฀John฀Hopkins,฀Baltimore
฀ 2.฀ Edeh฀J,฀Toone฀B฀(1987)฀Relationship฀between฀interictal฀psychopathology฀and฀type฀of฀epilepsy.฀
Results฀of฀a฀survey฀in฀general฀practice.฀Br฀J฀Psychiatry฀151:95–101
฀ 3.฀ Tellez-Zenteno฀ JF,฀ Patten฀ SB,฀ Jetté฀ N฀ et฀ al฀ (2007)฀ Psychiatric฀ comorbidity฀ in฀ epilepsy:฀ a฀
population-based฀analysis.฀Epilepsia฀48:2336–2344
฀ 4.฀ Ettinger฀A,฀Reed฀M,฀Cramer฀J฀et฀al฀(2004)฀Depression฀and฀comorbidity฀in฀community-based฀
patients with epilepsy or asthma. Neurology 63:1008–1014
฀ 5.฀ Jacoby฀A,฀Baker฀GA,฀Steen฀N฀et฀al฀(1996)฀The฀clinical฀course฀of฀epilepsy฀and฀its฀psychosocial฀
correlates:฀findings฀from฀a฀UK฀community฀study.฀Epilepsia฀37:148–161
6. O’Donoghue MF, Goodridge DM, Redhead K et al (1999) Assessing the psychosocial conse-
quences฀of฀epilepsy:฀a฀community-based฀study.฀Br฀J฀Gen฀Pract฀49:211–214
฀ 7.฀ Perrine฀K,฀Hermann฀BP,฀Meador฀KJ฀et฀al฀(1995)฀The฀relationship฀of฀neuropsychological฀func-
tioning to quality of life in epilepsy. Arch Neurol 52:997–1003
฀ 8.฀ Gilliam฀F,฀Kuzniecky฀R,฀Faught฀E฀et฀al฀(1997)฀Patient฀validated฀content฀of฀epilepsy฀specific฀
quality฀of฀life฀measurement.฀Epilepsia฀38:233–236
฀ 9.฀ Boylan฀LS,฀Flint฀LA,฀Labovitz฀DL฀et฀al฀(2004)฀Depression฀but฀not฀seizure฀frequency฀predicts฀
quality of life in treatment-resistant epilepsy. Neurology 62:258–261
10. Forsgren L, Nystrom L (1990) An incident case-referent study of epileptic seizures in adults.
Epilepsy฀Res฀6:66–81
11. Hesdorffer DC, Hauser WA, Annegers JF et al (2000) Major depression is a risk factor for
seizures in older patients. Ann Neurol 47:246–249
฀12.฀ Kanner฀ AM,฀ Balabanov฀ A฀ (2002)฀ Depression฀ and฀ epilepsy:฀ how฀ closely฀ related฀ are฀ they?฀
Neurology 58(8 suppl 5):S27–S39
13. Kanner AM (2006) Depression and epilepsy: a new perspective on two closely related disor-
ders.฀Epilepsy฀Curr฀6:141–146
14. Quiske A, Helmstaedter C, Lux S et al (2000) Depression in patients with temporal lobe
epilepsy฀is฀related฀to฀mesial฀temporal฀sclerosis.฀Epilepsy฀Res฀39:121–125
฀15.฀ Swinkels฀WA,฀van฀Emde฀BW,฀Kuyk฀J฀et฀al฀(2006)฀Interictal฀depression,฀anxiety,฀personality฀
traits,฀and฀psychological฀dissociation฀in฀patients฀with฀temporal฀lobe฀epilepsy฀(TLE)฀and฀extra-
TLE.฀Epilepsia฀47:2092–2103
฀16.฀ Bremner฀JD,฀Narayan฀M,฀Anderson฀ER฀et฀al฀(2000)฀Hippocampal฀volume฀reduction฀in฀major฀
depression. Am J Psychiatry 157:115–118
฀17.฀ Frodl฀T,฀Meisenzahl฀EM,฀Zetzsche฀T฀et฀al฀(2002)฀Hippocampal฀changes฀in฀patients฀with฀a฀first฀
episode of major depression. Am J Psychiatry 159:1112–1118
฀18.฀ Hermann฀BP,฀Seidenberg฀M,฀Haltiner฀A฀et฀al฀(1991)฀Mood฀state฀in฀unilateral฀temporal฀lobe฀
epilepsy.฀Biol฀Psychiatry฀30:1205–1218
฀19.฀ Schmitz฀EB,฀Moriarty฀J,฀Costa฀DC฀et฀al฀(1997)฀Psychiatric฀profiles฀and฀patterns฀of฀cerebral฀
blood flow in focal epilepsy: interactions between depression, obsessionality, and perfusion
related to the laterality of the epilepsy. J Neurol Neurosurg Psychiatry 62:458–463
฀20.฀ Bromfield฀ E,฀ Altschuler฀ L,฀ Leiderman฀ D฀ (1990)฀ Cerebral฀ metabolism฀ and฀ depression฀ in฀
patients฀with฀complex฀partial฀seizures.฀Epilepsia฀31:625
฀21.฀ Betts฀TA฀(1974)฀A฀follow฀up฀study฀of฀a฀cohort฀of฀patients฀with฀epilepsy฀admitted฀to฀psychiat-
ric฀care฀in฀an฀English฀city.฀In:฀Harris฀P,฀Mawdsley฀C฀(eds)฀Epilepsy:฀Proceedings฀of฀the฀Hans฀
Berger฀Centenary฀Symposium.฀Churchill฀Livingstone,฀Edinburgh,฀pp฀326–338
22. Mulder DW, Daly D (1952) Psychiatric symptoms associated with lesions of the temporal
lobe. JAMA 141:173–176
฀23.฀ Krishnamoorthy฀ ES,฀ Trimble฀ MR,฀ Blumer฀ D฀ (2007)฀ The฀ classification฀ of฀ neuropsychiatric฀
disorders฀ in฀ epilepsy:฀ a฀ proposal฀ by฀ the฀ ILAE฀ Commission฀ on฀ Psychobiology฀ of฀ Epilepsy.฀
Epilepsy฀Behav฀10:349–353
฀24.฀ Mendez฀ MF,฀ Cummings฀ JL,฀ Benson฀ DF฀ (1986)฀ Depression฀ in฀ epilepsy.฀ Significance฀ and฀
phenomenology. Arch Neurol 43:766–770
25. Kanner AM, Kozac AM, Frey M (2000) The use of sertraline in patients with epilepsy: is it
safe?฀Epilepsy฀Behav฀1:100–105
26. Kanner AM, Soto A, Gross-Kanner H (2004) Prevalence and clinical characteristics of pos-
tictal psychiatric symptoms in partial epilepsy. Neurology 62:708–713
27. Kanner AM (2008) Do peri-ictal psychiatric symptoms account for the differences between
depressive฀disorders฀in฀patients฀with฀and฀without฀epilepsy?฀In:฀Kanner฀AM,฀Schachter฀S฀(eds)฀
Psychiatric฀controversies฀in฀epilepsy.฀Elsevier,฀New฀York,฀pp฀201–209
฀28.฀ Kraepelin฀E฀(1923)฀Psychiatrie.฀Band฀3.฀Johann฀Ambrosius฀Barth,฀Leipzig
฀29.฀ Bleuler฀E฀(1949)฀Lehrbuch฀der฀Psychiatrie,฀8th฀edn.฀Springer-Verlag,฀Berlin
฀30.฀ Gastaut฀H,฀Morin฀G,฀Lesevre฀N฀(1955)฀Etude฀du฀comportement฀des฀epileptiques฀psychomo-
teurs dans l’intervalle de leurs crises: les troubles de l’activitè globale et de la sociabilitè. Ann
Med Psychol (Paris) 113:1–27
฀31.฀ Blumer฀D฀(2000)฀Dysphoric฀disorders฀and฀paroxysmal฀affects:฀recognition฀and฀treatment฀of฀
epilepsy-related psychiatric disorders. Harv Rev Psychiatry 8:8–17
฀32.฀ Himmelhoch฀JM฀(1984)฀Major฀mood฀disorders฀related฀to฀epileptic฀changes.฀In:฀Blumer฀D฀(ed)฀
Psychiatric aspects of epilepsy. American Psychiatric, Washington, DC, pp 271–94
33. Kanner AM (2003) Depression in epilepsy: a frequently neglected multifaceted disorder.
Epilepsy฀Behav฀4:S11–S19
฀34.฀ Blumer฀ D,฀ Montouris฀ G,฀ Davies฀ K฀ (2004)฀ The฀ interictal฀ dysphoric฀ disorder:฀ recognition,฀
pathogenesis,฀ and฀ treatment฀ of฀ the฀ major฀ psychiatric฀ disorder฀ of฀ epilepsy.฀ Epilepsy฀ Behav฀
5:826–840
35. Mula M, Jauch R, Cavanna A et al (2008) Clinical and psychopathological definition of the
interictal฀dysphoric฀disorder฀of฀epilepsy.฀Epilepsia฀49:650–656
฀36.฀ Mula฀M,฀Schmitz฀B,฀Jauch฀R฀et฀al฀(2008)฀On฀the฀prevalence฀of฀bipolar฀disorder฀in฀epilepsy.฀
Epilepsy฀Behav฀13:658–61
฀37.฀ Blumer฀D,฀Heilbronn฀M,฀Himmelhoch฀J฀(1988)฀Indications฀for฀carbamazepine฀in฀mental฀ill-
ness:฀ atypical฀ psychiatric฀ disorder฀ or฀ temporal฀ lobe฀ syndrome?฀ Compr฀ Psychiatry฀
29:108–122
38. Möller HJ, Curtis VA (2004) The bipolar spectrum: diagnostic and pharmacologic consider-
ations.฀Expert฀Rev฀Neurother฀4(6฀suppl฀2):S3–8
112 M. Mula
฀39.฀ Benazzi฀F฀(2007)฀Is฀there฀a฀continuity฀between฀bipolar฀and฀depressive฀disorders?฀Psychother฀
Psychosom 76:70–6
40. Hirschfeld RM, Holzer C, Calabrese JR et al (2003) Validity of the mood disorder question-
naire: a general population study. Am J Psychiatry 160:178–180
41. Akiskal HS, Pinto O (1999) The evolving bipolar spectrum. Prototypes I, II, III, and IV.
Psychiatr Clin North Am 22:517–34
42. Judd L, Akiskal HS (2003) The prevalence and disability of bipolar spectrum disorders in the
U.S.฀population:฀re-analysis฀of฀the฀ECA฀database฀taking฀into฀account฀subthreshold฀cases.฀
J Affect Disord 73:123–131
฀43.฀ Krishnamoorthy฀ES฀(2006)฀The฀evaluation฀of฀behavioral฀disturbances฀in฀epilepsy.฀Epilepsia฀
47(suppl 2):3–8
฀44.฀ Mintzer฀ S,฀ Lopez฀ F฀ (2002)฀ Comorbidity฀ of฀ ictal฀ fear฀ and฀ panic฀ disorder.฀ Epilepsy฀ Behav฀
3:330–337
฀45.฀ Krishnamoorthy฀ ES฀ (2005).฀ Epidemiology฀ and฀ assessment฀ of฀ psychiatric฀ disorders฀ of฀ epi-
lepsy. Ph.D. thesis, University College London
฀46.฀ Jones฀JE,฀Hermann฀BP,฀Woodard฀JL฀et฀al฀(2005)฀Screening฀for฀major฀depression฀in฀epilepsy฀
with฀common฀self-report฀depression฀inventories.฀Epilepsia฀46:731–735
฀47.฀ Gilliam฀FG,฀Barry฀JJ,฀Hermann฀BP฀et฀al฀(2006)฀Rapid฀detection฀of฀major฀depression฀in฀epi-
lepsy: a multicentre study. Lancet Neurol 5:399–405
฀48.฀ Blumer฀D,฀Montouris฀G,฀Davies฀K฀et฀al฀(2002)฀Suicide฀in฀epilepsy:฀psychopathology,฀patho-
genesis,฀and฀prevention.฀Epilepsy฀Behav฀3:232–241
฀49.฀ Mula฀M,฀Trimble฀MR฀(2008)฀What฀do฀we฀know฀about฀mood฀disorders฀in฀epilepsy?฀In:฀Kanner฀
AM,฀Schachter฀S฀(eds)฀Psychiatric฀controversies฀in฀epilepsy.฀Elsevier,฀New฀York,฀pp฀49–66
Neuropsychiatric Symptoms of Seizure
Disorders with Special Reference
to the Amygdala
Michael Trimble
Abstract In this chapter, the anatomy and function of the amygdala in relationship
to emotional processing are explored. It is now known that the amygdala can be
activated by certain emotional stimuli, and the fearful faces paradigm has been well
tested experimentally. Studies with epilepsy reveal that amygdala sclerosis often
accompanies hippocampal sclerosis. Studies of patients with amygdala sclerosis
show that this affects the activity to emotional stimuli of the amygdala but also the
fusiform and related cortical areas distant from the amygdala. Studies of patients who
have undergone temporal lobectomy show the influence of the amygdala in relation
to both preoperative and postoperative affective states, especially of the nondominant
hemisphere. It is concluded that further studies of the amygdala in epilepsy and other
neurological disorders are valuable in studying the functions of the limbic system.
Keywords Amygdala •฀ Psychiatry • Epilepsy •฀ Fusiform area
Introduction
The clinical associations between epilepsy and psychiatric syndromes have now
been widely accepted, and the term comorbidity is often used to express such a
relationship. In the past, psychological and psychosocial explanations were widely
used to explain links between such syndromes as anxiety and depression in epi-
lepsy, although the more severe syndromes such as psychoses or the controversial
personality disorders were less likely to be accounted for without considering the
underlying biology of the epilepsy [1].
Part of this confusion was the result of the almost exclusive psychological
approach to neuropsychiatric disorders taken by psychiatrists, and the relative
neglect by neurologists of behavior problems that could be associated with
M. Trimble (*)
Institute of Neurology, Queen Square, London, WC1N3BG, UK

DOI 10.1007/978-4-431-53871-4_9, © Springer 2010
114 M. Trimble
neurological disorders. Further, in the field of epilepsy there was confusion over the
distinction between seizures and epilepsy. Many people equated the two, but seizures
as signs and causing symptoms are quite distinct from the underlying pathological
processes of the epilepsy. The ongoing interictal electrophysiological disturbances,
which presumably reflect underlying electrochemical aberrations within the brain,
which are easily identifiable by various imaging techniques, may be expected to lead
to continuing interictal disturbances of cerebral function, and if these occur in areas
of the central nervous system that have an impact on emotion and behavior, then
psychiatric disturbances may be the expected outcome for at least some people with
epilepsy, depending upon the site and type of the underlying epileptic discharge.
There has been a growing literature that emphasizes not only the possible neuro-
logical underpinnings of psychiatric disorders generally, but also the psychiatric com-
plications of neurological disorders, including epilepsy. From a purely anatomical
point of view, the unravelling of the concept of the limbic system, from the earlier
circuitry proposed by Papez, to the later more sophisticated elaborations of people
such as MacLean, has emphasized that within the brain there were neuronal structures
and circuits which have specifically to do with modulation of emotion. This was a new
idea, as before the development of the limbic system concept there was no clear cere-
bral framework for an understanding of how the brain felt and expressed emotion.
It was crucial to elaborating on the link between epilepsy and emotion to realize that
two key limbic structures, the hippocampus and the amygdala, were frequently
involved in the underlying pathology of epilepsy, particularly in the localization-
related epilepsies, and newly developed techniques of recording from sites within the
brain revealed that between seizures, interictal abnormalities were recorded from such
structures. More recently, the uncovering and elaboration of the direct associations
between medial temporal structures and limbic forebrain structures, and the unraveling
of the neuroanatomy of the limbic forebrain by authors such as Heimer and colleagues,
have given clear neurological underpinnings for an understanding of the behavioral
consequences of neurological disorders, epilepsy being no exception [2].
The Amygdala
That the amygdala plays a central role in animal behaviour has been known for many
years, although its precise role, and its relative importance across different species,
have yet to be fully determined. Until recently several lines of evidence have pointed
to the role of the amygdala in human behavior, and there is considerable evidence that
this structure is closely involved with emotional responsivity in humans. Using func-
tional magnetic resonance imaging (fMRI), it has become commonplace to image the
amygdala in vivo, and there are case histories of patients who have had either damage
to the amygdala or degeneration of the amygdala, revealing behavioral problems [3].
The amygdala is located at the anterior part of the temporal lobes, in front of and
above the temporal horn of the lateral ventricle. It abuts the rostral part of the
hippocampus and is a composite of several neuronal aggregates. There are two main
components, a larger basolateral complex, which has extensive connections with the
Neuropsychiatric Symptoms of Seizure Disorders with Special Reference to the Amygdala 115
neocortex and from which it receives polysensory information, and a central-medial

division, extending medially and establishing continuity with the bed nucleus of the
stria terminalis (extended amygdala; see following). The laterobasal complex is
cortical, whereas the centromedial nucleus is striato-pallidal like.
The main afferent and efferent pathways traverse the stria terminalis and the ventral
amygdalofugal pathway. The latter is a longitudinal association bundle linking to the
ventral striatum and the medial frontal cortex. There is also a caudal part going to the
lateral hypothalamus and, via the medial forebrain bundle, to the brainstem. The
uncinate fasciculus that projects to the frontal cortex. The connections to the brainstem
come almost exclusively from the central nucleus, the fibers ending in structures that
serve autonomic and visceral functions: these include the hypothalamus, the cate-
cholamine and serotonin brainstem nuclei, the ventral tegmental area (VTA) and the
substantia nigra, the central grey matter, the dorsal motor nucleus of the vagus, and the
nucleus of the solitary tract (NTS). There are also connections to the midbrain and
medullary tegmentum. Those to the hypothalamus may influence the control of pitu-
itary hormone release, especially the projections to the ventromedial nucleus, which
itself projects to the arcuate nucleus. In the cortex, amygdaloid fibers are found in the
orbital and medial frontal lobe, the rostral cingulate gyrus, and most of the temporal lobe [3].
It is further appreciated that the amygdala has extensive distributions to sensory
cortical areas, especially the visual cortex, which presumably modify early sensory
inputs [4]. The connections of the amygdala to the hippocampus are primarily via
the entorhinal cortex, which is a major source of hippocampal afferents. There are
direct connections to the subiculum part of the hippocampus.
Some of the widespread connections of the amygdala are shown diagrammati-
cally in Fig. 1. Thus, the amygdala has extensive afferent and efferent connections,
and when the amygdala speaks, the rest of the brain listens. The amygdala provides
affective valence to sensory representations and is crucial for the emotional tone of
memories. The reciprocal connections with the same cortical structures from which
it receives information, including even the primary sensory cortical areas, allow for
an influence of emotional tone directly on cortical sensory impressions.
Thus the structures of the limbic system, but especially the amygdala, are of great
importance for the interpretation of sensory stimuli, and its efferents directly influence
motor output. A reliable finding from fMRI studies is that emotional stimuli, notably
emotional facial expression, enhance amygdala activity, and there is accumulating
evidence that it is also associated with decision making, guiding and driving human
behavior [5]. The latter may include the social appraisal of the emotional state of others
and the making of value judgements in complex social situations.
The Amygdala in Epilepsy
One of the main pathologies of treatment-resistant epilepsy is mesial temporal scle-

rosis; this is usually linked with hippocampal lesions, of varying severity, but in
some 10% of cases isolated amygdala damage can be seen, and amygdala sclerosis
often accompanies hippocampal sclerosis [6]. MRI technology has now been widely
116 M. Trimble
Fig. 1 The amygdala has widespread influence on cortical and subcortical structures. L lateral;
CE central; M medial; B basal; AB accesory basal nucleus; PAC periamygdaloid cortex. (Reproduced
with permission from Asla Pitkanen)
used to explore the brains of patients with epilepsy, and data from both structural
volumetric analyses and functional data using fMRI have drawn attention to the
importance of the amygdala for regulating behavior in patients with epilepsy.
Structural Changes
van Elst et al. 2000 [7, 8] carried out a series of studies examining the volume of the
amydala in different groups of patients with epilepsy. In the first investigation, they
examined a group of patients with intermittent explosive disorder (DSM4) associated
with epilepsy, comparing their data to patients with epilepsy without such behaviors.
They reported that the aggression group contained a subgroup of patients with very
small amygdala, and there was a higher prevalence of amygdala sclerosis in the
aggressive patients. Twenty percent of their sample had severe amygdala atrophy in
the context of a history of encephalitis. Left-sided lesions were overrepresented.
In further studies, they looked at the volumes of the amygdala in patients with
epilepsy and psychosis. Two patient groups were examined: the first were patients
with epilepsy and interictal psychosis (n = 11), and the second had post-ictal
psychosis (n = 15). Two control groups consisted of 20 healthy volunteers and 20
randomly selected cases of temporal lobe epilepsy who had not displayed any
psychopathology; these were matched for age, sex, duration of epilepsy, and anti-
epileptic medication to the study group. The psychotic episodes were defined
according to ICD10 criteria for the paranoid subtype of schizophrenia; the mini-
mum requirement for the diagnosis of psychosis was the presence of delusions or
hallucinations. The relationship of the psychopathology to the seizures was also
determined, and the groups therefore divided into those with post-ictal and those
with interictal psychoses. Further, patients with other first-axis psychiatric disor-
ders were excluded from the study except for those with minor affective symptoms
that are common in patients with temporal lobe epilepsy.
The results from the study are shown in Fig. 2. When adjusted for cerebral size
(patients with psychoses of epilepsy had significantly smaller total brain volumes
Results
MRI-Volumetry฀:฀Amygdala฀volumes
R F = 8.211; P฀=฀0.001
L ANOVA
F = 9.079; P฀<฀0.000
***
cm3 ***
**
**
2,2
2,1
1,9
1,8
1,7
1,6
1,749 1,756 1,798 1,826 2,056 2,067
CON TLE-CON TLE฀&฀POE
= right amygdala = left amygdala
Fig. 2 Results of amygdala volumetry in epileptic psychoses. MRI magnetic resonance imaging;
CON control; TLE temporal lobe epilepsy; POE psychoses of epilepsy. (From van Elst et al. [8])
118 M. Trimble
compared with both healthy controls and patients without psychopathology), a

highly significant (16–18%) enlargement of both the right and left amygdala vol-
umes was found in the patients with the psychoses of epilepsy. Neither gender or
age contributed to this variance, and post hoc subgroup analysis revealed that the
bilateral enlargement of the psychotic patients was responsible for the overall sig-
nificant findings in a factorial analysis of variance (ANOVA). When the data from
the patients with post-ictal psychoses were compared with those of the interictal
psychoses, no significant volumetric differences emerged. Interestingly, no signifi-
cant differences in hippocampal volumes were noted.
Functional Studies
Maier et al. [9] examined patients with schizophrenia-like psychoses of epilepsy,

and schizophrenia in the absence of epilepsy, using magnetic resonance spectros-
copy. The hippocampus and amygdala complex were examined, and differences
were noted from healthy controls. In particular, they noted a decrease of NAA in
the left-sided medial temporal structures in the psychotic patients, which was maxi-
mal in the patients with psychoses and epilepsy. However, in this study the
amygdala were not well defined or examined separately from the hippocampus.
More recent data have been published using fMRI. Richardson et al. [10] exam-
ined patients with epilepsy who had varying degrees of hippocampal and amygdala
pathology. They gave patients a task of emotional memory encoding, comparing
amygdala responses to neutral emotional stimuli. All their patients had left hip-
pocampal sclerosis, and the responses were compared with normal controls. The
extent of the medial temporal damage, in particular the severity of amygdala
pathology, was reported. They showed that the encoding-related hippocampal activ-
ity for successfully remembered emotional items correlated with a degree of
amygdala pathology, and the amygdala-evoked activity to remembered emotional
items correlated with the degree of left hippocampal pathology. There were no cor-
relations between measures of pathology between the examined hippocampus and
amygdala. They considered that the influence of the amygdala on hippocampal
encoding was expressed through effects on the hippocampus because the pathology
in the left amygdala (assessed by T2 measurements) predicted reduced activity in
the adjacent hippocampus for emotional stimuli, but not for neutral items.
In a subsequent investigation, the same group [11] examined the influence of
viewing fearful faces on areas of cortex distant from the amygdala, again comparing
patients with hippocampal as opposed to hippocampal plus amygdala pathology.
Thus, seeing fearful faces not only produces a greater activation of the amygdala in
healthy volunteers, but it also produces a greater activation in the face-responsive
areas of the fusiform gyrus than does seeing faces with neutral expressions.
In these studies, healthy volunteers were shown to have higher bilateral activity
in the fusiform and extra striate cortex in response to the fearful as opposed to the
neutral faces. In the epilepsy patients, when they examined the amygdala T2 values
they found a significant relationship between the amount of sclerosis and reduced
emotional activation, especially in the posterior fusiform and left occipital areas.
These data reveal that the visual responsiveness of the occipital cortical areas was
intact, but the enhanced emotional responses did not occur.
These data are complemented by neurophysiological studies, and also studies of
patients who have had a temporal lobe removed to treat intractable epilepsy. Vuilleumier
and Driver [12], using a similar experimental paradigm, reported that amygdala damage
reduced or completely eliminated the enhancement of the P1 component of the visual
evoked potential for fearful faces, relative to neutral faces. These findings supported the
view of the distance effects of amygdala lesions on emotional processing.
Bonelli et al. [13] examined patients with anterior temporal lobe resections hav-
ing assessed the preoperative amygdala activation of these patients using the fearful
face paradigm. The responses of patients with refractory epilepsy were compared
with healthy controls, and measures of anxiety and depression were taken preopera-
tively and 4 months postoperatively, being assessed with standardized anxiety and
depression rating scales.
Preoperatively, the patients with left temporal lobe epilepsy had significantly
reduced activation of the amygdala bilaterally, whereas patients with right temporal
lobe epilepsy showed bilateral amygdala activation. Patients with right temporal
lobe epilepsy revealed left and right amygdala activation that was correlated to the
preoperative anxiety and depression levels, and the preoperative right amygdala
activation was correlated significantly with the postoperative increases of both
anxiety and depression scores. Similar correlations were not found for patients with
left-sided temporal lobe epilepsy.
These data, in accordance with the other findings reported above, not only sup-
port the view that the amygdala is of considerable importance in relationship to the
affective state of patients with epilepsy, but they also contributed to the studies of
laterality. Thus, these data suggest that the right amygdala is of more importance in
relationship to affective disorders, in keeping with the known role of the nondomi-
nant hemisphere in relationship to control of affect, and predict that resection of the
right amygdala with patients who have surgery for epilepsy is more likely to lead
to emotional disturbances.
Conclusions
Studies of temporal lobe epilepsy have until recently concentrated much more on
the hippocampus than on the amygdala. However, particularly since the advent of
modern brain imaging, with the ability to examine not only the structure, but also
the function, of the amygdala, the role of the amygdala in emotional processing in
a variety of settings has become clear. Further, there are studies that show that
alteration of the function of the amygdala, either from structural lesions or from
epilepsy, have an influence on the processing of emotional stimuli in patients with
such pathologies.
120 M. Trimble
In the studies reviewed in this chapter, the influence of amygdala pathology on

emotional processing is revealed to be not only related to the pathology at the
amygdala, but distant in its effect, influencing areas of cortex connected with the
amygdala that are normally activated to a greater degree when emotional process-
ing is required. The findings from the temporal lobe surgery studies suggest that
more attention should be paid to the amygdala preoperatively in assessing patients
who are more likely to develop psychiatric disturbances following surgery, post-
operative depression being a particularly problematic clinical problem [14].
In contrast to the direct link shown between emotional processing and emotional
responsivity in patients with epilepsy, the study with epileptic psychoses is particu-
larly revealing. In the past there has been much discussion on the relationship between
the schizophreniform psychoses of epilepsy and schizophrenia in the absence of epi-
lepsy. In the studies of Slater and in subsequent work there has remained the sugges-
tion that the main differences are related to the lack of the long-term deterioration of
people with the schizophrenia-like psychoses of epilepsy and the maintenance of
affective warmth and responsiveness. The increased size of the amygdala as reported
by van Elst et al. may reflect on these phenomenological differences. Thus, outside
the studies of epilepsy, an increased size of the amygdala has been noted in a number
of studies of affective disorder and particularly in bipolar disorder (for review [15]).
Whether the findings of increased volumes and also activity of the amygdala [with
positron emission tomography (PET) studies] reflect on state or trait factors is
unknown, but the findings in the psychoses of epilepsy are quite distinct from the
findings in schizophrenia without epilepsy, where the consensus of studies is that the
amygdala are reduced as opposed as being increased in size [15].
These studies reveal the importance of further evaluation of the amygdala in rela-
tionship not only to the psychiatric syndromes encountered outside epilepsy, but also
to the importance of epilepsy as a potential model for studying links between the brain
and behavior, particularly those structures intimately related to the limbic system.
References
1. Trimble MR (1991) The psychoses of epilepsy. Raven, New York

2. Heimer L, Van Hoesen GW, Trimble MR et al (2008) Anatomy of neuropsychiatry. Academic,
Amsterdam
3. Adolphs RD, Tranel D, Hamann S et al (1999) Recognition of facial emotion in nine subjects
with bilateral amygdala damage. Neuropsychologia 37:111–117
4. Amaral DJ, Avendano C, Benoit R (1989) Distribution of somatostatin-like immunoreactivity
in the monkey amygdala. J Comp Neurol 284:284–313
5. Dolan R (2007) The human amygdala and orbital prefrontal cortex in behavioural regulation.
Philos Trans R Soc Lond B Biol Sci 362:787–799
6. Van Paesschen W, Connelly A, Johnson CL et al (1996) The amygdala and intractable tempo-
ral lobe epilepsy: a quantitative magnetic resonance imaging study. Neurology
47:1021–1031
7. van Elst LT, Woermann FG, Lemieux L et al (2000) Affective aggression in patients with
temporal lobe epilepsy: a quantitative MRI study of the amygdala. Brain 123:234–243
8. van Elst L, Baeumer D, Lemeiux L et al (2002) Amygdala pathology in psychosis of epilepsy:

a magnetic resonance imaging study in patients with temporal lobe epilepsy. Brain
125:140–149
9. Maier M, Mellers J, Toone B et al (2000) Schizophrenia, temporal lobe epilepsy and psycho-
sis: an in vivo MRS and imaging study of the hippocampus/amygdala complex. Psychol Med
30:571–581
10. Richardson MP, Stange BA, Dolan RJ (2004) Encoding of emotional memories depends on
amygdala and hippocampus and their interactions. Nat Neurosci 7:278–285
11. Vuilleumier P, Richardson MP, Armorny JL et al (2004) Distant influences of amygdala
lesion on visual cortical activation during emotional face processing. Nat Neurosci
7:1271–1278
12. Vuilleumier P, Driver J (2007) Modulation of visual processing by attention and emotion:
windows on causal interactions between human brain regions. Philos Trans R Soc Lond B
Biol Sci 362:837–855
13. Bonelli B, Powell R, Yogarjah M et al (2009) Preoperative amygdala fMRI in temporal lobe
epilepsy. Epilepsia 50:217–227
14. Ring HA, Moriarty J, Trimble MR (1988) A prospective study of the early postsurgical psy-
chiatric associations of epilepsy surgery. J Neurosurg Psychiatry 64:601–604
15. Trimble MR, George M (2010) Biological psychiatry, 3rd edn. Wiley-Liss, Chichester
Neuropsychiatric Assessment of Traumatic
Brain Injury During Acute Neurorehabilitation*
David B. Arciniegas
Abstract Traumatic brain injury (TBI) is a common and costly problem worldwide.
In the United States, 1.5 million people sustain TBI each year, and approximately
230,000 of these require hospitalization for management of their injury. The majority
of TBI resulting in hospitalization are moderate to severe in nature and produce
significant mortality and morbidity. Among those surviving their injuries, most
will develop cognitive, emotional, and behavioral (collectively referred to here as
neuropsychiatric) disturbances in the acute postinjury period and will require acute
rehabilitation management. These posttraumatic neuropsychiatric sequelae present
substantial clinical management challenges that the consulting neuropsychiatrist is
well suited to evaluate and manage. In the service of offering the consulting neuro-
psychiatrist with information that may be of use in the care of persons with TBI
receiving care in the acute neurorehabilitation setting, this chapter first defines and
describes TBI and reviews the neuroanatomical and neurobehavioral consequences
of TBI relevant to understanding posttraumatic neuropsychiatric disturbances.
These disturbances are organized under the framework of posttraumatic enceph-
alopathy, and the characteristic forms and stages of recovery of this condition are
discussed. Finally, a neuropsychiatric approach to the evaluation of persons with
TBI in the acute inpatient neurorehabilitation setting is described.
Keywords Cognitive฀impairment฀•฀Encephalophathy฀•฀Frontal฀assessment฀battery฀
(FAB)฀•฀Mini-mental฀state฀exam฀(MMSE)฀•฀Traumatic฀brain฀injury฀(TBI)
*This฀work฀was฀supported฀in฀part฀by฀HealthONE฀Spalding฀Rehabilitation฀Hospital
D.B. Arciniegas (*)
Brain฀Injury฀Rehabilitation฀Unit,฀HealthONE฀Spalding฀Rehabilitation฀Hospital,฀
Aurora, CO, USA
and
Neurobehavioral Disorders Program, Department of Psychiatry,
School฀of฀Medicine,฀University฀of฀Colorado฀Denver,฀13001฀East฀17th฀Place,฀
Campus Box F546, Aurora, CO, 80045, USA
K.฀Miyoshi฀et฀al.฀(eds.),฀Neuropsychiatric Disorders, 125

DOI฀10.1007/978-4-431-53871-4_10,฀©฀Springer฀2010
126 D.B. Arciniegas
Introduction
Neuropsychiatrists and behavioral neurologists are increasingly involved in the

early postinjury and neurorehabilitation management of persons hospitalized after
traumatic brain injury (TBI). In the United States, approximately 230,000 persons
annually are hospitalized in the acute injury period [1, 2].฀Most฀of฀these฀individuals฀
sustain TBI as a result of road traffic accidents, transportation, falls, or assaults,
including incidents involving firearms. Among those whose injuries require hospi-
talization, adolescents, young adults, and older persons are overrepresented, and
most of these sustained TBI of moderate or greater severity [1, 2]. Between the
early฀1980s฀and฀late฀1990s,฀the฀overall฀annual฀rate฀of฀hospitalization฀following฀TBI฀
declined by 51% [1, 2].฀This฀decline฀is฀generally฀attributed฀to฀61%฀and฀19%฀reduc-
tion in hospital-based care of persons with mild and moderate TBI, respectively.
At฀the฀same฀time,฀annual฀hospitalization฀rates฀following฀severe฀TBI฀increased฀90%,฀
from฀ 10฀ to฀ 19฀ per฀ 100,000฀ persons.฀ Additionally,฀ in-hospital฀ mortality฀ following฀
TBI฀declined฀by฀17%฀as฀a฀result฀of฀advances฀in฀pre-hospital฀and฀in-hospital฀trauma฀
care [1, 2]. As a result of these changes in the epidemiology of TBI, individuals
admitted to hospital following TBI are more likely than in past decades to have
sustained a relatively severe injury and to survive it.
More฀ than฀ 40%฀ of฀ persons฀ hospitalized฀ following฀ moderate-to-severe฀ TBI฀
(or about 125,000 persons in the United States annually) are expected to develop
permanent disability as a result of that injury [3]. Posttraumatic neuropsychiatric
disturbances – a term used here to denote the broad spectrum of impairments in
cognition, emotional regulation, behavior, and elementary neurological function
produced by mechanical trauma to the brain – are particularly common among persons
with moderate or severe TBI [4–8]. Neuropsychiatric disturbances are substantial
contributors to postinjury disability [9–11] and reduced quality of life for patients
and their families during and after the early postinjury period [10, 12–14].
The care provided to persons with TBI in acute inpatient rehabilitation settings is
intrinsically neuropsychiatric. The neurorehabilitation of persons with moderate-
to-severe TBI requires identification and management of cognitive impairments
(e.g., disturbances of arousal, attention, processing speed, memory, and executive
function, among others), emotional disturbances (e.g., irritability, liability, depression,
anxiety), behavior (e.g., restlessness, agitation, disinhibition, aggression, apathy), and
elementary neurological functions (e.g., sleep–wake cycle disturbances, seizures,
motor impairments, sensory impairments). Identifying and treating neuropsychiatric
disturbances as early as possible during the course of postinjury care as well as avoiding
interventions฀with฀the฀potential฀for฀acute฀and/or฀long-term฀neuropsychiatric฀complica-
tions will reduce long-term posttraumatic neuropsychiatric morbidity. Accordingly,
developing further the consulting neuropsychiatrists’ expertise in the neuropsychiatric
assessment and management of persons with TBI is an important objective.
With these goals in mind, this chapter begins by defining TBI and reviewing the
commonly used methods of identifying TBI and characterizing its severity. The
neurobiology of TBI is reviewed briefly, including the neuroanatomy, neurochem-
istry, and brain–behavior relationships relevant to the management of acute and
Neuropsychiatric Assessment of Traumatic Brain Injury During Acute Neurorehabilitation 127
subacute posttraumatic neuropsychiatric disturbances. Finally, a neuropsychiatric

approach to the evaluation of persons with TBI in the acute neurorehabilitation
setting is described.
Defining TBI
TBI is defined as a functionally significant disruption of brain function produced

by฀blunt฀or฀penetrating฀trauma฀or฀rapid฀acceleration/deceleration฀forces฀that฀results฀
in immediately apparent cognitive or physical impairments [15]. Although the CDC
clinical case definition permits skull fracture to serve as a proxy marker for TBI, in
this chapter we exclude from consideration those injuries that produce only skull
fracture: although the association between skull fracture and TBI is well described
[16–18], this association is neither invariate nor a sufficiently reliable predictor of
TBI to permit skull fracture to serve as the sole clinical finding upon which to
predicate a TBI diagnosis [19]. Additionally, brain injuries from other causes such
as birth trauma, hypoxic-ischemic (anoxic), inflammatory, toxic, or metabolic
encephalopathies, primary ischemic or hemorrhagic strokes, seizure disorders,
intracranial surgery, and cerebral neoplasms, although these are all causes of
acquired brain injury, are excluded from this definition of TBI (Table 1).
Table 1 Clinical case definition of traumatic brain injury (adapted from the Center for Disease
Control Guidelines for the Surveillance of Central Nervous System Injury, 2002)
Clinical phenomena Description
Objective neurological Focal motor, sensory, or reflex abnormalities
abnormality Seizures (focal or generalized)
Alteration of consciousness Loss of consciousness (LOC)
Impairment฀of฀wakefulness฀(arousal)฀and/or฀awareness
Amnesia Loss or impairment of peri-event memory
Retrograde amnesia (RGA): impaired memory for events
immediately preceding the injury
Anterograde amnesia (AGA): impaired memory for the
injury or the events that follow it
Posttraumatic amnesia (PTA): the period of dense
impairment in new learning following TBI; inclusive of
both AGA and RGA
Objective neuropsychological Standardized neuropsychological examination (in the
abnormality immediate postinjury period) reveals impairment of
cognition (e.g., disorientation, confusion), disturbances
of behavior (e.g., agitation), or other abnormalities in
neuropsychiatric status (e.g., personality change)
Diagnosed intracranial lesion On computed tomography (CT), magnetic resonance imaging
(MRI),฀or฀another฀neurodiagnostic฀(i.e.,฀neuroimaging)฀
study,฀there฀is฀evidence฀of฀diffuse฀axonal฀injury,฀and/
or epidural, subdural, subarachnoid, or intracerebral
hematoma,฀and/or฀cerebral฀contusion฀or฀laceration,฀and/or฀
penetration of brain by foreign body (e.g., gunshot wound)
128 D.B. Arciniegas
With respect to the cognitive manifestations of brain dysfunction at the time of

injury, no single symptom or sign is pathognomic of TBI. Instead, any one (or
more) of several features, including loss of consciousness (LOC), dense impair-
ment in declarative new learning (posttraumatic amnesia, PTA), and alteration in
higher cognitive functions (e.g., feeling “dazed and confused” without LOC or
PTA), is sufficient evidence of brain dysfunction to merit assignment of this diag-
nosis, regardless of the duration of these disturbances. With regard to elementary
neurological impairments, the intended referents of this term are focal neurological
signs (e.g., hemiparesis, hemianopia), focal neurological symptoms (e.g., hemisen-
sory loss), or seizure. Nonlocalizing or generalized neurological symptoms such as
headache, fatigue, dizziness, blurred vision, and so forth, although common post-
concussive symptoms, are frequently produced by peripheral nervous system
injury,฀musculoskeletal฀(i.e.,฀cervicospinal)฀injury,฀and฀facial/head฀(without฀brain)฀
trauma. Accordingly, these are less useful as indicators of brain injury and therefore
not used as evidence of TBI in the standard definition of this condition [15].
Characterizing TBI Severity
TBI severity is generally divided into three categories: mild, moderate, and severe.
Among hospitalized patients, the Glasgow Coma Scale (GCS) [20] is the most com-
monly฀used฀metric฀for฀determining฀TBI฀severity.฀Mild,฀moderate,฀and฀severe฀TBI฀are฀
defined฀by฀GCS฀scores฀of฀13–15,฀9–12,฀and฀3–8,฀respectively,฀reflecting฀performance฀
on three relatively elementary assessments of verbal, eye opening, and motor responses.
While the GCS is an excellent research and clinical measure when administered in a
consistent and timely manner [6, 21, 22], its use in many hospitals is inconsistent, at
best, and the data it yields are frequently confounded by other non-TBI factors [23].
In the absence of GCS scores, or as a supplement or complement to them, determi-
nation of the duration of PTA is also a useful gauge of TBI severity [24]. PTA describes
the period of dense impairment in the ability to learn new information (with or without
some degree of retrograde amnesia). Although PTA is most accurately understood as
one of the later stages within the larger condition of posttraumatic encephalopathy
(PTE;฀discussed฀later฀in฀this฀chapter)฀[25], the conventional assessment of PTA dura-
tion encompasses the entire period between injury and the recovery of reasonably
continuous and accurate memory for daily events. There are several measures with
which to formally assess PTA severity and duration, the most commonly used of which
are the Galveston Orientation and Amnesia Test (GOAT) [26] and the Orientation Log
(O-Log) [27, 28]; among these, we prefer the O-Log given its ease of administration
and interpretation and its excellent statistical comparison to the GOAT [29].
When neither GCS nor prospective PTA data are available, TBI severity may be
characterized retrospectively using the American Congress of Rehabilitation
Medicine฀(ACRM)฀definition฀of฀mild฀TBI฀[30, 31]. These criteria define TBI as a
physiological disruption in brain function resulting from the application of an exter-
nal฀physical฀(including฀acceleration/deceleration)฀force,฀as฀evidenced฀by฀any฀one฀
(or more) of the following: LOC, PTA, altered mental state (“dazed and confused”),
and/or฀a฀focal฀neurological฀deficit฀that฀may฀or฀may฀not฀be฀transient.฀To฀remain฀in฀
the mild category, LOC must be less than 30 min, after which GCS scores are in
the฀13–15฀range,฀and/or฀PTA฀duration฀is฀no฀longer฀than฀24฀h.฀Injuries฀that฀produce฀
LOC of 30 or more min, GCS scores less than 13 at 30 min (or later) post injury,
and/or฀PTA฀longer฀than฀24฀h฀are฀classified฀as฀moderate฀to฀severe.฀McMillan฀and฀
colleagues฀in฀1996฀[31] demonstrated that retrospective interview-based estimates
PTA of duration among hospitalized individuals with TBI correlate highly with
prospective, GOAT-determined duration of PTA. Among patients whose PTA dura-
tion is longer than 24 h, practical classification of injuries as moderate or severe
may be made according to PTA duration (whether prospectively or retrospectively
determined)฀of฀1–7฀days฀and฀more฀than฀7฀days,฀respectively.
For the consulting neuropsychiatrist, the usefulness of measured or estimated
PTA duration and PTA-based severity classifications lies in the prognostic utility of
this value: PTA duration (as a continuous variable) is a robust predictor of functional
independence [29, 34] and disability [34] at the end of acute inpatient rehabilitation,
Glasgow Outcome Scale [35] scores at 6 and 12 months post injury [36, 37], long-
term cognitive recovery [38–40], productivity [41], employment [42], and commu-
nity reintegration [43]. As with the GCS, noninjury factors (e.g., sedating medications,
severe communication impairments) must be considered when estimating PTA
duration, particularly among subjects with more severe general physical injuries
and complications. Nonetheless, in our clinical experience time between injury and
emergence from PTA – regardless of the TBI and concurrent factors contributing to
the duration of that period – define usefully the severity of injury and offer valuable
prognostic information that the consulting neuropsychiatrist can use when commu-
nicating with patients and their families as well as other healthcare providers about
the patient’s prognosis and likely posthospital treatment and resource needs.
An฀important฀qualifier฀on฀ACRM-based฀TBI฀severity฀classification฀of฀which฀the฀
consulting neuropsychiatrist should be aware is “complicated mild TBI” [32, 33].
This฀subtype฀of฀mild฀TBI฀is฀used฀to฀denote฀individuals฀who฀meet฀ACRM฀criteria฀
for mild TBI but whose computed tomography (CT) or magnetic resonance imaging
(MRI)฀ of฀ the฀ brain฀ demonstrates฀ abnormalities฀ consistent฀ with฀ TBI.฀ The฀ impor-
tance of noting this subtype is that the outcome of subjects with complicated mild
TBI more closely resembles that of persons with moderate TBI than those with
uncomplicated (i.e., “simple”) mild TBI; awareness of this issue will allow the
consulting neuropsychiatrist to interpret the patient’s clinical presentation more
accurately and to offer more fully informed education, counseling, and prognostic
information to patients and their families.
Neurobiology of TBI
In addition to understanding the diagnosis and implications of TBI severity, the

consulting neuropsychiatrist needs also to be familiar with the neuroanatomy, neuro-
chemistry, and typical brain–behavior relationships that inform on neuropsychiatric
outcome following TBI.
130 D.B. Arciniegas
The injurious biomechanical effects of TBI consist primarily of two general

types: contact and inertial. Contact injuries refer to those resulting from the pene-
tration of the brain by material (e.g., projectiles, bone fragments) entering the
intracranial space, as well as those injuries produced by movement of the brain
within the intracranial space that results in the brain striking or being abraded by
the inner surface of skull. The movement of the brain against the various ridges and
bony protuberances of the anterior (frontal) and middle (temporal) fossae is espe-
cially injurious to the temporal and frontal poles as well as the ventral anterior,
medial, and lateral temporal and frontal cortices (see Bigler [44] for a review of this
subject).฀In฀case฀of฀penetrating฀injuries,฀tissue฀displacement/destruction฀by฀a฀pro-
jectile, fragmentation and deposition of bone or a projectile within brain tissue, and
contamination of the intracranial space by potential infectious material on a projec-
tile or the tissues through which it passes may all contribute to brain injury. The
damage sustained in penetrating injuries is relatively focal, involving most brain
tissue in the linear path of the material penetrating the intracranial space. In non-
penetrating and penetrating contact injuries types of injuries, subarachnoid, sub-
dural,฀and/or฀epidural฀hematomas฀may฀complicate฀this฀type฀of฀injury.
Inertial forces include linear translation and rotation, which in combination
produce฀angular฀acceleration/deceleration฀forces.฀These฀forces฀strain,฀shear,฀and/or฀
compress brain tissue [45–50]. Although all these forces are potentially injurious,
strain and shear forces are tolerated particularly poorly by brain tissue and are
major contributors to TBI at all levels of severity. These forces are maximal in brain
areas฀experiencing฀high฀angular฀acceleration/deceleration฀forces฀(superficial฀>฀deep฀
tissues,฀anterior฀>฀posterior฀regions฀of฀the฀brain);฀at฀the฀junctions฀between฀tissues฀
of different densities and elasticities (i.e., gray–white junctions); and at the intrac-
ranial rotational center of mass (i.e., rostral brainstem). High-speed, long-duration
acceleration/deceleration฀ injuries฀ exert฀ their฀ greatest฀ effect฀ on฀ axonal฀ projections฀
and small blood vessels within and projecting from the brainstem, on parasagittal
cerebral white matter, on the corpus callosum, and at the superficial cortical gray–
white junctions [51], particularly in the ventral and anterior frontal and temporal
lobes (see Bigler [44] for review). In light of these patterns of neuropathology,
“diffuse axonal injury” (DAI) is probably a misnomer and is more accurately under-
stood as “multifocal,” rather than diffuse, axonal injury [51]. Although inertial
forces may play a role in the pathophysiology of penetrating TBI [52], this type of
TBI tends to be relatively stroke-like with respect to the pattern of tissue involve-
ment฀(focal฀vs.฀multifocal/diffuse),฀the฀neuropsychiatric฀problems฀it฀produces,฀and฀
long-term functional outcomes.
As reviewed in Povlishock and Katz [53], Bigler [54],฀and฀Meythaler฀et฀al.฀[51],
injurious cytotoxic processes are initiated by biomechanical injury; these processes
both add to and also complicate biomechanical injury in TBI. Injury-induced cal-
cium and magnesium dysregulation, free radical formation, and excitatory amino
acid and neurotransmitter disturbances are the principal contributors from this cyto-
toxic฀ cascade฀ to฀ neuronal฀ injury฀ and฀ cell฀ death.฀ Excitatory฀ amino฀ acid฀ excesses฀
facilitate calcium influx into neurons, resulting in neuronal depolarization, initiation
of oxidative processes, activation of proteolytic enzymes, and eventually injury to or
destruction฀of฀neurons฀and/or฀their฀axonal฀termini.฀Excitatory฀amino฀acid฀excesses฀
also overdrive glucose utilization, and oxidative metabolism, and produce poten-
tially toxic accumulations of lactate. Concurrent excess of acetylcholine also appear
to be excitotoxic and may amplify the destructive effects of excitatory amino acid
excesses and be particularly injurious to brain areas where these neurotransmitters
are densely colocated (i.e., hippocampus, frontal cortices; see Phillips and Reeves
[55], Arciniegas [56], and Arciniegas and Silver [57] for review). The effects, benign
or malignant, of acute cerebral monoaminergic (i.e., dopamine, norepinephrine, and
serotonin) excesses that are part of the cytotoxic cascade remain uncertain. All these
neurotransmitter excesses appear to wane over the first several weeks following TBI
[58, 59], although the exact time course over which these excesses abate is not char-
acterized fully. It is clear, however, that by several weeks post-TBI there is a relative
cholinergic deficit resulting from injury to ventral forebrain cholinergic nuclei and
their cortical projections [56, 57]. It is possible that TBI also results in primary or
secondary disturbances in cerebral monoaminergic, and particularly noradrenergic
and dopaminergic, systems [60], the effects of which may be modified by geneti-
cally mediated variations in catecholamine metabolism. These issues are particularly
important for the consulting neuropsychiatrist, as the types and timings of post-
traumatic neurotransmitter disturbances carry implications for pharmacotherapies
directed at cognitive, emotional, and behavioral problems during the acute rehabili-
tation period and thereafter.
In addition to biomechanical and cytotoxic injury processes, persons with TBI
who require hospitalization often experience other secondary neurological and
systemic problems, whether as a consequence of TBI or as a comorbid process, that
may complicate or exacerbate TBI. Such problems include traumatic intracerebral
hematomas, focal or diffuse cerebral edema, elevated intracranial pressure (ICP),
obstructive฀ hydrocephalus,฀ hypoxic-ischemic฀ injury,฀ intracranial/intracerebral฀
infection, and subfalcine or transtentorial herniation. These latter problems may be
fatal or, if not fatal, may compromise vascular supply in the areas of brain compres-
sion and thereby superimpose acute ischemic stroke on TBI. Additionally, systemic
medical฀complications฀such฀as฀volume฀depletion/blood฀loss,฀hypoperfusion,฀hypo-
thermia or hyperthermia, hypoxia, infection, and related problems may further
complicate TBI. Aggressive treatment directed at these problems during acute care
and, when necessary, in the acute rehabilitation period, therefore is essential.
Brain–Behavior Relationships and TBI
As noted in the prior section of this chapter, TBI disproportionately affects the
anterior and ventral aspects of the frontal and temporal lobes, medial frontal and
temporal areas, ventral forebrain, the diencephalon (thalamus, hypothalamus), the
rostral and ventral areas of the upper brainstem, and the white matter within and
between these areas [44, 53, 54, 61, 62]. Injury to these neuropsychiatrically salient
areas produces typical, but not invariate, patterns of posttraumatic neuropsychiatric
132 D.B. Arciniegas
Table 2 Brain–behavior relationships relevant to understanding the neurobehavioral sequelae of

TBI commonly encountered in the acute rehabilitation setting
Structure injured Neuropsychiatric consequence
Upper brainstem
Reticulothalamic systems Loss or impairment of consciousness caused by
rotational฀strain/shear฀on฀ascending฀reticular฀
activating system (ARAS) and ACh
Reticulocortical system Acute and functionally disruptive GLU, ACh,
DA,฀NE,฀5HT
Ventral forebrain (cholinergic nuclei 1–4) Acute and functionally disruptive AChChronic
and functionally impairing ACh
Cerebral white matter Slowed and inefficient information processing
Medial฀temporal฀areas
฀ ฀Entrorhinal-hippocampal฀complex Impaired sensory gating, attention, working
memory, and declarative memory
Amygdala Affective placidity, Klüver–Bucy-like syndromes
Anterior temporal cortices Impaired sensory-limbic integration (cortical),
declarative memory (uncinate fasciculus)
Ventral (orbital) prefrontal cortices Behavioral dyscontrol (e.g., impulsivity,
disinhibition, irritability, agitation,
aggression)
Medial฀prefrontal฀(cingulate)฀cortex Decreased goal-directed cognition, emotion, and
behavior (apathy)
Inferior (inferolateral) prefrontal cortex Impaired working memory
Dorsolateral prefrontal cortex Impaired executive function, including executive
control of other basic cognitive functions
disturbances in the acute and subacute postinjury periods (Table 2). These patterns
of neuropsychiatric disturbances evolve in the days to weeks following TBI and are
subsumed฀under฀the฀heading฀of฀PTE฀[25].
Posttraumatic Encephalopathy
Posttraumatic฀encephalopathy฀(PTE)฀is฀characterized฀by฀five฀stages:฀posttraumatic฀
coma, posttraumatic delirium, PTA, posttraumatic dysexecutive syndrome, and
recovery (Fig. 1). These stages are named according to the most salient (although
clearly not the only) neurobehavioral feature of the clinical presentation. During
posttraumatic coma, the most salient feature of the patient’s presentation is complete
impairment of arousal. The transition from posttraumatic coma to posttraumatic
delirium is marked by the return of wakefulness (arousal), albeit sometimes in a
fluctuating manner, and marked impairments in selective, sustained, and other aspects
of attention; in the parlance of the American Psychiatric Association’s Diagnostic
and฀Statistic฀Manual,฀Fourth฀Edition,฀Text฀Revised฀[63], “reduced clarity of aware-
ness of the environment.” Although posttraumatic delirium also entails other distur-
bances in cognition, emotion, and behavior, profound inattention is the most salient
and฀characteristic฀feature฀of฀this฀stage฀of฀PTE.
TBI
Brief
LOC, Posttraumatic Dysexecutive Syndrome to recovery...
PTA,
or Mild TBI
altered Posttraumatic Dysexecutive Syndrome to recovery...
mentation
Moderate TBI
Severe TBI
Posttraumatic Amnesia
Posttraumatic
Dysexecutive
Syndrome to
recovery...
Posttraumatic Delirium
Functional Cognition
Posttraumatic Amnesia
Posttraumatic
Coma
Posttraumatic Delirium
Posttraumatic Coma
Time
Neuropsychiatric Assessment of Traumatic Brain Injury During Acute Neurorehabilitation
Fig. 1 Typical฀course฀of฀recovery฀through฀the฀stages฀of฀posttraumatic฀encephalopathy฀(PTE)฀following฀mild,฀moderate,฀and฀severe฀traumatic฀brain฀injury.฀TBI
traumatic brain injury; LOC loss of consciousness; PTA posttraumatic amnesia
133
134 D.B. Arciniegas
As the patient emerges from this stage, basic selective and sustained attention
improve markedly; as a consequence, the patient’s striking and dense impairment in
declarative new learning becomes the most salient feature of the clinical presenta-
tion, and marks the patient’s transition into PTA. As with posttraumatic delirium,
the period of PTA also entails impairments in other aspects of cognition, especially
executive function and executive control of attention, language, memory, and
praxis. The patient is regarded as “in PTA” until his or her declarative new learning
improves to the point that he or she is able to construct a reasonably continuous
narrative of daily events from that point forward (formal criteria for emergence
from PTA using the GOAT or O-Log are described in the next section of this chap-
ter). The interval between onset of injury and subsequent recovery of declarative
new learning defines the duration of PTA.
Unfortunately, the measured period of PTA duration is sometimes misunder-
stood as suggesting that the entire period measured is first and foremost character-
ized by impaired declarative new learning (i.e., amnesia); this clearly is not the
case. It is important to be clear that although the formally measured duration of
PTA necessarily encompasses posttraumatic coma, posttraumatic delirium, and
(by some accounts) any preinjury period of retrograde amnesia, neither the con-
cept of PTA nor its clinical manifestations are synonymous with posttraumatic
delirium or, more obviously, posttraumatic coma. It is true that declarative new
learning฀is฀impaired฀in฀these฀earlier฀stages฀of฀PTE;฀however,฀each฀of฀these฀entails฀
other, and more salient, cognitive impairments. Nonetheless, duration of PTA as
defined and used in the TBI literature is useful for both TBI severity characteriza-
tion as well as a predictor of TBI outcomes and is, in this author’s view, the most
useful฀of฀the฀early฀stages฀of฀PTE฀to฀measure฀assiduously฀when฀offering฀prognoses฀
to patients, their families, and other rehabilitation clinicians.
Upon emergence from PTA, impairments of executive function are the most
salient฀feature฀of฀the฀clinical฀presentation;฀accordingly,฀this฀stage฀of฀PTE฀is฀referred฀
to as the posttraumatic dysexecutive syndrome. Common clinical features of this
syndrome include impairments of intrinsic executive function (e.g., abstraction,
problem solving, the ability to generate, shift, and alter cognitive sets independent
of environmental contingencies, judgment, and insight) as well as impaired execu-
tive control of other, more basic, cognitive functions. As illustrated in Fig. 1, some
patients฀emerge฀from฀this฀stage฀of฀PTE฀into฀complete฀cognitive฀recovery฀whereas฀
for others this becomes a chronic posttraumatic neurocognitive disorder.
The฀impairments฀that฀comprise฀each฀stage฀of฀PTE฀occur฀on฀a฀continuum฀clini-
cally฀and฀temporally:฀patients฀at฀the฀transition฀between฀stages฀of฀PTE฀may฀vacillate฀
for฀days฀(or฀longer)฀between฀those฀stages.฀Nonetheless,฀identifying฀the฀stage฀of฀PTE฀
that best describes that patient is useful in that it facilitates the development of a
treatment plan which is appropriate to the patient’s current clinical status and also
allows clinicians and the patient’s family members to anticipate the course of
continued฀ recovery.฀ By฀ extension,฀ this฀ approach฀ to฀ PTE฀ also฀ helps฀ clinicians฀ to฀
identify deviations from the expected course of recovery after TBI and therefore the
need to evaluate the patient for conditions that explain such deviations.
Neuropsychiatric Evaluation of TBI in the Acute

Rehabilitation Setting
The neuropsychiatric assessment of patients with TBI begins with corroboration of

the diagnosis of TBI and entails characterization of its type and severity in the manner
described in the preceding sections of this chapter. Next, identifying the stage of
PTE฀ using฀ the฀ framework฀ described฀ above฀ is฀ essential.฀ It฀ then฀ is฀ important฀ to฀
contextualize฀ TBI฀ and฀ PTE฀ by฀ comprehensively฀ assessing฀ the฀ patient’s฀ preinjury฀
medical, neurological, psychiatric, and substance histories. It is particularly impor-
tant to obtain collateral history on these issues from reliable informants (family,
close฀friends,฀employers,฀etc.)฀because฀patients฀in฀the฀midst฀of฀PTE฀are฀frequently฀
unable to provide this information themselves. Concurrently, assessment of the
patient’s social history (e.g., level of education, developmental history, legal history,
military experience) and social supports should be obtained. This information often
identifies strengths and limitations in the patient’s personal and social contexts that
may influence long-term outcomes and community reintegration, as well as the
financial resources (or lack thereof) available to support the rehabilitation process.
The assessment then moves from history-taking to examinations, including general
physical, neurological, and neurobehavioral status examinations, as well as review
of neuroimaging and other neurodiagnostic studies.
Bedside Assessment Methods
Standardized฀ assessments฀ appropriate฀ to฀ the฀ phase฀ of฀ PTE฀ in฀ which฀ the฀ patient฀
presents facilitate accurate diagnosis and guide prognostic and therapeutic formula-
tions. Data derived from these measures may be used to gauge not only the extent
and rate of recovery but also responses to treatment.
Although it is uncommon in the United States for patients to present to rehabili-
tation settings in posttraumatic coma, presentation of patients in this and other
states of impaired arousal and awareness (i.e., with disorders of consciousness) is
not฀ uncommon฀ in฀ other฀ parts฀ of฀ the฀ world.฀ The฀ Coma/Near-Coma฀ Scale฀ [64] is
particularly useful as an assessment of coma severity and recovery.
Upon emergence from posttraumatic coma, patients enter the period of post-
traumatic delirium; at this point, it is very common for patients to be admitted to an
acute฀ inpatient฀ rehabilitation฀ hospital.฀ The฀ Delirium฀ Rating฀ Scale-Revised-98฀
(DRS-R-98)฀[65] or the Confusion Assessment Protocol (CAP) [66] are appropriate
and useful measures for the consulting neuropsychiatrist to apply to the evaluation
and monitoring of patients in posttraumatic delirium. The period of posttraumatic
delirium corresponds to levels II–V of the Rancho Los Amigos Scale (RLAS) [67].
This scale and the descriptors of these lower levels of recovery after TBI are used
frequently by rehabilitation physicians and therapists; the consulting neuropsychiatrist
136 D.B. Arciniegas
will be well served to be familiar with this scale to ensure proper interdisciplinary
communication when discussing patients in posttraumatic delirium.
Consistent with the description of RLAS levels II–V, posttraumatic delirium
generally begins as a state of impaired arousal and profound inattention (RLAS
level II). As arousal improves, inattention and behavioral disturbances (agitation)
become prominent features of the clinical presentation (RLAS levels III–IV).
As agitation remits and attentional disturbances become less problematic (RLAS
level V), patients transition into a state in which impaired declarative new learning
is the most salient clinical problem, or PTA. Identifying the point of transition
between these states may be facilitated by the use of appropriate cutoff scores from
delirium฀on฀the฀DRS-R-98฀or฀the฀CAP฀and฀continued฀impairment฀on฀measures฀of฀
PTA such as the O-Log or the GOAT [26].
With this in mind, it is useful to begin the assessment of PTA using the O-Log
or the GOAT early during the course of posttraumatic delirium. Assessment using
the O-Log of the GOAT continues until the patient meets criteria for emergence
from PTA (on two consecutive days, O-Log scores ³25 or GOAT scores ³76).฀
Although the validity of assessing orientation and memory function in the severely
delirious patient is dubious, early and daily assessment with these measures ensures
that the end of PTA will be captured accurately; as noted earlier, and as demon-
strated by our own work [29], duration of PTA offers short- and long-term prognostic
information that is useful to clinicians and also to patients and their families.
Neuropsychiatric assessment is most often undertaken when patients are in
posttraumatic delirium or PTA. Our service, which provides Behavioral Neurology
and Neuropsychiatry consultations on an acute inpatient neurorehabilitation unit,
integrates neurological and neuropsychiatric assessments to offer diagnostic and
treatment recommendations as well as guidance on rehabilitation prognosis and the
types of support and caregiving resources that are likely to be needed during these
periods฀of฀PTE฀as฀well฀as฀during฀and฀after฀subsequent฀rehabilitation฀care.฀In฀addi-
tion to elementary neurological and general mental status examinations, our
consultations include detailed examination for subtle neurological signs (SNS)
and a thorough bedside cognitive examination.
The assessment for SNS focuses on paratonia (mitgehen฀ and/or฀ gegenhalten)
and also several primitive reflexes (also known as “frontal release signs”): gla-
bellar response, snout response, suck reflex, palmomental response (left and right),
grasp response (left and right), and rooting response. These simple additions to
the neurological examination, from which we have developed a preliminary metric
referred to as the SNS score [68], yield important information regarding neurobehav-
ioral status and rehabilitation outcome: SNS score predicts raw and Z-transformed
mini-mental฀ state฀ examination฀ (MMSE)฀ and฀ frontal฀ assessment฀ battery฀ (FAB)฀
scores (all P฀<฀0.003),฀FIM฀scores฀at฀consultation฀(all฀P < 0.04), and rehabilitation
discharge (all P < 0.03), and RLOS (P < 0.0002). Accordingly, inclusion of these
items in the neuropsychiatric assessment of persons with TBI during the acute
rehabilitation period is recommended.
The bedside cognitive examination used on our service includes, among other
items,฀the฀MMSE฀[69] and FAB [70]. Because performance on these measures is
influenced strongly by the effects of age and education, our interpretation of a

patient’s฀ performance฀ on฀ them฀ is฀ normatively฀ adjusted฀ (for฀ the฀ MMSE,฀ we฀ use฀
norms developed by Crum et al. [71], and for the FAB we use norms developed by
Appollonio et al. [72]).฀After฀Z-transforming฀these฀data,฀the฀MMSE฀and,฀particu-
larly, the FAB predict functional status and rehabilitation length of stay [73]. While
other measures such as the Neurobehavioural Rating Scale – Revised [74, 75] may
also฀be฀useful,฀the฀combination฀of฀the฀MMSE฀and฀FAB฀is฀time฀efficient฀and฀unlikely฀
to overlap substantially with the assessments performed by neuropsychologists and
rehabilitation therapists concurrently assessing these patients. For these reasons, this
brief bedside battery of cognitive assessments is used in our clinical practice.
After patients emerge from PTA, neuropsychiatric assessment is most usefully
directed toward disturbances in frontally mediated cognition, emotion, and behavior;
in other words, at the posttraumatic dysexecutive syndrome. As noted previously,
we have found the FAB particularly valuable for the evaluation of the cognitive
components of this syndrome [73] but have employed other measures such as the
Executive฀ Interview฀ (EXIT)฀ [76] and the Behavioral Dyscontrol Scale (BDS)
[77, 78] as well.
Assessment of other neuropsychiatric disturbances such as depression, mania,
pathological laughing and crying, anxiety disorders, psychosis, and nondelirium-
related impulse control problems and aggression also require neuropsychiatric
assessment฀ and฀ treatment฀ during฀ PTE฀ –฀ and฀ may฀ require฀ more฀ specific฀ assess-
ment during PTA and posttraumatic dysexecutive syndrome in light of the fact that
emotional฀and฀behavioral฀disturbances฀that฀occur฀during฀these฀stages฀of฀PTE฀cannot฀
be dismissed as features of posttraumatic delirium. The Neurobehavioural Rating
Scale – Revised [74, 75] is particularly well suited to the identification of such
problems among patients able to participate in direct interview and examination.
Among patients too impaired (neurologically or neuropsychiatrically) to engage
effectively in interview and examination, assessment of posttraumatic emotional
and behavioral disturbances may be performed productively by using the Neuropsychiatric
Inventory (NPI) [79] as a guide to interviews of nursing and rehabilitation staff
familiar฀with฀the฀patient.฀Our฀group฀at฀HealthONE฀Spalding฀Rehabilitation฀Hospital฀
in Aurora, Colorado, is presently engaged in the development of an assessment
instrument modeled after the NPI and adapted specifically for the assessment of
persons with TBI in the acute neurorehabilitation setting; we expect to publish find-
ings pertaining to this project in the near future.
Neurodiagnostic Methods
There is considerable debate regarding the timing of formal neuropsychological

testing after TBI [80]. This debate generally centers around the validity of testing
before the resolution of PTA and the potential bias of premature testing (due to test
exposure) on later assessments. Recent studies [80, 81] suggest that a brief battery
composed฀ of฀ the฀ GOAT,฀ California฀ Verbal฀ Learning฀ Test-II,฀ Trail฀ Making฀ Test,฀
138 D.B. Arciniegas
Symbol฀Digit฀Modalities฀Test,฀grooved฀pegboard,฀phonemic฀and฀categorical฀word฀
generation tasks, Wechsler Test of Adult Reading, and Wisconsin Card Sorting
Test-64 may be a useful and practical brief neuropsychological assessment battery
in the inpatient neurorehabilitation setting. Additionally, this battery – and, more
specifically,฀ its฀ Weschler฀ Test฀ of฀ Adult฀ Reading฀ and฀ Trail฀ Making฀ Test-Part฀ B฀
components – are significant predictors of 1-year outcome after TBI as measured
by the Disability Rating Scale, Supervision Rating Scale, and Glasgow Outcome
Scale-Extended฀ [81]. When it is feasible to obtain neuropsychological testing of
this type in the acute neurorehabilitation setting, it is advisable to do so as a comple-
ment to other data obtained during the neuropsychiatric assessment.
Structural neuroimaging is an integral component of the neuropsychiatric assess-
ment of patients receiving acute neurorehabilitation after TBI. In many (perhaps
most) cases, CT of the brain will be performed in the acute care setting; unfortunately,
CT is sensitive to gross abnormalities (i.e., skull fracture, acute hemorrhage or hem-
orrhagic contusion, severe DAI) but its value is generally limited to cases in which
very฀severe฀injuries฀were฀sustained.฀MRI฀of฀the฀brain฀is฀frequently฀more฀useful฀as฀a฀
neuroimaging guide to the severity of TBI; as a tool with which to determine the cor-
respondence฀ between฀ bedside฀ examination-identified฀ neurological/neuropsychiatric฀
problems and neuroimaging abnormalities; and as a guide to prognosis and treatment
planning. For example, ventral prefrontal cortical and white matter injury is a rela-
tively common consequence of severe TBI (see Table 2) and frequently is associated
with฀ impulsive,฀ disinhibited,฀ and/or฀ aggressive฀ behavior.฀ MR฀ evidence฀ of฀ overtly฀
destructive damage (i.e., traumatic ablation) to these structures influences the selec-
tion of pharmacologic agents directed at these behaviors: selective serotonin reuptake
inhibitors, anticonvulsants, or atypical antipsychotics suppressing brain (limbic) areas
driving these behaviors is likely to be more useful than are agents (e.g., stimulants or
cholinesterase inhibitors) intended to augment the function of the ventral prefrontal-
subcortical circuit. Accordingly, we recommend obtaining (or reviewing one previ-
ously฀ obtained)฀ an฀ MRI฀ of฀ the฀ brain฀ in฀ all฀ neurorehabilitation฀ inpatients฀ receiving฀
neuropsychiatric฀assessment฀after฀TBI.฀When฀MRI฀is฀performed,฀T1, fluid-attenuated
inversion recovery (FLAIR), T2* gradient echo, susceptibility-weighted, and diffu-
sion-weighted sequences are the most useful sequences to obtain [82].
Electroencephalography฀ (EEG),฀ including฀ evoked฀ potentials,฀ event-related฀
potentials,฀and฀quantitative฀EEG฀(qEEG),฀does฀not฀usually฀contribute฀usefully฀to฀the฀
neuropsychiatric assessment of patients undergoing acute neurorehabilitation after
TBI [83]. When clinical history suggests the possibility of seizures (particularly
complex partial seizures with post-ictal confusion or behavioral disturbances), then
it฀is฀appropriate฀to฀obtain฀EEG฀to฀identify฀potentially฀epileptiform฀abnormalities.฀
However,฀it฀is฀important฀to฀remain฀mindful฀that฀interictal฀EEG฀is฀relatively฀insensi-
tive to epileptiform abnormalities and that the decision to treat patients for post-
traumatic seizures rests on the event semiology and not on the presence or absence
of electroencephalographic abnormalities.
The literature guiding the selection of laboratory assessments relevant to the neurop-
sychiatric assessment in the acute neurorehabilitation setting is underdeveloped.
It฀is฀reasonable฀and฀appropriate฀to฀review฀and/or฀obtain฀laboratory฀data฀(including฀
serum and urine studies) that may inform on contributors to, or alternate explana-
tions for, delirium and cognitive impairments experienced by persons with TBI.
Recent reviews suggest that neuroendocrine disturbances are common and under-
diagnosed in this population [84]; other than assessment of thyroid-stimulating
hormone and thyroid hormone levels, however, the optimal methods for assessing
and treating other posttraumatic neuroendocrine disturbances remains uncertain.
Review of Concurrently Prescribed Treatments
An essential component of the neuropsychiatric assessment of persons with TBI

receiving acute neurorehabilitation services is a review of pharmacologic treat-
ments that may be causing or contributing to neurological and neuropsychiatric
problems identified during that assessment.
Treatment with anticonvulsant medications is common in this population, but
this requires careful consideration with respect to both benefits and adverse effects
on posttraumatic neurological and neuropsychiatric status. Persons with TBI are at
risk for the development of posttraumatic seizures [85], and these are generally
divided into two types according to the timing of their onset post injury: early
(within 1 week of injury) and late (after the first week post injury). Administration
of anticonvulsant medications (so-called seizure prophylaxis) during the first week
after TBI decreases the incidence of early posttraumatic seizures [86], although this
does not appear to reduce mortality, long-term neurological disability, or the risk of
late posttraumatic seizures [86].฀More฀important฀in฀the฀acute฀rehabilitation฀setting฀
is the now well-established finding that prophylactic administration of anticonvul-
sants after the first week post-TBI does not prevent the development of late post-
traumatic seizures, reduce short- or long-term neurological disability, or influence
post-TBI mortality [86]. Additionally, many of these agents – particularly phenytoin
[87, 88] and carbamazepine [88] – worsen cognitive and motor function in this
population. Despite its increasingly common use as an alternate “seizure prophylactic”
in this setting [89, 90], levetiracetam has not been shown to be effective for the
prophylaxis of either early or late posttraumatic seizures and is known to produce
agitation and other neurobehavioral disturbances (“psychiatric adverse events”)
[91, 92]. Valproate is less problematic with respect to its effects on cognition after
TBI [93]; accordingly, when prophylaxis against early posttraumatic seizures is
undertaken or if an anticonvulsant is used for behavior- or mood-stabilizing
purposes, valproate is preferable to phenytoin, carbamazepine, and levetiracetam
for this purpose. However, continued use of any of these or other anticonvulsants
as prophylaxis against new-onset seizures after the first week post injury (i.e., late
posttraumatic seizures) is discouraged [94].
A variety of similarly problematic medications are administered commonly to
persons with TBI during the acute hospital and inpatient neurorehabilitation phases
of฀care.฀Antagonists฀of฀type-2฀dopamine฀(D2)฀receptors฀and/or฀benzodiazepines฀are฀
used in many settings as treatments for posttraumatic delirium (particularly agitation
140 D.B. Arciniegas
and aggression) [95] and as agents with which to improve compliance with mechanical
ventilation [96]. Agents that attenuate noradrenergic function, including clonidine,
propranolol,฀ and฀ other฀ antihypertensives,฀ are฀ commonly฀ used฀ for฀ medical฀ and/or฀
behavioral purposes as well. However, dopaminergic and noradrenergic antagonists
delay neuronal recovery and impair neuronal plasticity [97–103]. Among persons
with TBI, typical antipsychotics exacerbate cognitive impairments [104] and prolong
the period of PTA [105]. Benzodiazepines are well known to impair memory and
other aspects of cognition [106] in healthy adults and among persons with TBI [107].
In light of these findings, use of agents with potent antidopaminergic, antinoradren-
ergic,฀ and/or฀ GABA-ergic฀ properties฀ is฀ best฀ avoided฀ during฀ the฀ neurorehabilitative฀
care of persons with TBI. When evaluating neuropsychiatrically patients receiving
these agents, considering their potential effects on neurological and cognitive func-
tion before making definitive diagnostic or prognostic statements is prudent.
With respect to the effects of other agents on posttraumatic neuropsychiatric func-
tion, medications possessing potent in vivo anticholinergic properties are of concern as
well. These medications are commonly prescribed for posttraumatic dizziness and
urinary incontinence. Antidepressants with potent anticholinergic properties (e.g.,
tricyclic and tetracyclic antidepressants and also paroxetine [108]) are often prescribed
by rehabilitation physicians for pain, headaches, and emotional disturbances. However,
TBI produces acute and chronic disturbances of cerebral cholinergic function [56], and
cholinergic deficits become prominent and functionally significant in many patients
over the first several weeks after TBI. As a result of these deficits, patients with TBI
are vulnerable to the adverse cognitive and behavioral effects of agents with anti-
cholinergic properties. In general, prescription of agents with potent anticholinergic
properties for persons with TBI should be avoided whenever possible.
Finally, pain and spasticity are common problems among persons with TBI,
most often as a result of injury to the head or other orthopedic or soft tissue injuries
that are sustained concurrently with TBI. Among the agents used for these prob-
lems, opiate analgesics are particularly likely to adversely affect cognitive and
neuropsychiatric function. At typical analgesic doses, these agents produce impair-
ments in memory among persons without TBI of severities comparable to those
encountered among persons in PTA [109]. These agents may exacerbate, prolong,
or mimic posttraumatic coma, posttraumatic delirium, PTA, and the posttraumatic
dysexecutive syndrome. Using the minimum necessary dose of any of these agents
for as brief a time as is feasible clinically, or, better, avoiding or eliminating these
whenever possible, is recommended.
Conclusion
TBI is a significant public health problem that produces substantial neurological

and neuropsychiatric morbidity. The biomechanical and cytotoxic processes incited
by TBI produce a predictable injury profile that involves anterior, and predominantly
ventral, frontal, and temporal cortex, frontal subcortical white matter, and midbrain
areas. Damage to these structures explains, in large part, the anatomic contributions
to the neurobehavioral sequelae of TBI, including alterations of arousal, attention,
processing speed, memory, functional communication, executive function, emotional
regulation, and behavior.
As discussed in this chapter, the period of neuropsychiatric disturbance that imme-
diately฀follows฀TBI฀is฀understood฀usefully฀as฀posttraumatic฀encephalopathy฀(PTE),฀a฀
condition with several stages through which patients proceed during recovery from
TBI. These stages include, in typical sequence, posttraumatic coma, posttraumatic
delirium, posttraumatic amnesia (PTA), posttraumatic dysexecutive syndrome, and full
recovery. Among these, duration of PTA is particularly useful to measure accurately:
duration of PTA is strongly predictive of short- and long-term neurorehabilitation
outcomes. Additionally, data developed on our neuropsychiatric consultation service
suggest that several elements of the neuropsychiatric assessment, including the number
of SNS (paratonia, primitive reflexes) and also a brief bedside neurobehavioral status
examination฀(normatively฀interpreted฀MMSE฀and฀FAB),฀yield฀data฀that฀allow฀neurop-
sychiatrists to assess functional status, functional prognosis, and rehabilitation lengths
of stay among persons with TBI receiving inpatient neurorehabilitative care.
Treatment approaches based on data yielded by the neuropsychiatric assessment
vary widely among institutions, both nationally and internationally. These treatment
issues are beyond the scope of this chapter but are well described elsewhere [57,
110–117]. Independent of specific treatment recommendations, the principles of
neuropsychiatric assessment of TBI in the neurorehabilitation setting described in this
chapter apply broadly. Well informed and equipped with this information, neuropsy-
chiatrists will contribute importantly and effectively to multidisciplinary teams work-
ing to improve the neuropsychiatric and functional outcomes of persons with TBI.
References
1.฀ Thurman฀ D,฀ Guerrero฀ J฀ (1999)฀ Trends฀ in฀ hospitalization฀ associated฀ with฀ traumatic฀ brain฀
injury.฀JAMA฀282:954–957
2.฀ Thurman฀DJ,฀Alverson฀C,฀Dunn฀KA฀et฀al฀(1999)฀Traumatic฀brain฀injury฀in฀the฀United฀States:฀
a public health perspective. J Head Trauma Rehabil 14:602–615
3.฀ Selassie฀AW,฀Zaloshnja฀E,฀Langlois฀JA฀et฀al฀(2008)฀Incidence฀of฀long-term฀disability฀follow-
ing traumatic brain injury hospitalization, United States, 2003. J Head Trauma Rehabil
23:123–131
4.฀ Levin฀HS฀(1995)฀Neurobehavioral฀outcome฀of฀closed฀head฀injury:฀implications฀for฀clinical฀
trials. J Neurotrauma 12:601–610
5.฀ severe฀head฀injury.฀Experience฀of฀the฀Traumatic฀Coma฀Data฀Bank.฀J฀Neurosurg฀73:699–709
6.฀ Rapoport฀M,฀McCauley฀S,฀Levin฀H฀et฀al฀(2002)฀The฀role฀of฀injury฀severity฀in฀neurobehavioral฀
outcome 3 months after traumatic brain injury. Neuropsychiatry Neuropsychol Behav Neurol
15:123–132
7.฀ Hart฀T,฀Whyte฀J,฀Polansky฀M฀et฀al฀(2003)฀Concordance฀of฀patient฀and฀family฀report฀of฀neurobe-
havioral฀symptoms฀at฀1฀year฀after฀traumatic฀brain฀injury.฀Arch฀Phys฀Med฀Rehabil฀84:204–213
8.฀ Kaufman฀HH,฀Levin฀HS,฀High฀WM฀Jr฀et฀al฀(1985)฀Neurobehavioral฀outcome฀after฀gunshot฀
wounds฀to฀the฀head฀in฀adult฀civilians฀and฀children.฀Neurosurgery฀(Baltim)฀16:754–758
9.฀ Dikmen฀S,฀Machamer฀J,฀Miller฀B฀et฀al฀(2001)฀Functional฀status฀examination:฀a฀new฀instru-
ment฀for฀assessing฀outcome฀in฀traumatic฀brain฀injury.฀J฀Neurotrauma฀18:127–140
142 D.B. Arciniegas
10.฀ Dikmen฀SS,฀Machamer฀JE,฀Powell฀JM฀et฀al฀(2003)฀Outcome฀3฀to฀5฀years฀after฀moderate฀to฀
severe฀traumatic฀brain฀injury.฀Arch฀Phys฀Med฀Rehabil฀84:1449–1457
11.฀ Hall฀KM,฀Bushnik฀T,฀Lakisic-Kazazic฀B฀et฀al฀(2001)฀Assessing฀traumatic฀brain฀injury฀out-
come฀ measures฀ for฀ long-term฀ follow-up฀ of฀ community-based฀ individuals.฀ Arch฀ Phys฀ Med฀
Rehabil฀82:367–374
12. Doctor JN, Castro J, Temkin NR et al (2005) Workers’ risk of unemployment after traumatic
brain฀injury:฀a฀normed฀comparison.฀J฀Int฀Neuropsychol฀Soc฀11:747–752
13.฀ Guilmette฀TJ,฀Paglia฀MF฀(2004)฀The฀public’s฀misconception฀about฀traumatic฀brain฀injury:฀a฀
follow฀up฀survey.฀Arch฀Clin฀Neuropsychol฀19:183–189
14.฀ Swift฀TL,฀Wilson฀SL฀(2001)฀Misconceptions฀about฀brain฀injury฀among฀the฀general฀public฀
and฀non-expert฀health฀professionals:฀an฀exploratory฀study.฀Brain฀Inj฀15:149–165
15.฀ Marr฀AL,฀Coronado฀VG฀(2002)฀Central฀Nervous฀System฀Injury฀Surveillance฀Data฀Submission฀
Standards – 2002
16.฀ Kraus฀JF,฀Rice฀TM,฀Peek-Asa฀C฀et฀al฀(2003)฀Facial฀trauma฀and฀the฀risk฀of฀intracranial฀injury฀
in฀motorcycle฀riders.฀Ann฀Emerg฀Med฀41:18–26
17.฀ Johnston฀JJ฀(2007)฀The฀Galasko฀report฀implemented:฀the฀role฀of฀emergency฀medicine฀in฀the฀
management฀of฀head฀injuries.฀Eur฀J฀Emerg฀Med฀14:130–133
18.฀ Palchak฀MJ,฀Holmes฀JF,฀Vance฀CW฀et฀al฀(2003)฀A฀decision฀rule฀for฀identifying฀children฀at฀
low฀risk฀for฀brain฀injuries฀after฀blunt฀head฀trauma.฀Ann฀Emerg฀Med฀42:492–506
19.฀ Borg฀ J,฀ Holm฀ L,฀ Cassidy฀ JD฀ et฀ al฀ (2004)฀ Diagnostic฀ procedures฀ in฀ mild฀ traumatic฀ brain฀
injury:฀results฀of฀the฀WHO฀Collaborating฀Centre฀Task฀Force฀on฀Mild฀Traumatic฀Brain฀Injury.฀
J฀Rehabil฀Med฀(Suppl฀43):61–75
20.฀ Teasdale฀G,฀Jennett฀B฀(1974)฀Assessment฀of฀coma฀and฀impaired฀consciousness.฀a฀practical฀
scale. Lancet 2:81–84
21.฀ Clifton฀GL,฀Hayes฀RL,฀Levin฀HS฀et฀al฀(1992)฀Outcome฀measures฀for฀clinical฀trials฀involving฀
traumatically brain-injured patients: report of a conference. Neurosurgery (Baltim)
31:975–978
22.฀ Cowen฀TD,฀Meythaler฀JM,฀Devivo฀MJ฀et฀al฀(1995)฀Influence฀of฀early฀variables฀in฀traumatic฀
brain injury on functional independence measure scores and rehabilitation length of stay and
charges.฀Arch฀Phys฀Med฀Rehabil฀76:797–803
23.฀ Gabbe฀BJ,฀Cameron฀PA,฀Finch฀CF฀(2003)฀The฀status฀of฀the฀Glasgow฀Coma฀Scale.฀Emerg฀
Med฀(Fremantle)฀15:353–360
24.฀ Russell฀ WR,฀ Smith฀ A฀ (1961)฀ Post-traumatic฀ amnesia฀ in฀ closed฀ head฀ injury.฀ Arch฀ Neurol฀
5:4–17
25.฀ Arciniegas฀ DB,฀ McAllister฀ TW฀ (2008)฀ Neurobehavioral฀ management฀ of฀ traumatic฀ brain฀
injury฀in฀the฀critical฀care฀setting.฀Crit฀Care฀Clin฀24:viii,฀737–viii,฀765
26.฀ Levin฀HS,฀O’Donnell฀VM,฀Grossman฀RG฀(1979)฀The฀Galveston฀Orientation฀and฀Amnesia฀
Test.฀ A฀ practical฀ scale฀ to฀ assess฀ cognition฀ after฀ head฀ injury.฀ J฀ Nerv฀ Ment฀ Dis฀
167:675–684
27.฀ Jackson฀WT,฀Novack฀TA,฀Dowler฀RN฀(1998)฀Effective฀serial฀measurement฀of฀cognitive฀ori-
entation฀in฀rehabilitation:฀the฀Orientation฀Log.฀Arch฀Phys฀Med฀Rehabil฀79:718–720
28. Novack TA, Dowler RN, Bush BA et al (2000) Validity of the Orientation Log, relative to
the฀Galveston฀Orientation฀and฀Amnesia฀Test.฀J฀Head฀Trauma฀Rehabil฀15:957–961
29.฀ Frey฀ KL,฀ Rojas฀ DC,฀ Anderson฀ CA฀ et฀ al฀ (2007)฀ Comparison฀ of฀ the฀ O-Log฀ and฀ GOAT฀ as฀
measures of posttraumatic amnesia. Brain Inj 21:513–520
30.฀ Kay฀ T,฀ Harrington฀ DE,฀ Adams฀ RE฀ et฀ al฀ (1993)฀ Definition฀ of฀ mild฀ traumatic฀ brain฀ injury:฀
Report฀from฀the฀Mild฀Traumatic฀Brain฀Injury฀Committee฀of฀the฀Head฀Injury฀Interdisciplinary฀
Special฀Interest฀Group฀of฀the฀American฀Congress฀of฀Rehabilitation฀Medicine.฀J฀Head฀Trauma฀
Rehabil฀8:86–87
31.฀ McMillan฀ TM,฀ Jongen฀ EL,฀ Greenwood฀ RJ฀ (1996)฀ Assessment฀ of฀ post-traumatic฀ amnesia฀
after severe closed head injury: retrospective or prospective? J Neurol Neurosurg Psychiatry
60:422–427
32.฀ Williams฀DH,฀Levin฀HS,฀Eisenberg฀HM฀(1990)฀Mild฀head฀injury฀classification.฀Neurosurgery฀
(Baltim)฀27:422–428
33.฀ van฀der฀Naalt฀J,฀Hew฀JM,฀van฀Zomeren฀AH฀et฀al฀(1999)฀Computed฀tomography฀and฀magnetic฀
resonance imaging in mild to moderate head injury: early and late imaging related to out-
come.฀Ann฀Neurol฀46:70–78
34.฀ Zafonte฀RD,฀Mann฀NR,฀Millis฀SR฀et฀al฀(1997)฀Posttraumatic฀amnesia:฀its฀relation฀to฀func-
tional฀outcome.฀Arch฀Phys฀Med฀Rehabil฀78:1103–1106
35.฀ Jennett฀ B,฀ Bond฀ M฀ (1975)฀ Assessment฀ of฀ outcome฀ after฀ severe฀ brain฀ damage.฀ Lancet฀
1:480–484
36.฀ Katz฀ DI,฀ Alexander฀ MP฀ (1994)฀ Traumatic฀ brain฀ injury.฀ Predicting฀ course฀ of฀ recovery฀ and฀
outcome฀for฀patients฀admitted฀to฀rehabilitation.฀Arch฀Neurol฀51:661–670
37.฀ Ellenberg฀JH,฀Levin฀HS,฀Saydjari฀C฀(1996)฀Posttraumatic฀amnesia฀as฀a฀predictor฀of฀outcome฀
after฀severe฀closed฀head฀injury.฀Prospective฀assessment.฀Arch฀Neurol฀53:782–791
38.฀ Brooks฀DN,฀Aughton฀ME,฀Bond฀MR฀et฀al฀(1980)฀Cognitive฀sequelae฀in฀relationship฀to฀early฀
indices of severity of brain damage after severe blunt head injury. J Neurol Neurosurg
Psychiatry฀43:529–534
39.฀ Geffen฀GM,฀Encel฀JS,฀Forrester฀GM฀(1991)฀Stages฀of฀recovery฀during฀post-traumatic฀amne-
sia and subsequent everyday memory deficits. NeuroReport 2:105–108
40.฀ Haslam฀C,฀Batchelor฀J,฀Fearnside฀MR฀et฀al฀(1994)฀Post-coma฀disturbance฀and฀post-traumatic฀
amnesia as nonlinear predictors of cognitive outcome following severe closed head injury:
findings฀from฀the฀Westmead฀Head฀Injury฀Project.฀Brain฀Inj฀8:519–528
41.฀ Sherer฀M,฀Sander฀AM,฀Nick฀TG฀et฀al฀(2002)฀Early฀cognitive฀status฀and฀productivity฀outcome฀
after฀traumatic฀brain฀injury:฀findings฀from฀the฀TBI฀model฀systems.฀Arch฀Phys฀Med฀Rehabil฀
83:183–192
42. Avesani R, Salvi L, Rigoli G et al (2005) Reintegration after severe brain injury: a retrospec-
tive฀study.฀Brain฀Inj฀19:933–939
43.฀ Doig฀ E,฀ Fleming฀ J,฀ Tooth฀ L฀ (2001)฀ Patterns฀ of฀ community฀ integration฀ 2-5฀ years฀ post-dis-
charge฀from฀brain฀injury฀rehabilitation.฀Brain฀Inj฀15:747–762
44.฀Bigler฀ED฀(2007)฀Anterior฀and฀middle฀cranial฀fossa฀in฀traumatic฀brain฀injury:฀relevant฀neu-
roanatomy and neuropathology in the study of neuropsychological outcome. Neuropsychology
21:515–531
45.฀ Sabet฀AA,฀Christoforou฀E,฀Zatlin฀B฀et฀al฀(2008)฀Deformation฀of฀the฀human฀brain฀induced฀by฀
mild฀angular฀head฀acceleration.฀J฀Biomech฀41:307–315
46.฀ Besenski฀N฀(2002)฀Traumatic฀injuries:฀imaging฀of฀head฀injuries.฀Eur฀Radiol฀12:1237–1252
47.฀ Ryan฀ GA,฀ McLean฀ AJ,฀ Vilenius฀ AT฀ et฀ al฀ (1994)฀ Brain฀ injury฀ patterns฀ in฀ fatally฀ injured฀
pedestrians.฀J฀Trauma฀36:469–476
48.฀ Misra฀JC,฀Chakravarty฀S฀(1984)฀A฀study฀of฀rotational฀brain฀injury.฀J฀Biomech฀17:459–466
49.฀ Fijalkowski฀RJ,฀Stemper฀BD,฀Pintar฀FA฀et฀al฀(2007)฀New฀rat฀model฀for฀diffuse฀brain฀injury฀
using฀coronal฀plane฀angular฀acceleration.฀J฀Neurotrauma฀24:1387–1398
50.฀ Margulies฀SS,฀Thibault฀LE,฀Gennarelli฀TA฀(1990)฀Physical฀model฀simulations฀of฀brain฀injury฀
in the primate. J Biomech 23:823–836
51.฀ Meythaler฀ JM,฀ Peduzzi฀ JD,฀ Eleftheriou฀ E฀ et฀ al฀ (2001)฀ Current฀ concepts:฀ diffuse฀ axonal฀
injury-associated฀traumatic฀brain฀injury.฀Arch฀Phys฀Med฀Rehabil฀82:1461–1471
52. Black KL, Hanks RA, Wood DL et al (2002) Blunt versus penetrating violent traumatic brain
injury: frequency and factors associated with secondary conditions and complications. J
Head฀Trauma฀Rehabil฀17:489–496
53. Povlishock JT, Katz DI (2005) Update of neuropathology and neurological recovery after
traumatic฀brain฀injury.฀J฀Head฀Trauma฀Rehabil฀20:76–94
54.฀ Bigler฀ED฀(2003)฀Neurobiology฀and฀neuropathology฀underlie฀the฀neuropsychological฀deficits฀
associated฀with฀traumatic฀brain฀injury.฀Arch฀Clin฀Neuropsychol฀18:595–621
55.฀ Phillips฀LL,฀Reeves฀TM฀(2001)฀Interactive฀pathology฀following฀traumatic฀brain฀injury฀modi-
fies฀hippocampal฀plasticity.฀Restor฀Neurol฀Neurosci฀19:213–235
56. Arciniegas DB (2003) The cholinergic hypothesis of cognitive impairment caused by trau-
matic฀brain฀injury.฀Curr฀Psychiatry฀Rep฀5:391–399
57.฀ Arciniegas฀DB,฀Silver฀JM฀(2006)฀Pharmacotherapy฀of฀posttraumatic฀cognitive฀impairments.฀
Behav฀Neurol฀17:25–42
144 D.B. Arciniegas
58.฀ Markianos฀M,฀Seretis฀A,฀Kotsou฀S฀et฀al฀(1992)฀CSF฀neurotransmitter฀metabolites฀and฀short-
term฀outcome฀of฀patients฀in฀coma฀after฀head฀injury.฀Acta฀Neurol฀Scand฀86:190–193
59.฀ Markianos฀M,฀Seretis฀A,฀Kotsou฀A฀et฀al฀(1996)฀CSF฀neurotransmitter฀metabolites฀in฀comatose฀
head฀injury฀patients฀during฀changes฀in฀their฀clinical฀state.฀Acta฀Neurochir฀(Wien฀)฀138:57–59
60.฀ McAllister฀ TW,฀ Flashman฀ LA,฀ Sparling฀ MB฀ et฀ al฀ (2004)฀ Working฀ memory฀ deficits฀ after฀
traumatic brain injury: catecholaminergic mechanisms and prospects for treatment – a
review. Brain Inj 18:331–350
61.฀ Povlishock฀JT฀(1992)฀Traumatically฀induced฀axonal฀injury:฀pathogenesis฀and฀pathobiologi-
cal implications. Brain Pathol 2:1–12
62.฀ Salmond฀ CH,฀ Chatfield฀ DA,฀ Menon฀ DK฀ et฀ al฀ (2005)฀ Cognitive฀ sequelae฀ of฀ head฀ injury:฀
involvement฀of฀basal฀forebrain฀and฀associated฀structures.฀Brain฀128:189–200
63.฀ American฀ Psychiatric฀ Association฀ (2000)฀ Diagnostic฀ and฀ Statistical฀ Manual฀ of฀ Mental฀
Disorders, Text Revision, 4th edn. American Psychiatric Association, Washington, DC
64.฀ Rappaport฀M฀(2005)฀The฀Disability฀Rating฀and฀Coma/Near-Coma฀scales฀in฀evaluating฀severe฀
head injury. Neuropsychol Rehabil 15:442–453
65.฀ Trzepacz฀ PT,฀ Mittal฀ D,฀ Torres฀ R฀ et฀ al฀ (2001)฀ Validation฀ of฀ the฀ Delirium฀ Rating฀ Scale-
Revised-98:฀comparison฀with฀the฀delirium฀rating฀scale฀and฀the฀cognitive฀test฀for฀delirium.฀
J฀Neuropsychiatry฀Clin฀Neurosci฀13:229–242
66.฀ Sherer฀ M,฀ Nakase-Thompson฀ R,฀ Yablon฀ SA฀ et฀ al฀ (2005)฀ Multidimensional฀ assessment฀ of฀
acute฀confusion฀after฀traumatic฀brain฀injury.฀Arch฀Phys฀Med฀Rehabil฀86:896–904
67.฀ Hagen฀C,฀Malkmus฀D,฀Durham฀P฀(1972)฀Rancho฀Los฀Amigos฀Scale.฀http://www.rancho.org/
patient_education/bi_cognition.pdf
68.฀ Wortzel฀HS,฀Frey฀KL,฀Anderson฀CA,฀Arciniegas฀DB฀(2009).฀Subtle฀neurological฀signs฀pre-
dict the severity of subacute cognitive and functional impairments after traumatic brain
injury. J Neuropsychiatry Clin Neurosci 21:463–466
69.฀ Folstein฀ MF,฀ Folstein฀ SE,฀ McHugh฀ PR฀ (1975)฀ Mini-mental฀ state:฀ a฀ practical฀ method฀ for฀
grading฀the฀cognitive฀state฀of฀patients฀for฀the฀clinician.฀J฀Psychiatry฀Res฀12:189–198
70.฀ Dubois฀ B,฀ Slachevsky฀ A,฀ Litvan฀ I฀ et฀ al฀ (2000)฀ The฀ FAB:฀ a฀ frontal฀ assessment฀ battery฀ at฀
bedside. Neurology 55:1621–1626
71.฀ Crum฀RM,฀Anthony฀JC,฀Bassett฀SS฀et฀al฀(1993)฀Population-based฀norms฀for฀the฀mini-mental฀
state฀examination฀by฀age฀and฀education฀level.฀JAMA฀269:2386–2391
72.฀ Appollonio฀I,฀Leone฀M,฀Isella฀V฀et฀al฀(2005)฀The฀frontal฀assessment฀battery฀(FAB):฀norma-
tive values in an Italian population sample. Neurol Sci 26:108–116
73.฀ Arciniegas฀DB,฀Frey฀K,฀Alderfer฀B฀et฀al฀(2006)฀Impairments฀of฀frontally-mediated฀cognition฀
characterize posttraumatic encephalopathy following resolution of posttraumatic amnesia.
J Neuropsychiatry Clin Neurosci 18:281
74.฀ Vanier฀M,฀Mazaux฀JM,฀Lambert฀J฀et฀al฀(2000)฀Assessment฀of฀neuropsychologic฀impairments฀
after head injury: interrater reliability and factorial and criterion validity of the Neurobehavioral
Rating฀Scale฀–฀Revised.฀Arch฀Phys฀Med฀Rehabil฀81:796–806
75.฀ McCauley฀SR,฀Levin฀HS,฀Vanier฀M฀et฀al฀(2001)฀The฀neurobehavioural฀rating฀scale-revised:฀sensi-
tivity฀and฀validity฀in฀closed฀head฀injury฀assessment.฀J฀Neurol฀Neurosurg฀Psychiatry฀71:643–651
76.฀ Royall฀DR,฀Mahurin฀RK,฀Gray฀KF฀(1992)฀Bedside฀assessment฀of฀executive฀cognitive฀impair-
ment: the executive interview. J Am Geriatr Soc 40:1221–1226
77.฀ Grigsby฀ J,฀ Kaye฀ K,฀ Robbins฀ LJ฀ (1992)฀ Reliabilities,฀ norms฀ and฀ factor฀ structure฀ of฀ the฀
Behavioral฀Dyscontrol฀Scale.฀Percept฀Mot฀Skills฀74:883–892
78.฀ Kaye฀K,฀Grigsby฀J,฀Robbins฀LJ฀et฀al฀(1990)฀Prediction฀of฀independent฀functioning฀and฀behavior฀
problems in geriatric patients. J Am Geriatr Soc 38:1304–1310
79.฀ Cummings฀JL,฀Mega฀M,฀Gray฀K฀et฀al฀(1994)฀The฀Neuropsychiatric฀Inventory:฀comprehen-
sive assessment of psychopathology in dementia. Neurology 44:2308–2314
80. Kalmar K, Novack TA, Nakase-Richardson R et al (2008) Feasibility of a brief neuropsycho-
logic test battery during acute inpatient rehabilitation after traumatic brain injury. Arch Phys
Med฀Rehabil฀89:942–949
81.฀ Hanks฀ RA,฀ Millis฀ SR,฀ Ricker฀ JH฀ et฀ al฀ (2008)฀ The฀ predictive฀ validity฀ of฀ a฀ brief฀ inpatient฀
neuropsychologic฀battery฀for฀persons฀with฀traumatic฀brain฀injury.฀Arch฀Phys฀Med฀Rehabil฀
89:950–957
82.฀ Akiyama฀Y,฀Miyata฀K,฀Harada฀K฀et฀al฀(2009)฀Susceptibility-weighted฀magnetic฀resonance฀
imaging for the detection of cerebral microhemorrhage in patients with traumatic brain
injury.฀Neurol฀Med฀Chir฀(Tokyo)฀49:97–99
83.฀ Arciniegas฀DB,฀Anderson฀CA,฀Rojas฀DC฀(2005)฀Electrophysiological฀techniques.฀In:฀Silver฀
JM,฀ McAllister฀ TW,฀ Yudofsky฀ SC฀ (eds)฀ Textbook฀ of฀ traumatic฀ brain฀ injury.฀ American฀
Psychiatric Publishing, Washington, DC
84.฀ Rothman฀MS,฀Arciniegas฀DB,฀Filley฀CM฀et฀al฀(2007)฀The฀neuroendocrine฀effects฀of฀trau-
matic฀brain฀injury.฀J฀Neuropsychiatry฀Clin฀Neurosci฀19:363–372
85.฀ Frey฀LC฀(2003)฀Epidemiology฀of฀posttraumatic฀epilepsy:฀a฀critical฀review.฀Epilepsia฀44(suppl฀
10):11–17
86. Schierhout G, Roberts I (2000) Anti-epileptic drugs for preventing seizures following acute
traumatic฀brain฀injury.฀Cochrane฀Database฀Syst฀Rev฀4:CD000173
87.฀ Dikmen฀SS,฀Temkin฀NR,฀Miller฀B฀et฀al฀(1991)฀Neurobehavioral฀effects฀of฀phenytoin฀prophy-
laxis฀of฀posttraumatic฀seizures.฀JAMA฀265:1271–1277
88.฀ Smith฀KR฀Jr,฀Goulding฀PM,฀Wilderman฀D฀et฀al฀(1994)฀Neurobehavioral฀effects฀of฀phenytoin฀
and carbamazepine in patients recovering from brain trauma: a comparative study. Arch
Neurol 51:653–660
89.฀ Szaflarski฀ JP,฀ Meckler฀ JM,฀ Szaflarski฀ M฀ et฀ al฀ (2007)฀ Levetiracetam฀ use฀ in฀ critically฀ ill฀
patients.฀Neurocrit฀Care฀7:140–147
90.฀ Ruegg฀S,฀Naegelin฀Y,฀Hardmeier฀M฀et฀al฀(2008)฀Intravenous฀levetiracetam:฀treatment฀experi-
ence฀with฀the฀first฀50฀critically฀ill฀patients.฀Epilepsy฀Behav฀12:477–480
91.฀ Mula฀M,฀Trimble฀MR,฀Yuen฀A฀et฀al฀(2003)฀Psychiatric฀adverse฀events฀during฀levetiracetam฀
therapy.฀Neurology฀61:704–706
92.฀ Mula฀M,฀Trimble฀MR,฀Sander฀JW฀(2004)฀Psychiatric฀adverse฀events฀in฀patients฀with฀epilepsy฀
and฀learning฀disabilities฀taking฀levetiracetam.฀Seizure฀13:55–57
93.฀ Dikmen฀SS,฀Machamer฀JE,฀Winn฀HR฀et฀al฀(2000)฀Neuropsychological฀effects฀of฀valproate฀in฀
traumatic฀brain฀injury:฀a฀randomized฀trial.฀Neurology฀54:895–902
94.฀ Marion฀ DW฀ (2006)฀ Evidenced-based฀ guidelines฀ for฀ traumatic฀ brain฀ injuries.฀ Prog฀ Neurol฀
Surg฀19:171–196
95.฀ Fugate฀ LP,฀ Spacek฀ LA,฀ Kresty฀ LA฀ et฀ al฀ (1997)฀ Measurement฀ and฀ treatment฀ of฀ agitation฀
following traumatic brain injury: II. A survey of the Brain Injury Special Interest Group of
the฀American฀Academy฀of฀Physical฀Medicine฀and฀Rehabilitation.฀Arch฀Phys฀Med฀Rehabil฀
78:924–928
96.฀Milbrandt฀EB,฀Kersten฀A,฀Kong฀L฀et฀al฀(2005)฀Haloperidol฀use฀is฀associated฀with฀
lower฀ hospital฀ mortality฀ in฀ mechanically฀ ventilated฀ patients.฀ Crit฀ Care฀ Med฀
33:226–229
97.฀ Goldstein฀LB฀(1993)฀Basic฀and฀clinical฀studies฀of฀pharmacologic฀effects฀on฀recovery฀from฀
brain฀injury.฀J฀Neural฀Transplant฀Plast฀4:175–192
98.฀ Goldstein฀ LB฀ (1999)฀ Pharmacological฀ approach฀ to฀ functional฀ reorganization:฀ the฀ role฀ of฀
norepinephrine.฀Rev฀Neurol฀(Paris)฀155:731–736
99.฀ Goldstein฀ LB฀ (2003)฀ Neuropharmacology฀ of฀ TBI-induced฀ plasticity.฀ Brain฀ Inj฀
17:685–694
100. Goldstein LB (2006) Neurotransmitters and motor activity: effects on functional recovery
after฀brain฀injury.฀NeuroRx฀3:451–457
101. Hoffman AN, Cheng JP, Zafonte RD et al (2008) Administration of haloperidol and risperi-
done after neurobehavioral testing hinders the recovery of traumatic brain injury-induced
deficits.฀Life฀Sci฀83:602–607
102.฀ Kline฀ AE,฀ Hoffman฀ AN,฀ Cheng฀ JP฀ et฀ al฀ (2008)฀ Chronic฀ administration฀ of฀ antipsychotics฀
impede behavioral recovery after experimental traumatic brain injury. Neurosci Lett
448:263–267
103.฀ Kline฀AE,฀Massucci฀JL,฀Zafonte฀RD฀et฀al฀(2007)฀Differential฀effects฀of฀single฀versus฀multiple฀
administrations of haloperidol and risperidone on functional outcome after experimental
brain฀trauma.฀Crit฀Care฀Med฀35:919–924
104.฀ Stanislav฀ SW฀ (1997)฀ Cognitive฀ effects฀ of฀ antipsychotic฀ agents฀ in฀ persons฀ with฀ traumatic฀
brain injury. Brain Inj 11:335–341
146 D.B. Arciniegas
105.฀ Rao฀ N,฀ Jellinek฀ HM,฀ Woolston฀ DC฀ (1985)฀ Agitation฀ in฀ closed฀ head฀ injury:฀ haloperidol฀
effects฀on฀rehabilitation฀outcome.฀Arch฀Phys฀Med฀Rehabil฀66:30–34
106.฀ Buffett-Jerrott฀SE,฀Stewart฀SH฀(2002)฀Cognitive฀and฀sedative฀effects฀of฀benzodiazepine฀use.฀
Curr Pharm Des 8:45–58
107.฀ Bleiberg฀J,฀Garmoe฀W,฀Cederquist฀J฀et฀al฀(1993)฀Effects฀of฀dexedrine฀on฀performance฀con-
sistency following brain injury: a double-blind placebo crossover case study. Neuropsychiatry
Neuropsychol Behav Neurol 6:245–248
108.฀ Schmitt฀JA,฀Kruizinga฀MJ,฀Riedel฀WJ฀(2001)฀Non-serotonergic฀pharmacological฀profiles฀and฀
associated cognitive effects of serotonin reuptake inhibitors. J Psychopharmacol
15:173–179
109.฀ McCarter฀RJ,฀Walton฀NH,฀Moore฀C฀et฀al฀(2007)฀PTA฀testing,฀the฀Westmead฀post฀traumatic฀
amnesia฀scale฀and฀opiate฀analgesia:฀a฀cautionary฀note.฀Brain฀Inj฀21:1393–1397
110.฀ Warden฀DL,฀Gordon฀B,฀McAllister฀TW฀et฀al฀(2006)฀Guidelines฀for฀the฀pharmacologic฀treat-
ment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma 23:1468–1501
111.฀ Cicerone฀KD,฀Dahlberg฀C,฀Kalmar฀K฀et฀al฀(2000)฀Evidence-based฀cognitive฀rehabilitation:฀
recommendations฀for฀clinical฀practice.฀Arch฀Phys฀Med฀Rehabil฀81:1596–1615
112.฀ Cicerone฀KD,฀Dahlberg฀C,฀Malec฀JF฀et฀al฀(2005)฀Evidence-based฀cognitive฀rehabilitation:฀
updated฀ review฀ of฀ the฀ literature฀ from฀ 1998฀ through฀ 2002.฀ Arch฀ Phys฀ Med฀ Rehabil฀
86:1681–1692
113.฀ Cappa฀SF,฀Benke฀T,฀Clarke฀S฀et฀al฀(2005)฀EFNS฀guidelines฀on฀cognitive฀rehabilitation:฀report฀
of฀an฀EFNS฀task฀force.฀Eur฀J฀Neurol฀12:665–680
114.฀ Cappa฀SF,฀Benke฀T,฀Clarke฀S฀et฀al฀(2003)฀EFNS฀guidelines฀on฀cognitive฀rehabilitation:฀report฀
of฀an฀EFNS฀task฀force.฀Eur฀J฀Neurol฀10:11–23
115.฀ Tate฀ RL,฀ Moseley฀ A,฀ Perdices฀ M฀ et฀ al฀ (2006)฀ Update฀ on฀ Cicerone’s฀ systematic฀ review฀ of฀
cognitive฀rehabilitation:฀the฀PsycBITE฀perspective.฀Arch฀Phys฀Med฀Rehabil฀87:446
116.฀ Cicerone฀KD,฀Mott฀T,฀Azulay฀J฀et฀al฀(2008)฀A฀randomized฀controlled฀trial฀of฀holistic฀neurop-
sychologic฀ rehabilitation฀ after฀ traumatic฀ brain฀ injury.฀ Arch฀ Phys฀ Med฀ Rehabil฀
89:2239–2249
117.฀ Cicerone฀ KD,฀ Mott฀ T,฀ Azulay฀ J฀ et฀ al฀ (2004)฀ Community฀ integration฀ and฀ satisfaction฀ with฀
functioning฀after฀intensive฀cognitive฀rehabilitation฀for฀traumatic฀brain฀injury.฀Arch฀Phys฀Med฀
Rehabil฀85:943–950
Neuropsychiatric Aspects of Vascular
Cognitive Impairment
Ingmar Skoog
Abstract Neuropsychiatric disorders such as dementia and depression are common

in the elderly. After the age of 85, the prevalence of dementia is 30%, that of depres-
sion 10%, and that of psychotic symptoms 10%. The lifetime prevalence of depression
approaches 50% in women and 25% in men. Cognitive dysfunction is common
both in depression and in individuals with psychotic symptoms, and it is the core
manifestation in dementia disorders, such as Alzheimer’s disease. Cognitive symp-
toms are also included in the criteria for major depression in the DSM-IV. There is
controversy about whether depression is a risk factor for dementia, but depression
is common in individuals with dementia. Cognitive dysfunction in elderly individuals
may also be caused by prodromal symptoms of dementia. Cerebrovascular diseases
are also common in the elderly and are related to both cognitive impairment and
depression. Vascular cognitive impairment is a term encompassing vascular causes
of cognitive impairment, including dementia. The two most common cerebrovascular
diseases are stroke and ischemic white matter lesions (WMLs). Stroke and ischemic
WMLs increase the risk for dementia and depression. The latter is a reason for the
introduction of the concept of vascular depression in the elderly. However, most
depressions in the elderly are not related to vascular disease. Adding to the complexity,
associations between cerebrovascular and neuropsychiatric disorders may also go in
the opposite direction, as several studies report that depression may increase the risk
for stroke. There is thus a complex interaction between depression, dementia, and
vascular diseases. It is important to detect neuropsychiatric syndromes in patients
with cardiovascular diseases as this has implications for their management and
prognosis. Vascular disorders and risk factors are also important to detect as they
are targets for prevention of dementia and depression.
Keywords Alzheimer’s฀disease฀•฀Cerebrovascular฀disease฀•฀Dementia฀•฀Depression฀
•฀White฀matter฀lesions
I. Skoog (*)
Neuropsychiatric Epidemiology Unit, Department of Psychiatry, Institute of Neuroscience
and Physiology, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

DOI 10.1007/978-4-431-53871-4_11, © Springer 2010
150 I. Skoog
Background
Cognitive function declines with increasing age. This decline differs between
individuals, probably as a consequence of genetic predisposition and educational
and professional background. The decline may be accelerated by different insults
to the brain, for example, cardiovascular and cerebrovascular diseases, other brain
disorders, preclinical dementia, and terminal decline. The cognitive dysfunction in
individuals with cardiovascular and cerebrovascular disease is often subsumed
under the term vascular cognitive impairment (VCI) [1]. Neuropsychiatric condi-
tions, such as Alzheimer’s disease (AD), depression, and psychotic disorders, are
also related to cognitive dysfunction, and in addition they have all been associated
with cardiovascular and cerebrovascular diseases. AD and cerebrovascular disease
often coexist in the same patient, being then labeled mixed dementia [2]. Vascular
depression is the term for coexistent depression and cerebrovascular disease [3].
Neuropsychiatric Disorders Associated

with Cognitive Impairment
Alzheimer’s Disease
The typical clinical picture of AD is dementia with insidious onset and a slowly
progressive loss of memory and other cognitive functions, such as language, visuo-
spatial abilities, executive function, orientation, praxis, and behavior. NINCDS-
ADRDA criteria [4] state that the diagnosis of probable AD requires the absence of
systemic disorders or other brain diseases that alone could account for dementia.
Clinical AD has a long preclinical phase [5, 6]. Thus, some cognitive dysfunctions
in elderly nondemented persons are caused by preclinical AD.
AD in the brain is characterized by marked neuronal and synaptic degeneration
and the presence of extensive amounts of senile plaques, neurofibrillary tangles,
and deposition of the beta-amyloid peptide in specific regions of the brain [7].
However, a large proportion of individuals who were cognitively normal before
death have numerous histopathological hallmarks of AD in the brain at autopsy
[8–11]. Several population-based neuropathological studies suggest that only
approximately 50% of individuals who fulfill neuropathological criteria for AD had
dementia or significant cognitive decline during life [8, 9, 12]. These neuropatho-
logical findings have recently been confirmed by positron emission tomography
studies using the Pittsburgh compound B to detect amyloid deposition in living
individuals [13]. In this study, 21% of normal elderly showed beta-amyloid deposi-
tion compatible with AD. Based on known figures on age-related prevalence of
dementia, this finding indicates that less than 50% of individuals with AD in the
brain show cognitive impairment during life. This finding implies that AD often
does not present with the clinical picture of dementia.
Neuropsychiatric Aspects of Vascular Cognitive Impairment 151
Depression
A depressive syndrome includes symptoms of depressed mood, tearfulness, diminished

pleasure or interest, excessive guilt feelings, low self-esteem, feelings of worthless-
ness, hopelessness, pessimism, and emotional flatness, poor appetite, weight loss,
low energy or increased fatigue, sleep problems, poor concentration, difficulty
making decisions, intellectual problems, psychomotor retardation or agitation,
reduced talkativeness, and suicidal ideations [14].
Most cross-sectional studies report that the prevalence of depression is around
10% [15–24], with higher prevalence in women than in men. The lifetime preva-
lence of depression in persons reaching the age of 85 is 45% in women and 23% in
men [25]. Cognitive symptoms are one of the core symptoms of major depression
according to DSM-IV [14]. In line with this, population studies show that nonde-
mented individuals with depression perform worse on cognitive testing [26].
Whether depression also increases the risk for later development of dementia is not
clear. Three prospective population studies did not find an increased rate of depres-
sion before the onset of dementia [27–30]. In contrast, a meta-analysis including
22 studies suggested that depression increased the risk for later development of
dementia [31]. However, this meta-analysis included a mixture of population-based
studies and studies from memory clinics, which made it difficult to evaluate whether
depression increases risk for dementia in cognitively intact individuals from the
general population.
Psychotic Symptoms
Psychotic symptoms, such as hallucinations and delusions, are common in

demented elderly [32–34] but are reported to be uncommon in the nondemented
elderly. However, these symptoms may be underrated in traditional epidemiological
studies, which generally rely on self-reports. We examined psychotic symptoms in
85-year-olds using several sources of information, including self-report, key-informant
interviews, and medical record reviews [35], and found that 10% of nondemented
85-year-olds had psychotic symptoms and 7% had paranoid ideation during the
preceding year. Hallucinations were found in 7% and delusions in 6%. These figures
were considerable higher than findings that had been reported previously in the
nondemented elderly. With the same method, we also found high rates in nonde-
mented 95-year-olds [36], whereas the prevalence was considerably lower in
70-year-olds [37]. Nondemented 85-year-olds with psychotic symptoms or para-
noid ideation performed worse on psychometric tests measuring verbal ability,
inductive logical reasoning/problem solving, and tests of spatial ability [38].
Hallucinations, delusions, and paranoid ideation at age 85 were each related to an
increased incidence of dementia from age 85 to 88 years, but only one-third of
those with these symptoms developed dementia [35]. Paranoid ideation was associ-
ated with myocardial infarction in this study.
152 I. Skoog
Cerebrovascular Diseases Associated with Cognitive

Impairment and Neuropsychiatric Conditions
Many different cerebrovascular diseases have been related to cognitive decline,

dementia, and other neuropsychiatric conditions. These cerebrovascular disorders
include stroke, silent infarcts, ischemic white matter lesions (WMLs), hereditary
cerebral hemorrhage with amyloidosis, granular cortical atrophy, hypertensive
encephalopathy, cerebral amyloid angiopathy, and cerebral vasculitis [39]. Most
often there is a mixture of different cerebrovascular changes, which could be
expected as different cerebrovascular diseases share similar risk factors. The two
most common cerebrovascular diseases are stroke and ischemic WMLs.
Cerebrovascular disorders are generally believed to be the second most common
cause of dementia, after AD. Dementia caused by cerebrovascular disease is often
labeled vascular dementia (VaD). AD and cerebrovascular disease often coexist
in the same patient. This condition is termed mixed dementia [2]. Cerebrovascular
disorders are also associated with cognitive decline that does not reach the diagnostic
threshold for dementia [40–44]. The term VCI was introduced by Bowler and
Hachinski [1] to capture the whole range of cognitive dysfunction associated with
vascular disease. This term thus includes VaD, mixed dementia, and other forms of
cognitive decline caused by cerebrovascular and cardiovascular diseases.
Cerebrovascular diseases have also been associated with other neuropsychiatric
manifestations, mainly depression
It is important to recognize that cognitive impairment and neuropsychiatric
conditions associated with cerebrovascular or cardiovascular disorders are poten-
tially preventable or treatable.
Stroke
Stroke patients typically have history of stroke or transit ischemic attacks (TIA),
including acute focal neurological symptoms and signs, such as hemiparesis or
acute aphasia [39]. The symptoms must be present for 24 h or more for a diagnosis
of stroke. If they are present for a shorter duration, a diagnosis of TIA is given. The
cerebral infarcts are most often caused by thromboembolism from extracranial
arteries and the heart and are often related to large vessel disease. Other cardiovas-
cular manifestations, including myocardial infarction and hypertension, are common
in the patients. The most important risk factors for stroke are hypertension, diabetes
mellitus, atherosclerosis, atrial fibrillation, smoking, overweight, and hypercholes-
terolemia, especially high levels of low-density lipoprotein cholesterol [45]. All these
risk factors are potentially preventable or treatable.
Most epidemiological studies report an increased frequency of dementia in indi-
viduals with stroke. In the studies by Tatemichi et al. [46–48], relatively young
individuals with ischemic stroke had at least nine times greater risk for dementia
than stroke-free controls. Those persons with dementia after stroke had a higher
mortality rate and worse prognosis than those without dementia, which was inde-
pendent of stroke severity. Also, Pohjasvaara et al. [49] reported an increased
prevalence of dementia in stroke victims, as well as a decrease in independent living
for those with dementia. Lindén et al. [44] reported that stroke victims aged above
70 had an odds ratio of 4.7 for dementia. The odds for dementia was higher in those
aged 70 to 80 [odds ratio (OR), 6.7] than in those aged over 80 years, but the
frequency of dementia after stroke was higher after age 80 (34% vs. 18%). In addition,
60% of nondemented stroke victims had some cognitive dysfunction, showing that
very few elderly stroke victims are free from cognitive disturbances. In a population
study on 85-year-olds, Liebetrau et al. [50] reported that the odds ratio for dementia
in stroke was 4.3 and the prevalence of dementia after stroke was 57%. It may be that
the increased risk for dementia with stroke decreases with age at the same time as the
prevalence increases, both among those with and those without a history of stroke.
The pathogenesis of stroke-related dementia is not settled. The main hypothesis
is that dementia is related to the location or the volume of the infarcts, but there are
also other possibilities. The risk factors for dementia in individuals with stroke can be
divided into stroke-related and non-stroke-related factors [51]. The stroke-related
factors are similar to those in stroke, such as male sex, hypertension, diabetes
mellitus, smoking, and cardiac diseases. Non-stroke-related risk factors are similar
to those found in sporadic AD and include higher age, lower level of formal education,
family history of dementia, and the presence of cerebral atrophy. This combination of
risk factors supports the view that stroke-related dementia often is a consequence
of both stroke and preexisting AD pathology. According to neuropathological studies,
pure VAD, without any AD brain changes, is rare [52].
Stroke is an essential part of most criteria for VaD or VCI. The typical clinical
course of stroke-related dementia is sudden onset, stepwise deterioration, and a fluctu-
ating course. In the early stages, the cognitive symptoms may vary between individuals
depending on the site of the lesions. A large proportion of patients with cerebrovas-
cular disease have a gradual onset of dementia with a slowly progressive course [53],
with or without focal signs or infarcts on brain imaging, which makes it difficult to
differentiate from AD or other types of dementia. Changing risk factor patterns
(e.g., decrease in the frequency of smoking, better treatment of hypertension) have
decreased the incidence of stroke and may thus decrease the frequency of VaD. On the
other hand, more individuals survive after stroke, which may act in the opposite direc-
tion. It is not yet known if the prevalence or incidence of VaD increases or decreases.
The associations may also go in the opposite direction, as individuals with cognitive
impairment may be at increased risk for stroke and cerebral infarction. Three studies
[54–56] reported that elderly individuals with decreased cognitive ability and without
previous stroke at baseline were at increased risk for later incidents of stroke. In addi-
tion, one of these studies reported that also mild dementia at baseline was associated
with an increased incidence of new strokes [56]. One reason may be that these indi-
viduals already had silent cerebrovascular disease, such as silent infarcts or WMLs.
Depression is common after stroke [57], both in the acute [58], subacute [59–61],
and long-term perspective [62–64]. The frequency estimates varies from 25% to
154 I. Skoog
48% in the acute stage, from 14% to 50% at 1–12 months after stroke, and from
12% to 42% after a year or more following stroke [62]. In the study by Linden et al.
[62], stroke was related to an odds ratio (OR) for depression of 3.2 in women and
4.0 in men 1.5 years after the index stroke. A systematic review from 51 observa-
tional studies [65, 66] found a pooled estimate of 33% for depression after stroke.
Depression is important to detect in stroke patients, as it has been associated with
worse outcome in numerous studies [67–69]. Depressed stroke patients have more
cognitive impairments [61], spend more days in hospital [70], utilize more care, and
are more often institutionalized than the nondepressed [71]. The etiology of depres-
sion after stroke is debated. Some authors suggest biological factors, such as
disruption of frontostriatal [72] or left-sided prefrontosubcortical pathways [73], or
infarcts in strategic locations, such as right hemisphere strokes [74]. However, a
meta-analysis found no consistent location of infarcts to be associated with depres-
sion after stroke [75]. Others suggest that depression could be a reaction to disability
and loss of autonomy after stroke [76]. However, frequency of depression is increased
after stroke, also when controlling for stroke severity and disability [62].
Also, this association may go in the opposite direction, as several studies have
shown that depression increases the risk for first incidence stroke [77–79]. Reasons
include that depression has been associated with risk factors for stroke, such as
myocardial arrhythmia [80], increased platelet activation [81] and increased insulin
resistance [82]. However, in the study by Liebetrau et al. [78], depression was
related to lower diastolic blood pressure, and not to any other vascular factors.
Another explanation may be that late-life depression has been suggested to be
related to silent cerebrovascular diseases, such as ischemic WMLs, which may
increase the incidence of stroke.
Silent Infarcts
Cerebral infarcts often occur without focal symptoms. The frequency of these silent
infarcts increases with age [83]. These lesions were until recently believed to be
benign incidental findings on brain imaging. It has now been shown that individuals
with silent infarcts are at increased risk for clinical stroke [83] and dementia [84].
Among 85-year-olds, 10% had silent infarcts on CT, and these lesions doubled the
prevalence of dementia [85]. These lesions are thus important to detect, as treatment
of vascular risk factors, such as hypertension, may decrease the risk of new strokes
and thus potentially delay the onset of dementia in these high-risk patients.
White Matter Lesions
White matter lesions (WMLs) are common in the elderly [86]. Subcortical areas of
both hemispheres are affected by marked or diffuse ischemic demyelination and
moderate loss of axons with astrogliosis and incomplete infarction. In addition,
arteriosclerotic changes with thickening of the vessel walls and narrowing of the
lumina of the small penetrating arteries and arterioles caused by hyalinization or
fibrosis are also present [87, 88].
The cause of WMLs is probably that long-standing hypertension causes lipohy-
alinosis and thickening of the vessel walls with narrowing of the lumen of the small
perforating arteries and arterioles that nourish the deep white matter [87]. It has
been suggested that the arterial changes are caused by the exposure of vessel walls
to increased pressure over time. The greater the pressure and/or lifespan, the more
likely are these changes to be present; this may be one reason for the observed
increase with age reported in most studies. Episodes of hypotension may lead to
further hypoperfusion and hypoxia-ischemia, leading to more loss of myelin in
subcortical areas. The deep white matter has few collaterals, which makes it more
vulnerable to ischemia than the cortex. Furthermore, myelin is probably more vulner-
able than axons to ischemia [89]. The cortex, the subcortical U-fibers, and corpus
callosum are thus generally well preserved [89].
The main risk factors for WMLs are high age, hypertension, and hypertension
clustering factors [90]. It was recently shown that increased diastolic blood pressure
and mean arterial pressure in midlife were related to the presence of WMLs in late life,
supporting both the theory that long-standing high blood pressure is significant and
that resistance of the smaller arteries and microvascular network is important [91].
In living individuals, WMLs can be detected on brain imaging. On computerized
tomography (CT) scans they appear as low-density areas and on magnetic reso-
nance imaging (MRI) as hyperdense areas. MRI and CT may not always capture
the same WMLs. WMLs on MRI often show no correlation with cognitive decline
and dementia and correspond to several different histological findings, for example,
état crible. WMLs on CT are most often related to cognitive impairment and
dementia and generally correspond to the histopathological picture described above
[92]. Furthermore, it has been shown that CT is better than MRI in predicting
symptomatic cerebrovascular disease in individuals with AD [93]. MRI is thus
more sensitive than CT to detect changes in the white matter but has a lower speci-
ficity in relation to neuropathological and clinical manifestations.
On CT, WMLs were found in 35% of nondemented 85-year-olds in a study
conducted in 1986–1987 [92], but a study conducted in 2000 found that 55% of
individuals aged 70–84 years had WMLs [94], illustrating that CT is becoming more
sensitive. MRI studies generally report much higher rates of WMLs than CT studies.
The Rotterdam population study [41] reported that 11% in the age strata 65–69 years,
21% in those aged 70–74 years, 27% in those aged 70–79 years, and 54% in those
aged 80–84 years had WMLs on MRI. A recent population-based neuropathological
study reported that 94% of demented subjects had WMLs [86], and another neuro-
pathological study found that 60% of individuals with AD had WMLs [88].
WMLs have been related to dementia both according to neuropathology [86, 88]
and in population-based CT studies [92], and among the nondemented it has been
related to visuo-spatial difficulties and psychomotor slowness [41, 43]. It has also
been found to be more common in individuals with AD than in individuals without
dementia [88, 92]. Investigations using CT of the brain in a population study of
156 I. Skoog
85-year-olds revealed that one-third of the nondemented and about two-thirds of the
AD patients had WMLs [92]. A similar proportion of AD patients had neuropatho-
logical evidence of ischemic WMLs when examined post mortem [88]. Based on
an autopsy study of nondemented individuals who had extensive AD neuropathol-
ogy, it was suggested that white matter degeneration precedes cortical atrophy in
AD [95]. A longitudinal population study also reported that WMLs predicted later
development of dementia [96]. Thus, WMLs seems to be strongly related to cogni-
tive decline and dementia in the elderly. It has even been suggested that individuals
with subcortical cerebrovascular disease show more decline in cognitive function
than those with cortical strokes [97].
The dementia related to WMLs often has an insidious onset and a slowly progres-
sive course [88, 97], which makes it difficult to distinguish from AD. WMLs seldom
occur as the sole cause of dementia, and the clinical picture may vary depending on
what other causes contribute to the dementia. Punctate WMLs on MRI do not prog-
ress, whereas confluent white matter abnormalities are progressive, and are thus
more malignant in the long term [98].
Ischemic WMLs are also related to late-life depression [99]. Two prospective
population-based studies using MRI report that white matter changes increase the
risk of subsequent occurrence of depression [100, 101]. In the latter study, it was
suggested that part of the relationship between white matter changes and depression
was mediated by loss of functional ability [101]. Also, cross-sectional studies
report that changes in the white matter detected with MRI are related to depression
[102]. The association between WMLs on CT and depression is less clear. Cross-
sectional studies from our group showed that WMLs on CT were associated with
dementia but not with depression [92]. WMLs in the frontal region have been asso-
ciated with depression in elderly patients [102], suggesting that WMLs disrupt the
frontostriatal circuitry and thereby lead to the development of depression. All these
findings are in line with the vascular depression hypothesis [3].
WMLs in depressed individuals may also influence outcome of depression.
It has been reported that severe WMLs on MRI predicted a shorter time to relapse
in elderly depressed individuals [103]. Furthermore, depressed individuals with
WMLs may also have a poorer response to antidepressant monotherapy than those
without WMLs [104].
Depression may also influence the development of WMLs. One recent study
reported that depression at baseline was associated with faster progression of
WMLs during follow-up [105].
Mixed Pathology
As already mentioned, only about half of individuals who fulfill neuropathological

and positron emission tomography (PET) criteria for AD are demented during life
[10, 13]. Furthermore, a considerable proportion of individuals who meet the clinical
criteria for a diagnosis of probable AD have mixed pathologies [106–108].
Concomitant cerebrovascular diseases may increase the possibility that individuals

with AD lesions in their brains will express a dementia syndrome [8, 12].
Furthermore, vascular pathology in AD may contribute to the clinical variability
in symptomatology and clinical course in individuals diagnosed with AD during
life [109]. To what extent cerebrovascular disease contributes to the clinical picture
of dementia in each individual case is impossible to determine both at clinical and
at neuropathological examination. A cerebrovascular disease may be the primary
cause of dementia in an individual, but it may also be the event that finally over-
comes the compensatory capacity of a brain that is already affected by AD pathology.
In many instances, a combination of minor pathologies related to both disorders
may cause dementia, when these minor pathologies would not have done so indi-
vidually [110]. Thus, AD and cerebrovascular disease, which for long were
regarded to be distinct and separate entities, often coexist and aggravate each other
[111]. The complexity of the diagnosis in cases with mixed pathology may be one
reason why the use of different diagnostic criteria for VaD result in substantial
differences in the proportion of demented individuals diagnosed with VAD or AD
[112–114]. The mixed cases are probably underestimated and may be the most
common cause of dementia. Their relation to depression is not known.
Conclusion
The reported association between cerebrovascular diseases and neuropsychiatric

disorders such as dementia and depression may teach us more about the pathogen-
esis of these disorders, but may also have implications for the clinical management.
It is important to search for treatable cardiovascular and cerebrovascular diseases
in the evaluation of patients with neuropsychiatric disorders, as these may influence
the expression and clinical manifestations of the disease. It is also important to
detect neuropsychiatric syndromes in patients with cardiovascular diseases as this
recognition has implications for management and prognosis and may decrease
patients’ compliance with treatment.
Vascular disorders and risk factors, which are common in the elderly, are there-
fore important targets for prevention of dementia and depression. Thus, even if they
only result in a moderately increased risk of neuropsychiatric disorders, such as
dementia and depression, they may have an immense effect on the total number of
affected individuals [115].
References
1. Bowler JV, Hachinski V (1995) Vascular cognitive impairment: a new approach to vascular
dementia. Baillieres Clin Neurol 4:357–376
2. Langa KM, Foster NL, Larson EB (2004) Mixed dementia. Emerging concepts and therapeu-
tic implications. JAMA 292:2901–2908
158 I. Skoog
3. Alexopoulos GS, Meyers BS, Young RC et al (1997) ‘Vascular depression’ hypothesis. Arch
Gen Psychiatry 54:915–922
4. McKhann G, Drachman D, Folstein M et al (1984) Clinical diagnosis of Alzheimer’s dis-
ease: Report of the NINCDS-ADRDA work group under the auspices of department of
health and human services task force on Alzheimer’s disease. Neurology 34:939–944
5. Sacuiu S, Sjögren M, Gustafson D et al (2005) Prodromal cognitive signs of dementia in
85-year-olds using four sources of information. Neurology 65:1894–1900
6. Sacuiu S, Gustafson D, Johansson B et al (2009) The pattern of cognitive symptoms predicts
time to dementia onset. Alzheimers Dement 5:199–206
7. Tomlinson B, Henderson G (1976) Some quantitative cerebral findings in normal and
demented old people. In: Terry RD (ed) Neurobiology of aging. Raven, New York
8. White L, Petrovich H, Hardman J et al (2002) Cerebrovascular pathology and dementia in
autopsied Honolulu-Asia Aging Study participants. Ann NY Acad Sci 977:9–23
9. Group N (2001) Medical Research Council Cognitive Function and Aging Study.
Pathological correlates of late-onset dementia in a multicentre, community-based population
in England and Wales. Lancet 357:169–175
10. Davies L, Wolska B, Hilbich C et al (1988) A4 amyloid protein deposition and the diagnosis
of Alzheimer’s disease: prevalence in aged brains determined by immunocytochemistry
compared with conventional neuropathologic techniques. Neurology 38:1688–1693
11. Delaère P, He Y, Fayet G et al (1993) bA4 deposits are constant in the brain of the oldest old:
an immunocytochemical study of 20 French centenarians. Neurobiol Aging 14:191–194
12. Snowdon D, Greiner L, Mortimer J et al (1997) Brain infarction and the clinical expression
of Alzheimer disease. The Nun Study. JAMA 277:813–817
13. Aizenstein HJ, Nebes RD, Saxton JA et al (2008) Frequent amyloid deposition without
significant cognitive impairment among the elderly. Arch Neurol 65:1509–1517
14. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disor-
ders, 4th edn. American Psychiatric Association, Washington, DC
15. Skoog I (2008) Mental disorders associated with aging. In: Heggenhougen K, Quah S (eds)
International encyclopedia of public health, vol 6. Academic, San Diego, pp 174–182
16. Ernst C, Angst J (1995) Depression in old age. Is there a real decrease in prevalence?
A review. Eur Arch Psychiatry Clin Neurosci 245:272–287
17. Riedel-Heller SG, Busse A, Angermeyer MC (2006) The state of mental health in old-age
across the ‘old’ European Union – a systematic review. Acta Psychiatr Scand 113:388–401
18. Skoog I, Nilsson L, Landahl S et al (1993) Mental disorders and the use of psychotropic
drugs in an 85-year-old urban population. Int Psychogeriatr 5:33–48
19. Beekman ATF, Deeg DJH, van Tilburg T et al (1995) Major and minor depression in later
life: a study of prevalence and risk factors. J Affect Disord 36:65–75
20. Ritchie K, Artero S, Beluche I et al (2004) Prevalence of DSM-IV psychiatric disorder in the
French elderly population. Br J Psychiatry 184:147–152
21. McDougall FA, Kvaal K, Matthews FE et al (2007) Medical Research Council Cognitive
Function and Ageing Study. Prevalence of depression in older people in England and Wales:
the MRC CFA Study. Psychol Med 37:1787–1795
22. Steffens DC, Skoog I, Norton MC et al (2000) Prevalence of depression and its treatment in
an elderly population: the Cache County study. Arch Gen Psychiatry 57:601–607
23. Jorm AF (2000) Does old age reduce the risk of anxiety and depression? A review of epide-
miological studies across the adult life span. Psychol Med 30:11–22
24. Palsson S, Skoog I (1997) The epidemiology of affective disorders in the elderly: a review.
Int Clin Psychopharm 12(suppl 2):S3–S13
25. Palsson SP, Östling S, Skoog I (2001) The incidence of first-onset depression in a population
followed from the age of 70 to 85. Psychol Med 31:1159–1168
26. Palsson S, Johansson B, Berg S et al (2000) A population study on the influence of depres-
sion on neuropsychological functioning in 85-year-olds. Acta Psychiatr Scand
101:185–193
27. Persson G, Skoog I (1992) Subclinical dementia: relevance of cognitive and affective symp-
toms and signs. A nine year prospective study. J Geriatr Psychiatry Neurol 5:172–178
28. Copeland JRM, Davidson IA, Dewey ME et al (1992) Alzheimer’s disease, other dementias,
depression and pseudodementia: prevalence, incidence and three-year outcome in Liverpool.
Br J Psychiatry 161:230–239
29. Henderson AS, Korten AE, Jacomb PA et al (1997) The course of depression in the elderly:
a longitudinal community-based study in Australia. Psychol Med 27:119–129
30. Palsson S (2000) Population studies on depression in the elderly. Prevalence, incidence and
relation to cognitive function and dementia. Dissertation, University of Gothenburg
31. Ownby RL, Crocco E, Acevedo A et al (2006) Depression and risk for Alzheimer disease:
systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry
63:530–538
32. Skoog I (1993) The prevalence of psychotic, depressive and anxiety syndromes in demented
and non-demented 85-year-olds. Int J Geriatr Psychiatry 8:247–253
33. Savva GM, Zaccai J, Matthews FE et al (2009) Medical Research Council Cognitive
Function and Ageing Study. Prevalence, correlates and course of behavioural and psycho-
logical symptoms of dementia in the population. Br J Psychiatry 194:212–219
34. Petrovic M, Hurt C, Collins D et al (2007) Clustering of behavioural and psychological
symptoms in dementia (BPSD): a European Alzheimer’s disease consortium (EADC) study.
Acta Clin Belg 62:426–432
35. Östling S, Skoog I (2002) Psychotic symptoms and paranoid ideation in a nondemented
population-based sample of the very old. Arch Gen Psychiatry 59:53–59
36. Östling S, Börjesson-Hansson A, Skoog I (2007) Psychotic symptoms and paranoid ideation
in a population-based sample of 95-year-olds. Am J Geriatr Psychiatry 15:999–1004
37. Sigström R, Skoog I, Sacuiu S et al (in press) The prevalence of psychotic symptoms and
paranoid ideation in a non-demented population sample of 70-82 year olds. Int J Geriatr
Psychiatry
38. Östling S, Johansson B, Skoog I (2004) Cognitive test performance in relation to psychotic
symptoms and paranoid ideation in non-demented 85-year-olds. Psychol Med 34:443–450
39. Skoog I (2006) Vascular dementia. In: Pathy MSJ, Sinclair AJ, Morley JE (eds) Principles
and practice of geriatric medicine, 4th edn. Wiley, Chichester, pp 1103–1110
40. Breteler MMB, Claus JJ, Grobbee DE et al (1994) Cardiovascular disease and distribution of
cognitive function in elderly people: the Rotterdam Study. BMJ 308:1604–1608
41. Breteler MMB, van Swieten JC, Bots ML et al (1994) Cerebral white matter lesions, vascular
risk factors, and cognitive function in a population-based study: the Rotterdam Study.
Neurology 44:1246–1252
42. Breteler MMB, van Amerongen NM, van Swieten JC et al (1994) Cognitive correlates of
ventricular enlargement and cerebral white matter lesions on magnetic resonance imaging.
The Rotterdam Study. Stroke 25:1109–1115
43. Skoog I, Berg S, Johansson B et al (1996) The influence of white matter lesions on neurop-
sychological functioning in demented and non-demented 85-year-olds. Acta Neurol Scand
93:142–148
44. Linden T, Skoog I, Fagerberg B et al (2004) Cognitive impairment and dementia 20 months
after stroke. Neuroepidemiology 23:45–52
45. Qiu C, Skoog I, Fratiglioni L (2002) Occurrence and determinants of Vascular Cognitive
Impairment. In: Erkinjuntti T, Gauthier S (eds) Vascular cognitive impairment. Martin
Dunitz, London, pp 61–83
46. Tatemichi TK, Desmond DW, Mayeux R et al (1992) Dementia after stroke: baseline fre-
quency, risks, and clinical features in a hospitalized cohort. Neurology 42:1185–1193
47. Tatemichi TK, Desmond DW, Paik M et al (1993) Clinical determinants of dementia related
to stroke. Ann Neurol 33:568–575
48. Tatemichi TK, Paik M, Bagiella E et al (1994) Dementia after stroke is a predictor of long-
time survival. Stroke 25:1915–1919
160 I. Skoog
49. Pohjasvaara T, Erkinjuntti T, Vataja R et al (1997) Dementia three months after stroke.
Baseline frequency and effect of different definitions of dementia in the Helsinki Stroke
Aging Memory (SAM) cohort. Stroke 28:785–792
50. Liebetrau M, Steen B, Skoog I (2003) Stroke in 85-year-olds. Prevalence, incidence, risk
factors and relation to mortality and dementia. Stroke 34:2617–2622
51. Skoog I (1998) Guest editorial. Status of risk factors for vascular dementia. Neuroepidemiology
17:2–9
52. Barker WW, Luis CA, Kashuba A et al (2002) Relative frequencies of Alzheimer disease,
Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of
Florida Brain Bank. Alzheimer Dis Assoc Disord 16:203–212
53. Fischer P, Gatterer G, Marterer A et al (1990) Course characteristics in the differentiation
of dementia of the Alzheimer type and multi-infarct dementia. Acta Psychiatr Scand
81:551–553
54. Ferrucci L, Guralnik J, Salive M et al (1996) Cognitive impairment and risk of stroke in the
older population. J Am Geriatr Soc 44:237–241
55. Gale C, Martyn C, Cooper C (1996) Cognitive impairment and mortality in a cohort of
elderly people. Br Med J 312:608–611
56. Zhu L, Fratiglioni L, Guo Z et al (2000) Incidence of stroke in relation to cognitive function
and dementia in the Kungsholmen Project. Neurology 54:2103–2107
57. Folstein MF, Maiberger R, McHugh PR (1977) Mood disorder as a specific complication of
stroke. J Neurol Neurosurg Psychiatry 40:1018–1020
58. Rao R, Jackson S, Howard R (2001) Depression in older people with mild stroke, carotid
stenosis and peripheral vascular disease: a comparison with healthy controls. Int J Geriatr
Psychiatry 16:175–183
59. Burvill PW, Johnson GA, Jamrozik KD et al (1995) Prevalence of depression after stroke:
the Perth Community Stroke Study. Br J Psychiatry 166:320–327
60. Ng KC, Chan KL, Straughan PT (1995) A study of post-stroke depression in a rehabilitative
center. Acta Psychiatr Scand 92:75–79
61. Pohjasvaara T, Leppavuori A, Siira I et al (1998) Frequency and clinical determinants of
poststroke depression. Stroke 29:2311–2317
62. Linden L, Blomstrand C, Skoog I (2007) Depressive disorders after 20 months in elderly
stroke patients. A case-control study. Stroke 38:1860–1863
63. Astrom M, Adolfsson R, Asplund K (1993) Major depression in stroke patients. A 3-year
longitudinal study. Stroke 24:976–982
64. Kauhanen ML, Korpelainen JT, Hiltunen P et al (2000) Aphasia, depression, and non-verbal
cognitive impairment in ischaemic stroke. Cerebrovasc Dis 10:455–461
65. Hackett ML, Yapa C, Parag V et al (2005) Frequency of depression after stroke: a systematic
review of observational studies. Stroke 36:1330–1340
66. Hackett ML, Anderson CS (2005) Predictors of depression after stroke: a systematic review
of observational studies. Stroke 36:2296–2301
67. Ramasubbu R, Robinson RG, Flint AJ et al (1998) Functional impairment associated with
acute poststroke depression: the Stroke Data Bank Study. J Neuropsychiatry Clin Neurosci
10:26–33
68. Schulz R, Beach SR, Ives DG et al (2000) Association between depression and mortality in
older adults: the Cardiovascular Health Study. Arch Intern Med 160:1761–1768
69. Pohjasvaara T, Vataja R, Leppavuori A et al (2001) Depression is an independent predictor
of poor long-term functional outcome post-stroke. Eur J Neurol 8:315–319
70. Schubert DS, Taylor C, Lee S et al (1992) Detection of depression in the stroke patient.
Psychosomatics 33:290–294
71. Kotila M, Numminen H, Waltimo O et al (1999) Post-stroke depression and functional recov-
ery in a population-based stroke register. The Finnstroke study. Eur J Neurol 6:309–312
72. Beblo T, Wallesch CW, Herrmann M (1999) The crucial role of frontostriatal circuits for
depressive disorders in the postacute stage after stroke. Neuropsychiatry Neuropsychol
Behav Neurol 12:236–246
73. Vataja R, Pohjasvaara T, Leppavuori A et al (2001) Magnetic resonance imaging correlates
of depression after ischemic stroke. Arch Gen Psychiatry 58:925–931
74. Starkstein SE, Robinson RG, Honig MA et al (1989) Mood changes after right-hemisphere
lesions. Br J Psychiatry 155:79–85
75. Carson AJ, MacHale S, Allen K et al (2000) Depression after stroke and lesion location: a
systematic review. Lancet 356:122–126
76. Kneebone II, Dunmore E (2000) Psychological management of post-stroke depression. Br J
Clin Psychol 39:53–65
77. Bos MJ, Lindén T, Koudstaal PJ et al (2008) Depressive symptoms and risk of stroke: the
Rotterdam Study. J Neurol Neurosurg Psychiatry 79:997–1001
78. Liebetrau M, Steen B, Skoog I (2008) Depression as a risk factor for the incidence of first-
ever stroke in 85-year-olds. Stroke 39:1960–1965
79. Salaycik KJ, Kelly-Hayes M, Beiser A et al (2007) Depressive symptoms and risk of stroke:
the Framingham Study. Stroke 38:16–21
80. Frasure-Smith N, Lesperance F, Talajic M (1995) Depression and 18-month prognosis after
myocardial infarction. Circulation 91:999–1005
81. Musselman DL, Tomer A, Manatunga AK et al (1996) Exaggerated platelet reactivity in
major depression. Am J Psychiatry 153:1313–1317
82. Okamura F, Tashiro A, Utumi A et al (2000) Insulin resistance in patients with depression and its changes
during the clinical course of depression: minimal model analysis. Metabolism 49:1255–1260
83. Vermeer SE, Koudstaal PJ, Oudkerk M et al (2002) Prevalence and risk factors of silent brain
infarcts in the population-based Rotterdam Scan Study. Stroke 33:21–25
84. Vermeer SE, Prins ND, Den Heijer T et al (2003) Silent brain infarcts and the risk of demen-
tia and cognitive decline. N Engl J Med 348:1215–1222
85. Liebetrau M, Steen B, Hamann GF et al (2004) Silent and symptomatic infarcts on cranial
computerized tomography in relation to dementia and mortality. A population-based study in
85-year-olds. Stroke 35:1816–1820
86. Fernando MS, Ince PG, on behalf of the MRC Cognitive function and Ageing Neuropathology
Study Group (2004) Vascular pathologies and cognition in a population-based cohort of
elderly people. J Neurol Sci 226:13–17
87. Román GC (1987) Senile dementia of the Binswanger type. A vascular form of dementia in
the elderly. JAMA 258:1782–1788
88. Brun A, Englund E (1986) A white matter disorder in dementia of the Alzheimer type:
A pathoanatomical study. Ann Neurol 19:253–262
89. Englund E, Brun A (1990) White matter changes in dementia of Alzheimer’s type. The dif-
ference in vulnerability between cell compartments. Histopathology (Oxf) 16:433–439
90. Skoog I, Gustafson D (2003) Hypertension, hypertension-clustering factors and Alzheimer’s
disease. Neurol Res 25:675–680
91. Guo X, Pantoni L, Simoni M et al (2009) Midlife blood pressure and late-life white matter
lesions: the Prospective Population Study of Women in Gothenburg, Sweden. Hypertension
54:57–62
92. Skoog I, Palmertz B, Andreasson L-A (1994) The prevalence of white matter lesions on
computed tomography of the brain in demented and non-demented 85-year-olds. J Geriatr
Psychiatry Neurol 7:169–175
93. Lopez OL, Becker JT, Jungreis CA et al (1995) Computed tomography–but not magnetic
resonance imaging–identified periventricular white-matter lesions predict symptomatic cere-
brovascular disease in probable Alzheimer’s disease. Arch Neurol 52:659–664
94. Simoni M, Pantoni L, Pracucci G et al (2008) Prevalence of CT-detected cerebral abnormali-
ties in an elderly Swedish population sample. Acta Neurol Scand 118:260–267
95. De la Monte S (1989) Quantitation of cerebral atrophy in preclinical and end-stage
Alzheimer’s disease. Ann Neurol 25:450–459
96. Prins ND, van Dijk EJ, den Heijer T et al (2004) Cerebral white matter lesions and the risk
of dementia. Arch Neurol 61:1531–1534
97. Gunstad J, Brickman AM, Paul RH et al (2005) Progressive morphometric and cognitive
changes in vascular dementia. Arch Clin Neuropsychol 20:229–241
98. Schmidt R, Enzinger C, Ropele S et al (2003) Austrian Stroke Prevention Study. Progression
of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study.
Lancet 361:2046–2048
162 I. Skoog
99. Herrmann LL, Le Masurier M, Ebmeier KP (2008) White matter hyperintensities in late life
depression: a systematic review. J Neurol Neurosurg Psychiatry 79:619–624
100. Steffens DC, Krishnan KR, Crump C et al (2002) Cerebrovascular disease and evolution of
depressive symptoms in the cardiovascular health study. Stroke 33:1636–1644
101. Teodorczuk A, Firbank MJ, Pantoni L et al (2009) Relationship between baseline white-
matter changes and development of late-life depressive symptoms: 3-year results from the
LADIS study. Psychol Med 12:1–8
102. Greenwald BS, Kramer-Ginsberg E, Krishnan KR et al (1998) Neuroanatomic localization
of magnetic resonance imaging signal hyperintensities in geriatric depression. Stroke
29:613–617
103. O’Brien J, Ames D, Chiu E et al (1998) Severe deep white matter lesions and outcome in
elderly patients with major depressive disorder: follow up study. BMJ 317:982–984
104. Simpson S, Baldwin RC, Jackson A et al (1998) Is subcortical disease associated with a poor
response to antidepressants? Neurological, neuropsychological and neuroradiological find-
ings in late-life depression. Psychol Med 28:1015–1026
105. Chen PS, McQuoid DR, Payne ME et al (2006) White matter and subcortical gray matter
lesion volume changes and late-life depression outcome: a 4-year magnetic resonance imag-
ing study. Int Psychogeriatr 18:445–456
106. Lim A, Tsuang D, Kukull W et al (1999) Clinico-neuropathological correlation of Alzheimer’s
disease in a community-based case series. J Am Geriatr Soc 47:564–569
107. Nagy Z, Esiri M, Jobst K et al (1997) The effects of additional pathology on the cognitive
deficit in Alzheimer disease. J Neuropathol Exp Neurol 56:165–170
108. Heyman A, Fillenbaum G, Welsh-Bohmer K et al (1998) Cerebral infarcts in patients with
autopsy-proven Alzheimer’s disease: CERAD, part XVIII. Consortium to Establish a
Registry for Alzheimer’s Disease. Neurology 51:159–162
109. Etiene D, Kraft J, Ganju N et al (1998) Cerebrovascular pathology contributes to the hetero-
geneity of Alzheimer’s disease. J Alzheimers Dis 1:119–134
110. Erkinjuntti T, Hachinski V (1993) Dementia post stroke. In: Teasell R (ed) Physical medicine
and rehabilitation: state of the art reviews, vol 7. Hanley & Belfus, Philadelphia, pp 195–212
111. Pasquier F, Leys D (1997) Why are stroke patients prone to develop dementia? J Neurol
244:135–142
112. Skoog I, Nilsson L, Palmertz B et al (1993) A population-based study of dementia in
85-year-olds [see comments]. N Engl J Med 328:153–158
113. Wetterling T, Kanitz R-D, Borgis K-J (1996) Comparison of different diagnostic criteria for
vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN). Stroke 27:30–36
114. Amar K, Wilcock G, Scott M (1996) The diagnosis of vascular dementia in the light of the
new criteria. Age Ageing 25:51–55
115. Skoog I, Gustafson D (2006) Lessons learned from primary prevention trials in dementia. In:
Rockwood K, Gauthier S (eds) Trial designs and outcomes in dementia therapeutic research.
Taylor & Francis, Abingdon, pp 189–211
Neuropsychiatric Complications
of Cerebrovascular Disease
Moises Gaviria and Rhonda DePaul Verzal
Abstract This rendition delves into several of the neuropsychiatric manifestations

of cerebrovascular events, including mania, anxiety, apathy, disturbance of the
sleep –wake cycle, fatigue, sexual dysfunction, cognitive impairment, empathic
impairment, theory of mind, social-emotional dysfunction, involuntary emotional
expression disorder, irritability, psychosis, agitation, and depression. The focus is
on the manifestations of these presentations for proper diagnosis, as well as the
lesion localization particular to the respective symptomatology. Furthermore, the hope
is that this contribution allows for a greater awareness regarding the complications
of stroke and brings attention to the sequelae from which its victims suffer.
Keywords Cerebrovascular฀ disease฀ •฀ Involuntary฀ emotional฀ expression฀ disorder฀

•฀Neuropsychiatric฀complications฀•฀Stroke฀•฀Theory฀of฀mind
Introduction
Stroke฀is฀the฀third฀leading฀cause฀of฀death฀in฀the฀United฀States,฀the฀second฀leading฀
cause of death worldwide, and a major cause of long-term physical and mental dis-
ability฀in฀stroke฀survivors.฀With฀estimates฀by฀the฀American฀Stroke฀Association฀of฀
750,000฀ strokes฀ occurring฀ annually฀ in฀ the฀ United฀ States,฀ there฀ are฀ likely฀ about฀
4.5 million stroke survivors in America today [1]. Additionally, economic costs of
M. Gaviria (*) and R.D. Verzal

University฀of฀Illinois฀at฀Chicago,฀1853฀West฀Polk฀Street,฀Room฀130฀CMW,฀
Mail฀Code฀784,฀Chicago,฀IL,฀60612,฀USA
M. Gaviria
Advocate฀Christ฀Medical฀Center,฀4440฀West฀95th฀Street,฀Oak฀Lawn,฀IL,฀60453,฀USA
and
14636฀Golf฀Road,฀Orland฀Park,฀IL,฀60462-7427,฀USA
R.D. Verzal
133฀Edgewater฀Drive,฀Crystal฀Lake,฀IL,฀60014,฀USA

DOI฀10.1007/978-4-431-53871-4_12,฀©฀Springer฀2010
164 M. Gaviria and R.D. Verzal
stroke฀in฀the฀United฀States฀have฀been฀estimated฀to฀be฀at฀least฀$43฀billion฀each฀year฀
[2]. A major portion of these costs are allocated toward the treatment of secondary
complications, especially disability caused by depression, cognitive impairment,
and other neuropsychiatric complications.
The symptomatology of stroke survivors is an array of comorbid symptoms,
many of which were previously assumed to be of the same etiology or interrelated.
However, given recent research among this patient population, more understanding
has been gathered regarding the individual pathogenesis for many of these complica-
tions.฀Some฀of฀the฀neuropsychiatric฀sequelae฀secondary฀to฀cerebrovascular฀disease฀
and their hypothesized mechanisms will be discussed here as the individual entities
that฀they฀are.฀It฀is฀in฀this฀way฀that฀the฀clinician฀can฀more฀closely฀examine฀each฀symp-
tom the individual patient suffers from and appropriately treat the exact cause of that
symptom rather than approaching collective complaints and applying a generalized
treatment plan. This approach may prove to be useful in the rehabilitation and treatment
of neuropsychiatric complications in stroke patients leading to historical recovery in
the quality of life of these patients and their loved ones.
Mania
Mania secondary to stroke, given its rarity and likely underdiagnosis, has limited
appearance฀throughout฀the฀neuropsychiatric฀literature.฀In฀prior฀studies฀looking฀at฀฀neu-
ropsychiatric complications following stroke, enrolled patients uncommonly suffered
from poststroke mania in comparison to other psychiatric complaints [1].฀Of฀two฀major฀
studies investigating poststroke complications, one following 700 consecutive stroke
patients [3] and another looking at 661 stroke survivors [4], only 6 patients in total
between the two studies presented with mania secondary to stroke. Additionally, in two
other฀ considerably฀ large฀ community฀ studies,฀ the฀ Oxfordshire฀ Community฀ Stroke฀
Project฀and฀the฀Perth฀Community฀Stroke฀Project,฀both฀of฀which฀were฀investigating฀the฀
prevalence of neuropsychiatric disorders following stroke, zero patients were found to
suffer from poststroke mania [1]. When witnessed, however, mania secondary to
stroke demonstrates very similar symptomatology in comparison to patients suffering
from primary mania. These frequently include elation, pressured speech, insomnia,
grandiosity, and flight of ideas with racing thoughts. Although the prognostic charac-
teristics of poststroke mania are limited, it does appear that a family history of mood
disorder is correlated with a higher risk of mania after stroke [1].
Despite the infrequency of poststroke mania, the lesion localization in patients
suffering from secondary mania is more definitively understood. Most hypotheses
related to mania and stroke location concur that right hemispheric strokes are likely
responsible฀for฀the฀manifestation฀of฀this฀symptom.฀Prior฀studies฀have฀discussed฀that฀
lesions in the right hemisphere lead to anterior limbic circuit dysfunction involving
the orbitofrontal and basotemporal cortex in addition to the head of the caudate and
dorsomedial฀ thalamic฀ nucleus.฀ It฀ has฀ been฀ hypothesized฀ that฀ a฀ more฀ generalized฀
cerebral distribution may be responsible for the rarity of this symptom, given that
both subcortical and limbic involvement is necessary for manic symptoms [1].
Neuropsychiatric฀Complications฀of฀Cerebrovascular฀Disease 165
The neuropathology of poststroke manic symptoms appears to be due to a

c฀ ontralateral฀release฀phenomenon.฀It฀is฀likely฀that฀after฀a฀right฀hemispheric฀lesion฀
there฀is฀subsequent฀activation฀of฀the฀contralateral฀left฀hemisphere.฀Both฀Starkstein฀
and Robinson, as well as Mimura et al., have discussed the concept of left hemi-
sphere release in postlesion mania [5]. This hypothesized pathogenesis originated
during a case involving a patient who suffered from acute onset of poststroke mania
after a right hemispheric infarction in the middle cerebral artery distribution. This
patient’s prestroke medical records included a single-photon emission computed
tomography฀(SPECT)฀study,฀which฀provided฀a฀postinfarction฀comparison.฀In฀evalu-
ation฀of฀these฀SPECT฀studies,฀it฀became฀evident฀that฀there฀was฀a฀definite฀pattern฀of฀
left-sided orbitofrontal hyperperfusion associated with severe right frontal hypop-
erfusion only observed during the patient’s poststroke manic episodes [5].
Given the rarity of this complication, information regarding its treatment is
limited.฀Lithium฀has฀been฀the฀most฀commonly฀used฀therapy฀for฀patients฀suffering฀
from mania secondary to stroke. However, pharmaceutical studies focused on post-
stroke mania are scarce to none, leaving only published case reports as the single
source of reference relating to its therapy. Treatment modalities discussed through-
out the literature include the use of olanzapine, carbamazepine, and valproic acid,
the last of which has demonstrated the greatest documented therapeutic results.
Filardi฀da฀Rocha฀et฀al.฀reported฀the฀use฀of฀750฀mg/day฀of฀valproic฀acid฀with฀good฀
improvement of symptomatology in their 57-year-old male patient with mania
secondary to a severe right temporal-parietal lobe stroke [6]. Because of the infre-
quency of reports investigating poststroke mania, clinicians must continue to thor-
oughly evaluate their stroke patients in order to ensure that this diagnosis is not
missed.฀ Once฀ the฀ diagnosis฀ of฀ mania฀ is฀ made,฀ much฀ benefit฀ could฀ be฀ gained฀ for฀
future stroke survivors if effective treatment options are compared and documented
by the neuropsychiatrists treating these patients.
Anxiety
The฀ DSM-IV-TR฀ criteria฀ for฀ primary฀ generalized฀ anxiety฀ disorder฀ includes฀ the฀
presence of a sustained worrying state, in addition to a minimum of three other anxiety
symptoms, such as concentration difficulties, irritability, muscle tension, sleep
disturbances, restlessness, and decreased energy, for a period of at least 6 months.
Although฀not฀as฀prevalent฀as฀poststroke฀depression฀(PSD),฀anxiety฀has฀also฀come฀to฀
be regarded as a major neuropsychiatric complication severely impacting the daily
functioning฀and฀quality฀of฀life฀of฀stroke฀survivors.฀In฀1997,฀Robinson฀reported฀a฀mean฀
prevalence฀of฀poststroke฀anxiety฀to฀be฀14.4%,฀with฀some฀studies฀reporting฀up฀to฀28%;฀
however, with improved screening and diagnosis, this value is surely more common
today [7]. Recent studies have demonstrated that patients who present with anxiety
disorder after suffering a stroke are more likely to have impairment in psychosocial
functioning฀and฀activities฀of฀daily฀living฀(AODL)฀than฀patients฀with฀generalized฀anxiety฀
disorder not suffering from cerebrovascular disease [7]. Additionally, these patients
were at a greater risk of comorbid insomnia and depression than their nonstroke
counterparts. These findings are not only significant for the increased burden of disease
on the patient but have ramifications regarding the prescribing of sleep-promoting and
anxiolytic drugs, which also contribute to further difficulty in daily functioning.
In฀contrast฀to฀studies฀investigating฀PSD,฀a฀previous฀history฀of฀migraines฀and/or฀
epilepsy before the insighting cerebrovascular event seem to increase the risk of
poststroke anxiety [7].฀In฀addition,฀anxiety฀secondary฀to฀stroke฀was฀related฀to฀the฀
following demographic and clinical factors: smoking, migraine, epilepsy, previous
mental disorders, comorbid depression and insomnia, stroke severity, and impair-
ment฀in฀psychosocial฀functioning฀and฀in฀AODL.฀Women฀also฀seem฀to฀be฀more฀likely฀
to suffer anxiety secondary to stroke than men, although reasons for this finding are
still under investigation.
Patients฀ diagnosed฀ with฀ generalized฀ anxiety฀ disorder฀ secondary฀ to฀ stroke฀
demonstrated lesion localization predominantly in the territory supplied by anterior
circulation.฀Stroke฀survivors฀who฀suffered฀a฀lesion฀in฀the฀anterior฀circulation฀demon-
strated worse scores on the anxiety scale than those survivors with lesions in the
posterior circulation [8]. This finding may support recent hypotheses that suggest a
distinction between the mechanism of poststroke anxiety and generalized anxiety.
Several฀recent฀studies฀report฀that฀although฀left฀hemispheric฀strokes฀were฀found฀
to cause comorbid depression and anxiety disorders, isolated anxiety secondary to
stroke was localized to right hemispheric lesions [5], although a more specific
lesion localization has yet to be identified.
Treatment modalities used for patients suffering from poststroke anxiety have
primarily been based on those implicated for patients with primary generalized
anxiety฀ disorder.฀ Studies฀ on฀ therapy฀ for฀ anxiety฀ secondary฀ to฀ stroke฀ are฀ limited.฀
Thus far, the recommended treatment is benzodiazepines, excluding the elderly
population given reports of significant side effects. The preferable therapeutic
modality in elderly patients who are unable to tolerate benzodiazepines are buspirone
and฀selective฀serotonin฀uptake฀inhibitors฀(SSRIs).
Apathy
Apathy can be defined as lack of emotion, feeling, or concern, not attributable to an

alteration฀in฀consciousness฀or฀cognition.฀It฀is฀prevalent฀in฀both฀the฀general฀psychi-
atric patient population, as well as in stroke survivors, with implications in the func-
tional฀recovery฀and฀rehabilitation฀of฀these฀patients.฀In฀patients฀who฀have฀suffered฀
from฀first-ever฀and/or฀recurrent฀strokes,฀there฀exists฀a฀frequency฀of฀apathy฀of฀approxi-
mately฀ 23%฀ [9]. This effect can be evaluated through the interpretation of the
Apathy฀Scale฀proposed฀by฀Starkstein฀et฀al.,฀which฀is฀a฀modified฀version฀of฀the฀apathy฀
evaluation฀scale฀originally฀designed฀by฀Marin฀et฀al.฀Interestingly,฀the฀occurrence฀of฀
depression is not significantly different when comparing patients with and without
apathy,฀ as฀ one฀ might฀ expect.฀ Poststroke฀ apathy฀ has฀ been฀ demonstrated฀ more฀ com-
monly in older patients when compared to nonapathetic stroke survivors, as well as
in those who suffered from an ischemic, rather than a hemorrhagic, stroke [10].
Symptomatic฀lesions฀have฀been฀found฀in฀even฀distribution฀bilaterally฀฀throughout฀
the brain among apathetic and nonapathetic stroke patients. Continued research is
warranted by the recurrent inconsistencies regarding lesion localization in patients
suffering from poststroke apathy. Chemerinski et al. reported a collective literature
review demonstrating the occurrence of 93 left-sided lesions, 77 right-sided
lesions, and 94 bilateral strokes resulting in secondary apathy [1].฀Several฀factors฀
that have been previously correlated with apathy following stroke include cogni-
tive฀dysfunction,฀advanced฀age,฀deficits฀in฀AODL,฀decreased฀attention฀and฀infor-
mation processing, and poor fluency [1]. When examining the functional level of
stroke survivors, apathetic patients demonstrate a significantly lower recovery
level in aspects of self-care. This aspect is of great importance when evaluating
caregiver burden and the long-term ramifications that these patients and their fami-
lies face during stroke rehabilitation.
Treatment recommendations for poststroke apathy include the use of various
stimulating antidepressants, such as fluoxetine, for first-line therapy. Additionally,
other stimulating agents, such as amphetamine, methylphenidate, selegiline, and
bupropion฀have฀been฀used฀successfully฀to฀treat฀apathy;฀however,฀only฀in฀case฀reports.฀
Recent studies have examined the role of cholinesterase inhibitors in the treatment
of apathy given the activating properties of these agents and the correlation with
poststroke apathy and cholinergic deficits [11].
Disturbance of the Sleep–Wake Cycle
Sleep฀disorders฀have฀recently฀become฀an฀area฀of฀medical฀interest฀given฀their฀significant฀
impact฀on฀a฀patient’s฀daily฀living.฀Pathology฀of฀sleep฀is฀a฀spectrum฀of฀abnormalities฀
that฀affect฀sleep฀time,฀the฀sleep฀cycle,฀and฀breathing฀and฀activity฀during฀sleep.฀One฀
example includes dyssomnias, such as insomnia and hypersomnia, in which a patient
has฀an฀alteration฀in฀the฀amount฀of฀time฀asleep฀within฀a฀given฀24-h฀period.฀On฀aver-
age,฀7–9฀h฀of฀sleep฀per฀night฀is฀considered฀adequate฀by฀the฀National฀Sleep฀Foundation฀
in฀the฀United฀States,฀although฀there฀are฀some฀normal฀variants฀that฀slightly฀deviate฀
from this amount. Chen et al. defined short-sleep duration as a night’s sleep of 6 h
or less and a long-sleep duration as more than 9 h of sleep [12].฀Other฀sleep฀disorders฀
involve disruption in the normal pattern of the sleep cycle between non-REM and
REM (rapid eye movement sleep). Abnormalities within either the amount or
cycling of the sleep cycle can consequentially lead to deficits in attention, memory,
daily functioning, an increase in accidents, and a diminishment of overall health.
In฀patients฀who฀have฀suffered฀stroke,฀the฀reduction฀in฀quality฀of฀life฀has฀evoked฀
great focus. Although the etiology of this change is multifactorial, disturbance of the
sleep–wake฀cycle฀in฀these฀patients฀appears฀to฀be฀a฀significant฀contributor.฀Long-term฀
follow-up฀ of฀ stroke฀ survivors฀ who฀ have฀ suffered฀ from฀ both฀ ischemic฀ stroke฀ and/or฀
subarachnoid hemorrhage reveals difficulty in initiation of sleep, irritability, loss of
interests, poor concentration, fatigue, and falling asleep at inappropriate times
throughout the day. Assessment of functional outcome, and therefore quality of life,
has฀been฀evaluated฀in฀stroke฀patients฀using฀the฀Rankin฀Scale,฀a฀6-point฀handicap฀scale฀
focusing on restrictions of lifestyle in coordination with polysomnographic studies.
It฀ appears฀ that฀ up฀ to฀ one-third฀ of฀ stroke฀ survivors฀ suffer฀ from฀ either฀ insomnia,฀
excessive daytime sleepiness, or both, resulting in lower values when scoring quality
of฀life.฀It฀is฀important฀to฀note฀that฀sleep฀disturbances฀caused฀by฀stroke฀must฀be฀differ-
entiated from sleep disturbances that are secondary to other neuropsychiatric compli-
cations฀of฀stroke,฀such฀as฀depression.฀For฀example,฀Schuiling฀et฀al.฀reported฀that฀sleep฀
disturbances resulting from depression are characteristically demonstrated by short-
REM sleep latency and an increased amount of REM sleep overall, whereas sleep
disturbances that do not show this pattern, but occur after stroke, are more likely a
result of the stroke alone and may secondarily lead to the initiation of sleep disturbance
depression [13].฀Landau฀et฀al.฀demonstrated฀lesion฀localization฀in฀patients฀with฀sleep฀
disturbances secondary to stroke concentrated in the right pons, followed by bilateral
pontine strokes, and then left pontine lesions [14].฀In฀patients฀diagnosed฀with฀restless฀
leg syndrome following stroke, Kim et al. demonstrated lesion topography predomi-
nantly in subcortical regions, such as the pyramidal tract and basal ganglia–brainstem
axis [15]. This result reinforces that compromise of cerebral perfusion in areas of the
brain controlling motor function and the sleep–wake cycles may result in restlessness
symptoms. Treatment modalities available for these symptoms include dopamine ago-
nists, which have delivered relatively significant relief in symptoms [15].
Fatigue
Fatigue has been known to be a common sequelae in stroke survivors, with a prevalence
ranging฀from฀38%฀to฀68%฀[16]. Treating this phenomenon has proven to be quite
challenging given the lack of established standards in its measurement and diffi-
culty in determining its exact etiology. Additionally, the diagnostician must take
into consideration other possible contributing factors associated with fatigue from
which฀numerous฀stroke฀patients฀suffer฀from฀months฀to฀years฀after฀the฀inciting฀event;฀
these include mental factors, such as depression and anxiety, but also might be
related to physical deconditioning and gross motor deficits. Because the etiology of
fatigue has proven to be so complex, it is not until recently that research has began
to control for some of these confounding factors and evaluate a more central origin
of fatigue in stroke survivors.
In฀a฀study฀investigating฀fatigue฀in฀stroke฀survivors,฀patients฀who฀suffered฀from฀
minor strokes were compared to those who experienced a transient ischemic attack
(TIA).฀While฀previous฀studies฀suggested฀that฀fatigue฀after฀stroke฀was฀attributable฀to฀
compensatory behaviors related to gross neurological deficits, the comparison used
in this study demonstrated that poststroke fatigue may be of central origin rather
than physical sequelae secondary to increased effort required after suffering a
stroke [16]. By investigating patients who suffered from minor rather than major
strokes, there were minimal to no residual neurological deficits to which secondary
poststroke fatigue might be attributable. These results were the first set of published
data investigating fatigue in relationship to stroke using this approach.
The study evaluated 149 patients: 73 status post minor stroke and 67 status post
TIA.฀Demographic฀characteristics,฀recent฀life฀events,฀vascular฀risk฀factors,฀medica-
tions, and mental and physical disabilities were all variables that were controlled
among the two patient groups. Fatigue was evaluated at 6 months after minor stroke
or฀TIA฀using฀the฀Chalder฀Fatigue฀Scale฀[17]. The results of the study demonstrated
that patients who suffered from a minor stroke had a 56% fatigue prevalence in
comparison฀to฀the฀TIA฀patients฀with฀a฀prevalence฀of฀29%.฀This฀finding฀is฀one฀that฀
should serve to motivate neuropsychiatrists and other clinicians to move toward
the consideration of a central mechanism underlying fatigue in patients who
have suffered a stroke. Additionally, collaborative efforts between researchers,
physicians, and pharmaceutical experts should investigate central-acting treatment
modalities for these patients. Treatment is mainly symptomatic, with the use of
stimulating agents, in addition to treating concurrent neuropsychiatric complaints.
Sexual Dysfunction
In฀adult฀patients,฀cerebrovascular฀disease฀causes฀greater฀secondary฀impairment฀than฀
any฀other฀major฀illness฀in฀the฀United฀States.฀Perhaps฀one฀of฀the฀most฀limited฀areas฀
of investigation among poststroke complications is that of sexual dysfunction.
Historically, the pathogenesis of sexual dysfunction was viewed as predominantly a
psychogenic฀ disorder;฀ however,฀ after฀ more฀ closely฀ investigating฀ patients฀ suffering฀
from various sexual impairments, additional hypotheses have begun to reveal them-
selves.฀Prior฀studies฀have฀demonstrated฀that฀sexual฀dysfunction฀after฀stroke฀is฀multi-
factorial,฀ with฀ both฀ organic฀ and฀ psychological฀ etiologies฀ at฀ its฀ origin.฀ Organic฀
influences on sexual function include certain comorbid medical conditions, such as
diabetes,฀hypertension,฀and฀cardiac฀disease.฀Psychosocial฀factors฀include฀loss฀of฀self-
esteem, fear of another stroke, and changes within the spousal relationship [18].
More recently, physicians have recognized that in stroke patients there likely exists
both a psychogenic and neurogenic pathophysiology to erectile dysfunction.
Although most research on sexual dysfunction has involved male patients, there
is no doubt that this is a complication experienced by both male and female patients.
One฀Scandinavian฀study฀reported฀a฀decline฀in฀sexual฀desire฀in฀three-quarters฀of฀male฀
stroke patients and two-thirds of female stroke patients [19]. From previous studies,
it is evident that major complications of concern include decreased sexual desire in
both male and female patients, diminished vaginal lubrication and orgasm in female
patients, and impairment in erection and ejaculation in men [18]. Additionally,
these poststroke consequences extend beyond the individual to also affect their
intimate relationships with their partners.
A recent study investigating sexual dysfunction in male stroke patients was aimed
at correlating this impairment with brain localization of the stroke lesions [20];฀this฀
appears to be the first study to correlate specific aspects of sexual dysfunction with
localization of strokes. The comparison was made between 109 male stroke patients
and฀ 109฀ aged-matched฀ controls.฀ A฀ five-item฀ version฀ of฀ the฀ International฀ Index฀ of฀
Erectile Function was use to evaluate changes in sexual desire, ejaculatory function,
and sexual satisfaction after stroke. These results were then analyzed with the
location of the respective patients’ brain lesions.
Overall,฀the฀study฀demonstrated฀a฀significant฀decrease฀in฀erectile฀function฀in฀the฀
stroke patient group. Frequency of sexual intercourse and sexual desire were both
significantly reduced in this patient group. The diminished frequency in intercourse
was found to be most commonly (almost 60%) secondary to the lack of sexual
desire after stroke. More specifically, stroke patients suffering from ejaculation
disorders demonstrated lesions in the right cerebellum. Additionally, patients expe-
riencing decreases in sexual desire showed imaging correlations such that their
brain฀ lesions฀ were฀ concentrated฀ to฀ the฀ left฀ basal฀ ganglia.฀ Overall,฀ these฀ findings฀
were able to localize patterns with certain aspects of sexual dysfunction. A larger
and more inclusive study would likely be helpful in confirming these associations
between sexual dysfunction and the respective neuroanatomy.
The common implication among studies evaluating poststroke sexual dysfunc-
tion is such that these impairments should be more frequently addressed and
aggressively treated during the rehabilitation process in stroke survivors so that
they can enjoy a healthier quality of life and continue to share and participate in
intimate relationships with their partners. Although poststroke rehabilitation has
shown to help in the recovery of sexual functioning, additional therapies used for
sexual dysfunction unrelated to stroke may also be used.
Cognitive Performance
Neuroscience฀has฀demonstrated฀the฀association฀between฀increased฀cognitive฀impairment฀
following฀infarction;฀however,฀the฀pathophysiology฀by฀which฀infarcts฀result฀in฀this฀
cognitive dysfunction is incompletely understood. A popular hypothesis involves the
disruption of the cerebral circuitry with resultant deficits in cognition, usually with
the฀frontal-subcortical฀circuits฀being฀affected.฀Injury฀to฀these฀circuits฀results฀in฀deficits฀
in memory, information processing, and executive dysfunction. Additionally, disrup-
tion of cerebro-cerebellar circuits often causes problems in higher cognitive functions.
In฀particular,฀many฀studies฀have฀examined฀the฀impact฀of฀location฀and฀number฀of฀
infarcts฀ on฀ cognitive฀ impairment.฀ In฀ a฀ recent฀ study฀ by฀ Saczynski฀ and฀ colleagues,฀
three separate cognitive domains were investigated following the diagnosis of
cerebral฀infarct:฀processing฀speed,฀memory,฀and฀executive฀dysfunction.฀In฀the฀4,030฀
nondemented฀ participants฀ enrolled฀ in฀ the฀ Age฀ Gene/Environment฀ Susceptibility฀ –฀
Reykjavik฀Study,฀it฀was฀found฀that฀those฀patients฀who฀suffered฀infarcts฀in฀multiple฀
locations had slower processing speed, poorer performance in memory, and execu-
tive dysfunction in comparison to patients with infarcts concentrated to a single
location.฀Interestingly,฀those฀participants฀who฀did฀suffer฀multiple฀infarcts฀within฀one฀
region did not demonstrate any cognitive discrepancies from the noninfarct control
group after model adjustment [21]. These findings are all independent of white matter
lesions, brain atrophy, cardiovascular comorbidities, and depressive symptoms.
Treatment modalities for post-stroke cognitive impairment include the use of acetyl-
cholinesterase inhibitors, in addition to recent developments, such as the use of
repetitive฀transcranial฀magnetic฀stimulation฀(TMS).฀฀A฀focal฀lesion฀such฀as฀a฀stroke฀
may฀ produce฀ a฀ state฀ of฀ hemispheric฀ imbalance.฀ TMS฀ can฀ be฀ used฀ to฀ repair฀ this฀
disequilibrium between the ipsi-lesional and contra-lesional cerebrum.
Involuntary Emotional Expression Disorder
The expression of human emotion allows individuals the potential to communicate

feelings฀to฀those฀around฀them;฀however,฀the฀pathology฀of฀emotional฀expression฀can฀
be consequentially devastating to an individual’s relationship with loved ones, the
overall functional quality of life, and the ability to relate, cope, and form new
bonds. Although this emotional disinhibition syndrome is observed in association
with numerous neurological conditions, its application to poststroke patients has
become a growing area of interest and research. Given the importance of identify-
ing and properly treating this neuropsychiatric condition, Cummings and col-
leagues proposed terminology and diagnostic criteria to be applied to this
involuntary฀emotional฀expression฀disorder฀(IEED)฀[22].฀IEED฀is฀defined฀as฀uncon-
trollable bouts of emotional expression that are incongruent with or disproportion-
ate to how the patient actually feels at the time of the episode.
The฀current฀definition฀of฀IEED฀likely฀results฀from฀a฀single฀pathological฀mecha-
nism but is inclusive of the following clinical observations: pathological crying and
laughing, emotional affective lability, emotionalism, emotional incontinence, emo-
tion or affective pathology, and emotional dyscontrol. This syndrome has previ-
ously been referred to as pseudobulbar affect, given its origin and possible
relationship to lesions damaging the neural networks or white matter tracts connect-
ing the frontal lobes, limbic system, brainstem, and cerebellum [22]. However,
because additional studies have shown that the majority of these cases of bilateral
corticobulbar or corticopontine infarcts are not associated with upper motor neuron
lesions, this term has more frequently been replaced by pathological affect [1].
It฀is฀crucial฀that฀the฀diagnostician฀differentiate฀between฀the฀aforementioned฀neuro-
logical disorder and others that may have a similar presentation, such as gelastic or
dacrystic฀epilepsy฀(ictal฀laughing฀and฀crying,฀respectively);฀this฀emotional฀lability฀
is associated with a seizure or as part of an aura [23].
The฀ diagnostic฀ criteria฀ for฀ IEED฀ include฀ episodes฀ of฀ involuntary฀ emotional฀
displays, such as laughing or crying, that are attributable to brain disease or injury
and deviate from the patient’s affective behavior before the onset of brain disease
or injury [22]. The episodes are either incongruent with the patient’s mood or are
congruent but occur with significant exaggeration. Additionally, they may occur
without any preceding stimulus. The emotional symptoms cannot be attributable to
another neuropsychiatric disorder nor can they be secondary to substance use [22].
Additional฀ clinical฀ observations฀ may฀ also฀ aid฀ in฀ the฀ diagnosis฀ of฀ IEED,฀ such฀ as฀
symptomatology stemming from geographically close cerebral pathology. This
definition includes the presence of autonomic changes, as well as pseudobulbar
palsy signs, such as increased jaw jerk and gag reflex, dysarthria, dysphagia, and
tongue weakness [22];฀however,฀the฀absence฀of฀these฀associated฀symptoms฀must฀not฀
exclude this diagnosis as most patients with corticobulbar infarcts will present
without them [1].฀ With฀ the฀ use฀ of฀ the฀ Pathological฀ Laughter฀ and฀ Crying฀ Scale,฀
previous studies have demonstrated the effectiveness of using nortriptyline for 4–6
weeks฀to฀treat฀patients฀with฀IEED฀[24]. Additionally, a double-blind drug trial using
citalopram฀in฀patients฀with฀poststroke฀IEED฀also฀demonstrated฀a฀reduction฀in฀the฀
number of crying spells by more than 50% [25].
Irritability
Irritability฀ remains฀ one฀ of฀ the฀ predominant฀ neuropsychiatric฀ complications฀ of฀

stroke, with recent studies reporting close to 33% of poststroke patients suffering
from irritability [26].฀ Irritability฀ is฀ one฀ of฀ the฀ most฀ common฀ chief฀ complaints฀ of฀
patients฀and฀patient’s฀families฀when฀presenting฀to฀the฀neuropsychiatrist.฀Poststroke฀
irritability is characterized by impatience with situations requiring delays and waiting,
flashes of anger, frequent and rapid mood fluctuations, and quarreling.
Cerebrovascular disease is a pathology that not only has serious consequences
for the patient himself, but also for members of the family, loved ones, or caretakers
of the patient. Certain neuropsychiatric complications of stroke have a greater
impact฀on฀the฀patient฀than฀the฀family;฀however,฀poststroke฀irritability฀oftentimes฀has฀
a greater impact on those people who interact with the patient than the patient him-
self. With this consideration, identifying and properly treating poststroke irritability
can฀ significantly฀ diminish฀ caregiver฀ burden.฀ One฀ study฀ evaluated฀ the฀ caregiving฀
experience฀ using฀ both฀ the฀ Brain฀ Impairment฀ Behavior฀ Inventory฀ (BIBI)฀ and฀ the฀
companion฀Brain฀Impairment฀Behavior฀Bother฀Scale฀(BIBBS)฀revealing฀the฀three฀
greatest stressors to them as caregivers. The results of this study demonstrated that
patient irritability was the greatest stressor for caregivers of stroke survivors [27].
The localization of lesions in patients presenting with poststroke irritability are
most commonly within the orbitofrontal lobe, the left cerebral cortex (greater than
right), anterior temporal lobes (amygdale), and the limbic system [28]. Risk factors
associated with increased rates of poststroke irritability include being aphasic and
younger at the occurrence of the stroke. Aphasia increased the irritability rate
fourfold,฀ and฀ patients฀ younger฀ than฀ 65฀ years฀ old฀ had฀ 2.5฀ times฀ the฀ incidence฀ of฀
poststroke irritability as their older counterparts [26]. Additionally, it has been
observed that irritable symptoms of stroke patients usually increase at 1 year
poststroke [26];฀therefore,฀if฀the฀clinician฀suspects฀poststroke฀irritability,฀screening฀
should take place at this time. Treatment regimens include mood stabilizers.
Psychosis
In฀comparison฀to฀many฀of฀the฀other฀neuropsychiatric฀complications฀of฀stroke,฀psychotic฀
symptoms,฀such฀as฀hallucinations฀and฀delusions,฀are฀rare.฀Only฀five฀patients฀followed฀
in a 9-year longitudinal study demonstrated symptoms consistent with poststroke
psychosis [29]. Another study following stroke patients up to 11 years later found a
total of eight patients who exhibited psychotic symptoms after right-sided temporopa-
rieto-occipital infarcts [30]. Many of these stroke patients also experienced seizures
close฀to฀the฀time฀at฀which฀psychosis฀was฀observed.฀Improvement฀of฀their฀psychotic฀
symptoms was noted after treatment with antiepileptic medications [30].
A frontal lobe syndrome and psychosis have been observed after infarction in
the brainstem dopaminergic nuclei, specifically at the ponto-mesencephalic junc-
tion.฀Stereotactic฀lesion฀localization฀on฀MRI฀in฀addition฀to฀concordant฀analysis฀of฀
regional cerebral blood flow demonstrated that infarction within these nuclei likely
has resultant disruption of the ascending dopaminergic projections to the frontal-
subcortical circuit components [31].฀ In฀ addition,฀ a฀ longitudinal฀ study฀ of฀ stroke฀
patients demonstrated that right frontoparietal lesions and subcortical atrophy were
significant risk factors for psychosis following stroke given that nonpsychotic
stroke survivors did not have these findings [29].
Agitation
Agitation฀following฀stroke฀is฀observed฀in฀approximately฀28%฀of฀patients฀who฀have฀
suffered฀from฀a฀cerebrovascular฀event.฀Poststroke฀agitation฀manifests฀primarily฀by฀
stubbornness฀(81%),฀noncompliance,฀such฀as฀with฀rehabilitation,฀refusal฀to฀cooperate฀
with the patient’s caregiver (75%), crying and cursing (75%), and less commonly
violence฀toward฀objects,฀such฀as฀slamming฀doors฀(2%),฀and฀never฀violence฀toward฀
people [26].฀Lesions฀resulting฀in฀poststroke฀agitation฀are฀neuroanatomically฀confined฀
to฀ the฀ bitemporal฀ lobes฀ and/or฀ the฀ amygdale฀ [28]. The current treatment recom-
mendation includes mood stabilizing agents.
Depression
Given that depression is the most prevalent neuropsychiatric complication of

cerebrovascular disease with the greatest quantity of studies and publications, this
discussion will devote less to it.
Depression฀is฀a฀frequent฀complication฀of฀stroke,฀affecting฀185,000฀stroke฀survivors฀
in฀ the฀ United฀ States฀ annually.฀ Patients฀ with฀ PSD฀ demonstrate฀ less฀ evidence฀ of฀
recovery from the functional impairments of stroke in comparison to their nonde-
pressed counterparts, and these patients are 3.4 times more likely to die during the
first 10 years following stroke [32]. Everson and colleagues [32] found that, in
patients with stroke, five or more depressive symptoms at baseline were associated
with significantly increased risk of mortality after adjusting for age, sex, ethnicity,
education, alcohol consumption, smoking, body mass index, hypertension, and
diabetes฀ mellitus.฀ Many฀ patients฀ with฀ PSD฀ also฀ suffer฀ from฀ significant฀ disability฀
and฀an฀inability฀to฀carry฀out฀AODL.
PSD,฀with฀documented฀frequencies฀of฀up฀to฀79%฀[33] of patients who have suf-

fered a cerebrovascular accident, manifests primarily as feelings of uselessness and
being฀a฀burden฀on฀caregivers฀and฀family฀(97%).฀It฀also฀frequently฀includes฀feelings฀
of฀sadness฀(85%),฀crying฀(85%),฀and฀less฀commonly,฀pessimism฀and฀suicidal฀ide-
ations, both of which are more common in primary depressive disorders [26].
Current evidence suggests that lesions in the basal ganglia or left frontal lobe
have฀ a฀ greater฀ association฀ with฀ PSD.฀ Narushima฀ et฀ al.฀ [34] performed a meta-
analysis฀of฀patients฀with฀PSD฀and฀noted฀that฀there฀was฀a฀significant฀inverse฀correla-
tion between severity of depression and distance of the lesion from the frontal pole
among 163 patients with left hemispheric stroke, but not among other 106 patients
with฀right฀hemispheric฀stroke.฀PSD฀is฀a฀reflection฀of฀failed฀functioning฀of฀critical฀
neural networks, and neurotrophic factors such as brain-derived neurotrophic factor
(BDNF)฀may฀induce฀antidepressant฀effects฀through฀neuronal฀plasticity฀and฀recovery฀
of neuronal networks [34].฀The฀most฀successful฀treatment฀regimens฀for฀PSD฀include฀
the use of fluoxetine, followed by nortriptyline, and in some cases, citalopram,
trazadone and methylphenidate [11] (Table 1).
Conclusion
This current rendition highlights some of the significant complications resulting

from฀ cerebrovascular฀ disease.฀ It฀ brings฀ to฀ attention฀ the฀ importance฀ of฀ correct฀
identification of these conditions to improve the quality of life, as well as the
economical and social effects on stroke patients and their families. With greater
awareness regarding these diagnoses, hospitalizations and caregiver burden can
be decreased, and the proper diagnosis will aid in the appropriate treatment of
these conditions.
References
฀ 1.฀ Chemerinski฀E,฀Levine฀SR฀(2006)฀Neuropsychiatric฀disorders฀following฀vascular฀brain฀injury.฀
Mt฀Sinai฀J฀Med฀73(7):1006–1014
฀ 2.฀ Hadidi฀N,฀Treat-Jacobson฀DJ,฀Lindquist฀R฀(2009)฀Poststroke฀depression฀and฀functional฀out-
come:฀a฀critical฀review฀of฀literature.฀Heart฀Lung฀38(2):151–162
฀ 3.฀ Starkstein฀SE,฀Boston฀J,฀Robinson฀RG฀(1988)฀Mechanisms฀of฀mania฀after฀brain฀injury:฀12฀case฀
reports฀and฀review฀of฀the฀literature.฀J฀Nerv฀Ment฀Dis฀176:87–100
฀ 4.฀ Dunne฀JW,฀Leedman฀PJ,฀Edis฀RH฀(1986)฀Inobvious฀stroke:฀a฀cause฀of฀delirium฀and฀dementia.฀
Aust฀N฀Z฀J฀Med฀16(6):771–778
฀ 5.฀ Braun฀CMJ,฀Daigneault฀R,฀Gaudelet฀S฀(2008)฀DSMIV฀symptoms฀of฀mania:฀which฀ones฀result฀
more฀often฀from฀right฀than฀left฀hemisphere฀lesions?฀Compr฀Psychiatry฀49:441–459
฀ 6.฀ Filardi฀da฀Rocha฀F,฀Horizonte฀B,฀Carneiro฀JG฀(2008)฀Poststroke฀manic฀symptoms:฀an฀unusual฀
neuropsychiatric฀condition.฀Rev฀Bras฀Psiquiatr฀30(2):168–176
฀ 7.฀ Leppavuori฀A,฀Pohjasvaara฀T,฀Vataja฀R฀et฀al฀(2003)฀Generalized฀anxiety฀disorders฀three฀to฀four฀
months฀alter฀ischemic฀stroke.฀Cerebrovasc฀Dis฀16:257–264
Table 1 Neuropsychiatric฀symptoms฀and฀lesion฀localization฀(modiied฀from฀[3])
Neuropsychiatric฀symptoms Lesion฀localization Treatment
Depression L฀cerebral฀cortex,฀frontal฀lobe,฀frontosubcortical฀circuits,฀ Fluoxetine, followed by nortriptyline, and in
basal ganglia and limbic system some cases, citalopram, trazadone, and
methylphenidate
Mania Anterior region of bilateral hemispheres, R temporal lobe, Olanzapine,฀carbamazepine,฀and฀valproic฀acid
R caudate nucleus, R subcortical region, R ventral pons,
L฀basal฀ganglia
Apathy Frontal lobe, cingulate gyrus, supplemental motor area, Stimulating฀a฀ntidepressants,฀i.e.,฀fluoxetine.฀
amygdala,฀capsule,฀insula,฀caudate฀nucleus/nuclei,฀ Stimulating฀agents,฀i.e.,฀amphetamine,฀
bilateral anterior thalamic nuclei methylphenidate,
selegiline,฀bupropion.฀AChE-I
IEED Bilateral฀corticobulbar฀tracts,฀L฀frontal฀cortex Nortriptyline,฀citalopram
Psychosis R hemisphere, especially temporo-parieto-occipital or Antiepileptics
frontoparietal, and thalamus
Agitation Bitemporal, amygdala Mood stabilizing agents
Disturbance of sleep–wake cycle Pons฀(R฀>฀bilateral฀>฀L),฀subcortical฀regions฀such฀as฀the฀ Dopamine agonists
Neuropsychiatric฀Complications฀of฀Cerebrovascular฀Disease
pyramidal tract and basal ganglia–brainstem axis

Irritability Orbitofrontal฀lobe,฀anterior฀temporal฀lobe฀(amygdala),฀ Mood stabilizers
limbic฀system,฀L฀cerebral฀cortex
Anxiety L฀cerebral฀hemisphere Benzidiazepines;฀in฀elderly,฀SSRIs,฀buspirone
Sexual฀dysfunction L฀basal฀ganglia,฀R฀cerebellum Poststroke฀rehabilitation,฀nonstroke฀sexual฀
dysfunction meds
Cognitive impairment Frontal-subcortical circuits, cerebro-cerebellar circuits Acetylcholinesterase฀inhibitors,฀TMS
Fatigue No฀specific฀localization Stimulating฀agents
IEED฀ involuntary฀ emotional฀ expression฀ disorder;฀ AChE-I฀ acetylcholinesterase฀ inhibitors;฀ SSRI฀ selective฀ serotonin฀ uptake฀ inhibitors;฀ TMS transcranial
magnetic stimulation
175
฀ 8.฀ Dennis฀ M,฀ O’Rrourke฀ S,฀ Lewis฀ S,฀ Sharpe฀ M,฀ Warlow฀ C฀ (2000)฀ Emotional฀ outcomes฀ after฀
stroke:฀factors฀associated฀with฀poor฀outcome.฀J฀Neurol฀Neurosurg฀Psychiatry฀68:47–52
฀ 9.฀ Starkstein฀SE,฀Fedoroff฀JP,฀Price฀TR฀et฀al฀(1993)฀Apathy฀following฀cerebrovascular฀lesions.฀
Stroke฀24:1625–1631
฀10.฀ Santa฀N,฀Sugimori฀H,฀Kusuda฀K฀et฀al฀(2008)฀Apathy฀and฀functional฀recovery฀following฀first-
ever฀stroke.฀Int฀J฀Rehabil฀Res฀31(4):321–326
฀11.฀ Paranthaman฀G,฀Balwin฀R฀(2006)฀Treatment฀of฀psychiatric฀syndromes฀due฀to฀cerebrovascular฀
disease.฀Int฀Rev฀Psychiatry฀18(5):453–470
฀12.฀ Chen฀JC,฀Brunner฀RL,฀Ren฀H฀et฀al฀(2008)฀Sleep฀duration฀and฀ischemic฀stroke฀in฀older฀women.฀
Stroke฀39:315–3192
฀13.฀ Schuiling฀ WJ,฀ Rinkel฀ GJE,฀ Walchenbach฀ R฀ et฀ al฀ (2005)฀ Disorders฀ of฀ sleep฀ and฀ wake฀ in฀
patients฀after฀SAH.฀Stroke฀36:578–582
฀14.฀ Landau฀ ME,฀ Maldonado฀ JY,฀ Jabbari฀ B฀ (2005)฀ The฀ effects฀ of฀ isolated฀ brainstem฀ lesions฀ on฀
human฀REM฀sleep.฀Sleep฀Med฀6:37–40
฀15.฀ Lee฀ SJ,฀ Kim฀ JS,฀ Song฀ IU฀ (2009)฀ Poststroke฀ restless฀ legs฀ syndrome฀ and฀ lesion฀ location:฀
anatomical฀considerations.฀Mov฀Disord฀24(1):77–84
฀16.฀Winward฀C฀et฀al฀(2009)฀Fatigue฀after฀TIA฀and฀minor฀stroke.฀Stroke฀40(3):757–766
฀17.฀ Chalder฀ T,฀ Berelowitz฀ G,฀ Pawlikowska฀ T฀ et฀ al฀ (1993)฀ Development฀ of฀ a฀ fatigue฀ scale.฀ J฀
Psychosom฀Res฀37(2):147–153
฀18.฀ Tamtam฀ Y,฀ Tamtam฀ L,฀ Akil฀ E฀ et฀ al฀ (2008)฀ Post-stroke฀ sexual฀ functioning฀ in฀ first฀ stroke฀
patients.฀Eur฀J฀Neurol฀15:660–666
฀19.฀ Sjogren฀K,฀Damber฀JE,฀Liliequist฀B฀(1983)฀Sexuality฀after฀stroke฀with฀hemiplegia:฀aspects฀of฀
sexual฀function.฀Scand฀J฀Rehabil฀Med฀15:55–61
฀20.฀Jung฀J-H,฀Kam฀S-C,฀Choi฀S-M฀(2008)฀Sexual฀dysfunction฀in฀male฀stroke฀patients:฀correlation฀
between฀brain฀lesions฀and฀sexual฀function.฀Urology฀71:99–103
฀21.฀ Saczynski฀JS,฀Sigurdsson฀S,฀Jonsdottir฀MK฀et฀al฀(2009)฀Cerebral฀infarcts฀and฀cognitive฀per-
formance.฀Stroke฀40:677–682
฀22.฀ Cummings฀JL,฀Arciniegas฀DB,฀Brooks฀BR฀(2006)฀Defining฀and฀diagnosing฀involuntary฀emo-
tional฀expression฀disorder.฀CNS฀Spectr฀11(6฀suppl฀6):1–7
฀23.฀ Cummings฀ JL฀ (2007)฀ Involuntary฀ emotional฀ expression฀ disorder:฀ definition,฀ diagnosis฀ and฀
measurement฀scales.฀CNS฀Spectr฀12(4฀suppl฀5):11–16
฀24.฀ Robinson฀RG,฀Parikh฀RM,฀Lipsey฀JR฀et฀al฀(1993)฀Pathological฀laughing฀and฀crying฀following฀
stroke:฀validation฀of฀a฀measurement฀scale฀and฀double-blind฀treatment฀study.฀Am฀J฀Psychiatry฀
150:286–293
฀25.฀ Andersen฀ G,฀ Verstergaard฀ K,฀ Riis฀ JO฀ et฀ al฀ (1993)฀ Citalopram฀ for฀ post-stroke฀ pathological฀
crying.฀Lancet฀342:837–839
฀26.฀ Angelelli฀P,฀Paolucci฀S,฀Bivona฀U฀et฀al฀(2004)฀Development฀of฀neuropsychiatric฀symptoms฀in฀
poststroke฀patients:฀a฀cross-sectional฀study.฀Acta฀Psychiatr฀Scand฀110:55–63
฀27.฀ Williams฀A฀(1994)฀What฀bothers฀caregivers฀of฀stroke฀victims?฀J฀Neurosci฀Nurs฀26(3):155–161
28.฀ Luna-Matos฀M,฀McGrath฀H,฀Gaviria฀M฀(2007)฀Neuropsychiatric฀manifestations฀in฀cerebro-
vascular฀diseases.฀Rev฀Chil฀Neuro-Psiquiatr฀45(2):129–140
฀29.฀ Rabins฀PV,฀Starkstein฀SE,฀Robinson฀RG฀(1991)฀Risk฀factors฀for฀developing฀atypical฀(schizo-
phreniform)฀psychosis฀following฀stroke.฀J฀Neuropsychiatry฀Clin฀Neurosci฀3:6–9
฀30.฀ Levin฀ DN,฀ Finklestein฀ S฀ (1982)฀ Delayed฀ psychosis฀ after฀ right฀ temporoparietal฀ stroke฀ or฀
trauma:฀relation฀to฀epilepsy.฀Neurology฀32:267–273
฀31.฀ Nishio฀Y,฀Ishii฀K,฀Kazui฀H฀(2007)฀Frontal-lobe฀syndrome฀and฀psychosis฀after฀damage฀to฀the฀
brainstem฀dopaminergic฀nuclei.฀J฀Neurol฀Sci฀260:271–274
฀32.฀ Everson฀SA,฀Robertson฀RE,฀Goldberg฀DE฀(1998)฀Depressive฀symptoms฀and฀increased฀risk฀of฀
stroke฀mortality฀over฀a฀29-year฀period.฀Arch฀Intern฀Med฀158:1133–1138
฀33.฀ Hadidi฀N,฀Treat-Jacobson฀DJ,฀Lindquist฀R฀(2009)฀Poststroke฀depression฀and฀functional฀out-
come:฀a฀critical฀review฀of฀litreature.฀Issues฀Neurol฀38(2):151–162
฀34.฀ Narushima฀K,฀Kosier฀JT,฀Robinson฀RG฀(2003)฀A฀reappraisal฀of฀PSD,฀intra-฀and฀inter-hemi-
spheric฀lesion฀location฀using฀meta-analysis.฀J฀Neuropsychiatry฀Clin฀Neurosci฀15:422–430
Systemic Inflammation and Cognition
in the Elderly
Julian Trollor and Emmeline Agars
Abstract A complex inflammatory cascade is an established part of the

pathophysiology of Alzheimer’s disease (AD), and preliminary studies have suggested
a link between systemic inflammation and AD. Recent research has extended this
theme by examining the influence of systemic inflammation on cognitive function
in community-dwelling elderly. Preliminary findings suggest that elevated levels
of some inflammatory markers such as interleukin-6 (IL-6) and C-reactive pro-
tein (CRP) are associated with poorer cognition at cross-sectional assessment.
Longitudinal studies suggest an impact of raised IL-6 and CRP, in terms of both
cognitive decline and outcome of dementia. Although findings vary considerably
between studies, systemic inflammation may have relevance for cognitive function
and cognitive decline in late life. Further comprehensive studies are required to
further explore the relationship between systemic inflammation and cognition in
the elderly.
Keywords Cognition฀ •฀ Cytokines฀ •฀ Dementia฀ •฀ Inflammation฀ •฀ Mild฀ cognitive฀

impairment
E. Agars and J. Trollor

Brain and Ageing Program, School of Psychiatry, University of New South Wales, Sydney,
NSW 2052, Australia
J. Trollor (*)
Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of
New South Wales, Sydney, NSW 2052, Australia
and
University of New South Wales, 34 Botany Street, UNSW, Sydney, NSW 2052, Australia

DOI 10.1007/978-4-431-53871-4_13, © Springer 2010
178 J. Trollor and E. Agars
Introduction
Systemic inflammation has been associated with increased risk of age-related

disorders such as AD. The cross-sectional relationship between systemic inflamma-
tion and cognition in nondemented elders is less clear. Furthermore, whether sys-
temic inflammation has relevance for change in cognition over time remains
uncertain. The way in which systemic inflammation influences cognition in ageing
and age-related cognitive disorders is complex and is likely modified by interplay
among many factors such as physical health, lifestyle, nutrition, and genes. Given
the findings in AD, it is important to clarify the relationship between systemic
inflammation and risk of cognitive decline in late life. If a significant relationship
is identified, moderation of systemic inflammation may be an important therapeutic
target that may ultimately reduce the burden of age-related neuropsychiatric disor-
ders. This chapter reviews the literature that examines the impact of systemic
inflammation and cognition in community-dwelling elders.
Background
Inflammation and Alzheimer’s disease
A link between inflammation and cognition was hypothesized after discovery of

upregulated inflammatory processes in post-mortem Alzheimer’s disease (AD)
brain specimens [1, 2]. Subsequent research has suggested a pivotal role of inflam-
mation in Alzheimer pathology involving activation of microglia, astrocytes, and
the complement system as well as increased cytokine expression and acute-phase
protein response [3, 4]. Support for a role of inflammation in AD also comes from
epidemiological studies that demonstrate a protective effect of anti-inflammatory
agents for AD [5]. A meta-analysis of seven small case-control studies [6] deter-
mined a substantially reduced odds ratio (0.556, P < 0.0001) for development of AD
in arthritis patients, but nonsteroidal anti-inflammatory drug trials in dementia have
thus far been unsuccessful [7].
The relationship between systemic inflammation and dementia has been inves-
tigated in several cross-sectional studies. Among the most consistent findings are
an association between cytokines such as interleukin-1a (IL-1a), IL-6, and tumor
necrosis factor-a (TNF-a) with dementia in clinical populations [8–12]. The rela-
tionship between inflammatory factors and dementia subtype has varied among
studies [11–13]. Recent work has also suggested a cross-sectional link between
TNF-a฀and฀mild฀cognitive฀impairment฀(MCI)฀[9].
Additional evidence for the role of inflammatory modulators in the pathogenesis
of AD comes from studies that show the risk of AD is affected by genetic variation
in inflammatory modulators such as IL-1a, interleukin-1b (IL-1b), IL-6, TNF-a,
a2-macroglobulin, and a1-antichymotrypsin [14]. Polymorphic variation in the
Systemic Inflammation and Cognition in the Elderly 179
IL-6 gene is associated with lower risk of developing AD [15], and IL-6 mRNA
levels may also predict the clinical progression of the disease [16]. Of interest is the
demonstration of interactive effects with other alleles known to confer risk for AD.
For฀example,฀McCusker฀et฀al.฀[17] demonstrated that, in those carrying the apoli-
poprotein E4 (ApoE 4) allele, TNF-a substantially increased the risk of AD. Nicoll
et al. [18] demonstrated that simultaneous inheritance of the high-risk alleles for
IL-1a (IL-1a-889) and IL-b (IL-b + 3953) increased the odds of developing AD by
10.8 [18]. Taken together, available data suggest that AD risk may be influenced by
inflammatory factors in relationship to both serum measures and “genetic suscep-
tibility profile.” The data not only underscore the importance of inflammation in
AD but raise the possibility that inflammatory processes may be relevant to cognitive
ageing in nonclinical populations. The relevance of inflammation in this context is
best examined in community-dwelling ageing populations, which are the main
focus in this chapter.
“Inflammaging”
The term “inflammaging” has been used to describe the progressive increase in
systemic inflammation with advancing age and is characterized by a decline in
adaptive immune mechanisms, upregulation of the innate immune system, and a
resultant low-grade, chronic inflammatory response. Central to this process is the
overactivation of mononuclear phagocytes, which results in elevation of cytokine
levels [19, 20]; this comes at a time when the brain may be more susceptible to
adverse effects of inflammation. For example, animal studies demonstrate an increased
susceptibility of the aged brain to oxidative stress and inflammation [21], affording
a greater potential impact of inflammation on cognitive function. The brain has
been traditionally viewed as an immune-privileged site. However, recent research
indicates the peripheral immune system and the central nervous system (CNS)
communicate extensively [22]. Such communication raises a number of possibili-
ties regarding the relationship between cognitive function and inflammation. For
example, peripherally generated inflammation may be a response or contributor to
CNS inflammation and pathology [7].
Whether “inflammaging” or increased susceptibility to its effects translates into
meaningful change in cognitive function or confers greater risk of cognitive decline
is฀uncertain฀and฀is฀the฀subject฀of฀this฀review.฀To฀explore฀this฀issue,฀a฀MEDLINE฀
search฀was฀conducted฀using฀the฀MESH฀term฀“inflammation”฀or฀keyword฀“inflam-
matory฀markers”฀and฀MESH฀terms฀“cognition”฀or฀“cognition฀disorders.”฀The฀search฀
strategy identified those articles published in the English language until July 2009.
Articles were examined in detail only if the participants were drawn from non-
clinical populations, and only if the study included participants ³65 years of age.
Reference lists were cross-checked for additional articles not initially identified by the
search strategy. The cross-sectional and longitudinal data from studies fulfilling
the selection criteria are summarized in Tables 1 and 2, respectively.
Table 1 Cross-sectional studies of circulating inflammatory markers and cognitive function in community-dwelling elderly populations
180
Inflammatory
marker/s Study population Cognitive tests Outcomes Covariates Results
Alley IL-6 851 Community- Similarities subset of Individual Age, sex, race, Before covariate
et al.[23] CRP dwelling elders, Wechsler Adult cognitive education, inclusion, raised
70–79 years, Intelligence Scale- tests/ income,฀DM,฀ IL-6 and CRP were
USA Revised, copying domains MI,฀stroke,฀hip฀ inversely associated
geometric figures, and #, BP, HbA1c, with abstraction and
delayed recognition global HDL, waist language ability
Span test, modified cognitive circumference, (P < 0.05) and
Boston Naming test, function NSAIDs, global cognition
incidental recall alcohol, (P < 0.001); IL-6
on naming items, smoking, alone associated
abbreviated short physical with poor spatial
portable mental activity ability (P < 0.01)
status questionnaire and CRP with short
portable mental
status questionnaire
(P < 0.01);
all results
nonsignificant
after inclusion of
covariates
Baune IL-1b 369 Community- Three word recall test Individual Age, gender, Increased IL-8 inversely
et al.[24] sIL-4R dwelling (Tulving and Colotla cognitive education, associated with
IL-6 participants, lag measures), word tests/ smoking, memory (P < 0.01),
IL-8 >65 years, mean fluency, Stroop color- domains depressive cognitive speed
IL-10 age 72.6 years, word test, Wechsler symptoms, TIA, (P < 0.001) and motor
IL-12 Germany Adult Intelligence stroke,฀DM function (P < 0.01)
TNF-a scales digit symbol
test, Purdue Pegboard
test,฀MMSE
J. Trollor and E. Agars
Sweat CRP 125 Community- California Verbal Learning Individual Age,฀education,฀DM,฀ Significant inverse
et al. [25] dwelling test,฀Wechsler฀Memory฀ cognitive statins association between
42–82-year-olds, Scale-Revised, Digit tests/ CRP and cognition
categorized by Span Backwards, domains only in overweight
BMI,฀USA Visual฀Memory฀Span฀ and obese women:
Backwards, Colorado executive function
Assessment tests: and figural memory
Tower of London, (P < 0.01), estimated
Shipley Institute of IQ and general
Living Scale cognitive functioning
(P < 0.05)
Schram
et al.[26]
1. Rotterdam IL-6 3,874 Community- MMSE,฀abbreviated฀ Individual Age, sex, education CRP and IL-6 inversely
Study CRP dwelling Stroop test part cognitive associated with
a1- elderly, mean 3, Letter Digit tests/ global cognition and
Antichymo- age, 72 years, Substitution Task, domains executive functioning
trypsin Netherlands word fluency, Geriatric (P < 0.01), IL-6
Mental฀Status฀schedule was also inversely
Systemic Inflammation and Cognition in the Elderly
associated with
MMSE฀score฀
(P < 0.05)
2. Leiden IL-6 491 Community- MMSE,฀abbreviated฀ Individual Age, sex, education No significant association
85-plus CRP dwelling 85-year- Stroop test part cognitive
Study olds, Netherlands 3, Letter Digit tests/
Substitution Task, domains
Geriatric฀Mental฀Status฀
schedule, 12-Picture
Learning test
Fischer CRP 606 Community- MMSE Global Sex, BP, total No significant association
et al.[27] Homocysteine dwelling 75-year- cognitive cholesterol,
Fibrinogen olds, Austria function LDL, HDL, TG,
antihypertensive
medications,
181
statins, smoking
(continued)
Table 1 (continued)
182
Inflammatory
marker/s Study population Cognitive tests Outcomes Covariates Results
Dik IL-6 1,284 Community MMSE,฀Auditory฀Verbal฀ Individual Age, sex, education Serum a1-
et al. [28] CRP dwelling Learning task, Raven’s cognitive antichymotrypsin
a1- 62–85-year-olds, colored progressive tests/ inversely associated
Antichymo- Netherlands matrices, Alphabet domains with delayed recall
trypsin coding task-15 (P < 0.05) and albumin
Albumin inversely associated
with฀MMSE฀score฀
(P = 0.05)
Ravaglia CRP 540 Cognitively MMSE Global Age, sex, education, Raised CRP inversely
et al. [29] intact elders, cognitive fibrinogen, associated with
mean age, function leukocyte count, MMSE฀score
73 years, Italy albumin,฀BMI,฀
DM,฀IHD,฀PVD,฀
cerebrovascular
disease, chronic
pulmonary
disease, peptic
ulcer, edentulism
Elwan IL-6 94 Neurologically Paced Auditory Serial Individual Age, sex, education Raised IL-6 inversely
et al. [30] ICAM-1 intact healthy Addition test, cognitive associated with
ApoE genot- Egyptians, age Intentional and tests/ attention and
yping range, 40–82 Incidental memory domains intentional (sensory)
years, mean, test, Digit Symbol memory (P < 0.05);
58.5 years Substitution test, Trail ApoE 4 genotype
Making฀test฀A฀and฀B,฀ associated with
Eysenck Personality significantly poorer
questionnaire intentional memory
(P < 0.05)
Teunissen IL-6 65 Community- MAAS฀protocol:฀Auditory฀ Individual Age, sex, education Serum haptoglobin
et al. [31] IL-6 receptor dwelling subjects, Verbal Learning task, cognitive and CRP inversely
CC16 mean age, Letter Digit coding test, tests/ correlated with Stroop
CRP 54 years baseline, Stroop color-word test domains test and delayed recall
Haptoglobin Netherlands (P < 0.05)
Weaver IL-6 779 Community- Boston naming test, Individual Age, sex, income, No significant
et al. [32] dwelling delayed verbal cognitive education, associations
70–79-year-olds, memory test, delayed tests/ ethnicity, alcohol,
USA recognition Span test, domains physical activity,
similarities subset of BMI,฀HbA1c,฀
the Weschler Adult DM,฀cancer
intelligence Scale-
revised, copying of
geometric figures
Bruunsgaard IL-6 126 Centenarians, 45 MMSE,฀Lawton’s฀ Dementia Age, cancer, acute TNF-a levels correlated
et al. [33] TNF-a 81-year-olds, 23 instrumental ADL severity and chronic with dementia severity
CRP 55–65-year-olds, scale, caregiver’s inflammatory (P < 0.05)
sTNFR-II 38 18–30-year- information, illness, anti-

olds, Denmark categorized by CDR inflammatory
scale drugs, antibiotics,
stroke, TIA,
atherosclerosis,
leukocyte subsets
IL interleukin; CRP C-reactive protein; USA United States of America; DM diabetes mellitus; MI myocardial infarction; Hip # hip fracture; BP blood pressure;
HbA1c glycated hemoglobin; HDL high-density lipoprotein; NSAIDs nonsteroidal anti-inflammatory drugs; sIL-4R serum interleukin-4 receptor; TNF-a tumor
necrosis factor-alpha; MMSE mini-mental state examination; BMI body mass index; TIA transient ischemic attack; HT hypertension; CVD cardiovascular dis-
ease; ApoE 4 apolipoprotein E4; CERAD Consortium to Establish a Registry for Alzheimer’s disease; LDL low-density lipoprotein; TG triglycerides; IHD
schemic heart disease; PVD peripheral vascular disease; ICAM-1 intracellular adhesion molecule-1; sTNFR-II serum tumor necrosis factor receptor-II; WHO
ICD-10 World Health Organization International Classification of Diseases, tenth revision; ADL activities of daily living; CDR clinical dementia rating
Note: Where unspecified, results are after adjustment for covariates listed
183
Table 2 Longitudinal studies of circulating inflammatory markers and cognitive function
184
Inflammatory Cognitive tests/

Duration marker/s Study population diagnostic tools Outcomes Covariates Results
Alley 7 years IL-6 851 Community Similarities (WAIS-R), Individual Age, sex, race, Highest tertile IL-6
et al.[23] CRP dwelling copying geometric cognitive education, was associated
elders, figures, delayed tests/ income,฀DM,฀ with Short Portable
70–79 years recognition Span domains MI,฀stroke, Mental฀Status฀
at baseline, test, modified and hip #, BP, Questionnaire
USA Boston Naming global HbA1c, decline (OR = 1.67,
test, incidental cognitive HDL, waist 95% CI, 1.04–
recall on naming function circumference, 2.67)
items, abbreviated NSAIDs,
Short Portable alcohol,
Mental฀Status฀ smoking,
Questionnaire physical activity
Haan 5 years CRP 1,118฀Mexican฀ Verbal episodic memory All cause Age,฀sex,฀DM,฀ CRP lower in ApoE 4
et al. [34] APOE Americans, and modified mini- dementia, stroke, carriers; in ApoE 4
genotype without mental state exam AD, CIND medications, carriers higher CRP
dementia/ (3MSE),฀DSM–IVR฀ total cholesterol, associated with lower
CIND criteria, NINCDS- LDL all cause dementia
and aged ADRDA criteria and AD but after
60–101 years adjustment for
at baseline, metabolic disease/
USA stroke only associated
with AD; in non-
ApoE 4 carriers there
was no effect of CRP
on dementia/CIND
Jordanova 3 years IL-6 216 African- MMSE฀(orientation),฀ Individual Age, sex, school Raised IL-6 associated
et al. [35] CRP Caribbean CERAD tests cognitive leaving age, with decline in
Serum amy- participants, (immediate/delayed tests/ HT, stroke, orientation and
loid A 55–75 years word list recall, domains DM,฀smoking,฀ immediate verbal
at baseline, delayed word list alcohol, anti- recall (P < 0.05); no
England recognition), Trail inflammatory association found
Making฀test฀A medications/ for CRP or serum
aspirin,฀BMI,฀ amyloid A
disability
Komulainen 12 years CRP 97 Women MMSE,฀Word฀Recall฀ Individual Age, education, Baseline CRP was
et al. [36] 50–60 years test, prospective cognitive depression, inversely related to
at baseline, memory test, Stroop tests/ hormone memory function at
Finland test, Letter digit domains replacement follow-up (P < 0.05);
Substitution test therapy, LDL, no association with
BMI cognitive speed or
MMSE
Rafnsson 4 years IL-6CRP 452 Community Weschler Logical Individual Age, sex, depressed Fibrinogen predicted
et al. [37] ICAM-I dwelling Memory฀test,฀Raven’s฀ cognitive mood, peak prior decline in non-verbal
VCAM-1 subjects, aged Standard Progressive tests/ cognitive ability, reasoning and logical
Fibrinogen 55–74 years, matrices, Verbal domains smoking, alcohol memory (P < 0.05),
Scotland fluency test, Digit consumption, IL-6 was inversely
Symbol-Coding test cardiovascular related to information
disease, glucose processing speed and
intolerance/DM ICAM-I฀associated฀
with decline in general
cognitive ability and
non-verbal reasoning
(P < 0.05)
(continued)
185
Table 2 (continued)
186

Ravaglia 4 years IL-6 804 Participants DSM-IV฀(Dementia),฀ All cause Age, sex, education, Combination of raised
et al. [38] CRP 65 years and NINCDS-ADRDA dementia, ApoE 4, physical CRP and IL-6
a1- older, mean (AD), NINDS- AD, VaD activity, stroke, predicted all cause
Antichym- 74 years AIREN (VaD) CVD,฀BMI,฀total฀ dementia [HR = 1.57
otrypsin baseline, Italy homocysteine, (1.03–2.41)] and VaD
creatinine, folate, [HR = 2.56 (1.21–
vitamin B12 5.50)]; combination
CRP, IL-6 and a1-
antichymotrypsin also
predicted all cause
dementia [HR = 1.70
(1.05–2.75)],
whilst elevated
CRP predicted
VaD [HR = 2.93
(1.39–6.18)]. No
inflammatory marker
predicted AD risk
Schram
et al. [26]
1. Rotterdam Mean฀ IL-6 3,874 Community MMSE,฀abbreviated฀ Individual Age, sex, education No significant
Study 4.6 years CRP dwelling Stroop test part cognitive associations
a1- elderly, mean 3, Letter Digit tests/
Antichy- age 72 years, Substitution Task, domains
motrypsin Netherlands word fluency, Geriatric
Mental฀Status฀schedule
2. Leiden Mean฀ IL-6 491 Community MMSE,฀abbreviated฀Stroop฀ Individual Age, sex, education Elevated IL-6 associated
85-plus 3.4 years CRP dwelling test part 3, Letter Digit cognitive with decline in
Study 85 year olds, Substitution Task, tests/ memory function
Netherlands Geriatric฀Mental฀Status domains (P < 0.05), in ApoE 4

schedule, 12-Picture carriers IL-6 and
Learning test CRP more strongly
associated with
annual decline in
global cognition and
memory function than
non-carriers (P < 0.05)
Tan Mean฀ IL-6CRP 691 Cognitively MMSE,฀CDR,฀DSM-I,฀ AD Age, sex, APOEe4, Neither serum CRP nor
et al. [39] 7 years intact, dementia symptoms stroke, education, IL-6 were related to
community >6 months smoking, AD risk
dwelling homocysteine,
participants, BMI,฀statins
mean age
79 years, USA
van den 5 years CRP 267 Cognitively MMSE,฀Geriatric฀ Global Sex, education, No relationship between
Biggelaar intact, depression scale cognitive MMSE CRP and cognitive
et al. [40] community (GDS-15) decline, decline. Higher
dwelling depression baseline CRP

85 year old predicted increase in
participants, depressive symptoms
Netherlands (P < 0.001)
Weuve 4.4– CRP 4,231 Female Telephone Individual Age, education, CRP not associated with
et al. [41] 7.8 years health interview for cognitive income, decline in cognitive
professionals cognitive status: East tests/ alcohol, HT, function
aged Boston฀Memory฀test,฀ domains BMI,฀strenuous฀
60–90 years, Wechsler฀Memory฀ physical activity,
USA Scale – Revised smoking, hormone
Logical฀Memory฀ replacement
subsets, delayed therapy, total
recall cholesterol:HDL,
TG,฀DM,฀MI
(continued)
187
188
Table 2 (continued)
Dik 3 years IL-6 1,284 Community MMSE,฀Auditory฀Verbal฀ Individual Age, sex, education Serum a1-antichymo-
et al. [28] CRP dwelling Learning task, cognitive trypsin associated
a1- 62–85 year Raven’s coloured tests/ with decline in
Antichym- olds, progressive matrices, domains MMSE,฀OR฀=฀1.60,฀
otrypsin Amsterdam alphabet coding 95% CI (1.05–2.43);
Albumin task-15 CRP, IL-6 and
albumin not related
to cognitive decline
Tilvis 10 years CRP 650 Community MMSE,฀CDR Dementia Age, sex, baseline Elevated CRP associated
et al. [42] dwelling 75, severity MMSE฀score with drop in CDR
80 and 85 year class at 5 years
olds, Finland (RR = 2.32, 95% CI
(1.01–5.46) but not at
10 years
Yaffe 4 years IL-6 2,632 Community Modified฀ Global Age, race, sex, Only in participants
et al. [43] CRP dwelling black mini-mental cognitive education, with metabolic
TNF-a and white state examination function alcohol, stroke, syndrome were
elders, mean (3MSE) depressive raised inflammatory
age 74 years, symptoms, markers significantly
USA statins, baseline associated with
cognitive score cognitive decline
(RR = 1.66, 95% CI
(1.19–2.32) those
with metabolic
syndrome and
low inflammation
(RR = 1.08, 95% CI
(0.89–1.30)
and those without
metabolic
syndrome and
high inflammation
(RR = 0.81, 95% CI
(0.60–1.08) were not
at elevated risk of
decline
Engelhart 4–9 years IL-6 727 (Random MMSE,฀Geriatric฀ All cause Age, sex, Elevated a1-
et al. [44] CRP subcohort of Mental฀State฀ dementia, education level, antichymotrypsin
a1- 6,713) and Schedule, AD, VaD smoking, anti- and IL-6 associated
Antichym- 188 cases Cambridge inflammatory with increased risk
otrypsin classified examination for medications, dementia, AD,
ICAM-1 dementia at mental disorders statins,฀BMI,฀ VaD; less strong
VCAM-1 follow-up in elderly persons, SBP,฀DM,฀Ankle- association present
Community DSM-III-R,฀ brachial index, CRP, no association
dwelling NINCDS-ADRDA intima media ICAM฀or฀VCAM
population, (AD), NINDS- thickness of

Netherlands, AIREN (VaD) carotid artery,
mean age carotid plaques
71.7 years, (measured 6
dementia free locations)
at baseline
Schmidt 25 years CRP 1,050 Japanese Cognitive Abilities All cause Age, education, Elevated CRP inversely
et al. [45] American Screening dementia, ApoE 4,฀BMI,฀ related with
men, instrument, AD, VaD smoking, BP, incidence of all cause
49–70 years at Informant total cholesterol, dementias, AD and
baseline, USA questionnaire on stroke, coronary VaD (P < 0.01)
Cognitive Decline in heart disease, LV
the Elderly, CERAD hypertrophy, AF,
battery,฀DSM-III-R฀ DM,฀ABI
(dementia), NINS-
189
ADRDA (AD)
(continued)
Table 2 (continued)
190

Weaver 2.5 and IL-6 779 Community Boston naming test, Individual Age, sex, income, Highest tertile IL-6
et al. [32] 7 years dwelling delayed verbal cognitive education, associated with
70–79 year memory test, delayed tests/ ethnicity, alcohol, cognitive decline at
olds, USA recognition Span test, domains physical activity, 2.5 (OR = 2.03, 95%
similarities subset of BMI,฀HbA1c,฀ CI (1.30–3.19) and
the Weschler Adult DM,฀cancer 7 year (OR = 1.90,
intelligence Scale- 95% CI (1.14–3.18)
revised, copying of follow-up
geometric figures
IL interleukin; CRP C-reactive protein; USA United States of America; DM diabetes mellitus; MI myocardial infarction; Hip # hip fracture; BP blood pressure;
HbA1c glycated hemoglobin; HDL high-density lipoprotein; NSAIDs nonsteroidal anti-inflammatory medications; OR odds ratio; CI confidence interval;
ApoE 4 apolipoprotein; CIND cognitive impairment no dementia; DSM-IVR฀ Diagnostic฀ and฀ Statistical฀ Manual฀ of฀ Mental฀ Disorders,฀ fourth฀ revision;฀
NINCDS–ADRDA National Institute for Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorder Association; AD
Alzheimer’s disease; LDL low-density lipoprotein; MMSE mini-mental states examination; CERAD Consortium to Establish a Registry for Alzheimer’s
Disease; HT hypertension; BMI body mass index; ICAM-1 intracellular adhesion molecule-1; VCAM-1 vascular cell adhesion molecule-1; VaD vascular
dementia; CVD cardiovascular disease; HR hazard ratio; CDR clinical dementia rating; TG triglycerides; RR risk ratio; LV left ventricle; AF atrial fibrillation;
ABI ankle–brachial index
Cross-Sectional Studies
Eleven studies report the relationship between various inflammatory markers and
cognitive function (see Table 1) from cross-sectional analyses. The studies vary in
size, ranging from a small Egyptian study (n = 94) [30] to a large study of community-
dwelling elders (n = 3,874) [26]. Studies involve a diverse range of ethnic groups [24,
29, 30, 35]. Some studies include participants from mid to late life [25, 30].
The most consistently reported finding is a cross-sectional association between ele-
vated levels of IL-6 and C-reactive protein (CRP) and poorer cognitive performance
[23, 26, 32, 36].฀The฀MacArthur฀Study฀of฀Successful฀Aging฀(n = 851) assessed IL-6 and
CRP in 70–79-year-olds [23]. Participants were selected on the basis of minimal cogni-
tive disability and intact functional status. Global cognitive function was derived from
a composite of five neuropsychological tests. Cross-sectional analysis revealed that both
CRP and IL-6 levels were inversely related to global cognitive function (P < 0.001) as
well as individual tests of abstraction and language (P < 0.05). IL-6 levels were inversely
related to spatial ability, and CRP was inversely related to the score on the short portable
mental status questionnaire. However, after inclusion of covariates in the analysis, the
results of the analyses were no longer significant for IL-6 or CRP.
Schram et al. [26] investigated inflammatory markers and cognitive function in
two large community-derived cohorts with conflicting results. Both were conducted
in the Netherlands: the Rotterdam Study investigated 3,874 individuals aged
55 years and over (age range, 55–99 years; mean, 72) and the Leiden 85-plus Study
investigated 491 individuals aged 85 years at baseline. Circulating levels of IL-6 and
CRP were measured in both studies, with the addition of a1-antichymotrypsin in the
Rotterdam Study. Neuropsychological testing measured mini-mental state examina-
tion฀score฀(MMSE),฀individual฀measures฀of฀executive฀function฀and฀memory,฀and฀a฀
global score derived from summation of individual neuropsychological test scores.
In cross-sectional analysis, the Rotterdam Study revealed that IL-6 and CRP were
inversely related to global cognition and executive function (P < 0.01) and IL-6 was
inversely฀associated฀with฀MMSE฀(P < 0.05). The Leiden 85-plus Study demonstrated
no significant cross-sectional associations between inflammatory markers and cog-
nition. This variability in results highlights the impact of methodological issues in
the wider literature and may arise from differences in cohort size and age, cytokine
assays (e.g., high-sensitivity CRP measured in Rotterdam Study, whole blood rather
than plasma in Leiden 85-plus analysis), and inclusion of different cognitive tests.
The Longitudinal Aging Study Amsterdam reported by Dik et al. [28] was a
similarly large prospective population-based cohort study. This study measured a1-
antichymotrypsin, albumin, CRP, and IL-6 in participants aged 65–88 years
(n = 1,284; mean age, 75.4 years). Cognitive testing included global cognition and
individual neuropsychological domains such as information processing speed, fluid
intelligence, and memory (see Table 1). After adjustment, only a1-antichymotrypsin
and฀albumin฀were฀significantly฀associated฀with฀delayed฀recall฀and฀MMSE,฀respec-
tively (P < 0.05). Similarly to observations by Schram et al. [26], Dik et al. [28]
found no effect of ApoE 4 on cross-sectional analysis. Dik et al. [28] categorized
markers into tertiles and dichotomized IL-6 around the detection limit to compensate
for reduced assay sensitivity. However, disparities in cytokine measurement and
analysis may in part explain the lack of significant results in this study. A number
of other studies of community-dwelling elders have failed to establish a relation-
ship between cognitive function and CRP [27, 28, 33]. The negative findings by
Fischer et al. [27] may relate to a number of methodological problems including a
very high dropout rate (60%), and the study by Bruunsgaard et al. [33] used a lim-
ited range of cognitive tests and, as it contained a large sample of centenarians, was
biased toward a very old population.
Interaction between inflammatory factors, gender, and other risk variables has
been demonstrated in some studies. For example, in a study of 125 community-
dwelling subjects 42–82 years old, Sweat et al. [25] demonstrated an association
between raised CRP and cognitive impairment in women only. As the relationship
was฀stronger฀in฀overweight฀and฀obese฀subjects฀[body฀mass฀index฀(BMI)฀>฀25]฀and฀
was particularly notable for frontal-executive function, the authors suggested vas-
cular mediation of the relationship.
Few studies have evaluated the relationship between cognitive function and a
comprehensive array of inflammatory markers while controlling for possible cova-
riates. A notable exception is the study by Baune et al. [24], which found an iso-
lated association between IL-8 levels and poorer memory, processing speed, and
motor function in a cohort of 369 older Germans [24]. This same study failed to
find an association between cognitive function and IL-6 or TNF-a.
Of additional note is that our literature search also identified a small number of
studies that explored the relationship between proinflammatory cytokines and cog-
nition in midlife (not tabulated). A small initial study [31] suggested an association
between higher CRP levels and poorer performance on a test of episodic verbal
memory in middle-aged participants. Another study in 460 middle-aged partici-
pants demonstrated an association between higher IL-6 levels and poorer perfor-
mance฀ on฀ tests฀ of฀ attention,฀ working฀ memory,฀ and฀ executive฀ function.฀ More฀
recently, in a large study (n = 4,200) of predominantly male office staff aged
between 35 and 55 years, Gimeno et al. [46] demonstrated an association between
higher levels of CRP and poorer memory function and between higher IL-6 levels
and performance on a semantic fluency task.
Longitudinal Studies
Sixteen studies reported on the relationship between inflammatory markers and

longitudinal cognitive outcome (see Table 2). Higher IL-6 levels at baseline have
been associated with cognitive decline in some longitudinal studies of elderly sub-
jects [23, 26, 32, 35, 37, 43, 44] but not in others [26, 28, 38, 39]. The variability in
findings in regard to IL-6 and long-term cognitive outcome is hard to explain.
Although obvious methodological differences exist between studies, there are few
consistent patterns that unite those studies with and without significant results. For
example, those studies that failed to find a relationship were of similar overall
duration, included participants of similar ages, and included similar covariates in
analyses as those which found a significant relationship between IL-6 at baseline and
long-term cognitive outcome. Of note is that several studies failing to find an asso-
ciation between cognition and IL-6 levels tended to use a less detailed cognitive
battery฀or฀employed฀less฀sensitive฀cognitive฀measures฀such฀as฀MMSE฀[26, 39].
Two studies evaluated IL-6 levels at baseline in nondemented community-dwelling
elders and specifically related this to dementia diagnosis at follow-up [38, 39]. The
Conselice Study of Brain Aging [38] investigated the role of inflammatory markers
on development of dementia in a community cohort of 804 elderly Italians cogni-
tively intact at baseline (mean age, 74 years). After 4 years, combination IL-6 and
CRP predicted all-cause dementia and vascular dementia (VaD) but not AD [hazard
ratio, 2.56; 95% confidence interval (CI), 1.21–5.20]. IL-6 alone did not predict
AD diagnosis. Tan et al. [39] followed 691 elders in the United States for a mean of
7 years but found no relationship between IL-6 and AD diagnosis. The small number
of studies in this area makes firm conclusions impossible. However, taken together
these results suggest that IL-6 levels at baseline are not strongly predictive of AD on
follow-up. There is some preliminary support for a longitudinal association between
IL-6 and VaD, which would be in keeping with a cross-sectional study by Zuliani
et al. [11] in a clinical cohort of 222 patients derived from outpatient clinics in which
higher IL-6 was associated with VaD but not AD (P < 0.05).
Fifteen studies have examined the relationship between raised CRP at baseline
and cognitive outcome at longitudinal follow-up in community-dwelling elders
who were nondemented at initial assessment. Studies are divided regarding the
presence of an association, with eight studies finding an association [23, 34, 36,
41–45] and seven studies failing to find an association [26, 28, 35, 37–40]. There
is no specific pattern of methodological differences between those studies that did
or did not find an association between CRP and cognitive outcome. Those studies
that have found an association between baseline CRP and change in cognition have
highlighted an association with decline in global measures of cognition [26, 43],
memory function [36], dementia diagnosis [34, 38, 45], or dementia severity [42].
A specific association with dementia subtype has not been observed, but available
data suggest that raised CRP at baseline is more strongly associated with VaD
rather than AD [38]. This issue is complicated by the association between CRP and
other known vascular risk factors, and can only be resolved by studies that compre-
hensively control for common vascular risks.
An interaction between CRP and some other risk variables for cognitive decline
has been observed. For example, Yaffe et al. [43] observed that inflammatory markers
only impacted on cognition in those with metabolic syndrome. An interaction
between CRP and ApoE 4 genotype in which CRP has greater impact on cognitive
decline in the presence of ApoE 4 genotype [26] has also been observed, but a
contrary finding has also been published [34].
A limited number of other inflammatory markers have been examined in com-
munity samples to determine any longitudinal impact on cognitive function. Serum
amyloid A (SAA) was measured in one study [35] but had no bearing on long-term
cognition. The acute-phase protein a1-antichymotrypsin has been linked to cognitive

decline in one study [28], but two other studies did not find an association [26, 38].
Two฀studies฀have฀evaluated฀the฀effect฀of฀vascular฀cell฀adhesion฀molecule-1฀(VCAM-1)฀
and฀ intercellular฀ adhesion฀ molecule-1฀ (ICAM)฀ [37, 44]. No association between
VCAM฀and฀cognitive฀decline฀has฀been฀demonstrated,฀but฀one฀study฀[37] did show
an฀ association฀ between฀ ICAM฀ and฀ decline฀ in฀ global฀ cognitive฀ measures฀ and฀
nonverbal reasoning after 4 years of follow-up.
It is noteworthy that a small number of longitudinal studies have examined the
relationship between inflammatory markers and cognition in midlife (not tabu-
lated). A very large cohort of 4,200 office staff aged 35–55 years was examined by
Gimeno et al. [46], but no association was found between IL-6 or CRP and cogni-
tive outcome after 11 years follow-up. In contrast, a small study [31] (n = 65) found
that CRP level was inversely related to memory function after 6 years follow-up.
This study did not control for lifestyle, cardiovascular, and metabolic variables
commonly associated with both raised CRP and cognitive function. The effect of
CRP on cognitive function may only be apparent after a lengthy period of elevation
and may increase with age and vascular burden.
Discussion
The review highlights a degree of inconsistency in results of studies that examine

the relationship between systemic inflammation and cognition. The most common
cross-sectional finding has been the relationship between cognition and both IL-6
and CRP. Longitudinal studies suggest an impact of raised IL-6 and CRP in terms
of both cognitive decline and outcome of dementia. The overall impression is that
systemic inflammation may have relevance for both cross-sectional cognitive func-
tion and decline in cognition in late life. Furthermore, it is apparent that important
interactions with other risk factors for cognitive disorders (e.g., ApoE 4 genotype)
are only just beginning to be explored.
As can be appreciated from Tables 1 and 2, considerable methodological varia-
tion exists between studies, and this in part may account for variability in reported
findings. Key issues that this review has highlighted and which could contribute to
this variability include the discrepancies in study populations (ethnicity, sample
size, and age); the varying sensitivity of assays for inflammatory markers; the
highly variable sophistication of the neuropsychological test battery; and, for lon-
gitudinal studies, variable duration of follow-up.
One of the main issues in understanding the conflicting studies is appreciating
the complexity of systemic inflammation. Peripheral measures of systemic inflam-
mation represent the sum total influence of multiple interacting factors, ranging
from inflammatory disorders to metabolic factors such as obesity through to life-
style factors such as diet and exercise and medications being consumed. Of key
importance for researchers is how to deal with multiple interacting factors as
covariates in analysis. Close examination of the data to determine the relationship

between the inflammatory marker of interest and other key demographic, medical,
or lifestyle variables should form part of an initial approach to analysis so that the
researcher can determine the range of covariates to be entered into the analysis.
A consistent approach is lacking in the literature in this regard.
Another issue in progressing research in this area is enhancement of the range of
inflammatory markers being studied. A more comprehensive approach could assist
in identifying an array of inflammatory variables that may have an impact on cogni-
tion. Comprehensive investigations have rarely been undertaken, particularly in
regard to longitudinal studies of cognition. It may be possible to build a picture of
an “at-risk” inflammatory profile if a clearer understanding of the range of factors
influencing cognition was appreciated. Furthermore, cohorts should ideally be char-
acterized in a comprehensive way so that data on physical health status, lifestyle,
nutritional status, and genetics can be examined and linked to inflammatory status.
Conclusion
Elevated levels of some systemic markers of inflammation, particularly CRP and

IL-6, may be associated with poorer cognitive function at baseline and decline in
cognition with time in the community-dwelling, nondemented elderly. Studies so
far are inconsistent in findings. Preliminary literature extending to midlife popula-
tions also suggests a cross-sectional association between poorer cognitive function
and elevated levels of IL-6 and CRP. Further longitudinal studies are required that
include more comprehensive measures of inflammation and cognition. In particu-
lar, studies in which detailed clinical, lifestyle, and genetic data are available would
help to elucidate the relationship between systemic inflammation and risk of cogni-
tive decline.
References
1. Ishii T, Haga S, Shimizu F (1975) Identification of components of immunoglobulins in senile

plaques by means of fluorescent antibody technique. Acta Neuropathol 32:157–162
2. Rogers J, Luber-Narod J, Styren SD et al (1988) Expression of immune system-associated
antigens by cells of the human central nervous system: relationship to the pathology of
Alzheimer’s disease. Neurobiol Aging 9:339–349
฀ 3.฀ McGeer฀PL,฀Rogers฀J,฀McGeer฀E฀(2006)฀Inflammation,฀anti-inflammatory฀agents฀and฀Alzheimer฀
disease: the last 12 years. J Alzheimers Dis 9:271–276
4. Akiyama H, Bargers S, Barnum S et al (2000) Inflammation and Alzheimer’s disease.
Neurobiol Aging 21:383–421
5. Breitner JC (1996) Inflammatory processes and antiinflammatory drugs in Alzheimer’s dis-
ease: a current appraisal. Neurobiol Aging 17:789–794
฀ 6.฀ McGeer฀PL,฀Schulzer฀M,฀McGeer฀EG฀(1996)฀Arthritis฀and฀anti-inflammatory฀agents฀as฀pos-
sible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies.
7. Wyss-Coray T (2006) Inflammation in Alzheimer’s disease: driving force, bystander or

฀beneficial฀response?฀Nat฀Med฀12(9):1005–1015
฀ 8.฀ Bermejo฀P,฀Martin-Aragon฀S,฀Benedi฀J฀et฀al฀(2008)฀Differences฀of฀peripheral฀inflammatory฀
markers between mild cognitive impairment and Alzheimer’s disease. Immunol Lett
117(2):198–202
9. Alvarez A, Cacabelos R, Sanpedro C et al (2007) Serum TNF-alpha levels are increased and
correlate negatively with free IGF-I in Alzheimer’s disease. Neurobiol Aging 28:533–536
10. Dimopoulos N, Piperi C, Salonicioti A et al (2006) Indices of low-grade chronic inflammation
correlate with early cognitive deterioration in an elderly Greek population. Neurosci Lett
398(1–2):118–123
฀11.฀ Zuliani฀G,฀Ranzini฀M,฀Guerra฀G฀et฀al฀(2007)฀Plasma฀cytokines฀profile฀in฀older฀subjects฀with฀
late-onset Alzheimer’s disease or vascular dementia. J Psychiatr Res 41:686–693
12. Licastro F, Pedrini S, Caputo L et al (2000) Increased plasma levels of interleukin-1, interleu-
kin-6 and a1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation
or signals from the brain? J Neuroimmunol 103:97–102
13. Singh VK, Guthikonda P (1997) Circulating cytokines in Alzheimer’s disease. J Psychiatr Res
31(6):657–660
฀14.฀ McGeer฀ PL,฀ McGeer฀ EG฀ (2001)฀ Polymorphisms฀ in฀ inflammatory฀ genes฀ and฀ the฀ risk฀ of฀
Alzheimer disease. Arch Neurol 58:1790–1792
15. Papassotiropolous A (1999) A genetic variation of the inflammatory cytokine interleukin-6
delays the initial onset and reduces the risk for sporadic Alzheimer’s disease. Ann Neurol
45:666–668
16. Luterman JD, Haroutunian V, Yemul S et al (2000) Cytokine gene expression as a function of
the clinical progression of Alzheimer disease dementia. Arch Neurol 57:1153–1160
฀17.฀ McCusker฀SM,฀Curran฀MD,฀Dynan฀KB฀(2001)฀Association฀between฀polymorphism฀in฀regula-
tory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer’s disease and
vascular dementia: a case-control study. Lancet 357(9254):436–439
฀18.฀ Nicoll฀ JA,฀ Mrak฀ RE,฀ Graham฀ DI฀ et฀ al฀ (2000)฀ Association฀ of฀ interleukin-1฀ gene฀ polymor-
phisms with Alzheimer’s disease. Ann Neurol 47(3):365–368
฀19.฀ Franceschi฀ C,฀ Capri฀ M,฀ Monti฀ D฀ et฀ al฀ (2007)฀ Inflammaging฀ and฀ anti-inflammaging:฀ a฀ sys-
temic฀perspective฀on฀aging฀and฀longevity฀emerged฀from฀studies฀in฀humans.฀Mech฀Ageing฀Dev฀
128:92–105
20. Giunta B, Fernandez F, Nikolic WV et al (2008) Inflammaging as a prodrome to Alzheimer’s
disease. J Neuroinflammation 5:51–66
21. Sparkman NL, Johnson RW (2008) Neuroinflammation associated with aging sensitizes the
brain to the effects of infection and stress. Neuroimmunomodulation 15:323–330
22. Wilson CJ, Finch CE, Cohen HJ (2002) Cytokines and cognition: the case for a head-to-toe
paradigm. J Am Geriatr Soc 50:2041–2056
฀23.฀ Alley฀ DE,฀ Crimmins฀ EM,฀ Karlamangla฀ A฀ et฀ al฀ (2008)฀ Inflammation฀ and฀ rate฀ of฀ cognitive฀
change฀in฀high-functioning฀older฀adults.฀J฀Gerontol฀A฀Biol฀Sci฀Med฀Sci฀63A(1):50–55
24. Baune BT, Ponath G, Golledge J et al (2008) Association between IL-8 cytokine and cognitive
performance฀ in฀ an฀ elderly฀ general฀ population:฀ the฀ MEMO-study.฀ Neurobiol฀ Aging฀
29:937–944
25. Sweat V, Starr V, Bruehl H (2008) C-reactive protein is linked to lower cognitive performance
in overweight and obese women. Inflammation 31(3):198–207
฀26.฀ Schram฀MT,฀Euser฀SM,฀de฀Craen฀AJM฀et฀al฀(2007)฀Systemic฀markers฀of฀inflammation฀and฀
cognitive decline in old age. J Am Geriatr Soc 55:708–716
27. Fischer P, Zehetmayer S, Bauer K et al (2006) Relation between vascular risk factors and
cognition at age 75. Acta Neurol Scand 114:84–90
฀28.฀ Dik฀MG,฀Jonker฀C,฀Hack฀CE฀et฀al฀(2005)฀Serum฀inflammatory฀proteins฀and฀cognitive฀decline฀
in older persons. Neurology 64:1371–1377
฀29.฀ Ravaglia฀G,฀Forti฀P,฀Maioli฀F฀et฀al฀(2005)฀Serum฀C-reactive฀protein฀and฀cognitive฀function฀in฀
healthy฀elderly฀Italian฀community฀dwellers.฀J฀Gerontol฀A฀Biol฀Sci฀Med฀Sci฀60A(8):1017–1021
฀30.฀ Elwan฀ O,฀ Madkour฀ O,฀ Elwan฀ F฀ et฀ al฀ (2003)฀ Brain฀ aging฀ in฀ normal฀ Egyptians:฀ cognition,฀
education, personality, genetic and immunological study. J Neurol Sci 211:15–22
฀31.฀ Teunissen฀CE,฀van฀Boxtel฀MPJ,฀Bosma฀H฀et฀al฀(2003)฀Inflammation฀markers฀in฀relation฀to฀
cognition in a healthy aging population. J Neuroimmunol 134:142–150
฀32.฀ Weaver฀ JD,฀ Huang฀ MH,฀ Albert฀ M฀ et฀ al฀ (2002)฀ Interleukin-6฀ and฀ risk฀ of฀ cognitive฀ decline:฀
MacArthur฀studies฀of฀successful฀aging.฀Neurology฀59:371–378
33. Bruunsgaard H, Andersen-Ranberg K, Jeune B et al (1999) A high plasma concentration of
TNF-a฀ is฀ associated฀ with฀ dementia฀ in฀ centenarians.฀ J฀ Gerontol฀ A฀ Biol฀ Sci฀ Med฀ Sci฀
54A(7):357–364
฀34.฀ Haan฀MN,฀Aiello฀AE,฀West฀NA฀et฀al฀(2008)฀C-reactive฀protein฀and฀rate฀of฀dementia฀in฀carriers฀
and non carriers of apolipoprotein APOE4 genotype. Neurobiol Aging 29:1774–1782
฀35.฀ Jordanova฀V,฀Stewart฀R,฀Davies฀E฀et฀al฀(2007)฀Markers฀of฀inflammation฀and฀cognitive฀decline฀
in an African-Caribbean population. Int J Geriatr Psychiatry 22:966–973
฀36.฀ Komulainen฀P,฀Lakka฀TA,฀Kivipelto฀M฀et฀al฀(2007)฀Serum฀high฀sensitivity฀C-reactive฀protein฀
and cognitive function in elderly women. Age Ageing 36:443–448
37. Rafnsson SB, Deary IJ, Smith FB et al (2007) Cognitive decline and markers of inflammation
and hemostasis: the Edinburgh artery study. J Am Geriatr Soc 55:700–707
฀38.฀ Ravaglia฀G,฀Forti฀P,฀Maioli฀F฀et฀al฀(2007)฀Blood฀inflammatory฀markers฀and฀risk฀of฀dementia:฀
the Conselice study of brain aging. Neurobiol Aging 28:1810–1820
39. Tan ZS, Beiser AS, Vasan RS et al (2007) Inflammatory markers and the risk of Alzheimer’s
disease: the Framingham study. Neurology 68:1902–1908
฀40.฀ Van฀den฀Biggelaar฀AHJ,฀Gussekloo฀J,฀de฀Craen฀AJM฀et฀al฀(2007)฀Inflammation฀and฀interleukin-1฀
signaling network contribute to depressive symptoms but not cognitive decline in old age. Exp
Gerontol 42:693–701
฀41.฀ Weuve฀J,฀Ridker฀PM,฀Cook฀NR฀et฀al฀(2006)฀High-sensitivity฀C-reactive฀protein฀and฀cognitive฀
function in older women. Epidemiology 17:183–189
฀42.฀ Tilvis฀RS,฀Kahonen-Vare฀MH,฀Jolkkonen฀J฀et฀al฀(2004)฀Predictors฀of฀cognitive฀decline฀and฀
mortality฀ of฀ aged฀ people฀ over฀ a฀ 10-year฀ period.฀ J฀ Gerontol฀ A฀ Biol฀ Sci฀ Med฀ Sci฀
59A(3):268–274
43. Yaffe K, Kanaya A, Lindquist K et al (2004) The metabolic syndrome, inflammation, and risk
of฀cognitive฀decline.฀JAMA฀292(18):2237–2242
฀44.฀ Engelhart฀M,฀Geerlings฀MI,฀Meijer฀J฀et฀al฀(2004)฀Inflammatory฀proteins฀in฀plasma฀and฀the฀risk฀
of dementia. Arch Neurol 61:668–672
45. Schmidt R, Schmidt H, Curb D et al (2002) Early inflammation and dementia: a 25-year
follow-up of the Honolulu-Asia aging study. Ann Neurol 52:168–174
฀46.฀ Gimeno฀D,฀Marmot฀MG,฀Singh฀et฀al฀(2008)฀Inflammatory฀markers฀and฀cognitive฀function฀in฀
middle-aged adults: the Whitehall II study. Psychoneuroendocrinology 33:1322–1334
Diagnosis and Clinical Relevance of Depression
and Apathy in Alzheimer’s Disease
Sergio E. Starkstein and Simone Brockman
Abstract Depression is one of the most common psychiatric disorders in

Alzheimer’s disease (AD), and depression is associated with poorer quality of life,
greater disability in activities of daily living, faster cognitive decline, and higher
frequency of depression and burden in caregivers. Depression in AD in usually
underdiagnosed, which may be related to the lack of validated diagnostic criteria
and specific instruments to assess depression in dementia. Left untreated, major
depression in AD may last for about 12 months. Apathy is increasingly recognized
as a major behavioral disorder in neuropsychiatric diseases, but confusion still exists
as to its proper definition and assessment and whether apathy should be considered
a symptom or a syndrome. Nevertheless, a variety of instruments have been devel-
oped to rate the severity of apathy in dementia, and a structured clinical interview
has been recently validated. Moreover, there is now international consensus for a
set of standardized diagnostic criteria to diagnose apathy in AD. Finally, apathy is
a significant predictor of faster functional, mood, and motor decline.
Depression and apathy are among the most common behavioral and psychological
disorders in AD. Both disorders have a strong negative impact on patients’ quality
of life and are related to increased burden and stress among caregivers. One of the
limitations in dealing with apathy and depression in dementia is that their respective
diagnoses are not straightforward. Several scales to rate the severity of depression
and apathy have been validated for use in AD, but standardized diagnostic criteria
have only recently been proposed. This chapter addresses different strategies
currently used to diagnose depression and apathy in AD and discusses the diagnostic
criteria recently proposed. Another aim of this chapter is to discuss the frequency
and clinical correlates of depression and apathy in AD.
S.E. Starkstein (*) and S. Brockman

School of Psychiatry and Clinical Neurosciences,
University of Western Australia, WA, Australia
and
Fremantle Hospital, Education Building T-7,
Fremantle 6959, WA, Australia

DOI 10.1007/978-4-431-53871-4_14, © Springer 2010
202 S.E. Starkstein and S. Brockman
Keywords Anxiety฀•฀Apathy฀•฀Dementia฀•฀Depression฀•฀Motivation
Depression in Alzheimer’s Disease
Diagnosis of Depression in AD
One of the major challenges in neuropsychiatry is how to obtain a valid and reliable
diagnosis of a psychiatric disorder when its symptoms overlap with the symptoms
of the neurological condition. Another limitation is that common disorders such as
depression in Alzheimer’s disease (AD) are rarely isolated phenomena and usually
coexist with other psychiatric conditions such as anxiety, apathy, pathological
affective display, psychotic symptoms, and poor insight. These confounding factors
may account for the lack of general consensus on the most valid and reliable
method to diagnose depression in AD.
Four different strategies have been used to diagnose depression in chronic
degenerative disorders. The “inclusive approach” [1] diagnoses depression based
on symptoms that may or may not be related to the physical illness. This approach
is the most commonly used diagnostic strategy in neuropsychiatry. The “exclusive
approach,” on the other hand, does not include for diagnosis those symptoms con-
sidered to be related to the physical illness [2]. The “substitutive approach” replaces
overlapping symptoms of depression with psychological symptoms [3]. Finally, the
“specific symptom approach” only considers for diagnosis those symptoms that
were identified as belonging to a “depressive cluster” using specific statistical tech-
niques, such as latent class analysis. In a recent study Verkaik and coworkers [4]
examined potential confounders for the diagnosis of depression in AD. One main
confounder is that some studies diagnosed depression on the basis of a cutoff score
on a depression scale (the “continuous method”) whereas other studies diagnosed
depression using standardized diagnostic criteria (the “categorical method”). Other
confounders identified by the authors are (1) the grouping of different types of
dementia, (2) different criteria to diagnose AD, (3) different instruments to assess
the severity of AD and depression, and (4) heterogeneous samples in terms of size
and sociodemographic characteristics.
Diagnostic Criteria for Depression in AD
Lyketsos and coworkers were the first to propose standardized criteria to diagnose
depression in AD [5]. They assessed a large sample of individuals living in the com-
munity using the Neuropsychiatric Inventory (NPI). A latent class analysis produced
three clusters, one of which was characterized by depression, anxiety, irritability, and
apathy. Based on this cluster, Lyketsos and coworkers proposed the diagnostic crite-
ria summarized in Table 1. One limitation of the study lies with the use of the NPI,
Depression and Apathy in Alzheimer’s Disease 203
Table 1 Diagnostic criteria for Alzheimer’s disease (AD)-associated neuropsychiatric distur-

bance (adapted from [5])
A. Meeting National Institutes of Neurology and Communicative Disorders/Alzheimer’s Disease
and Related Disorders Association (NINCDS/ADRDA) criteria for probable AD.
B. A prominent disturbance of affect, disruptive to the patient or the care environment, and
representing a change from the patient’s baseline, as evidenced by the presence of one or
more of the following symptoms:
(1) Depression
(2) Irritability
(3) Anxiety
(4) Euphoria
C. One or more of the following associated symptoms must be present:
(1) Aggression
(2) Psychomotor agitation
(3) Delusions
(4) Hallucinations
(5) Sleep disturbance
(6) Appetite disturbance
D. Symptoms from B and C co-occur most days, and the disturbance has a duration of at least
2 weeks.
E. The disturbance has its first onset within 2 years or after the onset of dementia.
F. The disturbance cannot be explained in its entirety by another cause (e.g., a general medical
condition, medications, life stressors).
a useful screening instrument but without the phenomenological detail necessary to

diagnose depression using diagnostic criteria such as in the DSM-IV.
A workgroup conveyed by the National Institutes of Mental Health (NIMH)
proposed standardized diagnostic criteria for depression in AD (NIMH-dAD) based
on expert advice [6] (Table 2). These criteria are similar to the DSM-IV criteria for
major depression; but with the inclusion of irritability and social withdrawal to
replace loss of libido, and loss of pleasure in response to social contact to replace loss
of interest. Finally, the NIMH-dAD diagnostic criteria require only three symptoms
for the diagnosis of depression, and these symptoms do not have to be present
every day.
An early study from our group assessed a consecutive series of AD patients attend-
ing a memory clinic using the structured clinical interview for the DSM-III-R (SCID)
[7]. The main finding was that the presence of sad mood was significantly associated
with most symptoms of depression assessed by the Hamilton depression scale, such as
guilt, suicidal ideation, insomnia, loss of interest, psychomotor retardation, worrying,
anxiety, loss of libido, and loss of energy. The question arises as to the specificity of
symptoms of depression in AD, that is, whether AD patients have symptoms of depres-
sion in the absence of sad mood or loss of interest/anhedonia (masked depression).
We found that only 2% of 233 AD patients had enough symptoms to meet the
DSM-IV criteria for major depression in the absence of sad mood or loss of interest/
anhedonia. Moreover, we also found that AD patients who reported no sad mood had
no more symptoms of depression than a group of age-comparable healthy controls.
Table 2 Provisional diagnostic criteria for depression of AD (adapted from [6])

A. Three or more of the following symptoms have been present during the same 2-week period
and represent a change from previous functioning: at least one of the symptoms is either (1)
depressed mood or (2) decreased positive affect or pleasure:
(1) Clinically significant depressed mood
(2) Decreased positive affect or pleasure in response to social contacts and usual activities
(3) Social isolation or withdrawal
(4) Disruption in appetite
(5) Disruption in sleep
(6) Psychomotor changes
(7) Irritability
(8) Fatigue or loss of energy
(9) Feelings of worthlessness, hopelessness, or excessive or inappropriate guilt
(10) Recurrent thoughts of death, suicidal ideation, plan, or attempt
B. All criteria met for dementia of the Alzheimer type.
C. The symptoms cause clinically significant distress or disruption in functioning.
D. The symptoms do not occur exclusively during the course of a delirium.
E. The symptoms are not caused by the direct physiological effects of a substance.
F. The symptoms are not better accounted for by other psychiatric conditions.
Specify if:
Co-occurring onset: if onset antedates or co-occurs with the AD symptoms
Post-AD onset: if onset occurs after AD symptoms
Specify:
With psychosis of AD
With other significant behavioral signs or symptoms
With past history of mood disorders
Taken together, these findings suggest that symptoms of depression are not rife among
euthymic AD patients. It is important to note that AD patients may have poor insight
into their own depressive symptoms and tend to minimize or deny their presence.
Therefore, it is important to obtain collateral information when assessing patients’
mood.
In a more recent study we assessed the construct of major and minor depression in
a series of 670 patients with AD [8]. In this cross-sectional study, we found that 26%
had major depression and an identical percentage had minor depression. The percentage
of patients with three or more symptoms of depression (as required by the NIMH-dAD
diagnostic criteria) but without sad mood was 22% among patients with mild AD, 23%
among patients with moderate AD, and 41% among patients with severe AD,
suggesting that the NIMH-dAD may have high sensitivity but poor specificity.
Another strategy to clarify the phenomenology of depression in AD is to assess the
pattern of symptom improvement on the remission of depression. To this end, we exam-
ined a series of 65 patients with AD and depression who received a follow-up assess-
ment 1–3 years later [9]. At follow-up, 33 patients had a full remission of depression
whereas 32 patients continued to be depressed (with major or minor depression).
The main finding was that patients with a full remission of depression had a significantly
lower score on the Hamilton depression scale for the symptoms of sad mood, guilt,
suicide ideation, insomnia, loss of interest, psychomotor changes, loss of energy, social
withdrawal, and loss of appetite/weight as compared to patients with no remission of
depression. Moreover, patients on remission also showed a significant decrease in the
severity of anxiety. On the other hand, there were no significant between-group differ-
ences in the severity of apathy, supporting previous findings that showed that apathy and
depression are overlapping but independent syndromes in AD [10].
Frequency of Depression in AD
Before discussing the frequency of depression in AD, it is important to note that esti-
mates of depression in AD depend on sampling issues, diagnostic methods, and clinical
manifestations. The prevalence of major and minor depression has been estimated to
range between 30% and 50% [3]. Population studies reported a prevalence of dysphoria
of 20% and an 18-month incidence of 18% [11, 12]. A population case-report study
from the United Kingdom diagnosed major depression in 24% of their sample [13],
and similar frequencies were reported in a recent study from Maastricht [14].
Clinical Correlates of Depression in AD
Depression in AD has been associated with worse quality of life, greater impair-
ments in activities of daily living, decrease in caregiver’s well-being [15], faster
cognitive decline, greater health care utilization [16], higher mortality rates [17],
and higher rates of nursing home placement [18]. Our group [8] found that patients
meeting DSM-IV criteria for either minor or major depression had more severe
social dysfunction and greater impairment in activities of daily living than AD
patients without depression. Furthermore, AD patients with major depression had
more severe anxiety, apathy, delusions, and parkinsonism than patients with minor
depression, suggesting that the severity of psychopathological and neurological
impairments in AD increases with increasing severity of depression. On the other
hand, patients with either major or minor depression had similar deficits on activi-
ties of daily living and social functioning, suggesting that even mild levels of
depression are significantly associated with increased functional impairment in
AD. Depression among nursing home patients with AD has been associated with
relatively more severe malnutrition, behavioral problems, noncompliance with treat-
ment, increased nursing staff time, and excessive mortality rate [19].
Conclusion
Depression is among the most frequent psychiatric disorders in AD. One important
limitation to the diagnosis of depression in AD is the lack of valid and reliable criteria.
Recent studies proposed standardized diagnostic criteria for depression in AD for

empirical validation. Our group demonstrated the validity of the DSM-IV criteria for
major depression in several studies [7, 8]. Depression is associated with a poor quality
of life for both patients and caregivers [15]. Depressed AD patients have a faster func-
tional decline, earlier admission to nursing homes, and higher mortality. Future studies
should examine whether the successful treatment of depression in AD may have a
beneficial impact upon the comorbid conditions of depression.
Apathy in AD
Apathy is defined as a psychiatric syndrome characterized by deficits in goal-

directed behaviors as manifested by the simultaneous diminution of cognitive and
emotional concomitants of goal-directed behavior [20]. A similar division of apathy
into emotional, cognitive and behavioral domains was proposed by van Reekum
and coworkers [21]. More recently, Levy and Dubois suggested that apathy should
be defined as an observable behavioral syndrome consisting of a quantitative
reduction in self-generated voluntary and purposeful behaviors [22].
One of the limitations for the diagnosis of apathy in AD is that this syndrome is
subsumed under different terms such as athymormia, psychic akinesia, abulia, and
the negative syndrome. There is also a paucity of structured interviews to diagnose
apathy in dementia, and specific diagnostic criteria have only recently been validated.
We discuss here the different instruments and strategies to diagnose apathy in AD,
and we also discuss the major comorbid disorders of apathy in dementia.
Diagnosis of Apathy in AD
Although the ICD-10 makes no reference to apathy, the DSM-IV mentions apa-
thy as a subtype of personality disorder caused by a General Medical Condition.
Our group has validated a set of standardized criteria for the diagnosis of apathy
in AD [23]. To this aim, we assessed a series of 319 patients with AD using the
apathy scale (a severity rating scale) and found that 13% of the sample met our
ad hoc criteria for apathy. These criteria have been recently updated by Starkstein
and Leentjens [24] (Table 3). On the other hand, none of a series of 46 age-
comparable healthy controls demonstrated apathy. It is important to note the
overlap between depression and apathy in AD: 13% of the AD sample had apa-
thy and no depression, but 24% had both depression and apathy. AD patients
with apathy only and patients with neither apathy nor depression had similar
scores on the Hamilton depression scale, suggesting that apathy does not artifi-
cially increase depression scores in this population.
The European Psychiatric Association Task Force on apathy has recently
published standardized diagnostic criteria for apathy in AD [25]. These criteria
Table 3 Diagnostic criteria for apathy (adapted from [24])

A. Lack of motivation relative to the patient’s previous level of functioning or the standards of
his or her age and culture as indicated either by subjective account or observation by others.
B. Presence for at least 4 weeks, during most of the day, of at least one symptom belonging to
each of the following three domains:
Diminished goal-directed behavior
(1) Lack of effort or energy to perform everyday activities
(2) Dependency on prompts from others to structure everyday activities
Diminished goal-directed cognition
(3) Lack of interest in learning new things, or in new experiences
(4) Lack of concern about one’s personal problems
Diminished concomitants of goal-directed behavior
(5) Unchanging or flat affect
(6) Lack of emotional responsivity to positive or negative events
C. The symptoms cause clinically significant distress or impairment in social, occupational,
or other important areas of functioning.
D. The symptoms are not caused by diminished level of consciousness or the direct
physiological effects of a substance.
follow the same general structure as the standardized criteria published by

Starkstein and Leentjens, but were made more sensitive by requiring symptoms on
two of the three domains rather than symptoms in each of the three domains.
Regardless of which criteria are used, it is important to note the suggestion by
Marin and Wilkosz [26] that apathy should be diagnosed only after a comprehen-
sive mental state examination, which should include assessments of the individu-
al’s social and physical environment, variability in human goals, interests,
emotional displays, and activities, as well as their level of education, social status,
age cohort, and other cultural factors.
Several instruments are currently used to measure the severity of apathy in AD.
Marin and coworkers were the first to develop a specific scale to measure the
severity of apathy. The apathy evaluation scale (AES) [27] has three versions: a
self-rated scale, a caregiver version, and a clinician version. Starkstein and
coworkers developed the apathy scale [28], an abridged and modified version of
Marin’s scale. This scale has been validated for use in AD, Parkinson’s disease, and
stroke. Cummings and coworkers developed the NPI [29], an instrument adminis-
tered to caregivers that includes a specific module on apathy. The dementia apathy
interview and rating [30] assesses dementia-related changes in motivation, emo-
tional responsiveness, and engagement. Finally, Robert and coworkers developed
the apathy inventory [31], which rates several dimensions of apathy such as emo-
tional blunting, lack of initiative, and loss of interest.
To our knowledge, there is one single structured interview for apathy in AD.
Starkstein and coworkers developed the structured clinical interview for apathy
(SCIA) to screen for symptoms of apathy into standardized diagnostic criteria
[23]. The SCIA includes a series of questions to assess the domains of lack of
motivation, lack of effort, dependency on others, lack of interest and concern, and
blunted affect. Based on responses to these questions, a diagnosis of apathy may
be made using the Starkstein and Leentjens’ or the European diagnostic criteria for
apathy.
Differential Diagnosis of Apathy in AD
The first differential diagnosis to be considered is abulia, defined by Ribot as a

“loss, lack or impairment of the power of the will to execute what is in mind” [32].
Marin considered abulia and apathy to be on a continuum of motivational and
emotional deficits, with abulia as the most severe manifestation [20]. Marin defined
abulia as poverty of behavior and speech output, lack of initiative, loss of emotional
responses, psychomotor slowing, and prolonged speech latency [20]. Akinetic
syndromes have been described to range from psychic akinesia (defined as the lack
of goal-directed activities among patients who are fully responsive), to akinetic
mutism (defined as a state of immutability caused by lack of voluntary movement,
mutism, and vigilant gaze) [33]. Laplane and Dubois [34] described the
“auto-activation deficit,” which is characterized by inertia, mental emptiness,
stereotyped activities, flat affect, and blunted emotional responses. A full reversal
of the negative state on external stimulation was suggested as the main difference
between this syndrome and abulia.
Frequency of Apathy in AD
In a recent study, Starkstein and coworkers [35] examined the frequency of apathy
in a series of 319 patients with AD, 117 patients with depression but no dementia,
and 36 age-comparable healthy individuals. Apathy was diagnosed in 37% of the
AD patients, in 32% of the depressed patients, and in none of the healthy controls.
A Latin American study [36] examined 60 AD patients with the NPI, reporting a
frequency of apathy of 53%. A similar frequency (59%) was recently reported by
an American study [37].
Clinical Correlates of Apathy in AD
In a recent series of longitudinal studies, our group examined the predictive validity
of apathy in AD. The first study included a series of patients who were followed for
1–4 years [38]. At baseline, apathy was significantly associated with older age and
depression (both major and minor). The frequency of apathy increased from 14%
in the stage of very mild AD to 61% in the stage of severe AD. Therefore, cognitive
deficits are not sufficient to produce apathy in AD because about half the patients
with moderate or severe dementia did not show apathy. Whether cognitive deficits
are necessary to produce apathy has not been yet determined, but most studies
assessing patients with a variety of neurological conditions such as stroke and
Parkinson’s disease found a significant association between greater apathy and
more severe cognitive impairments [39, 40]. At follow-up, patients with apathy at
baseline or patients who developed apathy during follow-up had a significant
increase in Hamilton depression scale scores compared to AD patients with no
apathy at baseline. Moreover, patients with apathy at baseline or those who devel-
oped apathy during follow-up had a significantly greater functional and cognitive
decline and more severe parkinsonism than patients without apathy at baseline [41].
Based on these findings, we proposed that apathy may be a behavioral marker of a
more “malignant” type of AD, with more severe behavioral problems and a faster
cognitive, functional, and motor decline.
Conclusions
Apathy is present in about half of patients with AD and is significantly related to

more severe dementia. There is a variety of instruments to rate the severity of apa-
thy in AD, but structured clinical interviews have been developed only recently.
There is now a consensus among international researchers on a common set of
standardized criteria to diagnose apathy in AD. Apathy is associated with poor
prognosis. Patients with apathy and dementia have a faster functional, cognitive,
and motor decline than patients without apathy. Future studies should aim at finding
successful therapies for apathy in dementia.
Acknowledgments This study was partially supported with grants from the University of
Western Australia, and the National Health and Medical Research Council.
References
1. Cohen-Cole SA, Stoudemire A (1987) Major depression and physical illness. Psychiatr Clin
North Am 10:1–17
2. Gallo JJ, Rabins PV, Anthony JC (1999) Sadness in older persons: 13-year follow-up of a
community sample in Baltimore, Maryland. Psychol Med 29(2):341–350
3. Olin JT, Katz IR, Meyers BS et al (2002) Provisional diagnostic criteria for depression of
Alzheimer disease: rationale and background. Am J Geriatr Psychiatry 10(2):129–141
4. Verkaik R, Nuyen J, Schellevis F et al (2007) The relationship between severity of Alzheimer’s
disease and prevalence of comorbid depressive symptoms and depression: a systematic
review. Int J Geriatr Psychiatry 22(11):1063–1086
5. Lyketsos CG, Sheppard JM, Steinberg M et al (2001) Neuropsychiatric disturbance in
Alzheimer’s disease clusters into three groups: the Cache County study. Int J Geriatr
Psychiatry 16(11):1043–1053 (see comment)
6. Olin JT, Schneider LS, Katz IR et al (2002) Provisional diagnostic criteria for depression of
Alzheimer disease. Am J Geriatr Psychiatry 10(2):125–128
7. Chemerinski E, Petracca G, Sabe L et al (2001) The specificity of depressive symptoms in

patients with Alzheimer’s disease. Am J Psychiatry 158(1):68–72
8. Starkstein SE, Jorge R, Mizrahi R et al (2005) The construct of minor and major depression
in Alzheimer’s disease. Am J Psychiatry 162:2086–2093
9. Starkstein SE, Mizrahi R, Garau LM (2005) Specificity of symptoms of depression in
Alzheimer disease: a longitudinal analysis. Am J Geriatr Psychiatry 13:803–807
10. Levy ML, Cummings JL, Fairbanks LA et al (1998) Apathy is not depression. J Neuro-
psychiatry Clin Neurosci 10(3):314–319
11. Lyketsos CG, Olin J (2002) Depression in Alzheimer’s disease: overview and treatment. Biol
Psychiatry 52(3):243–252
12. Starkstein SE, Chemerinski E, Sabe L et al (1997) Prospective longitudinal study of depres-
sion and anosognosia in Alzheimer’s disease. Br J Psychiatry 171:47–52
13. Burns A, Jacoby R, Levy R (1990) Psychiatric phenomena in Alzheimer’s disease. III:
Disorders of mood. Br J Psychiatry 157:81–86
14. Aalten P, de Vugt ME, Jaspers N et al (2005) The course of neuropsychiatric symptoms in
dementia. Part I: Findings from the two-year longitudinal Maasbed study. Int J Geriatr
15. Shin IS, Carter M, Masterman D et al (2005) Neuropsychiatric symptoms and quality of life
in Alzheimer disease. Am J Geriatr Psychiatry 13(6):469–474
16. Kunik ME, Snow AL, Molinari VA et al (2003) Health care utilization in dementia patients
with psychiatric comorbidity. Gerontologist 43(1):86–91
17. Suh GH, Kil Yeon B, Shah A et al (2005) Mortality in Alzheimer’s disease: a comparative prospec-
tive Korean study in the community and nursing homes. Int J Geriatr Psychiatry 20(1):26–34
18. Lee HB, Lyketsos CG (2003) Depression in Alzheimer’s disease: heterogeneity and related
issues. Biol Psychiatry 54(3):353–362
19. Cohen CI, Hyland K, Kimhy D (2003) The utility of mandatory depression screening of
dementia patients in nursing homes. Am J Psychiatry 160:2012–2017
20. Marin RS (1991) Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci
3(3):243–254
21. van Reekum R, Stuss DT, Ostrander L (2005) Apathy: why care? J Neuropsychiatry Clin
Neurosci 17(1):7–19
22. Levy R, Dubois B (2006) Apathy and the functional anatomy of the prefrontal cortex-basal
ganglia circuits. Cereb Cortex 16:916–928
23. Starkstein SE, Ingram L, Garau ML et al (2005) On the overlap between apathy and depres-
sion in dementia. J Neurol Neurosurg Psychiatry 76(8):1070–1074
24. Starkstein S, Leentjens AF (2008) The nosological position of apathy in clinical practice.
25. Robert P, Onyike CU, Leentjens AF et al (2009) Proposed diagnostic criteria for apathy in
Alzheimer’s disease and other neuropsychiatric disorders. Eur Psychiatry 24(2):98–104
26. Marin RS, Wilkosz PA (2005) Disorders of diminished motivation. J Head Trauma Rehabil
20(4):377–388
27. Marin RS, Biedrzycki RC, Firinciogullari S (1991) Reliability and validity of the apathy
evaluation scale. Psychiatry Res 38(2):143–162
28. Starkstein SE, Mayberg HS, Preziosi TJ et al (1992) Reliability, validity, and clinical corre-
lates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 4(2):134–139
29. Cummings JL (1997) The neuropsychiatric inventory: assessing psychopathology in dementia
patients. Neurology 48(suppl 6):S10–S16
30. Strauss ME, Sperry SD (2002) An informant-based assessment of apathy in Alzheimer dis-
ease. Neuropsychiatry Neuropsychol Behav Neurol 15(3):176–183
31. Robert PH, Clairet S, Benoit M et al (2002) The apathy inventory: assessment of apathy and
awareness in Alzheimer’s disease, Parkinson’s disease and mild cognitive impairment. Int
J Geriatr Psychiatry 17(12):1099–1105
32. Berrios GE, Gili M (1995) Abulia and impulsiveness revisited: a conceptual history. Acta
Psychiatr Scand 92(3):161–167
33. Sims A (2003) Symptoms in the mind. Saunders, Philadelphia

34. Laplane D, Dubois B (2001) Auto-activation deficit: a basal ganglia related syndrome. Mov
Disord 16(5):810–814
35. Starkstein SE, Petracca G, Chemerinski E et al (2001) Syndromic validity of apathy in
Alzheimer’s disease. Am J Psychiatry 158(6):872–877
36. Tatsch MF, Bottino CM, Azevedo D et al (2006) Neuropsychiatric symptoms in Alzheimer
disease and cognitively impaired, nondemented elderly from a community-based sample in
Brazil: prevalence and relationship with dementia severity. Am J Geriatr Psychiatry
14(5):438–445
37. Landes AM, Sperry SD, Strauss ME (2005) Prevalence of apathy, dysphoria, and depression
in relation to dementia severity in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci
17(3):342–349
38. Starkstein SE, Jorge R, Mizrahi R et al (2006) A prospective longitudinal study of apathy in
Alzheimer’s disease. J Neurol Neurosurg Psychiatry 77:8–11
39. Starkstein SE, Fedoroff JP, Price TR et al (1993) Apathy following cerebrovascular lesions.
Stroke 24(11):1625–1630
40. Starkstein S, Merello M, Jorge R et al (2009) The syndromal validity and nosological position
of apathy in Parkinson’s disease. Mov Disord 15:1211–1216
41. Starkstein SE, Merello M, Brockman S et al (2009) Apathy predicts more severe parkin-
sonism in Alzheimer’s disease. Am J Geriatr Psychiatry 17(4):291–298
Cognitive Decline and Treatment
of Alzheimer’s Disease
Luis Ignacio Brusco
Abstract Alzheimer’s disease (DTA) constitutes the most common cause of

dementia. Its prevalence is about 2–4% at the age of 70 and between 30% and 50%
in persons over the age of 85.
The prevalence doubles every 5 years, being even more prevalent in women,
which probably reflects their greater longevity. With the increase of life expectancy,
the impact of this disease will keep growing significantly unless prevention and/or
treatment actions are developed.
Many efforts in diagnostic methodology as well as trials used to stop the
progression in this preclinical stage of investigation have been made and still
continue, although at present there are not worldwide agreed or approved
treatments for it.
Nowadays, there are five drugs that were approved by the FDA for probable
DTA treatment; only four of them are used regularly.
Differential diagnosis of Alzheimer’s disease constitutes one of the most
complex challenges in medicine.
We could say that we can found five possible variables for the differential
diagnosis.
1. Clinical interpretation
2. Neuroimaging
3. Differential blood check for cognitive disorders
4. Genetic biomarkers (or data in lifetime clinical record, LCR)
5. Neurocognitive evaluation
L.I. Brusco (*)

School of Medicine, Buenos Aires University, Buenos Aires, Argentina
and
Alzheimer Argentina, www.alzheimer.org.ar
and
Argentine Neuropsychiatric Association, Buenos Aires, Argentina

DOI 10.1007/978-4-431-53871-4_15, © Springer 2010
214 L.I. Brusco
These items must be studied by a qualified stuff at specialized centers, if possible,

to arrive at the closest diagnosis to reality. Finally, biomarkers and genetics
constitute substantial progress that will lead to a sensitive and specific diagnosis at
the same time.
Keywords Alzheimer฀disease฀•฀Early฀diagnosis฀•฀Genetic฀biomarkers฀•฀Treatment
As longevity increases, aging-related diseases become more and more prominent.

Cognition disorders increase with the growing number of elderly individuals in
societies, turning the insanity syndrome into one of the main concerns of the elderly
populations.
Within dementia, Alzheimer’s disease (AD) is the most common cause of
dementia associated with age, with a frequency of presentation that increases
dramatically at 70 years of age. In 2000, it was estimated that there were
approximately 4.5 million individuals with AD in the United States, and that
that number is projected to become 14 million by 2050. This alarming statistic
has led to the identification and search for markers of early disease as well as
redefining the concept of minimal cognitive impairment and its potential
conversion to AD. Many efforts in diagnostic methods as well as trials aimed
at halting the progression of this preclinical research stage have been conducted
and continue to this day.
AD is a neurodegenerative disorder that produces progressive intellectual
decline, as well as a variety of neuropsychiatric and behavioral disorders.
This disease is one of the most important health, social, and cultural problems
of the new century, given the severity of the symptoms and their evolution, but
mainly its association with old age and the fact that our society, with the increasing
age of the population, is heading toward aging.
In the clinical framework of AD, we can recognize the effect on the following
areas:
1. Cognitive
2. Behavioral
3. Daily rhythms and sleep–wake cycles
Neuropsychological alterations of AD include abnormalities in memory (recent
and remote), aphasia, visuo-spatial and visuo-constructive disorders, calculation
defects, praxis, gnosias, difficulty in abstraction, and judgment.
The neuropsychiatric alterations include personality disorders, delusions and
confusion, hallucinations and depression, sleep, appetite, and sexuality disorders,
and abnormal motor behavior. Typically, the most severe and earliest AD symptoms
are the insidious problems and progressive memory loss in recalling the most recent
learning situations; this stage is followed by language disturbances, compromise of
visuo-spatial abilities, praxis, and attention impairment. A number of behavioral
Cognitive Decline and Treatment of Alzheimer’s Disease 215
symptoms that significantly affect the life quality of patients and cohabitants usually
appear in the intermediate and late stages of the disease.
Changes in the biological rhythms involve quantitative and qualitative alterations
of sleep, increase of evening symptoms when the sun sets (sundowning), and
flattening of biological rhythms, including plane body rhythm with a decline of the
patient’s daytime mobility and increased activity at night, thus affecting their
environment.
The diagnosis of AD is mainly clinical and, to date, we lack a biological marker
or diagnostic test that could positively and selectively identify the disease, beyond
the final anatomopathological assessment.
Accordingly, the clinical assessment remains the most important tool in the
diagnostic process, but neuropsychology and some complementary methods of
diagnosis also collaborate [1].
The distinction between the cognitive and noncognitive aspects (also called
primary and secondary) will be used with an organizational and didactic criterion
because the coexistence and overlapping of these phenomena is normal in the clinical
field and is beyond this dichotomy.
Current diagnostic criteria allow for high sensitivity and diagnostic efficiency in
close to 85% of cases. Standardizations propose a consensus of diagnostic standards
to be used in our environment, thus minimizing disputes arising from the use of the
different proposals.
The most commonly used criteria for disease diagnosis are based on the
Diagnostic and Statistical Manual, Fourth Revision (DSM IV TR), or the
National Institute of Neurologic, Communicative Disorders and Stroke/
Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA).
The American Academy of Neurology has evaluated these criteria and considered
them reliable. However, there are several points of evidence indicating the
need to update the current criteria for definition, such as inadequate diagnostic
specificity: the criteria of DSM IV TR and NINCDS–ADRDA have been vali-
dated using neuropathological gold standards, showing a diagnostic accuracy
that ranges between 65% and 96%. When the diagnosis was for other demen-
tias and not AD, it was only between 23% and 88%.
The patient’s medical history is a key element in the diagnosis of dementia
syndromes. Input from informants (not just the story of the patient) is also
important. A number of tools are available that can be used to obtain information
about the everyday activities and performance of these patients, although none
has been able to demonstrate superior efficacy over another; therefore, the doctor’s
careful inquiry about this item is crucial.
The differential diagnosis of AD is one of the most complex challenges of
medicine: not only because it is a disease that compromises the person’s thought
and behavior, dissocializing them and generating a substantial change in their
integrity, but also because it is based on a complex set of diagnostic premises
through which we reach a diagnosis that can only be confirmed by analyzing the
patient’s brain neuropathology, something that is generally not done.
216 L.I. Brusco
Also, the observational, supplementary, and semiological variables are increasingly

complex and difficult to correlate if you do not have the experience and logical
criteria that enable us to combine a thought that reaches a possible or probable diag-
nosis with that which would enable us to establish an adequate treatment for the
cognitive patient’s diagnostic and evolutional situation.
We could say then that there are five possible variables for the differential
diagnosis:
1. Clinical assessment (observation of a case history, etc.)
2. Neuroimaging
3. Differential blood screening for cognitive impairment
4. Genetic biomarkers and/or cerebrospinal fluid (CSF)
5. Neurocognitive assessment
These items should be examined by qualified staff and, if possible, at specialized
centers to reach a diagnostic certainty as close to reality as possible. Finally, bio-
markers and genetics are a significant advancement that will enable a sensitive and
specific diagnosis.
Genetic study currently enables a greater approach, particularly of the study of
the฀ apolipoprotein-E฀ (APO-E)฀ gene,฀ which฀ in฀ some฀ cases฀ enables฀ us฀ to฀ take฀ the฀
diagnosis to even more than 85% of certainty [2].
The approach to AD therapy implies recognizing the different types of symptoms
present: basically cognitive, noncognitive, and behavioral. The term “noncognitive” is
used to include behavioral, mood, and perception (illusions and hallucinations) altera-
tions, alterations in the course and content of thought, and changes in level of activity
(both motor and verbal) [3]. Verbal and physical aggression, apathy, social withdrawal,
depression, distrust, sleep disorders, increased or reduced sexual activity, and negativism
or resistance to treatment should be considered as noncognitive symptoms [4].
The term “noncognitive” has been chosen to differentiate these symptoms
from those that are cognitive in their origin, that is, symptoms that are a direct
result of the impairment of the memory, judgment, visuo-spatial function,
math abilities, object manipulation when the motor function is intact (praxia),
and language, among others. Although the distribution of noncognitive and
cognitive symptoms is clear in theory, it is not that clear in practice. For
instance, if a patient falsely accuses his relatives of stealing things from him,
this could be described as a paranoid-like idea. However, the patient’s
cognitive impairment may be the origin of the symptom, having himself
forgotten where he leaves his belongings. The noncognitive symptom is his
accusation against his relatives, but the cognitive symptom of origin is
fixation hypomnesia.
The clearest symptom of AD is the impairment of cognitive capacity as a
result of neuronal destruction. However, noncognitive symptoms occur
frequently and are a source of difficulty both for the patient and for the caretakers.
Some authors consider these are the real core symptoms of the dementia
syndrome.฀Even฀though฀we฀can฀admit฀that฀noncognitive฀symptoms฀do฀not฀appear฀
in all AD patients, they are often the main reason why a patient seeks medical attention.
It is therefore obvious that a correct treatment of the behavioral changes of an AD
patient not only generates an improvement of the behavioral performance of the
subject but also an increase of their intellectual possibilities [5]. Also, these
disorders limit the patient at a social level and may be the most frequent cause for
an early hospitalization, which undoubtedly changes the future situation and
clearly increases the costs generated by this disease.
Treatment of AD
The approach to AD therapy implies recognizing the different types of symptoms

present: basically cognitive, noncognitive, and behavioral.
The term “noncognitive” has been chosen to differentiate these symptoms
from those that are cognitive in their origin, that is, symptoms which are a direct
result of the impairment of the memory, judgment, visuo-spatial function, math
abilities, object manipulation when the motor function is intact (praxia), and
language, among others. Although the distinction of noncognitive and cognitive
symptoms is clear in theory, it is not that clear in practice. For instance, if a
patient falsely accuses his relatives of stealing things from him, this could be
described as a paranoid-like idea. However, the patient’s cognitive impairment
may be the origin of the symptom, having himself forgotten where he leaves his
belongings. The noncognitive symptom is his accusation against his relatives,
but the cognitive symptom of origin is fixation hypomnesia.
The clearest symptom of AD is the impairment of the cognitive capacity as
a result of neuronal destruction. However, noncognitive symptoms occur
frequently and are a source of difficulty both for the patient and for the care-
takers. Some authors consider these are the real core symptoms of the dementia
syndrome.฀ Even฀ though฀ we฀ can฀ admit฀ that฀ noncognitive฀ symptoms฀ do฀ not฀
appear in all AD patients, they are often the main reason why a patient seeks
medical attention. It is therefore obvious that correct treatment of the
behavioral changes of an AD patient not only generates an improvement of
the behavioral performance of the subject but also an increase of their intel-
lectual possibilities. Also, these disorders limit the patient at a social level
and may be the most frequent cause for an early hospitalization, which
undoubtedly changes the future situation and clearly increases the costs
generated by this disease.
Five drugs are currently approved by the U.S. Food and Drug Administration
(FDA) for the treatment of possible AD, of which only four are used regularly
[6]. Three of these commonly used drugs are acetylcholinesterase inhibitors, the
rational use of which is based on the literature evidence stating that AD patients
suffer from a cholinergic deficit [7]. These anticholinesterase drugs are used in
an independent manner; that is, only one is administered.
218 L.I. Brusco
The other drug used in combination with the aforementioned ones is memantine,
a partial antagonist of glutamate used in combination therapy with cholinergic
therapy [8].
Specific Goals of Treatment
Restoring Neuronal Function
It is generally accepted that the clinical course of neuropsychiatric and

behavioral symptoms of AD arises as a result of alterations in the complex
intracellular and intercellular communication system. It is currently known that
some of the AD symptoms result from the dysfunction of specific neuronal
systems caused by alterations in the transmission of signals and/or cell death.
The initial effect leading to the cascade of events that produce transmission
alterations is not yet known, and we cannot accurately state whether single or
multiple genetic factors, either in a sequence or in combination, are involved
in the degenerative process.
Preventing Synapse and Cell Death
There฀is฀evidence฀indicating฀that฀AE฀is฀associated฀with฀an฀important฀loss฀of฀syn-
apses, dendritic changes, and cell death. The severity of the dementia is clearly
related฀to฀the฀extension฀of฀the฀synaptic฀loss.฀Even฀though฀the฀exact฀cause฀and฀the฀
underlying mechanisms of neuronal loss are not clear, there are several possible
factors, such as endogenous and exogenous neurotoxins, metabolic alterations,
alterations in calcium homeostasis, abnormal processing of the amyloid precursor
protein, and changes in the proteins of neurons.
To delay the progression of the degenerative process, it is essential to develop
treatments that maintain synaptic stability and ensure the survival of neurons. Some
treatments that use neuronal growth factors and genetic therapy techniques could
be fruitful in the future [9].
Treatment of the Primary Cognitive Symptoms
The primary symptoms are defined as those that involve memory loss (both fixation
and evocation memory) and other cognitive disorders (such as aphasia, apraxia,
agnosia, and further impairment of the executive function).
Cholinergic Agents
Multiple data prove the significant role that cholinergic mechanisms play in AD:
1. Anticholinergic agents with core action produce cognitive deficit in humans
2. Cholinergic neurotransmission shapes memory and learning
3. The lesions that affect central cholinergic pathways cause learning and memory
impairment, which may be reversed through the administration of cholinomimetics
4.฀ Postmortem฀studies฀of฀AD฀patients฀show฀loss฀of฀cholinergic฀neurons฀in฀the฀sep-
tum and basal nucleus of Meynert, reduction of the cholines acetyltransferase
and acetylcholinesterase, and correlation between these changes and the level of
cognitive impairment
Relative to these points, it was theorized that increasing central cholinergic trans-
mission would be useful in the treatment of AD. This effect may be achieved by
using acetylcholine precursors, by inhibiting cholinesterase, the enzyme that
reduces it, or by using direct postsynaptic agonists.
Acetylcholine Precursors
At the beginning, the proposal was to increase the availability of acetylcholine

precursors, which would increase both its synthesis and neurotransmission. Lecitine
or choline was administered for that purpose. However, because the choline absorp-
tion system is usually saturated in normal conditions (from 98% to 99%), the
increase of extracellular precursors will not increase the synthesis of choline or its
release, and would only be useful when there is great cholinergic activity and an
increased demand of the precursor (not very probable in regular clinical conditions,
which would explain their limited clinical usefulness).
Acetylcholinesterase Inhibitors
Even฀though฀acetylcholinesterase฀inhibitors฀are฀not฀useful฀for฀all฀AD฀patients,฀there฀
is a group of subjects who might benefit from treatment with acetylcholinesterase
inhibitors; these are patients with late onset of the symptoms, initial stages of the
disease, and lack of a related organic disease.
Donepezil is a benzyl methyl piperidine, mixed inhibitor (competitive-
noncompetitive) of the enzyme, which shows a therapeutic profile similar to that of the
prototype drug, tacrine, although it is much more powerful [10]. It presents a pro-
longed half-life, more than 80 h, which facilitates its administration in just one daily
intake, 5 or 10 mg/day being the indicated dose [11]. In contrast to tacrine, it does not
show hepatotoxicity or high incidence of digestive intolerance. The most common
adverse effects are nausea, vomiting, anorexia, insomnia, cramps, and bradycardia.
Rivastigmine is an acetylcholinesterase inhibitor also approved by the FDA.
It is a pseudo-irreversible inhibitor that dissociates the enzyme slowly. It is
220 L.I. Brusco
administered twice a day and is also a butyrylcholinesterase inhibitor, which

would have certain implications in its adverse effects profile. It starts with a 1.5-
mg dose twice a day, and it is possible to increase the dose in 1.5-mg/day phases
up to 6 mg twice a day. The adverse effects profile is similar to that of donepezil,
although with greater incidence of gastrointestinal effects. To lessen this adverse
effects incidence, it is recommended that the dose increases be made every
2–4฀weeks.฀The฀effect฀of฀rivastigmine฀in฀the฀ADAS-Cog฀and฀the฀CIBIC฀Plus฀is฀
more or less the same as that of donepezil. The presentation in transdermal
absorption patches has been recently approved as a way to minimize the adverse
effects of the drug.
Galantamine is an amine tertiary phenantrene used in the treatment of paresis,
paralysis, and miasthenia gravis; the recommended dose is between 20 and 60 mg/
day. Its half-life is 8 h; among the most common adverse effects are agitation,
insomnia, and irritability. Nowadays there exists a form of presentation of prolonged
release and one intake per day.
Glutamate Regulators
Memantine is a new therapy that has recently been approved by the FDA for the
treatment of moderate to severe AD [12]. It belongs to the family of partial antago-
nists of the NMDA receptor and can added to the treatment with inhibitors [13]. Its
use has been approved both alone and in combination with the mentioned inhibitors.
It could also have an effect on the basic physiopathogenic process of the disease
through the inhibition of the entrance of calcium at rest, which would exist as a
pathological process in neurodegenerative disease. The adverse reactions are milder
than those with anticholinesterase drugs: anxiety, akathisia, and mild gastrointestinal
pain. There is a new presentation and administration of memantine, based on work
that guarantees the use in a single intake of 20 mg, with the same effect and
tolerance.
It is the only drug approved for the severe form of the disease: pharmacoeco-
nomic analyses have been conducted in most cases by comparing the drug to non-
pharmacological treatment [14].
In general, the different trials have shown that memantine is less costly and more
effective than nonpharmacological treatment, although, given the limited number of
pharmacoeconomic studies performed, it is still too early to draw conclusions on
the drug’s cost-effectiveness.
Antioxidants
Within฀ this฀ heterogeneous฀ group฀ we฀ must฀ mention฀ vitamin฀ E,฀ selegiline,฀ and฀
bifemelane.
Vitamin E (tocopherol) has been proved to have protective properties against

neuronal damage in animals. This finding inspired the conduction of clinical trials
in patients with dementia. It has been used in doses of 2,000 UI/day, showing a
7-month delay in the progression of the disease, but without improving the
symptoms.
It has proved to be a safe drug with low incidence of adverse events, among
which the most important ones are blood clotting disorders.
Research has shown oxidative damage is present in the brains of AD patients.
Consequently, the use of antioxidants in treatment has gained popularity. There are
considerable data suggesting that antioxidants are linked to a lower incidence of the
disease.฀A฀clinical฀trial฀in฀subjects฀with฀moderate฀disease฀has฀shown฀that฀vitamin฀E฀
and selegiline were effective in delaying the progression of moderate AD into more
severe฀stages.฀Doses฀of฀vitamin฀E฀1,000฀UI฀twice฀a฀day฀and฀selegiline฀10฀mg/day฀
were administered in this study. The results regarding selegiline have not been as
convincing; this, associated with its pharmacological interactions and potential
toxicity,฀ has฀ led฀ to฀ the฀ preference฀ of฀ vitamin฀ E.฀ There฀ exists฀ theoretical฀ concern฀
regarding the gastrointestinal toxicity and bleeding with the latter, although in
general it is well tolerated. These findings have not been argued, nor is there agree-
ment฀regarding฀the฀ideal฀dose฀of฀vitamin฀E.฀The฀American฀Academy฀of฀Neurology฀
(AAN)฀has฀indicated฀that฀1,000฀UI฀vitamin฀E฀twice฀a฀day฀can฀be฀considered฀in฀an฀
attempt to reduce the progression of AD. The risk–benefit ratio determined for
selegiline appears to be less favorable.
The฀use฀of฀vitamin฀E฀should฀be฀considered฀(despite฀this฀simple฀positive฀study)฀
in the face of a recent meta-analysis that indicates that with doses of 400 UI/day
or higher there would be an increased risk of death from cardiovascular conditions.
It is still uncertain whether this increased risk appears essentially in patients with
premorbid cardiologic conditions or if it is also applicable to patients without
significant cardiovascular history.
Selegiline is an irreversible inhibitor of monoaminoxidase B at low doses and
of monoaminoxidase A at high doses; used for the treatment of depression and
Parkinson’s฀disease,฀it฀is฀believed฀to฀act฀similarly฀to฀other฀antioxidants,฀that฀is,฀by฀
avoiding cell death and thus the progression of the disease [15]. Also, it interferes
with the hyperactivity of monoaminoxidase B observed in AD. It is effective at
low doses (10 mg/day); its improving effect is not related to the antidepressant
effect. The main adverse effects of this drug are nausea, dizziness, abdominal
pain, and mouth dryness, being the tyramine syndrome difficult to observe given
the doses used. This drug is not recommended for patients who receive tricyclic
antidepressants, selective serotonin reuptake inhibitor (SSRI), or mepridine.
Antiinflammatory Drugs
It is clinically observed that patients who received antiinflammatories in a clinical

manner, such as populations with rheumatoid arthritis or leprosy, present a much
222 L.I. Brusco
lower incidence of AD; therefore, the prolonged use of antiinflammatories such as

indometacine is considered beneficial for this disease.
Research on AD has shown the presence of an inflammatory component
involved in the degenerative process. Because this element can influence the
progression of the disease and increase its symptoms, some studies have suggested
the฀ possibility฀ of฀ using฀ antiinflammatory฀ agents฀ as฀ treatment.฀ Epidemiological฀
studies indicate that the use of nonsteroidal antiinflammatory drugs (NSAIDs)
could protect against the development of AD. Some NSAIDs, such as indometacine,
were suggested, but in the case of the latter, the abandonment rate by the patients
was very high because of the adverse effects.
Trials performed treating patients with glucocorticoids, such as prednisone or
NSAIDs, have been negative. One study with mild to moderate AD patients in the
course of a year showed no significant difference in the performance of the ADAS-Cog.
In fact, the group treated with prednisone showed greater behavioral worsening as
compared to the placebo group.
Recently, attention has been drawn to cyclooxygenase 2 (COX-2) inhibitors as
they are better tolerated than nonselective antiinflammatories. However, the beneficial
effect of these drugs has not been proved. There are currently a few positive studies
regarding the use of NSAIDs. There is a long trial still in course that assesses a
NSAID and a COX-2 inhibitor in the prevention of the onset of AD, the results of
which will be known in the years to come.
There are some recent negative studies in relationship to the use of NSAIDs and
steroids฀in฀the฀treatment฀of฀AD.฀Even฀though฀some฀epidemiological฀studies฀seem฀
to show a potential benefit in postponing the development of AD, none of the ran-
domized clinical trials has been able to prove these findings. Moreover, some con-
cerns regarding the safety of COX-2 inhibitors and other NSAIDs have emerged.
Therefore, none of them is currently recommended to prevent or treat the disease.
In contrast with these studies, there has been recent speculation that some
NSAIDs would have a specific property lowering the alpha-beta levels and would
therefore be useful in the treatment of AD through an alternative mechanism.
Estrogen Replacement Therapy
Similar to the use of the drugs already described, there has been epidemiological
proof that postmenopausal women who have received hormone replacement therapy
with estrogens would be more protected against AD. It is likely that estrogens may
have a neuroprotective effect in delaying the onset of the disease, but the data on
the use of estrogens have not been positive [16].
An open, randomized, double-blind, placebo-controlled trial on mild to moder-
ate AD failed to prove the benefits of hormone replacement after a term of
12 months. There were no changes in the primary measures of efficacy in this trial,
and concern was raised regarding deep vein thrombosis as a possible adverse effect.
An additional smaller trial of 16 weeks also failed to show benefits with this ther-
apy. Consequently, there are no data supporting the recommendation of the use.
There are longitudinal studies in course regarding a possible prophylactic effect of

estrogen in reducing the risk of developing dementia, but the data of this study are
still pending.
More recently, the Women’s Health Initiative Memory Study has proved that the
postmenopause use of estrogens may constitute a risk factor for the development of
AD and mild cognitive impairment (MCI) instead of having a protective effect.
Neurotrophic Factors
There is a new medication, Cerebrolysin, that is proposed for the treatment of

Alzheimer-like diseases and vascular dementia. This drug is a peptide preparation
produced by the standardized, controlled, enzymatic decomposition of purified brain
proteins; it consists of low molecular weight peptides (10 kDa) and amino acids.
The drug is provided as a watery solution and administered through intravenous
infusion. It has both neurotrophic and neuroprotective effects on the neuron. In
animal models with AD, cerebrolysin protects against the degeneration of cholin-
ergic neurons (producers of acetylcholine). Improvement has been shown in the
neuropathological and behavioral changes of the animals. There is basic work
showing that it directly influences the neuronal and synaptic plasticity, improving
neurotransmission [17]. It promotes neuronal sprouting and ramification and
induces neuronal repair processes.
Protection฀against฀cell฀death฀in฀different฀experimental฀animals฀and฀cell฀cultures฀
is also proposed. It has an antiapoptopic effect, in such a way that it promotes
neuronal survival.
There are various double-blind clinical trials that show cognitive and behavioral
improvement with the intravenous use of cerebrolysin [18–20]. It was proposed for
the treatment of Alzheimer-like diseases and vascular dementia in other trials [21].
Treatment of Secondary Noncognitive Symptoms
Although the primary symptoms of AD are memory impairment and loss of other
cognitive abilities, patients also develop secondary symptoms, among which are
depression, anxiety, agitation, delirium, hallucinations, and insomnia. It is recom-
mendable to manage with caution the use of antipsychotics and anxiolytics, keeping
in mind that both have side effects [22]. The first behavior is to wait for the
therapeutic effects of memantine and anticholinesterase medication as, besides
cognition, both drugs also improve the neuropsychiatric inventory [23].
With antipsychotics it is necessary to avoid the typical ones that cause parkin-
sonism, given the predisposition of elderly dementia patients to experience
extrapyramidal symptoms. However, the atypical drugs have proved an increase in
mortality in late-life psychosis. Quetiapine (with the family’s informed consent)
may be the drug to indicate in the psychotic disorders of dementia, given the low
production of extrapyramidal effects in low doses.
224 L.I. Brusco
These symptoms should not be minimized, as it is estimated that they occur in a

large majority of patients (around 60%), being in general the basis of most compli-
cations฀of฀the฀disease.฀Psychoactive฀drugs฀are฀the฀ones฀most฀used฀for฀these฀symp-
toms, but they carry potential adverse effects such as sedation, disinhibition,
depression, falls, incontinence, parkinsonism, and akathisia [24, 25]. Chronobiotics
such as melatonin have proved their benefit in the treatment of alterations of the
sleep–wake cycle and evening irritability that are typical of these patients.
The use of the antiepileptic drugs carbamacepine and valproic acid has also been
brought forward for the psychiatric disorders of these patients, particularly if there
are associated epileptic disorders [26, 27].
There are general principles to follow for the treatment of secondary AD
symptoms:
1. Define the type of symptoms as clearly as possible to focus the therapy and work
with monodrugs (one drug at a time) in combined treatments.
2. Assess the importance of the symptom both for the patient and for the
caretakers.
3. Take into account that some symptoms are temporary and typical of the natural
evolution of the disease.
4. Look for precipitating events.
5. Consider modifications of the environment and nonpharmacological therapies.
6. Start with low doses of drugs and slowly make necessary increases.
7. After controlling the symptoms, evaluate the possible reduction or withdrawal of
the medication, pursuant to each symptom.
New Nonpharmacological Possibilities of Treatment
It is important to consider not only the patient but also his or her caretaker, who in
general is a relative and is under chronic stress. Therefore, aid measures through
support groups for relatives and caretakers such as those at the Asociación
Alzheimer Argentina, that advise, orient, and support relatives and caretakers, are
particularly important.
Assistance to the patient involves not only medication, but also the work of
psychologists, occupational therapists, voice specialists, and physical therapists in
a treatment modality in which multiple stimulation is essential.
It is important to remember that this disease affects the entire family and that
interdisciplinary work is essential for the correct approach to the patient and his
or her environment.
References
1. American Academy of Neurology (2009) AAN guideline summary for clinicians: detection,
diagnosis and management of dementia. http://www.aan.com/professionals/practice/pdfs/
dementia_guideline.pdf. Accessed 15 April 2009
฀ 2.฀ Small฀ GW,฀ Siddarth฀ P,฀ Burggren฀ AC฀ et฀ al฀ (2009)฀ Influence฀ of฀ cognitive฀ status,฀ age,฀ and฀
APOE-4฀ genetic฀ risk฀ on฀ brain฀ FDDNP฀ positron-emission฀ tomography฀ imaging฀ in฀ persons฀
without฀dementia.฀Arch฀Gen฀Psychiatry฀66(1):81–87
฀ 3.฀ Reisberg฀B,฀Auer฀SR฀(1996)฀Behavioral฀pathology฀in฀Alzheimer’s฀disease.฀Psychogeriatrics฀
8:301–308
฀ 4.฀ Wragg฀RE,฀Jeste฀DV฀(1989)฀Overview฀of฀depression฀and฀psychosis฀in฀Alzheimer’s฀disease.฀
Am฀J฀Psychiatry฀146:577–587
฀ 5.฀ Salzman฀ C฀ (1997)฀ Treatment฀ of฀ the฀ elderly฀ agitated฀ patient.฀ J฀ Clin฀ Psychiatry฀ 48(5฀
suppl):19–22
6. Schatzberg A, Nemeroff C (1998) Textbook of psychopharmacology, 2nd edn. American
Psychiatric,฀Washington,฀DC
฀ 7.฀ American฀ Psychiatric฀ Association฀ (2009)฀ Practice฀ guideline฀ and฀ resources฀ for฀ treatment฀ of฀
patients with Alzheimer´s disease and other dementias, 2nd edn. http://www.psychiatryonline.
com/pracGuide/pracGuideTopic_3.aspx. Accessed 15 April 2009
฀ 8.฀ APA฀Work฀Group฀on฀Alzheimer´s฀Disease฀and฀other฀Dementias,฀Rabins฀PN,฀Blacker฀D฀et฀al฀
(2007)฀American฀Psychiatric฀Association฀practice฀guideline฀for฀the฀treatment฀of฀patients฀with฀
Alzheimer´s฀ disease฀ and฀ other฀ dementias.฀ Second฀ edition.฀ Am฀ J฀ Psychiatry฀ 164(12฀
suppl):5–56
฀ 9.฀ Moizeszowicz฀ J฀ (1998)฀ Psicofarmacología฀ psicodinámica฀ IV:฀ estrategias฀ terapéuticas฀ y฀ psi-
coneurobiológicas,฀4th฀edn.฀Paidós,฀Buenos฀Aires
฀10.฀ Raskind฀MA,฀Sadowsky฀CH฀et฀al฀(1997)฀Effect฀of฀tacrine฀on฀language,฀praxis฀and฀noncogni-
tive behavioral problems in Alzheimer’s disease. Arch Neurol 54:836–840
฀11.฀ Howard฀RJ,฀Juszczak฀E,฀Ballard฀CG฀et฀al฀(2007)฀Donepezil฀for฀the฀treatment฀of฀agitation฀in฀
Alzheimer´s฀disease.฀N฀Engl฀J฀Med฀357(14):1382–1392
฀12.฀ Tariot฀ PN,฀ Farlow฀ MR,฀ Grossberg฀ GT฀ et฀ al฀ (2004)฀ Memantine฀ treatment฀ in฀ patients฀ with฀
moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled
trial.฀JAMA฀291:317–324
13. Farlow M et al (2003) Memantine/donepezil dual therapy is superior to placebo/donepezil
therapy for treatment of moderate to severe Alzheimer´s disease. Neurology 60(suppl
1):A412
14. Reisberg B, Doody R, Söffler A et al (2003) Memantine in moderate to severe Alzheimer’s
disease.฀N฀Engl฀J฀Med฀348:1333–1341
15. Tolbert SR, Fuller MA (1996) Seleginine in treatment of behavioral and cognitive symptoms
of฀Alzheimer฀disease.฀Ann฀Pharmacother฀30:1122–1129
16. Kawas C, Resnik S, Morrison A (1997) A prospective study of estrogen replacement therapy
and the risk of developing Alzheimer disease: the Baltimore longitudinal study of aging.
฀17.฀ Rüther฀E,฀Ritter฀R,฀Apecechea฀M,฀Freytag฀S,฀Gmeinbauer฀R,฀Windisch฀M฀(2000)฀Sustained฀
improvements in patients with dementia of Alzheimer’s type (DAT) 6 months after termina-
tion฀of฀cerebrolysin฀therapy.฀J฀Neural฀Transm฀107:815–829
฀18.฀ Ruether฀E,฀Alvarez฀XA,฀Rainer฀M,฀Moessles฀H฀(2002)฀Sustained฀improvement฀of฀cognition฀
and global function in patients with moderately severe Alzheimer’s disease: a double-blind,
placebo-controlled฀study฀with฀the฀neurotrophic฀agent฀Cerebrolysin®.฀J฀Neural฀Transm฀Suppl฀
62:265–275
฀19.฀ Panisset฀ M฀ et฀ al฀ (2002)฀ Cerebrolysin฀ in฀ Alzheimer’s฀ disease:฀ a฀ randomized,฀ double-blind,฀
placebo-controlled฀trial฀with฀a฀neurotropic฀agent.฀J฀Neural฀Transm฀109:1089–1104
฀20.฀ Xiao฀ SF฀ et฀ al฀ (2000)฀ Efficacy฀ of฀ FPF฀ 1070฀ (Cerebrolysin)฀ in฀ patients฀ with฀ Alzheimer’s฀
disease: a multicentre, randomized, double-blind placebo-controlled trial. Clin Drug Invest
19:43–53
21. Alvarez XA et al (2006) A 24-week double blind, placebo-controlled study of three dosages
of฀ Cerebrolysin฀ in฀ patients฀ with฀ mild฀ to฀ moderate฀ Alzheimer’s฀ disease.฀ Eur฀ J฀ Neurol฀
13:43–54
฀22.฀ Barnes฀R,฀Veith฀R,฀Okimoto฀J฀et฀al฀(1992)฀Efficacy฀of฀antipsychotic฀medications฀in฀behavior-
ally฀disturbed฀dementia฀patients.฀Am฀J฀Psychiatry฀139:1170–1174
226 L.I. Brusco
฀23.฀ Qaseem฀A,฀Snow฀V,฀Cross฀JT฀et฀al฀(2008)฀Current฀pharmacologic฀treatment฀of฀dementia:฀a฀
clinical฀ practice฀ guideline฀ from฀ the฀ American฀ College฀ of฀ Physicians฀ and฀ the฀ American฀
Academy฀of฀Family฀Physicians.฀Ann฀Intern฀Med฀148(5):370–378
฀24.฀ Stern฀RG,฀Duffelmeyer฀ME฀et฀al฀(1991)฀The฀use฀of฀benzodiazepines฀in฀the฀management฀of฀
behavioral฀symptoms฀in฀dementia฀patients.฀Psychiatr฀Clin฀North฀Am฀14:375–384
฀25.฀ Tariot฀PN,฀Erb฀R฀et฀al฀(1994)฀Carbamazepine฀treatment฀of฀agitation฀in฀nursing฀home฀patients฀
with฀dementia:฀a฀preliminary฀study.฀J฀Am฀Geriatr฀Soc฀42:1160–1166
฀26.฀ Gleason฀RP,฀Schneider฀LS฀(1990)฀Carbamazepine฀treatment฀of฀agitation฀in฀Alzheimer’s฀outpatients฀
refractory฀to฀neuroleptics.฀J฀Clin฀Psychiatry฀51:115–118
27. Lott AD, Mcelroy SL, Keys MA (1995) Valproate in the treatment of behavioral agitation in
elderly฀patients฀with฀dementia.฀J฀Neuropsychiatry฀Clin฀Neurosci฀7:314–319
Alzheimer’s Disease in Japan: Current
Situation and Issues of the Care for Persons
with Dementia
Akira Homma
Abstract It is estimated that the number of persons with dementia in 2005 will
double in 2035 in Japan from more than 2 million to 4.5 million. In the wake
of the introduction of long-term care insurance in Japan in 2000, there have
been particularly marked changes in the awareness and recognition of dementia.
However, considering that the aim of the care for persons with dementia is to
support their independence or daily life, we envisage many more issues ahead of us.
Early detection and diagnosis are important for all diseases, and particularly in the
case of dementia. Underdetection of persons with dementia means underdiagnosis
and treatment. At present, no data are available on the proportion of persons with
dementia diagnosed and treated appropriately. Such a situation clearly indicates the
role of primary care physicians to detect persons with dementia in the early stage.
Also, “dignity” is emphasized in Article 1 of the Long-term Care Insurance Law
revised in 2006. That is, persons with dementia must not be discriminated for the
reason of dementia. However, persons with dementia are often discriminated in
various situations. Here, I consider some of these issues with a view to establishing
a future ideal model.
Keywords Alzheimer’s฀disease฀•฀Dementia฀care฀•฀Human฀right฀•฀Management฀
•฀Persons฀with฀dementia
Introduction
Dementia฀ is฀ an฀ umbrella฀ term฀ used฀ to฀ refer฀ to฀ pathology฀ from฀ various฀ causes.฀
According to the estimates made by Awata et al. [1], the number of persons with
dementia in 2005 will double in 30 years (in 2035) from more than 2 million to 4.5
A. Homma (*)
Center฀for฀Dementia฀Care฀Research฀and฀Training฀in฀Tokyo,฀Tokyo,฀Japan

DOI฀10.1007/978-4-431-53871-4_16,฀©฀Springer฀2010
228 A. Homma
Fig. 1 Projected฀increase฀of฀persons฀with฀dementia
million. In Japan, the number of persons with dementia will be increasing most
rapidly฀in฀Saitama฀Prefecture฀(3.2฀times).฀These฀estimates฀were฀obtained฀from฀the฀
epidemiological surveys that have been conducted by experts in certain areas
throughout฀Japan.฀Other฀estimates฀have฀been฀obtained฀by฀estimating฀the฀percentage฀
of persons with dementia among those designated for the long-term care insurance
[2].฀According฀to฀these,฀approximately฀half฀(48%)฀of฀those฀designated฀for฀long-term฀
care insurance are suspected of having dementia. Furthermore, a tentative report on
the฀long-term฀care฀insurance฀in฀September฀2008฀indicated฀that฀there฀were฀approxi-
mately 4.6 million individuals designated for this insurance in Japan. Forty-eight
percent of this figure is 2.21 million, which is comparable to the estimate made by
Awata et al. Given these numbers, dementia can be regarded as a very familiar
condition, as shown in Fig. 1.
In the wake of the introduction of long-term care insurance in Japan in 2000, there
have been particularly marked changes in the awareness and recognition of dementia.
However, considering that the aim of the care for persons with dementia is to support
their independence or daily life, we envisage many more issues ahead of us. Here, I
consider some of these issues with a view to establishing a future ideal model.
Early Detection and Diagnosis
Early detection and diagnosis are important for all diseases, and particularly in the
case of dementia, because persons with dementia are less likely to complain of
memory impairment and visit medical facilities by themselves than those with other
diseases such as hypertension and diabetes. Those with very mild dementia may,
Alzheimer’s฀Disease฀in฀Japan฀ 229
nevertheless, seek help for their memory loss as a chief complaint. However, most
of these individuals rarely visit a hospital, even if their family members, or others,
notice forgetfulness. Accordingly, the estimated number of persons with dementia
is relatively small compared to, for example, the estimated 16 million persons with
diabetes. However, it is critically important to determine the actual percentage of
potential persons with dementia who are able to visit a hospital and receive
appropriate diagnosis and treatment. Currently, there are no data available on the
number฀ of฀ such฀ persons.฀ Relatively฀ old฀ survey฀ results฀ provide฀ several฀ examples฀
demonstrating that early diagnosis in the community is not necessarily sufficient.
In an epidemiological survey of the elderly aged 65 and above, conducted
throughout Tokyo in 1995, approximately 5,000 persons were randomly sampled
from approximately 1.49 million people aged 65 and above [3]. Eventually, 123
persons฀were฀diagnosed฀as฀having฀dementia.฀Of฀these฀123฀individuals,฀only฀26.5%฀
were diagnosed as having dementia by their primary care physicians. Thus,
three-fourths of persons with dementia may not actually be diagnosed as having
dementia. The severity of dementia among these patients was classified as mild
(18.5%),฀moderate฀(12.5%),฀and฀severe฀(46.7%).฀Severe฀dementia฀is฀accompanied฀
by total disorientation and requires total care in daily life. We should note that half
of the elderly with severe dementia were not diagnosed as having dementia. In the
results, the diagnoses of dementia by primary care physicians were Alzheimer’s
dementia฀ (20.8%)฀ and฀ vascular฀ dementia฀ (56.8%).฀ The฀ percentage฀ of฀ those฀
diagnosed as having Alzheimer’s dementia was lower than those having vascular
dementia. These data seem very important, because primary care physicians were
the second person with whom family members taking care of the elderly with
dementia consulted at that time.
Further data were obtained from a questionnaire survey conducted to members
of the regional medical association in Tokyo before the introduction of the
long-term care insurance [4].฀The฀response฀rate฀was฀found฀to฀be฀as฀low฀as฀50%฀
(n = 56). However, a relatively high percentage of the physicians replying
commented that they took care of symptoms of dementia in their daily practice
(73.2%)฀and฀that฀they฀responded฀to฀consultations฀with฀patients’฀families฀regarding฀
dementia฀(69.6%).฀However,฀only฀19.6%฀of฀the฀physicians฀said฀that฀they฀referred฀
their patients to special medical facilities for diagnoses, etc., or that they used
public health centers. This situation is far from satisfactory. At this time,
฀immediately฀before฀the฀enforcement฀of฀the฀long-term฀care฀insurance,฀only฀32.1%฀
of physicians were aware of the criteria for determining the independence level of
the elderly with dementia, which was an item of attending physicians’ written
opinion to be submitted to municipalities to determine the eligibility for the
long-term care insurance.
I฀ give฀ a฀ third฀ example฀ here.฀ Diagnoses฀ of฀ dementia฀ made฀ by฀ physicians฀ and฀
experts immediately before the enforcement of the long-term care insurance were
directly compared [5].฀ Primary฀ care฀ physicians฀ and฀ experts฀ (four฀ persons)฀ made฀
diagnoses independently for 36 subjects, including healthy individuals, using the
NM฀ scale,฀ a฀ behavior฀ rating฀ scale฀ that฀ measures฀ the฀ severity฀ of฀ dementia.฀ The฀
results indicated that there was consistency in the diagnosis of severe dementia
230 A. Homma
between the physicians and specialists. However, of the eight persons diagnosed as
having mild dementia by the experts, the primary care physicians diagnosed four as
normal and one as having moderate dementia. Further, of the eight persons
diagnosed as having suspected dementia by the experts, the primary care physicians
diagnosed three as normal, another three as having mild dementia, and two as
฀having฀ moderate฀ dementia.฀ Thus,฀ the฀ diagnoses฀ were฀ inconsistent.฀ Of฀ the฀ eight฀
persons diagnosed with moderate dementia by the experts, six were diagnosed
similarly as having moderate dementia by the primary care physicians. Thus, the
less severe the disorder, the lower was the consistency rate.
Given these results, we can easily understand that primary care physicians play
a key role in early detection of dementia. However, in a paper entitled “Screening
for฀Cognitive฀Impairment฀In฀General฀Practice:฀Toward฀a฀Consensus”฀[6], Brodaty,
an Australian geriatric psychiatrist specializing in the community care of dementia,
considered various expenses, and concluded that it was inappropriate to seek
dementia screening from primary care physicians. I completely agree with this
view: one should not directly seek diagnosis from a primary care physician.
Establishing a network, including experts and health and welfare professionals with
whom you can consult at any time, is important. Also, in a model project of total
care collaborative system for the elderly with dementia, implemented by the Tokyo
Metropolitan฀ Government,฀ capable฀ experts฀ were฀ secured฀ in฀ areas฀ where฀ a฀
counseling system for the elderly with dementia was established [7]. Conversely,
experts skilled in clinical practice for dementia are indispensable for facilitating
consultation projects, including the early detection of dementia.
Responding฀to฀this฀situation,฀in฀2000฀we฀launched฀a฀training฀model฀for฀the฀early฀
detection฀and฀diagnosis฀of฀dementia฀by฀primary฀care฀physicians.฀On฀the฀basis฀of฀the฀
results฀ of฀ this฀ model,฀ in฀ 2006฀ the฀ Ministry฀ of฀ Health,฀ Labour฀ and฀ Welfare฀
commenced education for primary care physicians to improve medical skills for
treating persons with dementia. To date, approximately 21,000 primary care
physicians have undergone this training. Such training has been reported to improve
the diagnostic rate of dementia, including Alzheimer disease, by primary care
physicians [8]. Figure 2 shows a conceptual structure for early detection and
management of persons with dementia in the community. At present, although not
every resource shown in the figure works satisfactorily, it seems that the structure
itself is quite valid in the management of persons with dementia. Furthermore, the
former฀ Centers฀ for฀ Dementia฀ Disorders฀ were฀ abolished฀ in฀ 2008.฀ Subsequently,฀
Medical฀Centers฀for฀Dementia฀Disorders฀have฀been฀founded฀as฀core฀organizations฀
responsible for the local management of dementia (Fig. 3). The target is to establish
150 such centers throughout Japan. In addition, since June 2009, a screening test
for dementia has been introduced into the training course for driver license renewal
at the age of 75. Those suspected of having dementia should undergo diagnosis for
the presence or absence of dementia by primary care physicians or experts when
they have a history of specific traffic violations within the past year. Thus, in view
of the rapidly increasing number of persons with dementia, primary care physicians
in local areas will be required to play more important roles, because dementia
cannot be handled only by experts.
Supporting physicians
Physicians in 47 prefectures and cities
of 500,000 or more, granted special Consultation
rights by government (supporting Consultation฀and Care Managers
physicians/regional medical advice฀to฀PCPs Care staff
associations) Collaboration
Planning
Experts
Collaboration
Administration of educational Collaboration
program for PCPs “How to manage
persons with dementia”
Collaboration
Regional Medical Association Community
Primary Care Physicians Comprehensive
Support Center
Early detection placed in the
Referring to experts area of a junior
Management of physical Person฀with฀dementia high school
conditions Family Support
Emotional support to family Support
caregivers
Collaboration of health
professionals in the community
Collaboration
Fig. 2 Supporting system for persons with dementia in the community with the involvement of
primary฀care฀physicians฀(PCPs)
General hospital Psychiatric hospital

Behavioral and psychological
Physical and surgical complications
symptoms of dementia needed
needed to treat under the admission
Needed to treat under the admission
Referring Referring
Medical Center for Dementia Disorders

Medical treatment Enforcement of Community
collaboration Comprehensive
Providing information Including differential among health Support Center
to residents Diagnosis, decision of professionals Care
treatment plan, In the community, Referring Collaboration staff
including
management of acute liaison working
administration Liaison staff
psychotic symptoms, staff in
of educational
treatment of physical program, and facilities
complications consultation,. and in-
Referring home
Referring
service
Referring delivery
Persons with dementia Supporting Physicians agents
needing treatment
Referring
by experts due to BPSD
and physical complications Memory Clinic Referring Psychiatric Clinic
Primary care physicians
Persons with dementia/familys
Fig. 3 Medical฀Center฀for฀Dementia฀Disorders
232 A. Homma
Supporting the Human Rights of Persons with Dementia
The long-term care insurance has now been in force for 10 years. Certainly, our
understanding and recognition of dementia have improved markedly in some areas.
With this improvement, medical technology to facilitate early diagnosis has also
advanced, and the local network for early detection is also being consolidated. “Care
for the Elderly in 2015” [2], proposed by the Health and Welfare Bureau for the
Elderly,฀ the฀ Ministry฀ of฀ Health,฀ Labor฀ and฀ Welfare฀ in฀ 2003,฀ presents฀ care฀ for฀ the฀
elderly with dementia as a new care model. In addition, the following is described in
Article 1 of the Long-term Care Insurance Law revised in 2006: “This law will allow
persons under conditions requiring care, such as bathing, excretion, and feeding,
functional training, and medical care, such as nursing and care management because
of illness resulting from physical and mental changes with aging, to maintain dignity
and lead an independent daily life according to their abilities.” (The rest is omitted.)
Thus, the term “dignity” was used for the first time. However, discrimination continues
to remain in spite of the changes in attitudes toward dementia [9]. A revised adult
guardianship฀ law฀ was฀ introduced฀ in฀ April฀ 2000.฀ A฀ total฀ of฀ 24,988฀ applications฀
associated with the adult guardianship law were filed in the year between April 2007
and฀March฀2008.฀The฀long-term฀care฀insurance฀contracts฀accounted฀for฀6.2%฀(1,560฀
persons) of all the motives for the applications (Fig. 4; http://www.courts.go.jp/). In
2007, 2.3 million people were suspected of having dementia [1].฀Of฀these,฀those฀who฀
used the adult guardianship law for long-term care insurance contracts accounted for
only฀ 0.007%.฀ Not฀ all฀ people฀ suspected฀ of฀ having฀ dementia฀ seem฀ to฀ use฀ the฀ adult฀
guardianship law for long-term care insurance contracts. However, it does not
necessarily seem to be wrong to consider that those with dementia have slightly
impaired judgment. Thus, it is certainly desirable to use the adult guardianship law
more actively also for application for long-term care insurance contracts, because it is
Property management 21,733
Inheritance 3,050
Legal procedure 927
Long-term care insurance contracts 1,560
Everyday life guard 6,711
Others 2,005
0 10,000 20,000 30,000
Fig. 4 Number฀of฀applicants฀to฀the฀adult฀guardianship฀system฀and฀its฀motives:฀April฀2007–March฀
2008,฀n฀=฀24,988
a useful means for protecting the human rights of persons with dementia. All persons
involved should always consider health, medicine, welfare, care, and family in connec-
tion with dementia, thereby supporting the dignity of persons with dementia.
The second issue naturally concerns measures against behavioral and psychological
symptoms. According to the results of a questionnaire survey that we conducted
among members (n฀=฀1,049)฀of฀the฀Japanese฀Psychogeriatric฀Society฀and฀the฀Japanese฀
Association฀of฀Psychiatric฀Hospitals,฀which฀has฀established฀dementia฀treatment฀wards฀
and medical treatment wards [10], among behavioral and psychological symptoms, the
drug of first choice for hallucination, delusion, abusive language and violence, and
delirium was risperidone, an atypical antipsychotic agent. As yet, no final conclusion
has been reached concerning the effectiveness of antipsychotic drugs on the behavioral
and psychological symptoms of dementia. However, antipsychotic drugs are
indispensable for supporting the lives of the elderly with dementia, either at home or
in institutions, as a therapeutic procedure for hallucination and delusion that may cause
dangerous situations for persons with dementia and their families when they develop.
We should administer such medication with periodic monitoring, comprehensively
considering the actual needs and health conditions of the patients and the effectiveness
and side effects expected. In the present situation, off-label use of antipsychotic drugs
is inevitable for the behavioral and psychological symptoms of dementia. Experts are
expected to be skilled in the use of these drugs. However, the most serious issue in the
surveillance is the situation where no informed consent has been obtained in the more
than half of patients who are administered antipsychotic drugs. Although no stratified
analysis has been conducted on this data, regardless of use status, informed consent
should be obtained appropriately for any treatment using an antipsychotic drug.
Furthermore, the concept of informed consent should be examined for persons with
dementia with notably impaired mental capacity. This is one of the serious issues
regarding the current adult guardianship law and requires immediate revision.
The third issue is the response to caregivers and families. In recent years, many
outpatients with milder dementia have visited a hospital for diagnosis. In less severe
cases, disclosing to persons with dementia the proper name of their disease is more
important. Next, the circumstances of caregivers and families, as well as those of the
persons with dementia, should be accurately evaluated. Caregivers often find it difficult
to recognize the facts. Naturally, they may be unwilling to accept or want to deny the
reality, and may therefore be confused for a while. In such situations, it is impossible
for a caregiver to properly take in the variety of information that they may be provided.
As a matter of priority, caregivers’ feelings should be acknowledged with sympathy.
Such responses are required from all persons concerned, including physicians.
Issues for the Future
Early detection, precise diagnoses, and management are essential requirements for
persons with dementia. Simultaneously, support is needed to allow those with dementia
to live in the community. To meet these requirements, we should maintain close
234 A. Homma
communication with those involved in health, medicine, welfare, and care based on
appropriate diagnoses. This activity will greatly influence the therapeutic effects,
course, and prognosis. However, in view of the present educational curriculum described
above, we cannot deny the bias of its contents toward diagnostics. In contrast to
diagnosis or treatment skills, it is certainly difficult to evaluate these roles to support
persons with dementia in the community. Currently, five dementia-associated academic
฀societies฀(the฀Japan฀Psychogeriatric฀Society,฀the฀Japan฀Society฀for฀Dementia฀Research,฀
the Japanese Society of Neurology, the Japan Geriatrics Society, and the Japanese
Society of Neurological Therapeutics) are jointly drawing up a guideline for the
diagnoses and treatment of dementia. In this guideline, emphasizing their philosophy
for diagnoses, treatment, and care of persons with dementia is extremely important.
In addition, we should continuously construct a structure to maintain the quality
of care for dementia and simultaneously conduct positively educational and
enlightening activities, including familiarizing such care to the public.
References
฀ 1.฀ Awata฀ S฀ et฀ al฀ (2000)฀ Model฀ of฀ integrated฀ emergency฀ care฀ for฀ dementia;฀ Grants-in-Aid฀ for฀
Scientific฀ Research,฀ Ministry฀ of฀ Health,฀ Labour฀ and฀ Welfare,฀ 2007;฀ The฀ Health฀ Science฀
Research฀ of฀ Heart,฀ Psychiatric฀ Emergency฀ Care;฀ Study฀ report฀ on฀ treatment฀ of฀ physical฀
disorders and complications of dementia, pp 135–156
2. Elderly Care Study Group (2003) Elderly Care in 2015 – for the establishment of care to
support dignity of the elderly – Elderly Care Study Group. Houken, Tokyo
฀ 3.฀ Bureau฀ of฀ Social฀ Welfare฀ and฀ Public฀ Health,฀ Tokyo฀ Metropolitan฀ Government:฀ Special฀
investigation report on daily life and health of the elderly in 1995; 1995, Bureau of Social
Welfare฀and฀Public฀Health,฀Tokyo฀Metropolitan฀Government,฀1995
฀ 4.฀ Homma฀A฀(2000)฀Geriatric฀psychiatry:฀millennium.฀Jpn฀J฀Geriatr฀Psychiatry฀11:68–69
฀ 5.฀ Office฀ for฀ the฀ Promotion฀ of฀ Measures฀ for฀ the฀ Elderly,฀ Tokyo฀ Metropolitan฀ Government:฀
Summary฀of฀the฀interim฀report฀from฀the฀Committee฀for฀Establishment฀of฀Service฀Organization฀
for฀the฀Elderly,฀Tokyo฀Metropolitan฀Government฀in฀1998;฀1999,฀Office฀for฀the฀Promotion฀of฀
Measures฀for฀the฀Elderly,฀Tokyo฀Metropolitan฀Government,฀1999
฀ 6.฀ Brodaty฀ H฀ et฀ al฀ (1998)฀ Screening฀ for฀ cognitive฀ impairment฀ in฀ general฀ practice:฀ toward฀ a฀
consensus.฀Alzheimer฀Dis฀Assoc฀Disord฀12:1–13
฀ 7.฀ Office฀ for฀ the฀ Promotion฀ of฀ Measures฀ for฀ the฀ Elderly,฀ Tokyo฀ Metropolitan฀ Government:฀
Report฀from฀the฀Committee฀for฀Evaluation฀of฀Total฀Care฀Collaboration฀System฀for฀the฀Elderly฀
with฀Dementia,฀Tokyo฀Metropolitan฀Government฀2000,฀Office฀for฀the฀Promotion฀of฀Measures฀
for฀the฀Elderly,฀Tokyo฀Metropolitan฀Government,฀2000
฀ 8.฀ Homma฀ A,฀ Awata฀ S,฀ Ikeda฀ M,฀ Ueki฀ A,฀ Urakami฀ K,฀ Kitamura฀ S,฀ Shigeta฀ M,฀ Nakamura฀ Y,฀
Nakamura฀M,฀Ohta฀K฀(2006)฀Local฀collaboration฀for฀the฀elderly฀with฀dementia:฀model฀project฀
to฀improve฀diagnostic฀skills฀of฀dementia฀by฀primary฀care฀physicians.฀Jpn฀J฀Geriatr฀Psychiatry฀
17:483–489
9. Homma A (2007) Issues of the adult guardianship law concerning informed consent for
฀treatment฀ of฀ the฀ elderly฀ with฀ dementia.฀ In:฀ Arai฀ M฀ (ed)฀ Adult฀ guardianship฀ and฀ medical฀
practice. Nippon Hyoronsha, Tokyo, pp 19–31
10. Homma A (2006) Questionnaire survey about use status of antipsychotic drugs for behavioral
and฀psychological฀symptoms฀of฀dementia฀(BPSD).฀Jpn฀J฀Geriatr฀Psychiatry฀17:799–783
AD-FTLD Spectrum: New Understanding
of the Neurodegenerative Process
from the Study of Risk Genes
Masatoshi Takeda, Takashi Kudo, Toshihisa Tanaka, Masayasu Okochi,

Ryota Hashimoto, Takashi Morihara, and Shinji Tagami
Abstract Typical cases of primary neurodegenerative diseases causing dementia,

such as Alzheimer’s disease (AD), diffuse Lewy body disease, frontotemporal lobar
degeneration (FTLD), and corticobasal degeneration, show characteristic clinical signs
and symptoms, but there are some cases in which the differential diagnosis among
neurodegenerative dementias is difficult because of their atypical clinical presenta-
tion. Considering recent findings in molecular genetics of familial cases of AD and
FTLD, the relationship between causative genes and clinical signs is becoming more
complicated, and the concept of an AD-FTLD spectrum is proposed. Protein fragments
derived from amyloid precursor proteins, tau and TDP-43, are deposited in the cere-
bral tissue of patients with AD and FLTD in different degrees. In familial cases, these
deposited protein fragments are caused by mutations in the precursor protein genes. The
majority of cases of AD and FTLD are sporadic, wherein loss of function of presenilin
and progranulin increases the risk of these neurodegenerative disorders. Under the
concept of AD-FTLD, it is more helpful to elucidate the common neurodegenerative
pathway in which aggregated protein fragments are deposited after partial proteolysis,
phosphorylation, and ubiquitination, leading to the formation of amyloid angiopathy,
senile plaque, neurofibrillary tangles, and the inclusion body of FTLD.
Keywords Alzheimer’s฀disease฀•฀Frontotemporal฀lobar฀degeneration฀•฀Progranulin฀
•฀Tau฀•฀TDP-43
Introduction
Dementia is a neurodegenerative disease causing severe dysfunction in daily and

social life as a result of impairment in memory and cognitive function. Because of
the large number of patients, severity of dysfunction, long duration of the course,
M. Takeda (*), T. Kudo, T. Tanaka, M. Okochi, R. Hashimoto, T. Morihara, and S. Tagami


DOI 10.1007/978-4-431-53871-4_17, © Springer 2010
236 M. Takeda et al.
and burden to caregivers, dementia is regarded one of the most malignant diseases
in this century. There are 24.3 million dementia patients in the world, and 4.6
million people are newly diagnosed every year [1]. In Japan alone there are now 1.5
million dementia patients, and the number of dementia patients is steadily
increasing for reasons of the extension of the average lifespan. It is expected there
will be 3.5 million dementia patients in Japan by the year 2035.
Alzheimer’s disease (AD) is the most frequent primary neurodegenerative
disease, accounting for 50–70% of all dementia patients. Higher age, female
gender, family history of dementia, head injury, and lower education are reported
to be the risks for AD, among which higher age is the most significant. The
prevalence rate of AD increases age after 65, almost doubling by every 5 years, and
reaching more than 40% prevalence in the elderly over 85 years old [2].
Primary neurodegenerative diseases causing dementia include AD, diffuse Lewy
body disease (DLB), frontotemporal lobar degeneration (FTLD), and corticobasal
degeneration (CBD). Each disease shows characteristic clinical signs and symptoms.
The initial sign of AD is memory impairment, and later impairment in cognitive
function follows, such as aphasia, apraxia, agnosia, and executive dysfunction.
Those impaired cognitive functions together result in dysfunction in judgment. DLB
is the second most common disease among the elderly more than 75 years old, char-
acterized by varying levels of cognitive function, visual hallucination, and parkin-
sonism. The neuropathological feature of DLB is abundant Lewy bodies in the
cerebral cortical neurons. In persons of younger age, less than 65 years old, FTLD
is the second predominant dementing disease [3]; it is characterized by personality
change, dysinhibition, abnormal behavior, and language disability. In the early phase
of FTLD, memory can be preserved despite the deteriorating daily life of the
patients. The classification of frontotemporal dementia has been discussed for many
years, and FTLD is the broadest concept, which includes Pick’s disease and other
diseases characterized by progressive lobar atrophy of frontal and temporal lobe.
FTLD is classified into three types: (1) frontotemporal dementia (FTD), (2) progres-
sive aphasia, and (3) semantic dementia. FTD is further divided into frontal lobar
degeneration, Pick’s type, and motor neuron disease type (Fig. 1).
FLD type
fronto-temporal dementia(FTD) Pick’s type
Fronto-temporal progressive aphasia(PA) MND type

lobar degeneration
(FTLD)
semantic dementia(SD)
Fig. 1 Classification of frontotemporal lobar degeneration (FTLD) [4]

AD-FTLD Spectrum: New Understanding of the Neurodegenerative Process 237
Genes for AD and FTLD
AD is genetically heterogeneous and complex (Fig. 2). About 10% of AD is

early-onset AD, and about 60% of the early-onset type is inherited in an autosomal
dominant manner. Mutations in the amyloid precursor protein (APP) gene [5],
presenilin1 (PSEN1) gene [6], and presenilin 2 (PSEN2) gene [7] are identified as
causative genes of familial AD (Fig. 3).
Even though the pathological process of AD has not yet been fully elucidated,
the amyloid cascade hypothesis has been widely accepted [8], in which beta
amyloid (A beta) is produced by consecutive cutting by beta-secretase (BACE 1)
and gamma-secretase (PSEN complex). The presenilin complex is composed of
presenilin, nicastrin, Aph-1, and Pen-2, in which the presenilin molecule carries the
catalytical site of gamma-secretase in its molecular structure [9], whereas the other
three molecules are functioning in stabilizing the structure of gamma-secretase
complex. Gamma-secretase produces several different species of beta amyloid with
different C-terminal sites between 37 and 43 amino acids long. Beta amyloid with
40 amino acids is the most abundant, and beta amyloid with 42 amino acids is the
form most toxic to neurons.
The amyloid cascade hypothesis is supported by the finding that mutations in
APP, PSEN1, or PSEN2, which are found in some familial AD patients, are all
relevant key players in processing of APP, in which the core pathogenic process is
the increase in beta amyloid, caused by either overproduction, abnormal process-
ing, or delayed secretion of beta amyloid. Increased beta amyloid will be aggre-
gated and deposited, and it is believed to cause neurofibrillary tangle (NFT)
formation, or neuronal degeneration, resulting in the symptomatology of AD.
More than 75% of the late-onset AD is sporadic, but there are also some late-
onset cases showing familial aggregation [10]. Apolipoprotein E4 (APOe) is
involved in the familial cases of late-onset type AD [11]. An individual with one
APOe4 allele has 3–5 times higher risk and those with two APOe4 alleles have
10–15 times higher risk for AD [12]. In addition to the higher risk of AD, the
APOe4 allele causes the earlier onset of AD [13], and also makes the response to
the intervention much worse than in those without e4 [14].
Cause % of Cases
Chromosomal (Down syndrome) <1%
Familial ~25%
Late-onset familial (AD2) 15% -25%
Early-onset familial AD (AD1,AD3, AD4) <2%
Unknown (includes genetic/environment ~75%

Fig. 2 Causes of Alzheimer interactions)
disease
Early-onset familial Alzheimer disease (EOFAD)

Locus Proportion Gene Chromosomal Protein Test
name of EOFAD symbol locus name availability
AD3 20%-70% PSEN1 14q24.3 Presenilin-1 Clinical
Amyloid beta
AD1 10%-15% APP 21q21 Clinical
A4 protein
AD4 Rare PSEN2 1q31-q42 Presenilin-2 Clinical
Late onset familial Alzheimer’s disease
Chromosomal
Locus name Gene symbol Protein name Test availability
locus
AD2 APOE 19q13.2 Apolipoprotein E Clinical
Fig. 3 Early-onset familial Alzheimer disease (EOFAD)/late-onset familial Alzheimer’s disease
Apoe is the protein involved in lipid metabolism; however, the mechanism of

AD pathogenesis is not yet elucidated. Apoe is expected to function in cholesterol
transport, oxidative stress, neurite extension, tau phosphorylation, beta amyloid
aggregation, and beta amyloid metabolism. The APOe4 allele increases amyloid
deposition in the AD brain [15], and it is also shown that in human healthy elderly
subjects the APOe4 allele causes more amyloid load in the brain [16].
Most FTLD cases occur in the age groups of the fifties and sixties, which is much
earlier than those of AD. FTLD also shows more familial aggregation than AD. Even
though 40–50% of FTLD is claimed to be familial, no causative gene had been identi-
fied despite intensive research endeavors. It was only in 2007 that new genes were
discovered that are related to the pathogenesis of FTLD [17]. The first gene is the tau
gene (MAPT) on chromosome 17. Mutations in MAPT were originally identified
from patients of FTDP-17, a subtype of FTLD showing parkinsonism and genetic
correlation with chromosome 17 [18]. It was discovered that tau mutations are
involved in the formation of tau-positive inclusion bodies (FTLD-tau) in the FTDP-
17 patient brain. This finding had a high impact on understanding of neurodegenera-
tion because neurons of FTDP-17 are degenerated without amyloid cascade. In other
words, it is shown that neurodegeneration can be induced without amyloid involve-
ment. A single mutation in MAPT is enough to cause neurodegeneration in the corti-
cal neurons, leading to formation of NFTs and neuron loss.
In the brain tissue of FTLD patients, there are two types of inclusion body: one
is the inclusion body that is positive with anti-tau antibody (FTLD-tau) and the
other is negative with anti-tau antibody and positive with anti-ubiquitin antibody
(FTLD-U). The protein component of FTLD-tau is tau, but the component protein
of FTLD-U has been unidentified for many years. In 2004, valosin-containing
protein (VCP) was reported as the component of FTLD-U [19], and in 2005
charged multivesicular body protein (CHMP2B) was reported [20] as genes related
to FTLD-U inclusion body formation. However, there are only a few cases caused
by mutation in VCP or CHMP2B, and further search for the genetic cause of
FTLD-U has continued.
Progranulin and TDP-43
Tau is a microtubule-associated protein involved in stabilization and elongation of

microtubules. NFT in the AD brain and Pick bodies of the FTLD brain are known
to be composed of hyperphosphorylated tau. FTDP-17 is the first example of neu-
rodegenerative dementia caused by mutation of the MAPT gene, and it is well
accepted that mutated tau is the cause of the FTLD-tau inclusion body observed in
the brain of FTLD patients, including FTDP-17. However, the majority of FTLD
patients show tau-negative, ubiquitin-positive inclusion bodies (FTLD-U), and the
causative gene of FTLD with FTLD-U is yet to be identified.
Further search for genes causing FTLD with the FTLD-U inclusion body was
for long unsuccessful. The newly identified gene causing FTLD is the progranulin
(PGRN) gene, which is located in a position only 1.7 Mb apart from MAPT on
chromosome 17. PGRN is shown to be the causative gene of many FTLD patients
with FTLD-U inclusion bodies [21, 22].
PGRN, called by several other names such as acrogranin, epithelin precursor, or
proepithelin, classified in the epitherin family, is secreted protein having 7.5
repeated sequences after the signal peptide sequence. PGRN is cleaved by a pro-
tease, resulting in a peptide 6 kDa in size (granulin A-G and para granulin), which
functions in differentiation, wound healing, inflammation, and tumor formation.
Four peptides of PGRN are known to make up a stable structure through S–S bonds
[23, 24]. The function of PGRN in the brain is not yet fully elucidated but it is
speculated to be a neuronal growth factor [25].
Sixty-six mutations have been reported with 199 families of FTLD. The muta-
tions are spanning all genomic region of PGRN except exon 13. The types of muta-
tions are nonsense mutations (14 kinds), splice site mutations (11 kinds), and
deletion/insertion mutation causing frameshift (24 kinds). Loss of function (LOF)
of PGRN is speculated to be the cause of FTLD. A more important finding is that
PGRN mutations are observed in many neurodegenerative diseases including AD,
amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).
Soon after the discovery of PGRN mutations with FTLD, TDP-43 was identified
as the major protein component of the FTLD-U inclusion body [26]. In the brain
tissue of FTLD caused by mutations in PGRN, TDP-43 is deposited as an
intracellular inclusion body after hyperphosphorylation and ubiquitination.
TDP-43 (TAR-DNA-binding protein 43) is an intranucleus protein ubiquitously
expressed in all tissue, and it is speculated to be involved in transcription, splicing,
and stabilization of mRNA [27]. It is also speculated to be involved in biosynthesis
of micro-RNA (miRNA) [28]. TDP-43 is initially found accumulated in the brain

of ALS, and further studies have revealed that TOP-43-positive deposits are
observed in the brain with AD and DLB [29–31]. So, it is believed that TDP-43
and/or its gene (TARDBP) should be involved in the pathogenesis of AD and DLB
in addition to ALS and FTLD. Even though no mutation of TDP-43 has been
reported with either FTLD or AD, several mutations of TDP-43 are found with
patients with familial as well as sporadic ALS. Considering these findings,
TARDBP should be involved with the pathogenesis of neurodegenerative diseases
of many different kinds [32, 33].
So far, the three genes have been identified as the causative genes of FTLD, that
is, MAPT, PGRN, and TARDBP. Still another gene on chromosome 9 is speculated
to be causative for FTLD because there are papers reporting high association with
the 9p21–13 region in families with FTLD with motor neuron disease [34, 35].
The study of risk genes of neurodegenerative disease has opened up new under-
standing of neurodegenerative dementia. Of course, these implications should be
taken cautiously to apply to the pathogenesis of sporadic cases; involvement of
these genes should be some hint for understanding the pathogenesis of sporadic
cases of neurodegenerative dementia.
Copy Number Variation, miRNA, and Neurodegeneration
Copy number variation (CNV) is the repetition of a sequence 1 kb long and more
including several genes. CNV is now shown to be the causative factor of many dis-
orders, including chronic neuroimmunological (CND) disease. More than 20,000
CNVs exist in the whole genome, which has more than 7,000 genes. In 2006, CNV
including the APP gene was reported with five families of AD [36] whose CNV
region covers 0.58–6.37 M, including APP and 5–12 other genes. The phenotype of
the cases of this CNV is AD with cerebral amyloid angiopathy (CAA), and it was
implied that an increased copy number of APP results in AD pathogenesis [37].
Considering the pathogenesis of Down syndrome, which is caused by the increased
copy number of APP that is included in the 21q21region, it is quite reasonable to
understand this increased copy number of APP is causing AD pathology in the brain
of Down syndrome patients more than 30 years old [38]. CNV of the alpha-cynuclain
gene is also reported with familial PD patients [39, 40].
These findings support the notion that increased copy number of a certain gene
can lead to the deposition of abnormal protein, causing neurodegenerative demen-
tia. Increased numbers of APP may explain the pathogenesis of AD, and this also
supports the validity of the amyloid cascade hypothesis.
Increased expression of APP may be caused by several different mechanisms
other than CNV. For example, there might be mutations in promoter regions, which
could increase the expression level of APP gene up to 50%. Increased expression
of APP may increase the risk of AD. In fact, there are papers reporting that
mutations in the promoter region of APP cause a 1.2–1.8 increased expression level
of APP in Dutch and Belgium families with AD [41, 42].
In addition to gene replication, several different types of partial or complete
deletion of genes are reported with families with AD or FTLD. For example, exon
9 deletion of PSEN1 causes AD with massive deposition of characteristic cotton
wool plaques in the brain of the patients [43]. Deletion of PGRN or MAPT are
reported with FTLD families [44]. There is a paper reporting partial deletion of
exon 6–9 of MAPT gene [45], and the tau protein coded by the deleted MAPT gene
shows decreased binding activity with microtubules and shows more binding with
MAP1B, which might result in the neurodegeneration caused by defective tau
protein.
The importance of miRNA should be mentioned in this context. miRNA is an
endogenous small RNA molecule that supposedly stimulates mRNA degradation or
regulates gene expression after binding with the target mRNA. There are more than
1,000 different kinds of miRNA in the human genome, which are supposed to be
relevant to control of the expression level of more than 30% of genes. Especially,
more miRNA exist in brain tissue. Search with miRNA array has revealed the
significant reduction of miR-107 in the brain with AD [46], which is correlated
with the severity of AD pathology. It was also shown that miR-107 binds with
mRNA of BACE1 and speculated that reduction of miR-107 results in the increased
expression level of BACE1. It is quite reasonable that reduction in miRNA will
cause AD pathology through higher expression of BACE1. Significant increase of
miR-146a in the AD brain tissue is reported compared with that of the healthy
control brain by pooled RNA sample study [47].
These findings just described show the possibility that the change in expression
level of certain genes will increase the risk of neurodegenerative diseases such as
AD and FTLD, which may lead to a proposal that explains the common neuro-
pathological process among neurodegenerative dementia.
AD-FTLD Spectrum
In the brain of AD patients, there are abnormal depositions of beta amyloid and tau
protein. Beta amyloid deposits in the core of senile plaque as well as in the cerebral
vessel wall of CAA. Tau is deposited in the soma of degenerating neurons, in ghost
tangles, and in dystrophic neuritis as NFT. On the other hand, in the brain of FTLD,
tau protein is deposited in Pick body (FTLD-tau) and TDP-43 is deposited
intracellularly and intranuclearly as a ubiquitin-positive inclusion body as inclusion
body (FTLD-U).
There are 32 different missense mutations reported with the APP gene. Most of
these mutations cause AD pathology, such as KM670/671NL Swedish mutation,
V717I,P,G London mutation, V715M France mutation, V715A German mutation,
and I716V Florida mutation. However, some APP mutations are observed in
hereditary cerebral hemorrhage with angiopathy, such as HCHWA Dutch (E693Q)
and CAA Italian (E693K). Flemish-type APP mutation (Flemish A692G) causes
CAA as well as AD pathology.
There are 177 different mutations reported with the PSEN gene, most of which
cause early-onset type AD. The earliest onset of AD is reported with a subject of
24 years old, implying strong pathogenic effects of PSEN1 gene mutation. It should
be noticed that there are PSEN1 mutations whose phenotype is FTLD symptoms
(L113P, G183V, insArg352).
There are 44 different mutations reported with MAPT, most of which are
concentrated in 9–13 exons and an intron between exon 10 and 11. The major
phenotype of MAPT mutations is FTLD with typical Pick body and FTLD-tau inclu-
sion body in the intracellular and intranuclear space. The characteristics of MAPT
mutations is the fact that they show a wide range of symptoms of FTLD, whose
major symptom is parkinsonism (i.e., FTDP-17), or with behavioral abnormalities,
or aphasia. There are also tau mutations whose symptoms are very similar to those
of AD. For example, patients with the MAPT R406W mutation show memory
impairment in the initial stage and then gradually show FTLD symptoms.
FTLD-tau inclusion is observed in 25% of FTLD patients, and the majority of
FTLD patients show a tau-negative, ubiquitin-positive inclusion (FTLD-U), which
is composed of TDP-43. LOF of PGRN is closely related with pathogenesis of
FTLKD-U formation. Mutation of PGRN explains about 25% of familial FTLD,
which coincides with the frequency of the MAPT mutation among FTLD cases.
There is a wide variety of onset age with FTLD patients with MAPT or PGRN
mutations: 20–70 years for MAPT mutations and 30–80 years for PRGN mutations.
When the average onset age is compared between patients with PGRN mutation
(61 ± 9 years old) and those with MAPT mutations (48 ± 10 years old), the PGRN
mutation causes FTLD with later-onset age.
Furthermore, there are cases with AD phenotypes and ALS phenotypes among
the patients with PGRN mutations.
PSEN PGRN
A beta tau TDP-43
β-Amyloid NFT FTLD-tau FTLD-U
Fig. 4 AD-FTLD Spectrum

It is reasonable to speculate that there is a common pathogenic process among

different neurodegenerative dementia disorders (Fig. 4). APP is cleaved by consecu-
tive proteolysis by beta-secretase and gamma-secretase to produce beta amyloid,
which deposits in the core of senile plaques and the vascular walls of CAA. Tau protein
is phosphorylated and partially cleaved and deposited in NFT and in dystrophic
neurites. TDP-43 is also partially cleaved, phosphorylated, and ubiquitinated, and then
deposited in the FTLD-U inclusion body in the intracellular and intranuclear space.
Many types of mutations in the PSEN gene (177 kinds) and in the PGRN gene (68
kinds) are distributed through a wide area of the molecule, which is characterized by
LOF of the protein. It can be proposed that LOF mutations of PSEN induces beta amy-
loid and NFT deposition, whereas the LOF mutations of PGRN causes the deposition
of FTLD-tau and FTLD-U. However, it should be noted that there are intermediate
phenotypes between AD and FTLD, implying that both pathological processes share a
common path, which can be characterized by each extreme case of pathogenesis.
References
1. Ferri CP, Prince M, Brayne C et al (2005) Global prevalence of dementia: a Delphi consensus
study. Lancet 366:2112–2117
2. Breteler MM, Claus JJ, van Duijn CM et al (1992) Epidemiology of Alzheimer’s disease.
Epidemiol Rev 14:59–82
3. Graff-Radford NR, Woodruff BK (2007) Frontotemporal dementia. Semin Neurol 27:48–57
sus on clinical diagnostic criteria. Neurology 51(6):1546–1554
5. Goate A, Chartier-Harlin MC, Mullan M et al (1991) Segregation of a missense mutation in
the amyloid precursor protein gene with familial Alzheimer’s disease. Nature (Lond)
349:704–706
6. Sherrington R, Rogaev EI, Liang Y et al (1995) Cloning of a gene bearing missense mutations
in early-onset familial Alzheimer’s disease. Nature (Lond) 375:754–760
7. Levy-Lahad E, Wasco W, Poorkaj P et al (1995) Candidate gene for the chromosome 1
familial Alzheimer’s disease locus. Science 269:973–977
8. Hardy J (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci
20:154–159
9. De Strooper B (2003) Aph-1, Pen-2, and nicastrin with presenilin generate an active
gamma-secretase complex. Neuron 38:9–12
10. Bird TD (2008) Genetic aspects of Alzheimer disease. Genet Med 10:231–239
11. Strittmatter WJ, Saunders AM, Schmechel D et al (1993) Apolipoprotein E: high-avidity
binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial
Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981
12. Farrer LA, Cupples LA, Haines JL et al (1997) Effects of age, sex, and ethnicity on the
association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis.
APOe and Alzheimer disease meta analysis consortium. JAMA 278:1349–1356
13. Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4
allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923
14. Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: a causative factor and
therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci USA
103:5644–5651
15. Drzezga A, Grimmer T, Henriksen G et al (2009) Effect of APOe genotype on amyloid plaque
load and gray matter volume in Alzheimer disease. Neurology 72:1487–1494
16. Reiman EM, Chen K, Liu X et al (2009) Fibrillar amyloid-beta burden in cognitively normal
people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA
106:6820–6825
17. Rademakers R, Hutton M (2007) The genetics of frontotemporal lobar degeneration. Curr
Neurol Neurosci Rep 7:434–442
18. Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5¢-splice-site
mutations in tau with the inherited dementia FTDP-17. Nature (Lond) 393:702–705
19. Watts GD, Wymer J, Kovach MJ et al (2004) Inclusion body myopathy associated with Paget
disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.
Nat Genet 36:377–381
20. Skibinski G, Parkinson NJ, Brown JM et al (2005) Mutations in the endosomal ESCRTIII
complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37:806–808
21. Baker M, MacKenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause
tau-negative frontotemporal dementia linked to chromosome 17. Nature (Lond)
442:916–919
22. Cruts M, Gijselinck I, van der Zee J et al (2006) Null mutations in progranulin cause
ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature (Lond)
442:920–924
23. He Z, Bateman A (2003) Progranulin (granulin–epithelin precursor, PC-cell-derived growth
factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 81:600–612
24. He Z, Ong CH, Halper J et al (2003) Progranulin is a mediator of the wound response. Nat
Med 9:225–229
25. Van Damme P, Van Hoecke A, Lambrechts D et al (2008) Progranulin functions as a neurotrophic
factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 181:37–41
26. Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal
lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133
27. Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation,
and human disease. Front Biosci 13:867–878
28. Gregory RI, Yan KP, Amuthan G et al (2004) The microprocessor complex mediates the
genesis of microRNAs. Nature (Lond) 432:235–240
29. Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal
sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445
30. Higashi S, Iseki E, Yamamoto R et al (2007) Concurrence of TDP-43, tau and alpha-synuclein
pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res
1184:284–294
31. Nakashima-Yasuda H, Uryu K, Robinson J et al (2007) Co-morbidity of TDP-43 proteinopathy
in Lewy body related diseases. Acta Neuropathol 114:221–229
32. Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with spo-
radic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574
33. Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic
amyotrophic lateral sclerosis. Science 319:1668–1672
34. Morita M, Al-Chalabi A, Andersen PM et al (2006) A locus on chromosome 9p confers sus-
ceptibility to ALS and frontotemporal dementia. Neurology 66:839–844
35. Vance C, Al-Chalabi A, Ruddy D et al (2006) Familial amyotrophic lateral sclerosis with
frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain
129:868–876
36. Rovelet-Lecrux A, Hannequin D, Raux G et al (2006) APP locus duplication causes auto-
somal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet
38:24–26
37. Sleegers K, Brouwers N, Gijselinck I et al (2006) APP duplication is sufficient to cause early
onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129:2977–2983
38. Wisniewski KE, Dalton AJ, McLachlan C et al (1985) Alzheimer’s disease in Down’s syn-
drome: clinicopathologic studies. Neurology 35:957–961
39. Singleton AB, Farrer M, Johnson J et al (2003) Alpha-synuclein locus triplication causes
Parkinson’s disease. Science 302:841
40. Chartier-Harlin MC, Kachrgus J, Roumier C et al (2004) Alpha-synuclein locus duplication
as a cause of familial Parkinson’s disease. Lancet 364:1167–1169
41. Brouwers N, Sleegers K, Engelborghs S et al (2006) Genetic risk and transcriptional vari-
ability of amyloid precursor protein in Alzheimer’s disease. Brain 129:2984–2991
42. Theuns J, Brouwers N, Engelborghs S et al (2006) Promoter mutations that increase amyloid
precursor-protein expression are associated with Alzheimer disease. Am J Hum Genet
78:936–946
43. Crook R, Verkkoniemi A, Perez-Tur J et al (1998) A variant of Alzheimer’s disease with
spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med
4:452–455
44. Rovelet-Lecrux A, Deramecourt V, Legallic S et al (2008) Deletion of the progranulin gene in
patients with frontotemporal lobar degeneration or Parkinson disease. Neurobiol Dis
31:41–45
45. Rovelet-Lecrux A (2009) Partial deletion of the MAPT gene: a novel mechanism of FTDP-17.
Hum Mutat 30:E591–E602
46. Wang WX, Rajeev BW, Stromberg AJ et al (2008) The expression of microRNA miR-107
decreases early in Alzheimer’s disease and may accelerate disease progression through regula-
tion of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci 28:1213–1223
47. Lukiw WJ, Zhao Y, Cui JG (2008) An NF-kB-sensitive micro RNA-146amediated inflamma-
tory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem
283:31315–31322
Dementia with Lewy Bodies
Ian Grant McKeith
Abstract Dementia with Lewy bodies (DLB) has over the last two decades become
recognised as a common dementia subtype in older people. Since it shares clinical and
pathological features with both Alzheimer’s disease and Parkinson’s disease, knowl-
edge of DLB is essential not only in its own right, but also to obtain a full understand-
ing of its two prototypical boundary disorders. This chapter reviews what is currently
known about the clinical, pathological and management aspects of DLB.
Keywords Alpha-synuclein฀•฀Dementia฀•฀Diagnosis฀•฀Lewy฀body฀•฀Parkinson’s
Introduction
Dementia with Lewy bodies (DLB), which is now thought to be the second most
prevalent cause of degenerative dementia in older people [1] has previously carried
a variety of diagnostic labels, including diffuse Lewy body (LB) disease [2], LB
dementia [3], the LB variant of Alzheimer’s disease [4], senile dementia of LB type
[5], and dementia associated with cortical Lewy bodies [6]. The latest International
Consensus criteria describe a spectrum of LB disorders with DLB and Parkinson’s
disease (PD) dementia as two operationally defined phenotypes which are now in
widespread clinical use [7]. Primary autonomic failure, rapid eye movement sleep
disorder, and PD itself are other syndromes considered to lie along the same con-
tinuum. and debate continues about the nature of their interrelationships. The
importance of recognizing DLB relates particularly to its pharmacological man-
agement, with reports of good responsiveness to acetylcholinesterase inhibitors
(AChEIs)[8], extreme sensitivity to the side effects of neuroleptics [9, 10], and
limited responsiveness to levo-dopa [11].
I.G. McKeith (*)

Wolfson Research Centre, Institute for Ageing and Health, Campus for Ageing and Vitality,
Newcastle University, Newcastle upon Tyne NE4 5PL, UK

DOI 10.1007/978-4-431-53871-4_18, © Springer 2010
248 I.G. McKeith
Epidemiology
There is very little systematically collected information about the prevalence,

incidence, and associated risk factors for dementia with Lewy bodies (DLB).
A community study of individuals 85 and older found 5% met consensus criteria
for DLB, representing 22% of all demented cases [12]. This finding is similar to
other clinical estimates in research studies [13, 14] and consistent with estimates of
Lewy body (LB) prevalence (15%) in a dementia case register followed to autopsy
[1]. In routine clinical practice, it is likely, however, that DLB diagnosis rates are
significantly lower than this. Risk factors for DLB are unclear as prevalence studies
have been too small. It has however been suggested that APO-E4 status reduces
survival rate in DLB (as with AD), although its presence has little effect on disease
onset or duration [16].
Pathology and Etiology
Alpha (a)-synuclein-positive LBs and Lewy neurites (LNs) are the characteristic
autopsy lesions of DLB. Up to a quarter of LB disease cases show a pathological
distribution that has extensive neocortical and limbic involvement with relative
sparing of midbrain and subcortical structures, that is, not conforming to typical
“Braak-like” Parkinson’s disease (PD) spread. There is often also abundant
Alzheimer-type pathology, predominantly in the form of amyloid plaques.
Tau-positive inclusions and neocortical neurofibrillary tangles sufficient to
qualify for a diagnosis of concomitant AD (Braak stages V or VI) occur in only
10–25% of cases. Alzheimer pathology is not needed for dementia to occur
because a small number of “pure” DLB cases are seen with typical cognitive
impairment and neuropsychiatric features. Cortical LB and LN density is not
robustly correlated with either the severity or duration of dementia [17, 18], and
in some community-based series, Lewy-type pathologies are frequently seen in
nondemented, neurologically normal individuals [19, 20]. This finding raises the
intriguing possibility that LBs are a neurprotective response to the generation of
low molecular weight species of a-synuclein that are located in synaptosomes and
impair synaptic function [21]. Synaptic dysregulation and neurotransmitter defi-
cits may therefore be turn out to be better correlates of the fluctuating clinical
picture [22] and provide the best drug targets. a-Synuclein immunoreactive
deposits with many of the characteristics of LB have also been reported in a high
proportion of AD cases usually occurring exclusively in the amygdala [23]. In this
context they may simply reflect end-stage aggregation of a-synuclein in severely
dysfunctional neurons that are already heavily damaged by plaque and tangle
pathology [24, 25]. Triplication of the a-synuclein gene (SNCA) can cause DLB,
PD, and Parkinson’s disease dementia (PDD), whereas gene duplication is asso-
ciated only with motor PD, suggesting a gene dose effect [26]. However, SNCA
multiplication is not found in most LB disease patients [27]. Mutations in the
Dementia with Lewy Bodies 249
glucocebebrosidase (GBA) gene, previously associated with the lipid storage

disorder Gaucher’s disease, have also recently been reported in PD and DLB [28]
although the mechanism of this association remains speculative [29].
Clinical Features
DLB is recognized by progressive signs and symptoms of dementia, with marked

impairments in visuo-spatial, attentional, and executive functions. Episodic recall
can be relatively preserved in the early stages, in contrast to Alzheimer’s disease
(AD), in which memory failure is often the presenting complaint. The course is
generally progressive, with cognitive test scores declining about 10% per annum,
similar to AD [30]. Survival times from onset until death are generally similar to
AD [31], although DLB patients are at greater risk of hospital admission because
of fall-related injuries and bronchopneumonia [32] and sometimes have a very
rapid disease course [33]. Fluctuating cognition, recurrent visual hallucinations,
and extrapyramidal motor symptoms are the core features distinguishing DLB
clinically, although these features are now known to be absent in a significant
minority of cases [10], leading to difficulties in diagnosis. The onset tends to be
insidious, although reports of a period of increased confusion or prominent hallu-
cinations may give the impression of a sudden onset. Extrapyramidal symptoms
(EPS) are reported in 25–50% of DLB cases at diagnosis, and 75–80%, that is, not
all cases, develop some EPS during the natural course. The profile of EPS in DLB
is generally similar to that in age-matched, nondemented PD patients [34], with
greater postural instability and facial impassivity but less tremor [35]. Rate of
motor deterioration is about 10% per annum, similar to PD [36], but levo-dopa
responsiveness is reduced, possibly because of additional intrinsic striatal pathology
and dysfunction [37].
Fluctuations in cognitive function, which may vary over minutes, hours, or days,
occur in 50–75% of patients and are associated with shifting levels of attention and
alertness. The assessment of fluctuating cognitive impairment poses considerable
difficulty to most clinicians and has repeatedly been cited as a reason for low clinical
ascertainment of DLB. The use of caregiver- and observer-rated scales may be
particularly helpful in this regard [38]. Questions such as, “Are there episodes when
his or her thinking seems quite clear and then becomes muddled?” were originally
thought to be useful probes [39], until two studies [40, 41] found that most caregivers
responded positively to such questions regardless of whether the patient had AD or
DLB. More reliable predictors of DLB diagnosis are objective questions about
daytime sleepiness, episodes of staring blankly or incoherent speech, and qualitative
assessment of the range of fluctuation (e.g., best versus worst).
Persistent visual hallucinations in a patient with dementia are a strong
predictor of a DLB diagnosis, occurring in up to 80% of cases. Patients with
mild to moderate dementia can usually give a good account of these symptoms,
but in the later stages the clinician needs to use caregiver reports, and as with
250 I.G. McKeith
fluctuation, the use of specifically designed questionnaires is helpful [42].

Their presence early in the presentation and their persistence help distinguish
visual hallucinations from the transient perceptual disturbances that occur in
dementias of other etiology or during delirium. Well-formed, detailed, and
animate figures are experienced, provoking emotional responses varying through
fear, amusement, or indifference, usually with some insight into the unreality
of the episode once it is over. Auditory hallucinations also occur in about 20%
of cases and, together with olfactory and tactile hallucinations, may lead to
initial diagnoses of late-onset psychosis [43] or temporal-lobe epilepsy.
Delusions are also common in DLB and are usually based on recollections of
hallucinations and perceptual disturbances. Such delusions consequently have
a complex and bizarre content that contrasts with the mundane and often
poorly formed persecutory ideas encountered in AD patients, which are based
on forgetfulness and confabulation. The combination of prominent psychotic
symptoms and cognitive impairment in DLB may generate significant anxiety,
agitation, and behavioral disturbance.
Sleep disorders, in particular, rapid eye movement (REM)-sleep behavior
disorder, are also frequently associated with DLB. This parasomnia is characterized
by a loss of skeletal muscle atonia during REM sleep, and its onset often precedes
the onset of dementia by many years [44]. With associated daytime somnolence and
nocturnal restlessness, it has been suggested that REM-sleep behavior disorder may
contribute to the cognitive fluctuations and hallucinations and that its treatment
may improve fluctuations and quality of life.
Apathy and depression [45] are also frequently encountered, and their
assessment is complicated not only by each other, but also by facial and body
bradykinesia and attentional dysfunction.
Repeated falls may be caused by posture and/or gait and balance difficulties,
particularly in patients with parkinsonism. Syncopal attacks with complete loss
of consciousness and muscle tone also occur. These attacks may be secondary to
orthostatic hypotension and/or carotid sinus hypersensitivity, which are more
common in DLB than in AD or age-matched controls [46], or they may represent
one extreme of fluctuating attention and cognition. Early onset of urinary incon-
tinence has been reported in DLB compared with AD [47], reflecting the
involvement of autonomic systems.
Investigations
There are as yet no clinically applicable electrophysiological, genotypic, or cere-

brospinal fluid markers to support a DLB clinical diagnosis [48, 49], but neuroimaging
investigations may be helpful. Changes associated with DLB include preservation
of hippocampal and medial temporal-lobe volume on magnetic resonance imaging
(MRI) [50] and of occipital hypoperfusion on single-positron emission computerized
tomography (SPECT) [51]. Other features such as generalized atrophy, white
matter changes, and rates of progression of whole brain atrophy [52] appear to be
unhelpful in differential diagnosis. An important recent development for the diag-
nosis of DLB is the visualization of presynaptic dopaminergic deficits in the striatum
using 123I-radiolabeled 2-beta-carbomethoxy-3 beta-(4-iodophenyl)-N-(3-fluoropropyl)
nortropane (FP-CIT; trade name, DaTSCAN). This technique demonstrates high
sensitivity (78%) and specificity (90%) in identifying probable DLB versus
non-DLB dementia [53, 54]. Although the current (European) regulatory approval
for FP-CIT imaging is in distinguishing probable DLB from AD, the more valuable
clinical use may be in determining clinically uncertain cases [55].
Diagnostic Criteria
The diagnosis of probable or possible DLB is made by the application of inter-

nationally used consensus criteria that require the core features of fluctuating
cognitive impairment, recurrent visual hallucinations, and parkinsonism [7].
Features suggestive of DLB are REM-sleep behavior disorder, severe neuroleptic
sensitivity, and low dopamine transporter uptake in basal ganglia demonstrated
by SPECT/PET imaging. The presence of any one of these items is sufficient to
raise a diagnosis of possible DLB, which in turn requires further investigation to elicit
additional evidence for or against it. Two core features or one core accompanied
by one suggestive feature generates a diagnosis of probable DLB. Once made, a
clinical diagnosis of probable DLB is likely to remain stable, and autopsy studies
show that will be confirmed as correct in more than 80% of cases. Possible DLB
is a relatively unstable diagnosis, with 40% progressing to probable DLB over a
year’s follow-up, 20% reverting to non-DLB, and 40% remaining as possible
DLB [55].
One issue that repeatedly causes difficulty in diagnosing DLB is uncertainty
about its relationship with idiopathic PD, a disorder in which dementia may eventually
develop in up to 75% [56, 57]. Dementia in PD is often similar to DLB [58] with
respect to fluctuating neuropsychological function [59], neuropsychiatric features
[60], and extrapyramidal motor features [34]. There has been considerable debate
as to whether PD, PDD, and DLB are simply different clinical presentations of the
same underlying biological process, that is, LB disease, and indeed whether LB
disease might be a better clinical term to use in all circumstances [61, 62]. The
current resolution is to apply an arbitrary 1-year rule that proposes that the onset of
dementia within 12 months of the onset of parkinsonism qualifies as DLB, and that
more than 12 months of parkinsonism before the onset of dementia qualifies as
PDD [7]. Using diagnostic labels such as PDD and DLB that describe the order of
onset of symptoms is generally helpful in the diagnosis and management of most
clinical cases, and clinicians need to decide which term is the most appropriate for
each individual patient and carefully explain the terminology to the patient and his
or her caregivers [63].
252 I.G. McKeith
References
1. McKeith IG, Galasko D, Kosaka K et al (1996) Consensus guidelines for the clinical and
pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB
International Workshop. Neurology 47:1113–1124
2. Kosaka K, Yoshimura IK et al (1984) Diffuse type of Lewy body disease: progressive dementia
with abundant cortical Lewy bodies and senile changes of varying degree – a new disease?
Clin Neuropathol 3(5):185–192
3. Gibb WRG, Esiri MM, Lees AJ (1987) Clinical and pathological features of diffuse cortical
Lewy body disease (Lewy body dementia). Brain 110:1131–1153
4. Hansen L, Salmon D, Galasko D et al (1990) The Lewy body variant of Alzheimer’s disease:
a clinical and pathologic entity. Neurology 40:1–8
5. Perry RH, Irving D, Blessed G et al (1990) Senile dementia of Lewy body type. A clinically and
neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci 95:119–139
6. Byrne EJ, Lennox G, Godwin-Austen LB et al (1991) Dementia associated with cortical Lewy
bodies. Proposed diagnostic criteria. Dementia 2:283–284
Lewy bodies. Third report of the DLB consortium. Neurology 65:1863–1872
8. McKeith I, Del Ser T, Spano P et al (2000) Efficacy of rivastigmine in dementia with Lewy
bodies: a randomised, double-blind, placebo-controlled international study. Lancet
356:2031–2036
9. McKeith I, Fairbairn A, Perry R et al (1992) Neuroleptic sensitivity in patients with senile
dementia of Lewy body type. Br Med J 305:673–678
10. Ballard C, Grace J, McKeith I et al (1998) Neuroleptic sensitivity in dementia with Lewy
bodies and Alzheimer’s disease. Lancet 351:1032–1033
11. Molloy S, McKeith IG, O’Brien JT et al (2005) The role of levodopa in the management of
dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 76:1200–1203
12. Rahkonen T, Eloniemi-Sulkava U, Rissanen S et al (2003) Dementia with Lewy bodies
according to the consensus criteria in a general population aged 75 years or older. J Neurol
Neurosurg Psychiatry 74(6):720–724
13. Shergill S, Mullen E, D’Ath P et al (1994) What is the clinical prevalence of Lewy body
dementia? Int J Geriatr Psychiatry 9:907–912
14. Stevens T, Livingston G, Kitchen G et al (2002) Islington study of dementia subtypes in the
community. Br J Psychiatry 180:270–276
15. Holmes C, Cairns N, Lantos P et al (1999) Validity of current clinical criteria for Alzheimer’s
disease, vascular dementia and dementia with Lewy bodies. Br J Psychiatry 174:45–51
16. Singleton AB, Wharton A, O’Brien KK et al (2002) Clinical and neuropathological correlates
of apolipoprotein E genotype in dementia with Lewy bodies. Dement Geriatr Cogn Disord
14:167–175
17. Harding AJ, Halliday GM (2001) Cortical Lewy body pathology in the diagnosis of dementia.
Acta Neuropathol 102:355–363
18. Gómez-Tortosa E, Newall K, lrizarry MC et al (1999) Clinical and quantitative pathological
correlates of dementia with Lewy bodies. Neurology 53:1284–1291
19. Parkkinen L, Kauppinen T, Pirttilä T et al (2005) Alpha-synuclein pathology does not predict
extrapyramidal symptoms or dementia. Ann Neurol 57:82–91
20. Zaccai J, Brayne C, McKeith I et al (2008) Patterns and stages of alpha-synucleinopathy:
relevance in a population-based cohort. Neurology 70:1042–1048
21. Kramer ML, Schulz-Schaeffer WJ (2007) Presynaptic alpha-synuclein aggregates, not Lewy
bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci 27:1405–1410
22. Perry EK, Piggott MA, Johnson M et al (2003) Neurotransmitter correlates of neuropsychiatric
symptoms in dementia with Lewy bodies. In: Bedard M-A, Agid Y, Chouinard S et al (eds)
Mental and behavioral dysfunction in movement disorders. Humana, Totowa, NJ, pp. 285–294
23. Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145
cases using alpha-synuclein immunohistochemistry. Brain Pathol 10:378–384
24. Lippa CF, McKeith I (2003) Dementia with Lewy bodies: improving diagnostic criteria.
25. Uchikado H, Lin WL, DeLucia M et al (2006) Alzheimer disease with amygdala Lewy bodies:
a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65:685–697
26. Singleton A, Gwinn-Hardy K (2004) Parkinson’s disease and dementia with Lewy bodies:
a difference in dose? Lancet 364(9440):1105–1107
27. Johnson J, Hague SM, Hanson M et al (2004) SNCA multiplication is not a common cause of
Parkinson disease or dementia with Lewy bodies. Neurology 63(3):554–556
28. Clark LN, Kartsaklis LA, Wolf Gilbert R et al (2009) Association of glucocerebrosidase mutations
with dementia with Lewy bodies. Arch Neurol 66:578–583
29. Hardy J, Lewis P, Revesz T et al (2009) The genetics of Parkinson’s syndromes: a critical
review. Curr Opin Genet Dev 19:254–265
30. Ballard C, O’Brien J, Morris CM et al (2001) The progression of cognitive impairment in
dementia with Lewy bodies, vascular dementia and Alzheimer’s disease. Int J Geriatr
31. Walker Z, Allen RL, Shergill S et al (2000) Three years survival in patients with a clinical
diagnosis of dementia with Lewy bodies. Int J Geriatr Psychiatry 15:267–273
32. Hanyu H, Sato T, Hirao K et al (2009) Differences in clinical course between dementia with
Lewy bodies and Alzheimer’s disease. Eur J Neurol 16:212–217
33. Armstrong TP, Hansen LA, Salmon DP et al (1991) Rapidly progressive dementia in a patient
with the Lewy body variant of Alzheimer’s disease. Neurology 41:1178–1180
34. Aarsland D, Ballard C, McKeith I et al (2001) Comparison of extrapyramidal signs in dementia
with Lewy bodies and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 13:374–379
35. Burn DJ, Rowan EN, Minett T et al (2003) Extrapyramidal features in Parkinson’s disease
with and without dementia and dementia with Lewy bodies: a cross-sectional comparative
study. Mov Disord 18(8):884–889
36. Ballard C, O’Brien J, Swann A et al (2000) One year follow-up of parkinsonism in dementia
with Lewy bodies. Dement Geriatr Cogn Disord 11:219–222
37. Duda JE, Giasson BI, Mabon ME et al (2002) Novel antibodies to synuclein show abundant
striatal pathology in Lewy body diseases. Ann Neurol 52(2):205–210
38. Walker MP, Ayre GA, Cummings JL et al (2000) The Clinician Assessment of Fluctuation and
the One Day Fluctuation Assessment Scale. Two methods to assess fluctuating confusion in
dementia. Br J Psychiatry 177:252–256
39. Ballard CG, Mohan RNC, Patel A et al (1993) Idiopathic clouding of consciousness – do the
patients have cortical Lewy body disease? Int J Geriatr Psychiatry 8:571–576
40. Bradshaw J, Saling M, Hopwood M et al (2004) Fluctuating cognition in dementia with Lewy
bodies and Alzheimer’s disease is qualitatively distinct. J Neurol Neurosurg Psychiatry
75:382–387
41. Ferman T, Smith GE, Boeve BF et al (2004) DLB fluctuations: specific features that reliably
differentiate from AD and normal aging. Neurology 62(2):181–187
42. Mosimann UP, Rowan EN, Partington CE et al (2006) Characteristics of visual hallucinations
in Parkinson disease dementia and dementia with Lewy bodies. Am J Geriatr Psychiatry
14(2):153–60
43. Birkett DP, Desouky A, Han L et al (1992) Lewy bodies in psychiatric patients. Int J Geriatr
Psychiatry 7:235–240
44. Boeve BF, Silber MH, Ferman TJ (2004) REM sleep behavior disorder in Parkinson’s disease
and dementia with Lewy bodies. J Geriatr Psychiatry Neurol 17(3):146–157
45. Klatka LA, Louis ED, Schiffer RB (1996) Psychiatric features in diffuse Lewy body disease:
findings in 28 pathologically diagnosed cases. Neurology 46:A180
46. Ballard C, Shaw F, McKeith I et al (1998) High prevalence of neurovascular instability in
neurodegenerative dementias. Neurology 51:1760–1762
47. Del-Ser T, Munoz DG, Hachinski V (1996) Temporal pattern of cognitive decline and incontinence
is different in Alzheimer’s disease and diffuse Lewy body disease. Neurology 46:682–686
48. McKeith I, Mintzer J, Aarsland D et al (2004) Dementia with Lewy bodies. Lancet Neurol
3:19–28
254 I.G. McKeith
49. Mollenhauer B, Cullen V, Kahn I et al (2008) Direct quantification of CSF alpha-synuclein by

ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol
213(2):315–25
50. Burton EJ, Barber R, Mukaetova-Ladinska et al (2009) Medial temporal lobe atrophy on MRI
differentiates Alzheimer’s disease from in dementia with Lewy bodies and vascular cognitive
impairment. Brain 132:195–203
51. Lobotesis K, Fenwick JD, Phipps A et al (2001) Occipital hypoperfusion on SPECT in
dementia with Lewy bodies but not AD. Neurology 56:643–649
52. O’Brien JT, Paling S, Barber R et al (2001) Progressive brain atrophy on serial MRI in dementia
with Lewy bodies, AD, and vascular dementia. Neurology 56(10):1386–1388
53. Walker Z, Costa DC, Ince P et al (1999) In-vivo demonstration of dopaminergic degeneration
in dementia with Lewy bodies. Lancet 354:646–647
54. McKeith I, O’Brien J, Walker Z et al (2007) Sensitivity and specificity of dopamine transporter
imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study.
Lancet Neurol 6:305–313
55. O’Brien JT, McKeith IG, Walker Z et al (2009) Diagnostic accuracy of 123I-FP-CIT SPECT
in possible dementia with Lewy bodies. Br J Psychiatry 194:34–39
56. Emre M (2003) Dementia associated with Parkinson’s disease. Lancet Neurol 2(4):229–237
57. Aarsland D, Andersen K, Larsen JP et al (2003) Prevalence and characteristics of dementia in
Parkinson disease: an 8-year prospective study. Arch Neurol 60(3):387–392
58. Emre M, Aarsland D, Brown R et al (2007) Clinical diagnostic criteria for dementia associated
with Parkinson’s disease. Mov Disord 22:1689–1707
59. Ballard CG, Aarsland D, McKeith I et al (2002) Fluctuations in attention: PD dementia vs
DLB with parkinsonism. Neurology 59(11):1714–1720
60. Aarsland D, Ballard C, Larsen JP et al (2001) A comparative study of psychiatric symptoms
in dementia with Lewy bodies and Parkinson’s disease with and without dementia. Int
J Geriatr Psychiatry 16:528–536
61. McKeith I (2007) Dementia with Lewy bodies and Parkinson’s disease with dementia: where
two worlds collide. Pract Neurol 7:374–382
62. McKeith I (2009) Commentary: DLB and PDD: the same or different? Is there a debate? Int
Psychogeriatr 21:220–224
63. McKeith IG (2004) Dementia with Lewy bodies (DLB) and other difficult diagnoses.
Int Psychogeriatr 16(2):123–127
Dementia with Lewy Bodies and Parkinson
Disease with Dementia Within the Spectrum
of Lewy Body Disease
Kenji Kosaka
Abstract The history of Parkinson disease (PD) and dementia with Lewy bodies
(DLB) is briefly presented. Since Lewy reported Lewy bodies in the brainstem
nuclei of the PD brain in 1912, Lewy bodies had been considered an essential
pathological finding for the diagnosis of PD. It had been, however, considered that
there were almost no Lewy bodies occurring in the cerebral cortex. In 1976, we
reported our first autopsied case showing numerous Lewy bodies in the cerebral
cortex. In 1978, we reported the detailed characteristics and distribution pattern of
cortical Lewy bodies, based on three autopsied cases showing diffuse Lewy body
disease (DLBD), a term that we proposed in 1984. We also reported two German
autopsied cases showing DLBD in 1979, which were the first DLBD cases reported
in Europe. In 1980, we also proposed the term Lewy body disease and classified it
into three types: brainstem type, transitional type, and diffuse type. The brainstem
type is the same as PD, and the diffuse type was later designated DLBD. In 1990,
we reviewed all the 37 DLBD cases reported in Japan and classified DLBD into
two forms: a common form with more or less Alzheimer pathology and a pure form
without such pathology. Since then, we have reported many papers concerning
DLBD. The term dementia with Lewy bodies (DLB) was proposed at the first
international workshop held in 1995. CDLB guidelines were published in 1996, and
the CDLB guidelines–revised were reported in 2005. In the revised guidelines the
term Lewy body disease was used as a generic term that included DLB, PD, and
PDD, as we had insisted since 1980.
Keywords Dementia฀with฀Lewy฀bodies฀(DLB)฀•฀Diffuse฀Lewy฀body฀disease฀
•฀ Lewy฀ body฀ disease฀ •฀ Parkinson฀ disease฀ •฀ Parkinson฀ disease฀ with฀ dementia฀
(PDD)
K. Kosaka (*)
Yokohama Houyuu Hospital, Yokohama, Japan

DOI 10.1007/978-4-431-53871-4_19, © Springer 2010
256 K. Kosaka
Introduction
Dementia with Lewy bodies (DLB) is now the second most frequent dementing
illness in the elderly, following Alzheimer-type dementia (ATD). The term DLB
was proposed at the first International Workshop [1], which was held in Newcastle
upon Tyne in 1995. Lewy bodies are essential for the neuropathological diagnosis
of Parkinson’s disease (PD). PD patients frequently show dementia, and such
patients are diagnosed as having PD with dementia (PDD). Recently, it has usually
been considered that DLB and PDD are almost the same disease not only clinically
but also neuropathologically.
In this chapter, the author briefly introduces the history of PD and DLB, and
insists that DLB and PDD should be understood within the spectrum of Lewy body
disease, a term that we proposed in 1980 [2].
History of PD and DLB
James Parkinson [3] published the first report detailing the clinical features of
“shaking palsy” in 1817. Then, he described that cognition remained intact in this
disease. Charcot [4] proposed the term “Parkinson disease” in 1968, and described
cognitive disturbance in PD. In 1912, Lewy [5] reported eosinophilic round intra-
neuronal inclusions in the substantia innominata and dorsal vagal nuclei of PD
brain. Tretiakoff [6] nominated these inclusions “Lewy bodies” and indicated the
importance of the substantia nigra in PD in 1919. Thereafter, the difference of PD
and postencephalitic parkinsonism was discussed for a long time. Hassler [7]
reported the difference in the distribution of neuronal loss in the substantia nigra
between these two diseases in 1938. In 1953, Greenfield and Bosanquet [8] pointed
out for the first time that the presence of Lewy bodies is the essential pathological
finding for the diagnosis of PD whereas the presence of neurofibrillary tangles is
essential for the diagnosis of postencephalitic parkinsonism. Furthermore, den
Hartog Jager and Bethlem [9] described the detailed distribution of Lewy bodies in
the brainstem of PD brain in 1960. Thus, the pathological basis of PD was estab-
lished about one and a half centuries after the first report of Parkinson in 1817. It
had been, however, considered that there were almost no Lewy bodies occurring in
the cerebral cortex. In 1976, we [10] reported our first autopsied case showing
numerous Lewy bodies in the cerebral cortex as well as in the brainstem nuclei. In
1978, we [11] reported the detailed characteristics and distribution pattern of corti-
cal Lewy bodies, based on our own three autopsied cases with “diffuse Lewy body
disease (DLBD),” a term that we [12] proposed in 1984. We [13] also reported two
German autopsied cases showing DLBD in 1979, which were the first DLBD cases
reported in Europe. In 1980, we [2] proposed the term “Lewy body disease” and
classified it into three types: brainstem type, transitional type, and diffuse type. The
brainstem type is the same as PD, and the diffuse type was later designated DLBD
DLB and PDD as Lewy Body Disease 257
[12]. Furthermore, we [14] reviewed all 37 DLBD cases reported in Japan and clas-
sified DLBD into two forms: a common form with more or less Alzheimer pathol-
ogy and a pure form without such findings. Since then, we have published several
papers concerning DLBD. The term “dementia with Lewy bodies” (DLB) was
proposed at the first international workshop in 1995 [1]. The CDLB guidelines
were published in 1996 [15], and the CDLB guidelines–revised were reported in
2005 [16].
The most important recent findings in this field were (1) alpha-synuclein gene
mutation in familial PD [17] and (2) alpha-synuclein as the main component of
Lewy bodies [18]. Thereafter, alpha-synuclein has received considerable attention
in the research on Lewy body disease.
DLB and PDD Within the Spectrum of Lewy Body Disease
At the first international workshop held in 1995, the difference between DLB and
PDD was discussed. In the CDLB guidelines [15], the “1-year rule” was adapted.
According to these guidelines, PDD is differentiated from DLB by the appearance
of dementia at least 1 year after the onset of PD symptoms. At the third international
workshop held in 2003, not a few researchers insisted that this 1-year rule should
be abolished. This rule was, however, maintained even in the CDLB guidelines–revised
reported in 2005 [16]. Considerable evidence has been reported that DLB and PDD
are almost the same not only clinically but also neuropathologically. Therefore, in
the revised guidelines, the term “Lewy body disease” was used as a generic term
that includes DLB, PD, and PDD [16]. In the report of the DLB and PDD working
group in 2007 [19], a similar description was also introduced.
Since our proposal of Lewy body disease in 1980 [2], we have insisted that
Lewy body disease is a generic term that includes PD, PDD, and DLBD [12, 14,
20–22].
Lewy body disease is now defined as follows: “Lewy body disease is a chronic
neuropsychiatric disease characterized clinically by idiopathic parkinsonism of
early- or late-onset, frequently followed by progressive dementia. In many cases,
progressive dementia is the main symptom, followed frequently by idiopathic
parkinsonism. It is neuropathologically characterized by the presence of numerous
Lewy bodies and Lewy neurites in the central and sympathetic nervous systems.”
As indicated above, we classified DLBD into two forms: a common form with
more or less ATD pathology and a pure form without it [14]. Then, we described
differences in the clinical features between the common form and the pure form. In
the common form, most cases showed later onset, and the initial symptom was
memory disturbance followed by progressive dementia, and about 70% of patients
later developed parkinsonism. However, the pure form was characterized by younger
onset, idiopathic parkinsonism as the initial symptom and later followed by progres-
sive dementia. Therefore, the pure form can be diagnosed as PDD. In 1992, when
the 150th anniversary congress of the German Psychiatry Association was held
258 K. Kosaka
in Koeln, I was invited to a symposium and reported the differences in clinical

features between Japanese and European-American DLBD cases [23]. The features
of the common form do not show any differences between the two regions, while the
pure form showed marked differences between regions: most Japanese cases were
characterized, as indicated above, by younger onset and initial parkinsonism fol-
lowed by dementia, whereas most European-American cases demonstrated later
onset and progressive dementia followed by parkinsonism, as in the common form.
In 2003, when I was invited as a symposist at the annual meeting of the Japan
Neurology Association, I [24] reported a neuropathological study of 24 PDD cases.
The findings showed that all our 24 PDD cases were pathologically diagnosed as
DLB. Thus, PDD did not show neuropathological differences from DLB.
In 1996, we [21] proposed the term “cerebral type” of Lewy body disease. In the
cerebral type, the main symptom is progressive dementia without parkinsonism.
Neuropathologically, numerous Lewy bodies appeared in the cerebral cortex as in
DLBD, but only rare Lewy bodies were found in the brainstem nuclei. Braak’s
theory [25] insisted that Lewy bodies occur from the medulla oblongata through the
pons and midbrain to the cerebral cortex in PD. This cerebral type means suggests
that Lewy bodies occur at first in the cerebral cortex and then migrate down to the
brainstem nuclei . Therefore, the cerebral type of Lewy body disease should receive
more attention.
In conclusion, Lewy body disease is a generic term that includes PD, PDD, and
DLB. It is neuropathologically classified into four types: brainstem type, transitional
or limbic type, diffuse type, and cerebral type.
References
1. Perry R, McKeith I, Perry E (1996) Dementia with Lewy bodies. Cambridge University Press,
Cambridge
2. Kosaka K, Matsushita M, Oyanagi S, Mehraein P (1980) A clinicopathological study of Lewy
body disease. Psychiat Neurol Jap 82:292–311
3. Parkinson J (1817) An essay on the shaking palsy. Sherwood, Neely and Jones, Wittingham
and Rowland, London
4. Charcot JM (1892) De la paralysie agitante Euvures completes, 6th edn. Progres Medicale, Paris
5. Lewy FH (1912) Paralysis agitans. I. Pathologische anatomie. In: Lewandowsky M (ed)
Handbuch der neurologie, vol 3. Berlin, Springer, pp 920–958
6. Tretiakoff C (1919) Contribution a l’etude de l’Anatomie pathologique du Locus Niger de
Soemmerung avec quelques deductions relatives a la pathogenie des troubles du tonus mus-
culaire et de la Parkinson. These de Paris
7. Hassler R (1938) Zur pathologie der paralysis agitans und des postenzephalitischen parkin-
sonismus. J Psychol Neurol 48:387–476
8. Greenfield JG, Bosanquet FD (1953) The brain-stem lesions in Parkinsonism. J Neurol
9. Den Hartog Jager WA, Bethlem JU (1960) The distribution of Lewy bodies in the central and
autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry
23:283–290
10. Kosaka K, Oyanagi S, Matsushita M et al (1976) Presenile dementia with Alzheimer-, Pick-
and Lewy body changes. Acta Neuropathol 36:221–233
DLB and PDD as Lewy Body Disease 259
11. Kosaka K (1978) Lewy bodies in cerebral cortex; report of three cases. Acta Neuropathol
42:127–134
12. Kosaka K, Yoshimura M, Ikeda K, Budka H (1984) Diffuse type of Lewy body disease. A
progressive dementia with numerous cortical Lewy bodies and senile changes of various
degree. A new disease? Clin Neuropathol 3:185–192
13. Kosaka K, Mehraein P (1979) Dementia-Parkinsonism syndrome with numerous Lewy bodies
and senile plaques in cerebral cortex. Arch Psychiatr Nervenkr 226:241–250
14. Kosaka K (1990) Diffuse Lewy body disease in Japan. J Neurol 237:197–204
15. McKeith I, Galasko D, Kosaka K et al (1996) Consensus guidelines for the clinical and patho-
logical diagnosis of dementia with Lewy bodies (DLB). Neurology 47:1113–1124
Lewy bodies: third report of the DLB consortium. Neurology 65:1863–1872
17. Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the a-synuclein gene
identified in families with Parkinson’s disease. Science 276:2045–2047
18. Spillantini MG, Schmidt ML, Lee VMY et al (1997) a-Synuclein in Lewy bodies. Nature
(Lond) 388:839–840
19. Lippa CF, Duda JE, Grossman M et al (2007) DLB and PDD boundary issues. Diagnosis,
treatment, molecular pathology, and biomarkers. Neurology 68:812–818
20. Kosaka K, Iseki E (1996) Diffuse Lewy body disease within the spectrum of Lewy body
disease. In: Peery E, McKeith E, Perry E (eds) Dementia with Lewy bodies. Cambridge
University Press, Cambridge
21. Kosaka K, Iseki E, Odawara T et al (1996) Cerebral type of Lewy body disease.
Neuropathology 17:32–35
22. Kosaka K (2000) Diffuse Lewy body disease. Neuropathology 20 (suppl):73–78
23. Kosaka K (1992) Diffuse Lewy Koerperchen: vergleich klinisch- pathologischer Daten
zwischen Japanischen und Europaeischen/Amerikanischen Faellen. 150. Jahren Psychiatrie in
Deutschland, Koeln
24. Kosaka K (2004) Dementia with Lewy bodies and Parkinson’s disease with dementia. Do
most of the demented PD patients have DLBD? The 45th Annual Meeting of Japan Neurology
Association, Tokyo (panel discussion)
25. Braak H, Del Trediel K, Rub U et al (2003) Staging of brain pathology related to sporadic
Parkinson’s disease. Neurobiol Aging 24:197–211
Clinicopathological Characterization
of Frontotemporal Lobar Degeneration
Yoshio Mitsuyama
Abstract Frontotemporal lobar degeneration (FTLD) is a clinically, genetically,

and pathologically heterogeneous group of diseases, including Pick disease,
frontotemporal lobar dementia with lacking distinctive histology (FTLD-LDH),
and FTLD with motor neuron disease (FTLD-MND). Pick disease is essentially
taupathy. FTLD-LDH has inconsistent clinicopathological findings with different
immunohistochemical characterization.
FTLD-MND shows characteristic combinations with FTLD and MND. FTLD
and FTLD-MND represent distinct clinicopathological entities. The relationship
between FTLD-MND and amyotrophic lateral sclerosis is uncertain.
Keywords Frontotemporal฀lobar฀dementia฀•฀Motor฀neuron฀disease฀•฀Pick฀disease
Introduction
Frontotemporal lobar degeneration (FTLD) is one of the most common

neurodegenerative disorders among aging societies. FTLD accounts for
approximately 20% of neurodegenerative dementias [1, 2]. FTLD is the third most
common cause of neurodegenerative dementia syndrome after Alzheimer’s disease
and dementia with Lewy bodies. FTLD occurs primarily between the age of 35 and
75 years, and it is rare to have the onset after age of 75. The disease affects both
sexes approximately equally. Some cases may carry a diagnosis of Alzheimer’s
disease or rapidly dementing illness. Pathologically, it includes a heterogeneous
group of sporadic and familial neuropsychiatric diseases.
Y. Mitsuyama (*)
Psychogeriatric Center of Daigo Hospital, 1270 Nagata, Mimata-cho,
Miyazaki 889-1911, Japan

DOI 10.1007/978-4-431-53871-4_20, © Springer 2010
262 Y. Mitsuyama
In the 1980s and 1990s, several research groups recognized that there were
many patients with clinical features similar to those of patients with Pick disease
who had neither the classical lobar atrophy nor characteristic neuronal changes.
These disorders came to be known by several different names, including FTLD-
LDH, which consists of frontotemporal lobar degeneration lacking distinct histol-
ogy, Pick disease, and FTLD with motor neuron disease (FTLD-MND), primary
progressive aphasia (PPA), and semantic dementia (SD) [3–10]. As expected, all
variants of FTLD have neuronal loss and gliosis affecting the frontal and temporal
cortices in keeping with a diagnosis of FTLD. The research criteria have been
focused on the need to have subgroups of patients for study during life and accurate
pathological diagnosis on autopsy.
Clinical criteria for diagnosing FTLD include the Lund and Manchester Criteria
and the more recent consensus criteria [2, 11, 12]. Patients with FTLD present
gradual and progressive changes in behavior, or gradual and progressive language
dysfunctions. The most common psychiatric symptom of FTLD is an early change
in social and personal conduct, characterized by difficulty in modulating behavior
to the social demands of a situation. FTLD patients are impaired in the regulation of
conduct. This dysfunction is often associated with a lack of inhibition, resembling
in impulsive or inappropriate behavior. Progression of the disease may lead to poor
financial judgement, and compulsive-like behaviors are common presenting symptoms
among FTLD patients [12, 13]. Complex compulsive acts may result from temporal
lobe involvement [14]. In some individuals, inappropriate sexual behavior occurs.
Perseverative and stereotyped behaviors encompass simple repetitive acts and
verbal expression or stereotypies such as lip smacking, habitual hand rubbing or
clapping, and humming that may result from frontostriatal circuit dysfunction or
involvement of the caudate nuclei. Psychotic symptoms such as delusions and
hallucinations are uncommon in FTLD. Nevertheless, there have been patients with
an initial schizophrenia-like psychosis or a psychotic affective disorder such as a
sign of FTLD [15, 16]. Dietary habits and personal hygiene may also change.
Patients become inactive with decreased behavioral motivation and spontaneity,
loss of interest in personal hygiene with failure to wash, bathe, groom, and so on.
In FTLD, fragments of the Klüver–Bucy syndrome can occur, particularly the
hyperorality that manifests as cramming and bingeing, altered food performance
especially for sweets or food fads. They may attempt to eat inedible items. FTLD
patients can be so hyperoral that require restraint to prevent suffocation or
aspiration. There is a loss of concern for one’s personal appearance, and patients
may be increasingly unkempt early in the disease. Patients show loss of personal
concern for their actions.
FTLD patients tend toward decreased verbal output progressively to complete
mutism. Early language disturbances of FTLD are empty speech, nonfluent anomia,
especially for words connecting action, and semantic anomia where the word loses
its meaning. They usually do not have a true amnestic syndrome. In the FTLD,
spatial difficulties are seen in patients with mild or moderate impairments. Many of
these patients present with troubles in the expression of language, problems using
the correct words, including the naming of persons and things, or expressing
Clinicopathological Characterization of Frontotemporal Lobar Degeneration 263
oneself. Some patients with FTLD have a progressive aphasia several years before
other clinical manifestations; in such cases, speech and language changes predomi-
nate (PPA and SD) [17].
FTLD patients have relatively preserved visuo-spatial abilities such as spatial local-
ization and orientation in familiar surroundings. FTLD patients lack sympathy, empa-
thy, emotional warmth, or awareness of the needs of others and appear emotionally
shallow and indifferent. FTLD patients have deficits of insight, abstraction, planning,
and problem solving, in keeping with a frontal “dysexecutive” syndrome. Judgement
is abnormal. FTLD patients are often very concrete on proverb interpretation and tests
assessing comprehension of similarities and differences. On neuropsychological test-
ing, frontal-executive functions are compromised early in FTLD, and most memory
and occipitoparietal functions are compromised early in most Alzheimer patients.
In the early and middle stages, neurological signs are usually absent or confined
to the presence of primitive reflexes such as grasp, snout, and sucking reflexes.
Dystonia, ideomotor apraxia, dysphagia, or fasciculations and muscle wasting are
occasionally observed.
There are no laboratory findings pathognomonic of FTLD. Routine investigations
of blood and urine yield unremarkable results. Conventional EEGs tends to remain
normal until late in the course, when they show diffuse slowing and occasional
focal frontal or temporal slow wave activity. Structural neuroimaging, particularly
magnetic resonance imaging (MRI), can help confirmation in the presence of
FTLD. Most FTLD patients show frontal (and anterior temporal) atrophy,
enlargement of the Sylvius fissures, anterior callosal atrophy, and eventual
hippocampal and entorhinal volume loss. Computed tomography (CT)/MRI may
show atrophy of the anterior temporal and frontal lobes. Some FTLD patients may
have additional MRI evidence of bilateral caudate nuclear atrophy. Functional
imaging is more sensitive than structural imaging for the diagnosis of FTLD.
Single-photon emission computed tomography/18F-fluorodeoxyglucose-positron
emission tomography (SPECT/FDG-PET) typically demonstrates decreased
perfusion and metabolism of the frontal and temporal lobes.
The usual clinical duration of FTLD is about 8–11 years. The clinical course of
FTLD can be divided into three stages. In the initial stages, there are prominent
personality changes, emotional alterations, and impaired insight and judgement.
Speech and language changes also may occur. In the second stage, aphasia and
other cognitive changes become pronounced, but there is at least partial preservation
of memory, visuo-spatial skills, and computational ability. The third and final stage
of the disease is often dominated by progressive muteness, and the patients become
profoundly demented.
At autopsy, the brains of patients with FTLD show a lobar distribution of
atrophy involving the frontal lobes, temporal lobes, or both. Coronal sections reveal
deep sulci and may show knife-edged gyri in the atrophic area, especially in Pick
disease. The orbitofrontal cortex and the anterior and medial temporal areas show
the most severe atrophic changes. The predominant neuropathological abnormalities
are frontotemporal neuronal loss and gliosis with ubiquitin-positive, tau-negative
inclusions and without detectable amounts of insoluble tau, with MND or without
264 Y. Mitsuyama
MND. The cortical degeneration involves mainly the grey matter, including the
insula and the anterior cingulate gyrus. In the past, clinicians have referred to FTLD
patients as having “Pick bodies,” but on neuropathological examination, most
FTLD patients lack the pathognomonic Pick bodies. There has been continuing
controversy concerning whether identifiable cellular changes of Pick bodies and
ballooned neurons are a requirement for diagnosis. Smaller number of FTLD
patients have involvement of substantia nigra, striato-pallidum, parietal cortex,
thalamus, and other structures [18, 19]. Most FTLD patients do not have senile
plaques or neurofibrillary tangles, although some have amyloid beta deposition,
particularly late in the course and in patients with an APO-E epsilon 4-allele [20].
In FTLD, about one-third of patients have tau pathology and about 10% have a tau
gene mutation [21, 22]. Pathological findings have, to date, not been associated
with specific clinical manifestations.
Pick Disease
Arnold Pick [23–25], in a series of articles based on gross examination of the brain,
reported cases of dementia with severe circumscribed atrophy of the frontotemporal
regions. The definition of the clinical entity of what became known as Pick disease
was presented in a series of articles in the 1920s [26–28]. The initial stage is char-
acterized by prominent personality changes and emotional alterations. Judgment is
impaired early, and insight is compromised. Social behavior deteriorates, and lan-
guage abnormalities are among the earliest intellectual alterations to occur. In the
second stage of disease, deterioration of mental status becomes evident and aphasia
is more prominent. Cognitive changes are more pronounced, but memory and
visuo-spatial skills may remain relatively intact. In the final stage of the disease,
progressive extrapyramidal syndrome usually appears and the patient becomes
mute and incontinent. Pick disease has a longer illness duration (more than 10
years). CT/MRI may provide supportive evidence for the diagnosis.
Neuropathology shows severe frontotemporal atrophy, often with “knife-
edged” gyri (Fig. 1), and extensive neuronal loss with gliosis. An abrupt transi-
tion is sometimes evident between involved and uninvolved cortical regions.
There is a tendency for selective sparing of the precentral gyrus and the posterior
one-third of the superior temporal gyrus. The concept of Pick disease emphasized
the importance of Pick bodies and ballooned neurons in the pathological diagno-
sis and the clinical distinction of this disorder from Alzheimer disease. The diag-
nosis of Pick disease occurs when there are Pick bodies with or without Pick
cells. Pick bodies are spherical, silver-staining (argyrophilic), ubiquitin- and tau-
positive intraneuronal inclusions. Pick bodies are concentrated in frontotemporal
neocortical layers II–VI, and the hippocampal formation in the granular layer of
the dentate gyrus and sector CA1. Pick bodies do not occur in normal aging.
There are pathognomonic microscopic findings showing ballooned neurons or
Pick cells and definite positive tau and ubiquitin bodies in neurons of the
Fig. 1 “Knife-edged” atrophy of the brain
frontotemporal cortex and granule cells of dentate gyrus of the hippocampus

(Pick bodies). Pick disease is essentially taupathy, similar to corticobasal degen-
eration and progressive supranuclear palsy. The volume of the substantia nigra is
decreased, but the concentration of neurons is slightly reduced, and there is no
clinical parkinsonism until the terminal stages.
FTLD-LDH
FTLD is a clinical term applied to patients who present with progressive dementia
with an insidious onset, prominent behavioral or language dysfunction, or both. We
have recognized that this term includes groups of patients whose pathological con-
ditions and genetic mechanisms are heterogeneous. The clinical characteristics of
FTLD-LDH are almost similar to those of Pick disease. However, the severity of
intellectual and personality deterioration is less than those seen in Pick disease.
MRI shows frontotemporal atrophy, and SPECT shows selective hypoperfusion of
frontotemporal lobes. The most common pathology of FTLD-LDH is a nonspecific
frontotemporal atrophy, and FTLD-LDH is the usual FTLD pathology.
Microscopic study shows mild to slight neuronal loss and astrogliosis with
sponginess (minute cavities or microvacuolation) of the outer supragranular (II–III)
layers of the frontotemporal cortex with ubiquitin- and TDP-43-positive inclusions
266 Y. Mitsuyama
Fig. 2 Ubiquitin- and TDP-43-positive inclusions of the cerebral cortex
(Fig. 2). There is also variable involvement of subcortical and limbic structures.
The anterior hippocampal regions are also affected. FTLD-LDH has no Pick bod-
ies, plus depigmentation in the substantia nigra and striato-pallidum.
FTLD-MND
A subset of patients with FTLD develops symptoms suggestive of MND. The mean
age at onset and disease duration are 52 years and 2.3 years, respectively. FTLD-
MND is a clinicopathological entity characterized by the combination of FTLD and
MND. The link between FTLD and MND was suggested by the autopsy in 1984
[29], and the term FTLD-MND was subsequently proposed [30]. The development
of MND in patients presenting with a progressive behavioral disorder would strongly
support a clinical diagnosis of FTLD-MND. MND is also a clinical term, but it is
applied to patients with clinical evidence of corticospinal tract involvement, evi-
dence of brainstem or spinal cord anterior horn cell involvement, or both. FTLD-
MND have symptoms of mild forgetfulness and language output impairment, in
addition to the more prominent behavioral disorders. These symptoms include
weakness and muscle wasting. Symptoms of parkinsonism, such as rigidity, are
occasionally seen. Signs of MND may not always be present early. Most of the cases
of MND developed approximately 6–24 months after the onset of symptoms of
FTLD [29, 31]. Only features of dementia are noted early in the disease course, and
both initially carried a diagnosis of FTLD. MRI/SPECT reveals slight to moderate
atrophy and selective hypoperfusion in the frontotemporal regions. The patient
shows a relatively rapid clinical course, less than 5 years.
The pathological features of FTLD-MND are variable. Neuropathology of

FTLD-MND shows slight frontotemporal lobe atrophy and more characteristic
features of mild neuronal loss with cortical sponginess and subcortical gliosis,
affecting the frontal and temporal cortices in keeping with a diagnosis of FTLD.
In addition, all cases have pathological evidence of degeneration of lower motor
neurons that contain eosinophilic and ubiquitin-positive inclusions. There are also
ubiquitin-positive, tau-negative (nonargyrophilic) inclusions in the neurons of the
frontotemporal cortex and granule cells in the dentate fascia of the hippocampus,
which are characteristic of MND. Ubiquitin-positive and tau-negative inclusions
may be present in FTLD with or without MND. Ubiquitin- and TDP-43-positive
inclusions are present in the dentate fascia and neocortex in FTLD-MND. Some
cases have a mixture of lower motor neuron degeneration and corticospinal tract
degeneration (similar to amyotrophic lateral sclerosis, ALS) and the majority have
Bunina bodies, which are a histological hallmark of ALS. The severity of motor
neuron degeneration is variable, ranging from absent to severe. Some cases have a
predominance of corticospinal tract degeneration, but others have no corticospinal
tract degeneration. At the present time, there is no way to distinguish between cases
on the basis of extramotor ubiquitin-positive pathological features or on the basis
of predominant involvement of upper or lower motor neurons. A large sample size
would be needed to address possible clinically useful subtypes. FTLD-MND with
pathological changes in the hippocampus seems strikingly similar to other FTLD
and some evidence of MND, whereas FTLD-MND without hippocampal pathology
seems strikingly similar to ALS with some evidence of FTLD.
FTLD-MND should be taught as a spectrum of diseases and include FTLD-
MND with hippocampal pathology and FTLD-MND without hippocampal
pathology. Detection of signs of clinical MNDs is difficult when motor neuron
degeneration is mild. FTLD-MND is diagnosed if there is evidence of brainstem or
spinal cord anterior horn cell degeneration with or without ubiquitin-positive
inclusions [32–34], degeneration of the corticospinal tract, or both, in addition to
histological evidence of FTLD. Histological evidence of motor neuron degeneration
includes loss of large anterior horn cells in the spinal cord or hypoglossal neurons
plus (1) shrunken residual motor neurons, (2) evidence of neuronophagia, (3)
Bunina bodies, or (4) ubiquitin-immunoreactive intraneuronal inclusions. Evidence
of FTLD includes the presence of superficial sponginess, neuronal loss, and
astrogliosis affecting predominantly layer II of the cortex, with or without the
presence of ubiquitin immunoreactive neuronal cytoplasmic inclusions. Neuronal
intranuclear inclusions such as Pick bodies are not detected. The ubiquitin-positive
inclusions are negative for tau, alpha-synuclein, and neurofilament. Extramotor
ubiquitin-positive neuronal inclusions are present in all cases, in the dentate fascia,
neocortex, or both regions. Skeletal muscle has evidence of group atrophy with
small acutely angulated fibers consistent with neurogenic atrophy.
Neuronal loss and gliosis of the hypoglossal nucleus and spinal anterior horn
cells are variable and ranged from absent to severe. The severity of motor neuron
involvement tend to correlate with clinical evidence of MND. Corticospinal tract
degeneration also ranged from absent to severe. Severity of corticospinal tract
268 Y. Mitsuyama
degeneration does not correlate with clinical signs of MND or with severity of
neuronal loss and gliosis in the hypoglossal nucleus and spinal anterior horn cells.
Extramotor ubiquitin-positive inclusions are absent to sparse in all cortical regions.
Comments
Large clinicopathological series have been published that have clearly demon-
strated an overlap between the clinical syndromes subsumed under the term fronto-
temporal dementia and the progressive supranuclear palsy syndrome, corticobasal
degeneration syndrome, and MND. There have also been significant advancements
in brain imaging, neuropathology, and molecular genetics that have led to different
approaches to the classification.
FTLD and FTLD-MND represents a distinct clinicopathological entity that
shows essentially ubiquitin and TDP-43 proteinopathy. There are some cases of
FTLD with TDP-43-positive and ubiquitin-negative pathology. TDP-43 proteinop-
athy has been reported in many neurodegenerative diseases (filament inclusion
disease). TDP-43 might be more susceptible to neuronal damage. From these find-
ings, different pathoetiologies could lead to the varied clinicopathological presenta-
tions of FTLD.
The pathological features of FTLD-MND are variable. Most cases have a mix-
ture of lower motor neuron degeneration, occasionally associated with corticospi-
nal tract degeneration, similar to progressive spinal muscular atrophy or ALS, and
the majority have Bunina bodies, which are a histological hallmark of ALS.
The field is complicated by a barrage of overlapping clinical syndromes, and
neuropathological diagnosis that does not always respond to clinical presentations
and underlying neuropathology.
It is difficult to distinguish between cases on the basis of extramotor ubiquitin-posi-
tive pathological features or on the basis of predominant involvement of upper or lower
motor neurons. Hippocampal sclerosis with ubiquitin-positive inclusions in the dentate
fascia is a common feature of FTLD with ubiquitin-only immunoreactive changes.
Lower motor neuron involvement including spinal cord anterior horn cell and
hypoglossal nucleus degeneration is of the utmost importance for future clinico-
pathological studies with combined dementia and MND.
It is unclear how neurodegenerative diseases cause dysfunction and death of
brain cells or specific neuropsychiatric symptoms. Clinical manifestations of the
FTLD cannot accurately predict the nature of the underlying neurodegenerative
disease. The neuropathological findings alone cannot establish that a patient had
FTLD in the absence of documented clinical information. Although there is no
specific treatment for FTLD, many symptomatic therapies can be very helpful.
Many of the behavioral psychological symptoms of FTLD may respond to selective
serotonin uptake inhibitors (SSRI) [35]. Marked disinhibition, aggressive behavior,
or verbal outbursts may respond to small doses of major tranquilizers such as ris-
peridone, olanzapine, or quetiapine. FTLD is very stressful to the caregiver, and
support of the family is critically important.
References
1. Pasquier F, Delacourte A (1998) Non-Alzheimer degenerative dementias. Curr Opin Neurol

11:417–427
2. The Lund and Manchester Group (1994) Clinical and neuropathological criteria for fronto-
temporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry
57:416–418
3. Neary D, Snowden JS, Bowen DM et al (1986) Neuropsychological syndromes in presenile
dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry 49:163–174
4. Neary D, Snowden JS, Northen B et al (1988) Dementia of frontal lobe type. J Neurol
5. Brun A (1987) Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology. Arch
Gerontol Geriatr 6:193–208
6. Brun A (1993) Frontal lobe degeneration of non-Alzheimer type revised. Dementia
4:126–131
7. Gustafson L (1987) Frontal lobe degeneration of non-Alzheiemr type II. Clinical picture and
differential diagnosis. Arch Gerontol Geriatr 6:209–223
8. Gustafson L (1993) Clinical picture of frontal lobe degeneration of non-Alzheimer type.
Dementia 4:143–148
9. Snowden JS, Neary D, Mann DM (1996) Frontotemporal lobar degeneration: frontotemporal
dementia. Progressive aphasia, semantic dementia. Churchill-Livingston, London
10. Knopman DS (1993) Overview of dementia lacking distinctive histology: pathological desig-
nation of a progressive dementia. Dementia 4:132–136
sus on clinical diagnostic criteria. Neurology 51:1546–1554
12. Mendez MF, Perryman KM, Milker BL et al (1997) Comprehensive behaviours as presenting
symptoms of frontotemporal dementia. J Geriatr Psychiatry Neurol 10:154–157
13. Tonkonogy JM, Smith TW, Barreira PJ (1994) Obsessive-compulsive disorders in Pick’s dis-
ease. J Neuropsychiatry Clin Neurosci 6:176–180
14. Rosso SM, Roks G, Stevens M et al (1998) Complex compulsive behaviour in the temporal
variant of frontotemporal dementia. Ned Tijdschr Geneeskd 142:1962–1965
15. Waddington JL, Youssef HA, Farrell MA et al (1995) Initial “schizophrenia-like” psychosis
in Pick’s disease: case study with neuroimaging and neuropathology and implications for
frontotemporal dysfunction in schizophrenia. Schizophr Res 18:79–82
16. Gregory CA (1999) Frontal variant of frontotemporal dementia: a cross-sectioned and longi-
tudinal study of neuropsychiatric features. Psychol Med 29:1205–1217
17. Ostberg P, Bogdanovic N, Fernaeus SE et al (2001) Jargon aphasia in a case of frontotemporal
dementia. Brain Lang 79:333–339
18. Neary D, Snowden JS, Mann DM (1993) Familial progressive aphasia: its relationship of
other forms of lobar atrophy. J Neurol Neurosurg Psychiatry 56:1122–1125
19. Sam M, Gutmann L, Schochet SS et al (1991) Pick’s disease: a case clinically resembling
amyotrophic lateral sclerosis. Neurology 41:1831–1833
20. Gustafson L, Abramason M, Grubb A et al (1997) Apolipoprotein-E genotyping in
Alzheimer’s disease and frontotemporal dementia. Dement Geriatr Cogn Disord 8:240–243
21. Adams E, Chang HT, Stopa EG et al (2001) Tau protein expression in frontotemporal demen-
tias. Neurosci Lett 315:21–24
22. Poorkaj P, Grossmann M, Steinbart E et al (2001) Frequency of tau gene mutations in familial
and sporadic cases of non-Alzheimer dementia. Arch Neurol 58:383–387
23. Pick A (1882) Über die Beziehungen der senilen Hirnatrophie zur Aphasie. Prager Med
Wochenschr 17:165–167
24. Pick A (1901) Senile Hirnatrophie als Grundlage von Herd ersheinungen. Wien Klin
Wochenschr 14:403–404
270 Y. Mitsuyama
25. Oick A (1905) Zur Symptomatologie der linksseitigen Schlafen-lappenn Atrophie. Monatsschr
Psychiatr Neurol 16:378–388
26. Gans A (1922) Betrachtungen über Art und Ausbreitung des krankhaften Prozesses in einem
Fall von Pickscher Atrophie des Stirnhirns. Z Gesamte Neurol Psychiatr 80:10–28
27. Onari K, Spatz H (1926) Anatomische Beitrage zur Lehre von Pickschen umschriebenen
Grosshirnrinden-Atophie (“Picksche Krankheit”). Z Gesamte Neurol Psychiatr 101:470–511
28. Schneider C (1927) Über Picksche Krankheit. Monatsschr Psychiatr Neurol 65:230–275
29. Mitsuyama Y (1984) Presenile dementia with motor neuron disease in Japan: clinico-
pathological review of 26 cases. J Neurol Neurosurg Psychiatry 47:53–959
30. Neary D, Snowden JS, Mann DM et al (1990) Frontal lobe dementia and motor neuron dis-
ease. J Neurol Neurosurg Psychiatry 53:23–32
31. Mitsuyama Y (2000) Dementia with motor neuron disease. Neuropathology 20(Suppl):S79–S81
32. Mendez MF, Selwood A, Mastri AR et al (1993) Pick’s disease versus Alzheimer’s disease: a
comparison of clinical characteristics. Neurology 43:289–292
33. Schmitt HP, Yang Y, Fortstl H (1995) Frontal lobe degeneration of non-Alzheimer type and
Pick’s atrophy: lumping or splitting? Eur Arch Psychiatry Clin Neurosci 245:299–305
34. Josephs KA, Parisi JE, Knopman DS et al (2006) Clinically undetected motor neuron disease
in pathologically proven frontotemporal lobar degeneration with motor neuron disease. Arch
Neurol 63:506–512
35. Swartz JR, Miller BL, Lesser IM et al (2001) Frontotemporal dementia: treatment response to
serotonin selective reuptake inhibitors. J Clin Psychiatry 56:41–45
Diffuse Neurofibrillary Tangles
with Calcification
Shigetoshi Kuroda, Hideki Ishizu, Seishi Terada, Osamu Yokota,

Yasuyuki Tanabe, and Takashi Haraguchi
Abstract Diffuse neurofibrillary tangles with calcification (DNTC) is a primary

and sporadic presenile dementia that is characterized by temporal and/or frontal
atrophy with diffuse neurofibrillary tangles (NFTs) and Fahr-type calcification
without senile plaques (SPs).
We reviewed clinical symptoms in 21 autopsy-proven DNTC cases in Japan. It
is characterized by slowly progressive cortical dementia mimicking Alzheimer’s
disease (AD) because of the appearance of memory disturbance and disorientation
in the early stages, or simulating Pick’s disease as a result of the presence of
personality changes in the early to middle clinical stages, followed by various
psychiatric and neurological symptoms such as Parkinson’s symptoms, aphasia,
and apraxia.
In terms of neuropathology, DNTC is characterized by the appearance of
massive NFTs in the cerebral cortex and in Meynert’s nucleus and the locus
ceruleus/raphe nuclei as well. These sites are similar to those with AD. Differing
from AD, SPs were absent, or only a small number were detected. Ultrastructural
and immunohistochemical study revealed that NFTs with DNTC were morphologically
and biochemically the same with those in AD. Fahr-type calcification is also one of
the most characteristic findings; it was found in the basal ganglia and the cerebellum.
We conducted elementary analysis of the calcified sites. In addition to calcium
and iron, a higher level of lead was detected in comparison with control groups.
The etiology should be further investigated.
S. Kuroda (*) and H. Ishizu

Zikei Hospital, 100-2 Urayasu-Honmachi, Minami-ku, Okayama
702-8026, Japan
S. Kuroda, S. Terada, and O. Yokota
Department of Neuropsychiatry, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
Y. Tanabe and T. Haraguchi
Department of Neurology, South Okayama Medical Center, 4066 Hayashima, Tsukubo-gun,
Okayama 701-0304, Japan

DOI 10.1007/978-4-431-53871-4_21, © Springer 2010
272 S. Kuroda et al.
Keywords Dementia฀•฀DNTC฀•฀Neurofibrillary฀tangles฀•฀Calcification
Introduction
Diffuse neurofibrillary tangles with calcification (DNTC) is a primary and sporadic

presenile dementia. Ando et al. initially reported a patient with this disorder at an
annual meeting of the Japanese Society of Neuropathology in 1964 [1]. Because
atrophy of the temporal lobe was marked, how to differentiate this disorder from
Pick’s disease was discussed at that time. Thereafter, these cases were reported in
the literature as cases of atypical Alzheimer’s disease (AD), Pick’s disease, or com-
bined Alzheimer/Pick disease. After Shibayama et al. [2] and Kosaka [3] published
their manuscripts, interest in DNTC was particularly emphasized in Japan. More
than 20 autopsy cases have been reported. Pathologically, DNTC is characterized
by localized temporal and/or frontal lobe atrophy, numerous neurofibrillary tangles
(NFTs) without senile plaques (SPs), and calcification in the basal ganglia and
dentate nucleus of the cerebellum that exceeded the normal physiological level. The
term DNTC, which was proposed by Kosaka, has been used, because it represents
well these pathological characteristics.
Case Presentation
Case 1. A 75-year-old woman. Her medical history included hypertension. There

was no family history of dementia. At the age of 58 years, memory disturbance was
noted. At the age of 62 years, she was admitted to the hospital because she was
violent toward her husband. In the ward, her attitude was pleasant, but euphoric. She
showed a tendency to repeat the same questions. Disorientation regarding places and
persons, perseveration, and confabulation were noted. Neither apraxia nor agnosia
was observed. There was no neurological sign other than severe dementia. However,
hyperreflexia, tremor, and rigidity were noted at the age of 65 years. After the age
of 66 years, she was usually cheerful, but became irritable frequently, and she got
angry when displeased. Wandering was marked. Verbal output gradually decreased.
At 72 years, she became bedridden. Brain computed tomography (CT) at the age of
74 showed cerebral atrophy of temporal and frontal lobes and calcification in the
basal ganglia and cerebellum (Fig. 1). At the age of 75, she died of pneumonia. The
clinical course was similar to that of AD. However, intracerebral calcification sug-
gested DNTC. Autopsy was performed. The brain weighed 850 g. On the outer
surface, there was an enlargement of the bilateral Sylvian fissures, and the temporal
lobe showed marked atrophy. The right side of the temporal lobe showed more
marked atrophy. The atrophic sites were brown and hard. Atrophy of the frontal,
parietal, and occipital gyri was less marked. There were no marked changes in the
cerebellum or brainstem. The basilar arteries showed moderate arteriosclerotic
Diffuse Neurofibrillary Tangles with Calcification 273
Fig. 1 Brain computed tomography (CT) at the age of 74 (case 21). Cerebral atrophy of temporal
and frontal lobes and calcification in the basal ganglia and cerebellum
changes. Microscopically, neuronal loss and gliosis in the atrophic foci of the
cortices were observed in the temporal pole in particular. The amygdala,
hippocampus, and temporal lobe showed marked gliosis, and the white matter of the
frontal and occipital lobed had slight to moderate gliosis. Numerous NFTs were
observed in the cerebral cortex involving the frontal to occipital lobes. NFTs
contained both 3 repeat and 4 repeat tau. A few SPs were detected in the temporal
cortex; however, they were absent in other areas. The caudate nucleus showed atrophy,
and there were only a small number of NFTs and neuropil threads. There were a few
NFTs in the neurons of the substantia nigra and locus ceruleus. Calcification was
present in the pallidum, putamen, granular layer, and the dentate nucleus of the
cerebellum.
Case 2. A 48-year-old woman. There was no family history of dementia. At the
age of 45, she became unable to do housework. Memory disturbance and
disorientation gradually progressed, requiring caregiving for meals and excretion.
Neurologically, there were no abnormal findings other than dementia. The blood
pressure was normal. Personal contacts were maintained. Euphoria was noted.
Neither aggression nor negativism was observed. Wandering and yelling made keep-
ing her at home difficult, and the patient was admitted to a psychiatric hospital.
Dementia progressed, and she died of pneumonia, with a dementia follow-up of
3 years. Autopsy was performed. The brain weighed 1,000 g. The frontal lobes
showed atrophy bilaterally. On the cut surface, temporal lobe atrophy was noted. In
the temporal lobe, the myelin sheath was markedly lightened, and gliosis was
observed at the same site. In the frontal lobe, similar changes were also noted,
although the grade was lower. Numerous NFTs were observed in the amygdala,
hippocampus and inferior temporal gyrus. Calcification was observed in the vascular
wall and parenchyma of the basal ganglia and granular layer of the cerebellar vermian
cortex. In the substantia nigra, a small number of NFTs and Lewy bodies were present.
A SP-like structure was observed, but amyloid staining showed no amyloid
deposition in this structure.
Epidemiology of DNTC
Clinical and pathological reports of more than 30 patients with DNTC have been
reported in Japan. However, in Western countries, not much interest in this disorder
has been shown. Calcification was observed in the basal ganglia, dentate nucleus of
the cerebellum, and cerebral white matter in severe cases (Fahr type). Brain CT
scanning facilitates detection of atrophy and calcification at these sites. In our sur-
vey using the criteria proposed by Kosaka [4], DNTC was suspected in 4 of 3,053
patients (male:female = 1:2) with dementia residing in Okayama Prefecture. All
these cases were female. In one case, autopsy led to a definitive diagnosis of
DNTC. The incidence of DNTC was 0.13% in patients with dementia in Okayama.
However, it may be lower in the general population. In Japan, several patients have
been reported in Tokyo, Nagoya, Okayama, and Kochi, suggesting regional differ-
ences. In 21 autopsied patients, the male-to-female ratio was 1:3. Familial DNTC
has not been reported. The mean age at onset was 53.1 years. A presenile onset
(40–69 years of age) was frequent. The mean time of illness duration was 10.5
years (range, 3–24 years). In patients without complications, the clinical course
may be prolonged. Generally speaking, the longer the duration, the lower the brain
weight. The brain weight had decreased to approximately 800 g in patients with a
prolonged course. In some patients, however, cerebral atrophy was evident even in
the early stage.
Characteristics of Clinical Symptoms
We reviewed clinical symptoms in 21 patients whose pathological findings led to

a definitive diagnosis of DNTC in Japan (Fig. 2).
The most common primary symptoms were memory disturbance and disorienta-
tion. In the early stage, they were observed in 80% of the 21 patients. With a slow
course, personal contacts were maintained in the initial phase, and neurological
symptoms were absent. Therefore, most patients were diagnosed with AD.
However, personality changes such as irritability, aggression, euphoria, and disin-
hibition were noted in the initial phase, suggesting Pick’s disease. Some patients
showed a loss of spontaneity, depression, and apathy. In the middle phase, memory
Fig. 2 Clinical symptoms in diffuse neurofibrillary tangles with calcification (DNTC)
disturbance was advanced. During the course, schizophrenia-like symptoms such as

auditory hallucination, delusion of persecution, and hypochondriac delusion were
observed in some patients. However, no patient showed “delusion of being robbed
by a thief,” which is very common in patients with AD. Early DNTC did not
produce any neurological symptoms, such as Parkinson’s symptoms, or focal
symptoms, such as apraxia and agnosia. However, these symptoms appeared in
approximately 30% to 50% of the patients during the course [5]. When the
symptoms were advanced, dysphagia and primitive reflexes were noted, leading to
an apallic state. Disease progression varied; memory disturbances and disorientation
derived from hippocampal lesions were seen in the early stage, and personality
changes derived from frontal/temporal lobe lesions were complicated by
extrapyramidal symptoms and cerebrovascular diseases. In 6 of the 21 patients, a
diagnosis of schizophrenia was made based on psychiatric symptoms such as
hallucination and delusion during the course, and, later, cognitive impairment was
observed. In the future, the course of DNTC should be investigated with a large
number of cases.
Pathological Characteristics
NFTs
DNTC is characterized by appearance of massive NFTs. A large number of NFTs

were observed in the hippocampus and parahippocampal gyrus. They were widely
distributed in the cerebral isocortex. They were also found in Meynert’s nucleus
and the locus ceruleus/raphe nuclei of the brainstem. These sites were similar
to those frequently observed in patients with AD. On the other hand, there were no
NFTs in the basal ganglia or cerebellum. Differing from AD, SPs were absent, or
only a small number were detected.
Characteristics of Degenerative Tau Protein
There are six isoforms of tau protein. Among these, tau protein involving exon-10,
which exists in the microtubule-binding site, is termed “4-repeat tau protein,” and
exon-10-free tau protein is called “3-repeat tau protein.” In patients with AD, all
six isoforms are detected. In those with progressive supranuclear palsy or cortical
basal ganglia degeneration, 4-repeat tau protein is found. In those with Pick body
disease, 3-repeat tau protein is present. In patients with DNTC, 60-, 64-, and
68-kDa major and 72-kDa minor bands were recognized in the presence of various
anti-tau antibodies. On Western blotting of sarkosyl-insoluble tau protein after
dephosphorylation, six isoforms of tau protein were observed [6], indicating that
the biochemical features of degenerative tau protein in patients with DNTC were
similar to those in AD.
Electron Microscopy Findings
Electron microscopy examination was done with negative staining of sarkosyl-

insoluble tau protein. A large number of paired helical filaments (PHFs) measuring
8–20 nm in diameter, with a cycle of approximately 80 nm, and a small number of
straight tubules were observed [6]. These results suggest that degenerative tau
protein in patients with DNTC is morphologically and biochemically identical to
that in AD patients, and that PHFs are formed in the absence of b-protein [6].
Calcification
DNTC is characterized by the presence of calcification in the pallidum, putamen,

and dentate nucleus of the cerebellum. Calcification was found in the capillary walls
and parenchyma; this refers to false calcification with protein deposition. Calcification
is also observed in the cerebral cortex, white matter, and cerebellar cortex in some
cases. Neither loss of cells in the basal ganglia with calcification nor functional
disturbance is noted [7]. We conducted elementary analysis of the calcified sites. In
addition to calcium and iron, a higher level of lead was detected in comparison with
control groups. The etiology should be further investigated [8, 9].
Cerebrovascular Lesions
The cases with DNTC have often complications of cerebrovascular disorders.

Several studies have indicated the coexistence of cerebrovascular arteriolosclerosis,
hypertension, Binswanger’s disease-like white matter lesions, and multiple cerebral
infarctions [10].
Lewy Body Pathology
We reported that a-synuclein was accumulated in various sites in seven of eight

patients with DNTC [11]. a-Synuclein was accumulated in the amygdala, hip-
pocampus, substantia nigra, and temporal/frontal cortex. This pattern was similar
to the distribution of Lewy body disease (DLB). Among other types of tauopathy,
Lewy body formation has also been reported. However, this finding is the most
marked in patients with DNTC [11, 12]. The accumulation of Lewy bodies/neurites
may affect nerve cell function. However, it is unclear whether this finding reflected
clinical symptoms in DNTC patients. Advanced DNTC cases may have deposition
of a-synuclein. DNTC may also be closely associated with DLB as it is in AD
patients. Hallucination and Parkinson’s symptoms, as observed in DLB patients,
may appear in DNTC.
Conclusion
Although the number of patients is small, DNTC is recognized as a disease unit of

tauopathy. The pathogenesis remains to be clarified. This refractory disease should
be compared with other types of tauopathy to clarify its etiology. In the future, the
differentiation of DNTC from Fahr’s syndrome, correlation between calcification
and NFTs, and involvement of lead should be reviewed. Calcification may initiate
before the onset. When Fahr’s syndrome is suspected on brain CT, DNTC must be
considered. Epidemiologically, few studies have reported DNTC in other countries.
Although the reason for this is unclear, an increasing number of patients may be
reported in other countries in the future.
References
1. Ando J, Okaniwa T, Tachibana K (1965) An autopsy case of Pick’s disease. Shinkei Kenkyu-no-
Shinpo 9:181–182 (In Japanese)
2. Shibayama H, Kobayashi H, Nagasawa MI et al (1992) Non-Alzheimer non-Pick dementia
with Fahr’s syndrome. Clin Neuropathol 11:237–250
3. Kosaka K (1994) Diffuse neurofibrillary tangles with calcification: a new presenile dementia.
4. Kosaka K (1997) Non-Alzheimer degenerative dementias. J Senile Dement 11:63–70

(In Japanese)
5. Tsuchiya K, Nakayama H, Haga C et al (2005) Distribution of cerebral cortical lesions in
diffuse neurofibrillary tangles with calcification: a clinicopathological study of four autopsy
cases showing prominent parietal lobe involvement. Acta Neuropathol 110:57–68
6. Tanabe Y, Ishizu H, Ishiguro K et al (2000) Tau pathology in diffuse neurofibrillary tangles
with calcification (DNTC): biochemical and immunohistochemical investigation. Neuroreport
11:2473–2477
7. Ito Y, Kato T, Suzuki T et al (2003) Neuroradiologic and clinical abnormalities in dementia
of diffuse neurofibrillary tangles with calcification (Kosaka-Shibayama disease). J Neurol Sci
15(209):105–109
8. Haraguchi T, Ishizu H, Kawai K et al (2001) Diffuse neurofibrillary tangles with calcification
(a form of dementia): X-ray spectrometric evidence of lead accumulation in calcified regions.
Neuroreport 12:1257–1260
9. Haraguchi T, Ishizu H, Takehisa Y et al (2001) Lead content of brain tissue in diffuse neurofibrillary
tangles with calcification (DNTC): the possibility of lead neurotoxicity. Neuroreport
12:3887–3890
10. Terada S, Ishizu H, Tanabe Y et al (2001) Plaque-like structures and arteriosclerotic changes
in “diffuse neurofibrillary tangles with calcification” (DNTC). Acta Neuropathol
102:597–603
11. Yokota O, Terada S, Ishizu H et al (2002) NACP/alpha-synuclein immunoreactivity in diffuse
neurofibrillary tangles with calcification (DNTC). Acta Neuropathol 104:333–341
12. Hishikawa N, Hashizume Y, Ujihira N et al (2003) Alpha-synuclein-positive structures in
association with diffuse neurofibrillary tangles with calcification. Neuropathol Appl Neurobiol
29:280–287
Ayahuasca: Current Interest in an Ancient
Ritual
Abstract The amazonic brew ayahuasca, with strong psychoactive properties,

and which has been used probably for millennia by Amazon tribes as their main
“medicine,” is currently being used by some groups in cities in Latin America
and abroad by people seeking curative effects or transcendent and meaningful
experiences. At the same time, research on its effects in treating depression and in
neuroimaging is being carried out.
The brew is made of a blend of at least two different plants cooked together that
potentiate each other: the stem of a vine, called ayahuasca proper (Banisteropsis caapi),
and the leaves of a bush, chacruna (Psychotria viridis).
In this chapter, the ritual is described and the pharmacodynamics of the brew are
discussed, as well as some of its effects in the brain and in the subjective experience
of the self. Two vignettes of patients in analytical psychotherapy are presented to
illustrate its effects. Reflections on the risks and benefits of its use are then shared.
Keywords Ayahuasca฀•฀Consciousness฀•฀Depression฀•฀Ethnopsychiatry฀•฀Psychotropic
Introduction
Brazil,฀ Bolivia,฀ Colombia,฀ Ecuador,฀ the฀ Guyanas,฀ Peru,฀ and฀ Venezuela฀ share฀ the฀
Amazon rainforest. Hundreds of different tribes inhabit this huge area. At least 70
of those indigenous groups, primarily in the Upper Amazon and Orinoco basins,
E.฀Gastelumendi฀(*)
Peruvian฀Psychiatric฀Society,฀Ave.฀Angamos฀Oeste฀387/203,฀Miraflores,฀Lima฀18,฀Perú
and
Peruvian฀Psychoanalytic฀Society,฀Julio฀Becerra฀235,฀Miraflores,฀Lima฀18,฀Perú
and
International฀Committee฀of฀the฀INA,฀INA฀Secretariat฀Office,฀Neuropsychiatric฀Institute,฀
Euroa฀Centre,฀The฀Prince฀of฀Wales฀Hospital,฀Randwick,฀NSW฀2031,฀Australia
and
Calle฀Parque฀Armendariz฀119/4-E,฀Miraflores,฀Lima฀18,฀Perú

DOI 10.1007/978-4-431-53871-4_22, © Springer 2010
282 E.฀Gastelumendi
have used for millennia the blend known as ayahuasca for divination, healing, and
other cosmogonic and shamanic purposes [1]. In its original milieu, the ritual,
which has as its main vehicle the ayahuasca, with strong psychotropic activity in
virtue of its serotoninergic properties, allows the participants to contact the “other”
reality, or the “real aspect of the world,” where the spirits of plants, animals, and
dead people exist. It is also considered as a preparation for life after death [2]. The
shaman of the tribe usually conducts the rite. The ingestion of ayahuasca produces
intense visions. At first these are of geometric patterns (which can be seen as part
of the Amazon people’s crafts, in clothes, paintings, and pottery), and then the
visions become gradually more complex, with emotional, cognitive, and somatic
components, as we will see later.
The ayahuasca brew is a blend of two different plants cooked together. Ayahuasca
proper (Baninsteropsis caapi) is a vine native to the Amazon – currently it grows in
different parts of the world – that contains beta-carbolines such as harmine, harmaline,
and tetrahydroharmine, all of which are potent monoamine oxidase (MAO) inhibitors.
The฀ other฀ plant฀ is฀ the฀ Chacruna฀ (Psychoatria viridis), a bush that contains the
tryptamine alkaloid N,N-dimethyltriptamine (DMT). DMT is not orally active itself,
because it is inactivated by peripheral MAO of the liver and gut.
It is the blend that works: the beta-carbolines present in the ayahuasca vine
inhibit฀the฀MAO฀and฀allows฀the฀DMT฀to฀enter฀the฀internal฀milieu.฀The฀question฀of฀
how the indigenous people found the right combination remains unanswered, and
this is definitely a result of many years of investigation and combinations. Sometimes
the brew may include other plants, as tobacco, Toé (Brugmansia suaveolens), or
coca leaves.
In the last decades, this ceremony has come out from the rainforest and has
made its appearance in the main cities of many countries not only of South
America฀ but฀ abroad.฀ Conducted฀ also฀ by฀ a฀ leader฀ –฀ a฀ shaman,฀ Maestro, or
Curandero – the aim is to have an inner experience with intense visions,
somatic and emotional effects, and occasional key insights. During the ritual, in
both Amazon and urban settings, the participants drink the brew from a cup
(50–100 ml) and sit in silence waiting for the effects of the substance to occur.
In an urban setting, the conductor has previously evaluated the participants, by
overt฀questions฀or฀subtle฀observation,฀to฀determine฀the฀amount฀of฀brew฀each฀one฀
will have, if any. This evaluation is important to reduce the risks of a bad expe-
rience for the participant for reasons of psychic frailties or other health condi-
tions. In not rare occasions the shaman decides not to give the brew to a
participant.
This ritual would be of little importance to our field, or perhaps be taken as a
folkloric and curious issue, if it were not that some of our patients in psychotherapy
have participated in one or more of these ayahuasca sessions and have talked about
their experiences in their psychoanalysis and psychotherapies.
For฀ historical฀ and฀ affective฀ reasons,฀ I฀ would฀ like฀ to฀ mention฀ Carlos฀ Alberto฀
Seguin, who in the decade of 1960 was among the first psychiatrists to study the
brew฀in฀Peru.฀These฀studies฀vary฀from฀a฀phenomenological฀approach฀to฀฀ethnographic฀
psychiatry.
Ayahuasca:฀Current฀Interest฀in฀an฀Ancient฀Ritual 283
At the same time, neuropsychiatric research studies are been made on the effect
of ayahuasca in refractory depression [3] and on its effects in visualization,
memory, and consciousness [4].
I would like to suggest that the ayahuasca experience, because of its peculiarities,
has฀a฀unique฀value฀for฀research฀in฀both฀neural฀and฀mental฀fields.฀Let฀me฀share฀with฀
you a glimpse of what possibilities are open to research and theorization.
Description of an Ayahuasca Ceremony
The ceremony usually takes place at night. The participants and the shaman sit in
a circle. The shaman gives a small amount of the brew to each person and then
asks all to sit in silence. Shortly, about half an hour later, the visions begin. At first,
they are colorful geometric patterns, and then gradually become more complex.
Songs sung by the shaman during the session lead the participants to different
visions,฀ to฀ changes฀ in฀ mood฀ and฀ in฀ the฀ level฀ and฀ quality฀ of฀ consciousness.฀ The฀
participants describe themselves as entering another state of mind, with keen
awareness฀ of฀ the฀ body,฀ thoughts,฀ and฀ inner฀ images.฀ Very฀ elaborate฀ images฀ may฀
also appear.1
During the 4 or 5 hours that the experience lasts, old memories may appear, many
of them painful and formerly repressed, as well as images of plants, animals,
landscapes, and buildings. A numinous feeling or sometimes a feeling of awe may
occur. Issues regarding the meaning and direction we give to our lives are not rare.
The shaman closes the ceremony with a brief rite as the participants gradually
come back to a “normal” state. The following day there is a feeling of renovation.
Insights may still be very clear.
It is interesting to consider that in Brazil there are two organized religions that
have the ayahuasca as the core of their inner experience and their beliefs. Medical
members฀of฀one฀of฀these฀groups,฀the฀União฀do฀Vegetal฀(www.udv.org.br; the other
one is the “Igreja de Santo Daime”), have participated in research and publication
of their data [5].฀Also฀in฀Brazil,฀in฀the฀University฀of฀Ribeirão฀Preto,฀research฀has฀
been conducted on animals as well as in treating refractory depression in humans
in a strict medical setting [3]. Brazilian researchers have also published studies on
the nature of the visual imagery so vividly enhanced in the participants, using
functional magnetic resonance imaging (fMRI) [4].
From the psychodynamic perspective, what our patients bring to their sessions
is฀very฀impressive฀and฀requires฀an฀open฀attitude฀on฀our฀part฀as฀therapists฀to฀avoid฀
considering the experience as mainly an acting-out or a risk-seeking attitude.
1
There are many artists that have depicted their visual experiences, with more or less skill.
Among฀the฀most฀interesting฀of฀them฀is฀Pablo฀Amaringo฀(Peru,฀1943–2009),฀founder฀of฀the฀Art฀
school฀Usko-Ayar,฀in฀Pucallpa.
Let me share with you two experiences of patients who brought their ayahuasca
experience to their psychotherapeutic sessions.
In the first vignette, a woman in her sixties comes to analytical therapy because
she still feels somatic and psychic pains after a car accident suffered years ago. In
that accident, her teenaged nephew was killed and she was seriously injured.
When฀she฀came฀to฀analytical฀therapy,฀2฀years฀after฀the฀accident,฀she฀was฀somewhat฀
recovered, but still felt deep sadness, guilt, and constant pain in her head, side, and
legs. One of the issues that appeared during our work was the sadomasochistic
bond with her very old but still lucid mother, who lived nearby. It was in the sec-
ond฀year฀of฀therapy฀when฀she฀decided฀to฀participate฀in฀an฀ayahuasca฀session.฀Even฀
though some symptoms had become lighter (less guilt and a better disposition
toward life), the pain in her body remained, and the relationship with her mother
and daughters was still complicated. She talked for some sessions about her inter-
est in drinking the brew and finally decided to participate in one group session
with a shaman.
This is a summary of her experience:
After an hour or so after she drank the brew, the visions started and she entered into a calm
mood and heightened sense of awareness. After a while she found herself directing her
attention to her body and started exploring every part of it inch by inch. She felt she could
distinguish the different kinds of pain and, at the same time, the distinct emotions “tied” to
each part. She cried very deeply. After a while a sort of oneiric vision appeared: she saw
herself sitting in a chair in a dark room, with her mother behind her, and her grandmother
further behind. She could almost guess (or see?) the mother’s grandmother further back. In
front฀of฀her,฀her฀daughters฀were฀sitting.฀All฀these฀women฀formed฀a฀silent฀and฀quiet฀row.฀In฀
the same way that my patient had been able to observe every detail of her sore body, now
she could see the expressions and emotions of the women of her family. She noticed there
was a common pain that passed through all of them, a pain related to a way of being a
woman that had been transmitted through generations. Suddenly she had an insight: she
recognized the same style of hardening the hearts and controlling the emotions shared by
all the women in her family. They had lived doomed, so to say, to live that way.
What฀happened฀after฀her฀ayahuasca฀ceremony฀was฀a฀surprise฀for฀us.฀In฀a฀very฀natural฀way,฀
the next time she approached her mother, some days after the ceremony, her attitude was
quite฀different.฀When฀they฀met,฀she฀listened฀to฀the฀querulous฀old฀woman฀with฀her฀“heart฀
opened,” and then she hugged her with a tenderness she could not remember feeling or
having with her. This was the beginning of a new relationship, more kind and affectionate,
that lasted until her mother passed away. The relationship with her daughters also gained
new life and dimensions, as my patient felt free to express more openly her emotions and
to tolerate, and appreciate, the daughters’ own characteristics and decisions.
There are also other kinds of insights produced by the experience, as the
following vignette can show:
A man in his late thirties comes for reanalysis. Some years before he had started
participating in ayahuasca sessions in Lima and later went to the Amazon. He had his first
ayahuasca experience moved by curiosity. He thought he would “enjoy” a psychedelic trip
but found something else. Some of the visions he had were in a way similar to the one
already described. These visions consisted in seeing himself in relationship with people he
Ayahuasca:฀Current฀Interest฀in฀an฀Ancient฀Ritual 285
loved, and he felt he could understand the feelings of each one of them. He also saw himself
as a baby and mourned deeply – he felt it was the first time – for the loss of his grandfather,
which had occurred when he was 3 years old. He was also able to remember his childhood
and adolescent dreams, what he wanted for his life, and could see where he was now
professionally and personally. From this perspective he felt he could see what decisions
and changes he had to make and take in his present life to redirect it in consistency with
his desires, which also became clearer to his eyes. These could be considered important
biographical visions and insights.
But during the sessions he also had another kind of experience: he sensed very strongly
and deeply something he had known intuitively and by his studies and work: being an
ecology activist, he was convinced that the only path to a better life in society passes
through the development of a new way of relating to nature and to others. During the most
intense part of the experience, between the second and third hour, the patient had a sense
of awe of being alive. He felt he could perceive emotionally, not only understand rationally,
the interconnectedness of all things. He could feel that the air he inhaled had been just
exhaled by the surrounding trees, and that the moon in the sky and his retina receiving that
light were intimately connected. And that he shared an intimate “brotherhood” with all
forms of existence. He came out from the experience with a sense of profound gratitude.
These insights can be considered not as biographical but having to do with

฀consciousness฀and฀awareness.฀This฀is฀a฀subject฀to฀be฀treated฀elsewhere.฀What฀I฀can฀
say here is that I have listened to his associations with an open attitude and that an
important part of our work has consisted in helping the patient to find and value his
own style of searching, thinking, and expressing himself.
There are also risks that have to be taken into consideration. The experience can
trigger psychotic symptoms in some participants or enhance narcissistic pathological
traits in others. These possibilities are minimized if the shaman who will conduct
the session has the experience and skill to detect these structural frailties.
Conclusions
It is thus possible to consider the ayahuasca experience as especially valuable for

neuropsychiatric฀ research฀ as฀ well฀ as฀ psychoanalytical฀ investigation.฀ Published฀
papers,฀ as฀ well฀ as฀ conferences฀ on฀ this฀ subject,฀ have฀ become฀ frequent฀ in฀ the฀ past฀
decade. Traditional knowledge can lead us, as mental health professionals, to new
insights and ways of understanding health and suffering.
We฀can฀also฀state฀that฀the฀study฀of฀the฀ayahuasca experience provides areas of
reflection and research:
a. Depression and other mood disorders
b.฀ Visual฀imagery฀(and฀its฀relationship฀with฀dream฀images)
c. Memory (flashbacks, posttraumatic stress disorders, repression)
d.฀ Consciousness฀ and฀ awareness฀ (meaning฀ of฀ life,฀ ecologically฀ and฀ altruistically฀
driven motivations and acts, etc.)
References
1.฀ Luna฀ LE,฀ White฀ SF฀ (eds)฀ (2000)฀ Ayahuasca฀ reader:฀ encounters฀ with฀ the฀ Amazon’s฀ sacred฀
vine.฀Synergetic,฀New฀Mexico
2.฀ Luz฀P฀(2004)฀The฀American-Indian฀use฀of฀caapi฀(O฀uso฀ameríndio฀do฀caapi).฀In:฀Labate฀BC,฀
Araújo฀WS฀(eds)฀The฀ritual฀use฀of฀ayahuasca฀(O฀uso฀ritual฀da฀ayahuasca).฀Mercado฀das฀Letras,฀
Campinas,฀São฀Paulo
3.฀ Fortunato฀J,฀Réux฀G,฀Kirsch฀T฀et฀al฀(2009)฀Acute฀harmine฀administration฀induces฀antidepres-
sive-like฀effects฀and฀increases฀BDNF฀levels฀in฀the฀rat฀hippocampus.฀Prog฀Neuropsychopharmacol฀
Biol฀Psychiatry฀33(8):1425–1430
4.฀ De฀Araujo฀DB,฀Ribeiro฀STG,฀Cecchi฀G฀et฀al฀(2009)฀Neural฀basis฀of฀enhanced฀visual฀imagery฀
following Ayahuasca ingestion (Manuscript submitted for publication)
฀ 5.฀ Labate฀BC,฀Araújo฀WS฀(eds)฀(2004)฀The฀ritual฀use฀of฀ayahuasca฀(O฀uso฀ritual฀da฀ayahuasca).฀
Mercado฀das฀Letras,฀Campinas,฀São฀Paulo
Additional Reading
฀ 6.฀ Almendro฀M฀(2008)฀Chamanismo:฀La฀vía฀de฀la฀mente฀nativa.฀Editorial฀Kairos,฀Barcelona
฀ 7.฀ Chiappe฀M฀(1974)฀Curanderismo:฀Psiquiatría฀folklórica฀peruana.฀Tesis฀para฀obtener฀el฀doc-
torado฀en฀medicina฀para฀la฀Universidad฀Nacional฀Mayor฀de฀San฀Marcos,฀Perú
฀ 8.฀ Chiappe฀M,฀Lemlij฀M,฀Millones฀L฀(1985)฀Alucinógenos฀y฀shamanismo฀en฀el฀Perú฀contem-
poráteno.฀Ediciones฀El฀Virrey,฀Lima
฀ 9.฀ Gastelumendi฀E฀(2001)฀Madre฀ayahuasca฀y฀Edipo.฀In:฀Mabit฀J฀(ed)฀Memoria฀del฀Segundo฀foro฀
sobre฀Espiritualidad฀Indígena:฀ética,฀mal฀y฀transgresion.฀CISEI,฀Lima
10.฀ Narby฀J฀(1998)฀The฀cosmic฀serpent:฀DNA฀and฀the฀origins฀of฀knowledge.฀Jeremy฀P.฀Tarcher/
Putnam,฀New฀York
11.฀ Seguín฀CA฀(1988)฀Medicinas฀tradicionales฀y฀medicina฀folklórica.฀Fondo฀editorial฀del฀Banco฀
Central฀de฀Reserva฀del฀Perú,฀Lima
12.฀ Seguín฀CA฀(1979)฀Psiquiatría฀folklórica:฀shamanes฀y฀curanderos.฀Ediciones฀Ermar,฀Lima
13.฀ Dobkin฀de฀Rios฀M,฀Grob฀Ch฀(2005)฀Theme฀Eds.฀Ayahuasca฀Use฀in฀Cross-Cultural฀Perspective.฀
Journal฀of฀Psychoactive฀Drugs฀37฀(2).฀Haight-Ashbury฀Publications.฀San฀Francisco฀
14. Shanon B (2002) The antipodes of the mind: charting the phenomenology of the ayahuasca
experience.฀Oxford฀University฀Press,฀New฀York
The Molecular Genetics of Suicide
Kiyoshi Maeda, Osamu Shirakawa, Naoki Nishiguchi,

and Masaaki Fukutake
Abstract The increasing number of suicidal victims all over the world is a major
concern. There are three neurobiological systems involved in the pathophysiology
of suicidal behavior: dysfunction of the serotonergic system, hyperactivity of the
noradrenergic system, and increased activity of the hypothalamic–pituitary–adrenal
(HPA) axis appear to be involved. Increasing evidence points to an overlap between
neurobiological and cognitive psychological approaches to understanding suicidal
behavior. The authors reviewed the molecular genetics of suicidal behavior. A better
understanding of the neurobiology of suicide can help detect at-risk populations
and help develop better treatment interventions. Because suicide continues to be a
major public health problem, further studies are necessary, including research on
the effects of combined medical and psychosocial approaches.
Keywords Dopamine฀•฀Molecular฀genetics฀•฀Neurobiology฀•฀Noradrenalin฀•฀Serotonin฀
•฀Suicide
Introduction
The number of suicide victims in Japan in the recent 11 years (1998–2008) is

more than 30,000 a year, and in the year 2009 this number is 32,753. The suicide
rate (number of suicide victims per 100,000 population) in Japan is about 25, and
K. Maeda (*)
Department of Occupational Therapy, Kobe Gakuin University School of Rehabilitation,
Ikawadani-cho฀518,฀Nishi-ku,฀Kobe฀651-2180,฀Japan
O.฀Shirakawa฀and฀N.฀Nishiguchi
Department฀of฀Neuropsychiatry,฀Kinki฀University฀School฀of฀Medicine,
7-5-2,฀Kusunoki-Cho,฀Chuo-Ku,฀Kobe฀651-0017,฀Japan
M. Fukutake
Department of Psychiatry, Kobe University School of Medicine,
7-5-2,฀Kusunoki-Cho,฀Chuo-Ku,฀Kobe฀651-0017,฀Japan

DOI 10.1007/978-4-431-53871-4_23, © Springer 2010
288 K. Maeda et al.
this number is the fourth highest in the world. Suicide is one of the most
important public concerns and a major cause of death among young people
throughout฀ the฀ world.฀ No฀ remarkable฀ reduction฀ in฀ the฀ number฀ of฀ suicide฀
victims has yet been achieved, although there has been recent progress in the
treatment and management of psychiatric disorders. During the past two decades,
there has been a considerable accumulation of findings in the neurobiology of
suicide [1].
Although many factors such as biological, psychological, and social factors are
involved in suicide behavior, the presence of mental disorder is thought to play an
important role in suicide [2]. More than 90% of suicide victims or suicide attempters
are diagnosed having mental disorders such as depression, schizophrenia, or alcohol
dependence (Fig. 1). However, the underlying mental disorders are diverse, and
the severity of the mental disorders does not necessarily correlate with increased
risk of suicide.
Even in the psychiatric groups at the highest risk, most patients never attempt
suicide. These findings indicate the importance of a diathesis or predisposition to
suicidal behavior that is independent of the main psychiatric disorder.
[Suicide and Mental Disorders (n=15,629) ]
Other Diagnosis on Axis 5.5% No Diagnosis 2.0%
Adjustment Disorders 2.3%
Anxiety Disorders/
Somatoform Disorders 4.8%
Mood disorders
Other Mental Disorders
4.1% (Depression)
30.2%
Organic Mental Disorder
6.3%
Personality Disorders Substance-Related
13.0% Disorders
(Alcohol-Related
Schizophrenia Disorders)
14.1% 17.6%
Preventing Suicide; A Resource for General Physicians.
WHO/WNH/MBD/00.1, World Health Organization, Geneva, 2000.
Fig. 1 Mental disorders in suicide. In completed suicide, about 30% of all suicide victims occur
in relation to mood disorders, and the rest are related to various other psychiatric disorders, includ-
ing substance-related disorders, such as substance abuse and alcoholism, schizophrenia and per-
sonality disorders. Source: World Health Organization: preventing suicide; a resource for general
physicians.฀WHO/WNH/MBD/00.1,฀World฀Health฀Organization,฀Geneva,฀2000
The Molecular Genetics of Suicide 289
Molecular Genetics of Suicide
Numerous฀ studies฀ on฀ neurochemical฀ abnormalities฀ have฀ been฀ done;฀ the฀ results฀
obtained from those studies are summarized in Table 1. Recently, studies on the
biological aspect of suicide have been shifting from neurochemical to molecular
genetic approaches. Genetic studies on suicidal behavior have suggested that the
heritability of such behavior is independent of psychiatric diagnosis. Adoption
studies have shown a higher rate of suicide in the biological parents of adoptees
who commit suicide compared with biological relatives of control adoptees, even
after controlling for rates of psychosis and mood disorders (Table 2). Concordance
rates for suicide and suicide attempts are higher in monozygotic than dizygotic
twins, and the heritability of suicidal behavior was estimated to be approximately
55% based on twin studies in people with serious suicide attempts [3]. People who
commit suicide or make suicide attempts are those with a higher rate of familial
suicidal acts. These findings suggest the presence of hereditary and biological
factors that determine the threshold to commit suicide and which are independent
of specific psychiatric disorders. Thus, genetic factors in suicide have been a recent
focus, and recognition has been growing that suicide and suicidal behaviors are
highly familial and that genetics contributes to suicide and suicidal behaviors
(Table 3). In addition, completed suicides are thought to be more homogeneous
than suicide attempters in terms of inheritance of suicidal behavior [4].
Table 1 Risk factors for Biological factors

suicide: bio-psycho-social Mental disorders
Physical disorders
Family history of mental disorders or suicide
Age, sex, race, etc.
Psychological factors
Temperament/character
Coping skills/problem solving skills
Social factors
Economic and livelihood issues
Family problems
Table 2 Genetic studies •฀Adoption฀studies:฀~sixfold฀increased฀risk

on suicidal behavior
•฀Twin฀studies:฀38–55%฀heritability
No.฀of฀twins฀(%) Concordant for suicidal behavior
MZ DZ P
40/172 (23.0) 2/294 (0.7) <0.0001
•฀Family฀studies:฀2-฀to฀12-fold฀increased฀risk
Roy฀A,฀Segal฀NL฀(2001)฀[3]
290 K. Maeda et al.
Table 3 Exploration of susceptible genetic variants for completed suicide

Serotonergic system
Suicide-associated personality and cognitive dysfunction (aggressiveness, impulsiveness)
Noradrenergic฀and฀hypothalamic–pituitary–adrenal฀(HPA)฀system
Stress vulnerability (anxiety/agitation, hopelessness)
The sites of action of mood stabilizers
Antisuicidal effects of lithium
Gene expression analysis in postmortem brains of suicide victims
Table 4 Results of association between polymorphisms of serotonin-related genes and

completed suicide
Suicide Control
Gene Polymorphism Allele wt Allele vt Allele wt Allele vt OR 95% CI P value
5-HT1A Pro16Leu 320 ฀ 6 322 4 0.66 0.19–2.37 0.524
Gly272Asp 309 17 311 15 0.88 0.43–1.79 0.717
5-HT1B G861C 161 165 165 161 0.95 0.70–1.29 0.754
5-HT2A −1438A/G 157 145 157 169 1.17 0.85–1.59 0.338
5-HT6 u (GCC)2/3 239 87 237 95 1.1 0.78–1.55 0.581
267C/T 213 113 213 119 1.05 0.76–1.45 0.751
TPH −6526A/G 220 44 216 48 1.11 0.71–1.74 0.646
Int 218C/A 138 126 141 123 0.96 0.68–1.34 0.794
5-HTT Ins/del 148 44 205 ฀ 61 1 0.64–1.56 0.997
Int฀VNTR 331 41 331 29 0.71 0.43–1.17 0.173
MAO-A u฀VNTR 107 92 116 98 0.98 0.67–1.48 0.929
On the basis of these findings, we have conducted genetic association analysis of

completed suicides to explore the susceptible genetic variants for suicide. Up to the present
date, we have found a number of associations for genetic variations with completed
suicide. We have been focusing attention on several neurobiological factors including the
serotonergic system, noradrenergic and hypothalamic–pituitary–adrenal (HPA) system,
and the sites of action of mood stabilizers, especially the antisuicidal effects of lithium.
In addition, for the purpose of identifying new candidate systems and gaining
new insight into biological mechanisms mediating suicide, we have conducted gene
expression analysis in the postmortem brains of suicide victims [5–11, 13–18].
Recently, molecular genetic studies have been performed intensively to confirm
disturbance of serotonergic neurotransmission in suicide. We have performed asso-
ciation studies of polymorphisms and mutations of genes encoding synthesizing
and metabolic enzymes, receptors, and transporters involved in serotonergic neu-
rotransmission in suicide [5–11]. However, in our studies, we have not observed
any significant association between these polymorphisms and suicide (Table 4).
In addition, many other studies performed to date have not provided strong
evidence supporting such an association. The relative risk was small even when
association was detected by meta-analysis (Table 5).
Table 5 Summary of meta-analysis of association between serotonergic genes and suicidal

behavior
Gene Polymorphism No.฀of฀studies Subject origin OR 95% CI
TPH Intron 7 16 Inc. Asian 1.14 0.97–1.34
TPH Intron 7 A218C 7 Caucasian 1.33 1.17–1.50
5-HTT Ins/del 12 Inc. Asian 1.17 1.04–1.32
5-HT2A 102T/C 9 Inc. Asian 1.09 0.93–1.27
Anguelova M, Benkelfat C, Turecki G (2003) [12]
It has been suggested that noradrenergic system abnormalities are involved in

suicide [13, 14]. Recently, we have found that one promoter genetic variant
(C-1291G฀ SNP)฀ of฀ the฀ a2A-adrenergic receptor (ADRA2A) gene was signifi-
cantly associated with suicide in Japanese females (P = 0.043 and 0.013 for geno-
typic and allelic comparisons, respectively). One of the common haplotypes, CC
of฀this฀polymorphism฀and฀another฀variant฀of฀the฀ADRA2A฀gene฀(rs3750625C/A),฀
was also associated with suicide in females (P = 0.015). These associations were
also significant in the female violent suicide victims (P = 0.009 and 0.009 for
allelic and CC haplotypic comparisons, respectively; Table 6) [13]. In contrast,
neither฀of฀these฀two฀SNPs฀showed฀any฀association฀with฀violent฀and/or฀nonviolent฀
suicide in males. The noradrenergic system regulates activation of the HPA axis,
dysregulation of which might be involved in the pathogenesis of suicide.
Therefore, this promoter variant in the ADRA2A gene might be involved in the
pathogenesis of suicide as a result of the noradrenergic dysfunction that destabi-
lizes the HPA system.
The catechol-O-methyltransferase (COMT) gene, the catecholamine-degrading
enzyme, exhibits a functional common polymorphism (158Met/Val), and this variant
is considered to affect the HPA system. Individuals who are homozygous for the
low-activity form of COMT (A/A, Met/Met) would exhibit greater HPA-axis acti-
vation than those who are either homozygous or heterozygous for the high-activity
form of the enzyme. We found that the genotype distribution of the COMT 158Val/
Met polymorphism was significantly different between male suicide completers
and male controls (P฀=฀0.036),฀whereas฀the฀frequency฀of฀the฀Val/Val฀genotype,฀a฀
high-activity form of the enzyme, was significantly less in male suicide completers
than in male controls [odds ratio (OR) = 0.52; 95% confidence interval (CI) = 0.31–
0.89; P฀=฀0.016]฀[14]. These findings were not the case in females. We found that
this polymorphism was associated with suicide in males, and that high COMT
activity could exhibit a protective effect for suicide in males (Table 7) [15].
Table 8 shows the distributions of the four polymorphisms in the m-opioid receptor
(OPRM1) gene. The OPRM1 gene is implicated in stress responses through the HPA
system [16]. The substitution of A118G polymorphism in the OPRM1 gene, which
results in an Asn to Asp change at amino acid 40, is suggested to influence the HPA axis
response in an inhibitory manner and, possibly, decrease the HPA axis response to a
social stressor. Therefore, the suicide-protective G allele would be expected to inhibit the
HPA axis responses. We genotyped four single-nucleotide polymorphisms, including a
292
Table 6 Distribution of polymorphisms in the ADRA2A gene

Minor allele Minor allele Statistics genotype Statistics allele
Marker Controls frequency Suicide victims frequency P value c2 P value
Male and female
C-1291G CC CG GG C CC CG GG C
(n = 185) 0.086 0.422 0.492 0.297 (n = 171) 0.117 0.474 0.409 0.354 0.264 2.589 0.108฀(0.226)
rs3750625 CC CA AA A CC CA AA A
(n = 183) 0.536 0.404 0.06 0.262 (n = 181) 0.607 0.343 0.05 0.221 0.397 1.693 0.196฀(0.376)
Male
(n = 112) 0.089 0.446 0.465 0.312 (n = 118) 0.093 0.458 0.449 0.322 0.98 0.048 0.826฀(0.979)
(n = 120) 0.55 0.392 0.058 0.254 (n = 122) 0.631 0.328 0.041 0.205 0.426 1.66 0.198฀(0.386)
Female
(n = 73) 0.082 0.384 0.534 0.274 (n = 53) 0.17 0.509 0.321 0.425 0.043 6.228 0.013 (0.027)
(n฀=฀63) 0.508 0.429 0.063 0.278 (n = 59) 0.559 0.373 0.068 0.254 0.844 0.173 0.678฀(0.977)
Fukutake฀M,฀Hishimoto฀A,฀Nishiguchi฀N฀et฀al.฀(2008)฀[14]
K. Maeda et al.
Table 7 Genotype฀and฀allele฀frequencies฀of฀the฀COMT฀158Val/Met฀polymorphism
Genotype Allele
AA (%) AG (%) GG (%) A (%) G (%)
Suicides (n฀=฀163) 16฀(10) 79 (48) 68฀(42) 111 (34) 215฀(66)
Controls (n฀=฀169) 18 (11) 61฀(36) 90 (53) 97 (29) 241 (71)
Male suicides (n = 112) 9 (8) 60 (54) 43 (38) 78 (35) 146฀(65)
Male controls (n = 114) 10 (9) 42 (37) 62 (54) ฀ 62฀(27) 166฀(73)
Female suicides (n = 51) 7 (14) 19 (37) 25 (49) 33 (32) ฀ 69฀(68)
Female controls (n = 55) 8 (15) 19 (35) 28 (50) 35 (32) ฀ 75฀(68)
Total: genotype c2 = 5.4, df = 2, P฀=฀0.068;฀allele฀c2 = 2.2, df = 1, P = 0.14
Male: genotype c2฀=฀6.7,฀df = 2, P = 0.036; allele c2 = 3.1, df = 1, p = 0.080
Female: genotype c2฀=฀0.86,฀df = 2, P฀=฀0.96;฀allele฀c2 = 0.07, df = 2, P = 0.93
Ono฀H,฀Shirakawa฀O,฀Nishiguchi฀N฀et฀al.฀(2004)฀[15]
common฀A118G฀SNP.฀The฀genotypic฀and฀allelic฀distributions฀of฀the฀A118G฀SNP฀were฀
significantly different between the completed suicide and control groups (P = 0.014 and
0.039, respectively; Table 9). Moreover, the dominant model of genotype (AA vs. AG +
GG) analysis showed an enhanced association with suicide (P = 0.0041, OR = 0.575).
This finding means that individuals with one or two copies of the G allele of the A118G
SNP฀of฀the฀OPRM1฀gene฀are฀less฀vulnerable฀to฀suicide.฀These฀results฀raise฀the฀possibility฀
that฀the฀A118G฀SNP฀of฀the฀OPRM1฀gene฀is฀associated฀with฀suicide.
We have conducted another association study examining the functional gene
polymorphisms of angiotensin-converting enzyme (insertion/deletion), prostaglan-
din E receptor subtype EP1 [17],฀ and฀ neuronal฀ nitric฀ oxide฀ synthase฀ (nNOS฀ or฀
NOSI),฀ which฀ affect฀ the฀ HPA฀ system,฀ and฀ demonstrated฀ significant฀ associations฀
with suicide. These findings have suggested that the disturbance of the HPA system
plays an important role in suicide (Table 9).
Recently, we found an association between regulators of G-protein signaling
(RGS) 2 gene polymorphisms and suicide and observed increased RGS2 immu-
noreactivity in the postmortem brains of suicide victims (Tables 10, and 11) [18].
RGSs are a family of proteins that negatively regulate intracellular signaling
of G protein-coupled receptors (GPCRs), such as the serotonin receptor. RGS2 is
thought to play an important role in anxiety and/or aggressive behavior.
To explore the involvement of the RGS2 gene in vulnerability to suicide, we
screened฀Japanese฀suicide฀victims฀for฀sequence฀variations฀in฀the฀RGS2฀gene฀and฀car-
ried out an association study of RGS2 gene polymorphisms with suicide victims. In
the eight identified polymorphisms that were identified by mutation screening, we
genotyped four common single-nucleotide polymorphisms in the RGS2 gene and
found฀significant฀differences฀in฀the฀distribution฀of฀the฀SNP3฀genotypes฀and฀alleles฀of฀
the฀SNP2฀and฀the฀SNP3฀between฀completed฀suicides฀and฀the฀controls.฀The฀distribution฀
of the haplotype was also significantly different between the two groups (Table 11;
global < 0.0001). Furthermore, RGS2 immunoreactivity significantly increased in the
amygdala and the prefrontal cortex [Brodmann area 9] of the postmortem brain of the
suicide subjects (Fig. 2). These findings suggest that RGS2 is genetically involved in
the biological susceptibility to suicide in the Japanese population.
Table 8 Distribution฀of฀the฀single-nucleotide฀polymorphisms฀(SNPs)฀in฀the฀OPRM1 gene
Statistics Statistics allele
Minor allele Minor allele genotype
Marker Controls frequency Completed suicides frequency P value c2 P value
rs1074287 AA AG GG AA AG GG
(n = 373) 74.8% 23.9% 1.3% 0.132 (n = 179) 71.5% 26.8% 1.7% 0.151 0.706 0.666 0.414 (0.927)
rs12205732 GG GA AA GG GA AA
(n = 372) 78.0% 21.2% 0.8% 0.114 (n = 170) 80.6% 17.6% 1.8% 0.106 0.403 0.127 0.722 (0.998)
A118G AA AG GG AA AG GG
(n = 367) 26.2% 57.2% 16.6% 0.452 (n = 181) 38.1% 46.4% 15.5% 0.387 0.014 4.252 0.039 (0.198)*
IVS2฀+G691C GG GC CC GG GC CC
(n = 370) 4.1% 37.3% 58.6% 0.227 (n = 170) 6.4% 37.4% 56.2% 0.251 0.471 0.762 0.383 (0.840)
Hishimoto฀A,฀Cui฀H,฀Mouri฀K฀et฀al.฀(2008)฀[16]
* P < 0.05
Table 9 Susceptible polymorphisms for suicide associated with HPA system
Functional variants associated with suicide
COMT฀Val158Met฀SNP
OPRM1฀Asn40Asp฀SNP
ACE insertion/deletion polymorphism
฀ ADRA2A฀promoter฀C-1291G฀SNP
฀ Prostaglandin฀E฀receptor฀EP1฀gene฀SNPs
฀ Neuronal฀nitric฀oxide฀synthase฀SNP
Functional polymorphisms not associated with completed suicide
฀ FKBP5฀rs1360780฀T/C฀polymorphism
Peripheral benzodiazepine receptor gene polymorphism
Glucocorticoid receptor (BclIRFLP,฀N363S,฀ER22/23EK)฀polymorphism
Hishimoto฀A,฀Shirakawas฀O,฀Nishiguchi฀N฀et฀al.฀(2006)฀[17]฀
Table 10 Genotype฀distributions฀and฀allele฀frequencies฀of฀RGS2฀gene฀polymorphisms
Genotype฀frequency Allele฀frequency
SNPs Genotype Control Suicide P value Allele Control Suicide P value
SNP฀1 A/A ฀ 64฀(0.30) 39 (0.21) 0.068 A 228 (0.54) 176฀(0.47) 0.0293*
A/G 100 (0.48) 98 (0.52) df = 2 df = 1
G/G ฀ 46฀(0.22) 52 (0.27) c2฀=฀5.365 G 192฀(0.46) 202 (0.53) c2 = 4.749
SNP฀2 G/G 85 (0.40) 52 (0.28) 0.0383* G 260฀(0.62) 197 (0.53) 0.0175*
C/G 90 (0.43) 93 (0.51) df = 2 df = 1
C/C 35 (0.17) 39 (0.21) c2฀=฀6.527 C 160฀(0.38) 171 (0.47) c2฀=฀5.644
SNP฀3 C/C ฀ 68฀(0.32) 37 (0.20) 0.0105* C 243 (0.58) 179 (0.48) 0.0048**
C/G 107 (0.51) 105฀(0.56) df = 2 df = 1
G/G 35 (0.17) 45 (0.24) c2 = 9.119 G 177 (0.42) 195 (0.52) c2 = 7.939
SNP฀4 T/T 80 (0.38) ฀ 47฀(0.26) 0.0528 T 257฀(0.61) 189 (0.53) 0.0287*
C/T ฀ 97฀(0.46) 95 (0.54) df = 2 df = 1
C/C ฀ 33฀(0.16) 35 (0.20) c2 = 5.883 C 163฀(0.39) 165฀(0.47) c2 = 4.787
SNP1:฀−638฀A/G฀(rs2746071);฀SNP2:฀−395฀C/G฀(rs2746072);฀SNP3:฀2,971฀C/G฀(rs4606);฀SNP4:฀
3,438฀C/T฀(rs3767488)฀(db฀SNP฀ID)
Cui฀H,฀Nishiguchi฀N,฀Ivleva฀E฀et฀al.฀(2008)฀[18]
* P < 0.05, ** P < 0.01
Table 11 Haplotype฀analysis฀of฀RGS2฀gene฀SNP฀1–4
Frequency Global P฀value฀=฀0.000046
Haplotype฀of฀SNP฀1–2–3–4 Control Suicide c2 P value
1 A-G-C-T 0.5183 0.4382 4.8671 0.0274*
2 G-C-G-C 0.3479 0.427 5.0199 0.0251*
3 G-G-G-T 0.0565 0.0285 3.5473 0.0596
4 G-G-C-T 0.0201 0.0266 0.3563 0.5506
5 G-G-G-C <0.01 0.0295 12.5573 <0.01**
6 G-C-G-T <0.01 0.0144 1.9983 0.1575
7 G-C-C-C 0.0161 <0.01 5.6202 0.0178*
8 A-C-C-T <0.01 0.0121 1.2136 0.2706
9 A-G-G-T <0.01 0.012 1.1609 0.2813
10 G-G-C-C 0.0119 <0.01 4.1444 0.0418*
… … <0.01 <0.01 … …
SNP1:฀–638฀A/G฀(rs2746071);฀SNP2:฀–395฀C/G฀(rs2746072);฀SNP3:฀2,971฀C/G฀(rs4606);฀SNP4:฀
3,438฀C/T฀(rs3767488)
*P < 0.05, **P < 0.01
Cui฀H,฀Nishiguchi฀N,฀Ivleva฀E฀et฀al.฀(2008)฀[18]
296 K. Maeda et al.
Controls
Suicides
AMY
Suicides: 142.4 37.9 %
Controls: 100.0 37.9 %
BA9
Suicides: 133.2 34.1 %
Controls: 100.0 35.1 %
Fig. 2 Increased RGS2 immunoreactivity in suicides. RGS2 immunoreactivity significantly

increased in the amygdala and the prefrontal cortex [Brodmann area 9] of the postmortem brain of the
suicide subjects. These findings suggest that RGS2 is genetically involved in the biological suscepti-
bility฀to฀suicide฀in฀the฀Japanese฀population.฀Cui฀H,฀Nishiguchi฀N,฀Ivleva฀E฀et฀al.฀(2008)฀[18]
Conclusion
Taking into consideration the presence of mental disorders as underlying suicide, it

is natural that the recent trend tends to link early screening of depression to suicide
prevention as a medical approach. It is inadvisable to interpret suicide solely as a
symptom฀or฀outcome฀of฀disease.฀Expansion฀of฀the฀disease฀concept฀and฀subsequent฀
additional medical intervention may be inappropriate. However, the biological and
medical understanding of suicide, that is, interpretation as a condition that allows
or฀requires฀medical฀intervention,฀may฀encourage฀people฀at฀high฀risk฀for฀suicide฀to฀
visit psychological counselors and psychiatrists. In addition, although the processes
may be indirect or secondary, medical and biological approaches could have con-
siderable influence on individual views and social consciousness of life and death,
which may contribute to the prevention of suicide.
References
฀ 1.฀ Mann฀JJ฀(2003)฀Neurobiology฀of฀suicidal฀behavior.฀Nat฀Rev฀Neurosci฀4:819–828
2. Brent DA, Mann JJ (2005) Family genetic studies, suicide, and suicidal behavior. Am J Med
Genet C Semin Med Genet 133:13–24
฀ 3.฀ Roy฀A,฀Segal฀NL฀(2001)฀Suicidal฀behavior฀in฀twins:฀a฀replication.฀J฀Affect฀Disord฀66:71–74
฀ 4.฀ Bondy฀B,฀Buettner฀A,฀Zill฀P฀(2006)฀Genetics฀of฀suicide.฀Mol฀Psychiatry฀11:336–351
฀ 5.฀ Ono฀H,฀Shirakawa฀O,฀Nishiguchi฀N฀et฀al฀(2000)฀Tryptophan฀hydroxylase฀gene฀polymorphisms฀
are฀not฀associated฀with฀suicide.฀Am฀J฀Med฀Genet฀96:861–863
฀ 6.฀ Ono฀H,฀Shirakawa฀O,฀Nishiguchi฀N฀et฀al฀(2001)฀Serotonin฀2A฀receptor฀gene฀polymorphism฀is฀
not฀associated฀with฀completed฀suicide.฀J฀Psychiatr฀Res฀35:173–176
฀ 7.฀ Nishiguchi฀ N,฀ Shirakawa฀ O,฀ Ono฀ H฀ et฀ al฀ (2001)฀ No฀ evidence฀ of฀ an฀ association฀ between฀
5HT1B receptor gene polymorphism and suicide victims in a Japanese population. Am J Med
Genet 105:343–345
฀ 8.฀ Ono฀H,฀Shirakawa฀O,฀Kitamura฀N฀et฀al฀(2002)฀Tryptophan฀hydroxylase฀immunoreactivity฀is฀
altered by the genetic variation in postmortem brain samples of both suicide victims and
controls. Mol Psychiatry 7:1127–1132
฀ 9.฀ Nishiguchi฀N,฀Shirakawa฀O,฀Ono฀H฀et฀al฀(2002)฀Lack฀of฀an฀association฀between฀5-HT1A฀
receptor gene structural polymorphisms and suicide victims. Am J Med Genet 114:
423–425
฀10.฀ Ono฀ H,฀ Shirakawa฀ O,฀ Nishiguchi฀ N฀ et฀ al฀ (2002)฀ No฀ evidence฀ of฀ an฀ association฀ between฀ a฀
functional monoamine oxidase a gene polymorphism and completed suicides. Am J Med
Genet 114:340–342
฀11.฀ Okamura฀K,฀Shirakawa฀O,฀Nishiguchi฀N฀et฀al฀(2005)฀Lack฀of฀an฀association฀between฀5-HT6฀
receptor฀gene฀polymorphisms฀and฀suicide฀victims.฀Psychiatry฀Clin฀Neurosci฀59:345–349
12. Anguelova M, Benkelfat C, Turecki G (2003) A systematic review of association studies
investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal
behavior.฀Mol฀Psychiatry฀8:646–653
฀13.฀ Hattori฀H,฀Shirakawa฀O,฀Nishiguchi฀N฀et฀al฀(2006)฀No฀evidence฀of฀an฀association฀between฀
tyrosine hydroxylase gene polymorphisms and suicide victims. Kobe J Med Sci 52:
195–200
฀14.฀ Fukutake฀M,฀Hishimoto฀A,฀Nishiguchi฀N฀et฀al฀(2008)฀Association฀of฀a2A-aderenergic receptor
gene polymorphism with susceptibility to suicide in Japanese females. Prog
Neuropsychopharmacol฀Biol฀Psychiatry฀32:1428–1433
฀15.฀ Ono฀H,฀Shirakawa฀O,฀Nushida฀H฀et฀al฀(2004)฀Association฀between฀catechol-O-methyltrans-
ferase฀ functional฀ polymorphism฀ and฀ male฀ suicide฀ completers.฀ Neuropsychopharmacology฀
29:1374–1377
฀16.฀ Hishimoto฀A,฀Cui฀H,฀Mouri฀K฀et฀al฀(2008)฀A฀functional฀polymorphism฀of฀the฀m-opioid receptor
gene฀is฀associated฀with฀completed฀suicides.฀J฀Neural฀Transm฀115:531–536
฀17.฀ Hishimoto฀A,฀Shirakawa฀O,฀Nishiguchi฀N฀et฀al฀(2006)฀Association฀between฀a฀functional฀polymor-
phism฀in฀the฀renin-angiotensin฀system฀and฀completed฀suicide.฀J฀Neural฀Transm฀113:1915–1920
฀18.฀ Cui฀H,฀Nishiguchi฀N,฀Ivleva฀E฀et฀al฀(2008)฀Association฀of฀RGS2฀gene฀polymorphisms฀with฀
suicide and increased RGS2 immunoreactivity in the postmortem brain of suicide victims.
Neuropsychopharmacology฀33:1537–1544
Brief History and Current Status
of the International Neuropsychiatric
Association
Koho Miyoshi
Abstract The International Organization of Neuropsychiatry (ION) was

established by Spanish and American neuropsychiatrists in Seville in the year
1996. In conjunction with the second congress in Toronto (1998), the International
Neuropsychiatric Association (INA) was established to supersede the ION. Since
then, the International Congresses of Neuropsychiatry have been held every
2 years, namely in Kyoto (2000), Buenos Aires (2002), Athens (2004), Sydney
(2006), and Cancun (2008). Here, the brief history and topics of the plenary
lectures and symposia in the past congresses are reviewed. The current status of the
INA, including Mission Statement, Officers, Committees, and Regional Activities,
is also mentioned briefly.
Keywords Alwyn฀ Lishman฀ Award฀ •฀ International฀ Neuropsychiatric฀ Association฀

(INA)฀•฀Neuropsychiatric฀disorders฀•฀Neuropsychiatry฀•฀Ramon฀y฀Cajal฀Award
Introduction
The International Organization of Neuropsychiatry (ION), currently the International

Neuropsychiatric Association (INA), was established in 1996. According to the
Mission Statement, the INA aims to prevent or reduce the suffering of the patients
with neuropsychiatric disorders by studying the psychiatric symptoms or syndromes
in cerebral disorders and by investigating neurobiological bases of psychiatric
disorders. The INA provides a forum for interaction and exchange of ideas among
professionals in neuropsychiatry and endeavors to publicize and disseminate both
clinical and academic advances in the field of neuropsychiatry. Here, a brief history
of the association and current status are mentioned briefly as an introduction for
new INA members.
K. Miyoshi (*)
Jinmeikai Research Institute for Mental Health Kabutoyama-cho, Nishinomiya, Hyogo, Japan

DOI 10.1007/978-4-431-53871-4_24, © Springer 2010
302 K. Miyoshi
The Beginning: The First Congress in Seville
The ION was originally planned to be established by Spanish and American

neuropsychiatrists in Seville in 1996. The Organizing Committee consisted of four
persons: Dr. Barry S. Fogel, Brown University (USA); Dr. Moises Gaviria, the
University of Illinois at Chicago (USA); Dr. Jose Giner, The University of Seville
(Spain); and Dr. Robert Green, Emory University School of Medicine (USA). The
committee proposed to establish an international organization and to hold the con-
gress. In the flyer to call the congress, the intentions were described as follows.
Dear Colleague:
Neuropsychiatry is a burgeoning discipline not only in the United States, but
worldwide. Recent binational meetings sponsored by the American
Neuropsychiatric Association and the British Neuropsychiatric Association
not only attest to widespread interest in neuropsychiatry but also to meaning-
ful and interesting differences in neuropsychiatric training, practice, and
thinking among countries.
This summer’s World Congress of Psychiatry in Madrid, Spain, offers an
excellent opportunity to convene neuropsychiatrists from around the world to
encourage the development of a world neuropsychiatric community that could
subsequently maintain communications over the Internet. The American
Neuropsychiatric Association (ANPA), The University of Illinois at Chicago
Department of Psychiatry, and The University of Seville Department of
Psychiatry have undertaken to organize an International Congress of Neuro-
psychiatry, to be held in Seville, Spain, for three days immediately following the
World Congress. The program includes plenary presentations by major
American, British, European and Latin-American scientists and clinicians, poster
sessions, and round table discussions. All major speakers have agreed to be avail-
able on the day of their talk for informal interchanges with participants, and all
major speakers will participate in lunch round tables on a variety of topics.
Interpreters will be available to facilitate cross-national communications.
The Hotel Alfonso XIII, site for the meeting, is one of the finest hotels in
the world, and Seville offers a picturesque venue that is a short flight from
other European cities.
We look forward to seeing you at this meeting, the first of many such
international gatherings.
Sincerely,
The International Congress of Neuropsychiatry
Organizing Committee
Brief History and Current Status of the International Neuropsychiatric Association 303
The First Congress was held successfully at the Hotel Alfonso XIII in Seville,
August 29–31, 1996. Large numbers of neuropsychiatrists, approximately 400,
from Europe, North and South America, and Asia-Oceania gathered there and
discussed enthusiastically the new organization of neuropsychiatry (Fig. 1).
The Topics in the First Congress were as follows:
Creating a World Neuropsychiatric Community, New Developments in
Dementia, The Frontal Lobe System, Advances in Brain Imaging, Keynote
Lecture: The Past and the Future of Neuropsychiatry, Basic and Clinical Topics in
Neuropsychiatry, Round Table Discussion (Education and Training, Organization
and Financing of Health Care, Outcome Studies, AIDS Dementia Complex,
Aggression, Psychiatric Symptoms in Dementia), The Practice of Neuropsychiatry
and System Care, Clinical Perspectives in Neuropsychiatry (Neuropsychiatry in
Europe, SPECT and Depression, Schizophreniform Phenomena and the Temporal
Lobe, Biology of Melancholia, Laterality and Schizophrenia, Building a World
Neuropsychiatric Community)
Fig. 1 The flyer of the First

Congress in Seville, 1996
304 K. Miyoshi
Principal speakers in the First Congress were:

A. Ardila (US), S. Cervera (Spain), J. Cook (US), E. Costa (US), J. Cummings
(US), A. David (UK), B. Dubois (France), L. Farrer (US), B. Fogel (US), J. Giner
(Spain), P. Gorelick (US), P. Grasby (UK), R. Green (US), J. Guimon (Switzerland),
T. Jobe (US), C. Leal (Spain), A. Lishman (UK), H. Markowitsch (Germany), M.
Mesulam (US), M. Rasenick (US), S. Rauch (US), J. Vallejo-Ruiloba (Spain), M.
Spitzer (Germany), N. Vokow (US), P. Whitehouse (US), and others.
The Reorganization: The Second Congress in Toronto
Soon after the congress in Seville, Dr. Colin Shapiro (Toronto) and Dr. Koho
Miyoshi (Kyoto) expressed their intentions to the organizing committee to hold
the coming neuropsychiatric congress in their countries. The arrangement of the
future congress was discussed in Orlando, Florida, where the Eighth Annual
Meeting of American Neuropsychiatric Association was held, in 1997. Dr.
Moises Gaviria attended the meeting on behalf of the organizing committee of the
First Congress in Seville. It was decided to hold the Second Congress in
Toronto.
Dr. Shapiro, Dr. Gaviria, and Dr. Miyoshi gathered to discuss about the financial
issues of the INA in Hawaii, where the Ninth Annual Congress of American
Neuropsychiatric Association was held in January 1998, and decided to manage the
organization temporarily by their financial contributions.
The Second International Congress of Neuropsychiatry, which was called
formally the “International Neuropsychiatry Congress (INC) and American
Neuropsychiatric Association (ANPA) 1998 Joint Meeting,” was held May 31 in
Toronto, Canada. The INA sessions and the ANPA sessions were held in the
meeting. In conjunction with the Toronto meeting, the INA, dedicated to promoting
the study of the brain and behavior from a neuropsychiatric perspective, was
established to supersede the ION. Twenty-four countries from Europe, North and
South America, Asia, and Australia were represented. It was decided that the
association would hold a biennial meeting.
As the first president of the association, Dr. Colin Shapiro (Canada) was
elected. Dr. Koho Miyoshi (vice-president) and Dr. Moises Gaviria (secretary-
general) were elected as the officers. Drs. R.H. Belmaker (Israel), E.Y.H. Chen
(Hong Kong), D.D. Dikeos (Greece), M. Robertson (UK), P. Sachdev (Australia),
and P. Sandor (Canada) were elected as the members of the Executive Committee.
The office of the INA was decided to be located in the office of the president in
Toronto. Dr. Paul Sander (Canada) was elected as a newsletter editor, and Dr.
Sharon Chung (Canada) was appointed as the secretariat in the INA office
(Fig. 2).
Fig. 2 The Presidents of the INA: Dr. C. Shapiro (1998–2002), Dr. P. Sachdev (2004–2006),
Dr. K. Miyoshi (2008–), and Dr. M. Gaviria (2002–2004) in Buenos Aires, 2002 (from left)
The Mission Statement was proposed and accepted in the executive

committee.
Mission Statement of the International Neuropsychiatric Association (1998)
1. The INA aims to prevent or reduce the suffering of people with brain-behavior
disorders by increasing, integrating, and disseminating knowledge and
understand the relationships between brain function and human behavior.
2. The INA aims to accomplish this objective by providing a forum for inter-
action and exchange of ideas among a variety of professionals with an
interest in neuropsychiatric issues.
3. The INA endeavors to publicize and disseminate both clinical and academic
advances in the field to bring about improved health for people throughout
the world. Although rapidly advancing medical technology has greatly
expanded the frontiers of neuropsychiatry, the INA will strive to preserve
the humanistic values of medicine.
4. The INA endeavors to raise awareness of neuropsychiatry, particularly in
those countries where it is not well known or recognized.
306 K. Miyoshi
The scientific topics and principal speakers in the Second Congress were:
Neuropsychiatry of Tourettes’ Syndrome [M. Robertson (UK), E.C. Miquel
(Brazil), B.J.M. van de Wetering (the Netherlands)]; The Epidemiology of
Hallucinations [M. Ohayon (Canada)], Neuropsychiatry, and Neuroimaging
[L. Farde (Sweden), P. Martin (US), R. Dolan (UK)]; Genetics and Psychobiology
of Personality (Keynote Lecture) [C.R. Cloninger (US)]; Genetics of Neuropsychiatry
[K. Kidd (US), D. Black (US), M. Lepper (US), B. Clementz (US), P. Propping
(Germany)], and Art and the Mind [H. Walton (UK)].
The Springboard: The Third Congress in Kyoto
The executive committee was held in New Orleans, where the Tenth Annual Congress
of American Neuropsychiatric Association took place, on January 31, 1999. The pro-
posed by-laws of the INA were examined and accepted by the executive committee.
The Third Congress was held in Kyoto, Japan, April 9–13, 2000. The venue of
the Congress was The Kyoto International Conference Hall at Takaragaike, Kyoto.
At the Kyoto meeting, approximately 700 people participated. Thirty-one countries
and districts, including Australia, Belgium, Canada, Croatia, Egypt, France,
Germany, Greece, Hong Kong, India, Israel, Italy, Japan, Lithuania, Macedonia, the
Netherlands, the Philippines, Poland, Russia, Spain, Sweden, Switzerland, Taiwan,
Thailand, Turkey, the United Arab Emirates, the United Kingdom, the United
States, Uruguay, and Venezuela, sent delegates.
The topics of the plenary lectures in the Third Congress were:
Dementia with Lewy Body [I. McKeith (UK)]; Tourette Syndrome [M.M.
Robertson (UK)]; Neuropsychiatry in the Elderly [J.L. Cummings (US)]; Zen and
the Brain [J.H. Austin (US)]; Functional Neuroimaging [H. Shibazaki (Japan)]; Sex
Differences in Brain Aging [C.E. Coffey (US)]; Biological Substrate of Late Life
Depression [J. Schweitzer (Australia)]; Neuropsychiatry of Stroke [R.G. Robinson
(US)]; Neuropsychiatry of Limbic and Subcortical Disorders [S.P. Salloway (US)];
Neuroimaging and Neurobiology of Schizophrenia [N. Andreasen (US)]; Brain
Laterality and Psychopathology [G. Gainotti (Italy)]; Behavioral and Psychological
Symptoms of Dementia [S.I. Finkel (US)]; Neuropsychiatry in 21st Century [C.
Shapiro (Canada)]; Positron Emission Tomography Studies in Schizophrenia [J.J.
Lopez-Ibor (Spain)]; Neuropsychiatric Aspects of Sleep Disorders [C. Soldatos
(Greece)], Brain Pathology of Dementia [K. Kosaka (Japan)]; Non-Alzheimer Type
of Dementia [L. Gustafson (Sweden)]; New Trends of Pharmacological Treatment
of Dementia [K. Miyoshi (Japan)]; and Schizophrenia-like Psychoses and Epilepsy
[P. Sachdev (Australia)].
The topics of the symposia and workshop in the Third Congress were:
Worldwide Collaborations in Neuropsychiatry, Transcranial Magnetic
Stimulation, Advances in Psychooncology and Psychoimmunology, Behavioral
Genetics of Personality, Vulnerability Markers of Schizophrenia, Vascular Dementia,
Biology of Eating Disorders, Dementia in Asian Countries, Brain and Behavior,
Molecular Genetics of Stimulant-Induced Psychosis, Neuropsychiatric Disorders
and Related Conditions, Clinical Aspects of Dementing Disorders, Fronto-Temporal

Lobe Dementia, Genetics of Schizophrenia and Affective Disorders, Alzheimer’s
Disease, Neuropharmacology, Neuropsychiatric Aspects of Schizophrenia,
Anticonvulsants, Obsessive–Compulsive Disorders and Personality Disorders,
Diffuse Lewy Body Disease, Lithium and Signal Transduction, Genetics of
Personality, and Post-Mortem Brain Specimens to Study Affective Disorders.
The monograph, Contemporary Neuropsychiatry, which consists of selected
papers from the Third Congress, was edited by K. Miyoshi, C. Shapiro, M. Gaviria,
and Y. Morita, and published by Springer-Verlag Tokyo in 2001.
The Jump: The Fourth Congress in Buenos Aires
The Fourth Congress, chaired by Dr. Marquez (Buenos Aires), was held in Buenos
Aires in 2002. The venue was Hotel Crowne Plaza Panamericano in Buenos Aires.
Approximately 1,500 people participated in the Congress. The topics of the meeting
covered the neuropsychiatric field almost completely. As the Second INA president,
Dr. Moises Gavira (US) was elected for a 2-year term. Treasurer [G. Tortora
(Argentina)] and the members of Executive Committee [R. Belmaker (Israel),
K. Miyoshi (Japan), A. Kanner (US), E.S. Krishnamoorthy (India), M. Marquez
(Artentina), S. Shi (China), J. Tellez (Columbia), D. Dikeos (Greece), and C. Soldatos
(Greece)] were elected in the Executive Meeting.
Issues of the official journal and committees, such as the education committee
and membership committee, were discussed in the Executive Meeting.
The topics of the lectures in the Fourth Congress were:
Psychopathology in Epilepsy [A. Kanner (US)]; G-Protein Signaling in
Anti-Depressants [M. Rasenick (US)]; Tau Changes and Deficit in Episodic
Memory [L. Binder (US)]; Concussion in Sports [R. Bornstein (US)]; New
Trends in the Treatment of Dementia [K. Miyoshi (Japan)]; Cognitive Impairment
in Parkinson’s Disease [O. Gershanik (Argentine)]; Organic Psychosis as a Model
for Schizophrenia [P. Sachdev (Australia)]; Thyroid Hormone and Affective
Disorders [R. Bunevicius (Lithuania)]; Neuropsychological and Neuropsychiatric
Aspects of Electric Trauma [N. Pliskin (US)]; Mechanism and Action of mu-Opioides
[J. Lemos (US)]; Cognitive Therapy [R. Baber (US)]; Towards an Early and
Presymptomatic Diagnosis of Primary Degenerative Dementia [C. Mangone
(Argentine)]; Prion Disease [A.L. Taratuto (Argentine)], Sleep Disorders
[C. Shapiro (Canada)], Cognitive-Motor Disorder in Psychiatric Diseases
[R. Leiguarda (Argentine)]; Functional MRI in Neuropsychiatry [G. Stebbens
(US)]; Neurogenesis in Adult Hippocampus [A. Schinder (Argentine)]; Current
Status and Future Directions in Psychiatric Neurosurgery [K. Slavin (US)];
Music Brain and Culture [M. Gaviria (US)]; A Genetic Approach to the
Conceptual Nosological Continuum of Schizophrenia and Mood Disorders
[D. Dikeos (Greece)]; Vascular Dementia: an Overview [G. Roman (US)];
Chronobiology and Affective Disorders [D. Cardinali (Argentine)]; Attention
Deficit [J. Gutierrez (Mexico)]; Brain Damage and Recovery [M. Gaviria (US)];
308 K. Miyoshi
ECT in Neuropsychiatric Disorders [C. Campillo (Mexico)]; Neuropsycho

Immunology [R. Espaillat (Dominica)]; Neuropsychology of Memory [J. Medina
(Argentine)]; Neuronal Networks in OCD [M. Marquez (Argentine)]; and
Inflammation Transcription Factors [G. de Erausquin (US)].
The topics of the symposia in the Fourth Congress were:
Neuropsychiatry and Primary Care, Organic Bases of Psychopathology in
Epilepsy, Neuroimaging in Neuropsychiatry, Cognitive Assessment Tools for
Iberoamerica, Psychic Handicapped Condition, Pharmacological Management of
Tourette’s Syndrome and Associated Disorders, Alzheimer’s Disease, Diagnostic
Challenges in Neuropsychiatry, Frontal Lobe and Executive Function, Stress, New
Neuropsychiatrics Approaches, New Trends in Depression, Neuropsychiatric
Issues of Autism Spectrum, and Spectrum of the Frontotemporal Dementia.
In this conference, the Lishman Award and the Ramon Y. Cajal Award were
established. The Lishman Award was established to honor the modern pioneer of
Neuropsychiatry, Professor Alwyn Lishman of London. It is presented every 2 years
to an individual who has made a notable contribution to clinical neuropsychiatry at
the international level. The awardee will be a distinguished clinician and extend
practice, teaching, and/or service delivery of neuropsychiatry beyond the boundar-
ies of his or her own country. The Ramon Y. Cajal Award was established to honor
the Father of Neuroscience. This award is presented every 2 years to an individual
who has made a distinguished contribution to neuroscience with an application to
neuropsychiatry. The awardee will be an eminent neuroscientist who has made
salient contribution resulting in a paradigm shift or the development of novel diag-
nostic or management strategies.
Dr. Julio Vellejo Ruiloba (Spain) presented a lecture titled “Issues of Current
Neuropsychiatry” as the first awardee of the Ramón y Cajal Award, and Dr. Gustavo
Roman (US) gave a lecture on “Vascular Dementia. An Overview” as the first
awardee of the Alwyn Lishiman Award.
The Collaborations: The Fifth Congress in Athens
The Fifth International Congress, in conjunction with the First Mediterranean

Congress of World Federation of Societies of Biological Psychiatry, was held in
Athens, October 14–18, in 2004. The venue of the meeting was the International
Conference Center at Megaron. Dr. Constantin Soldatos chaired the Congress.
The possibilities to stimulate activities of the INA by collaborating with closely
related scientific societies were clearly shown in this meeting.
This was the First Congress in a European country, and approximately 1,000
people participated in this meeting. The scientific topics covered the field of
neuropsychiatry very widely as well as biological psychiatry. Since then, the
regional INA meeting, named the European Congress of the INA, has been held
every 2 years. Dr. Perminder Sachdev (Sydney) was elected as the third INA
president, and the INA office was moved to Sydney.
Dr. M Trimble (UK), the awardee of the Alwyn Lishman Award, presented the
lecture “The Evolution of the Limbic System and Epilepsy as a Clinical Model of
Dissolution,” and Dr. V.S. Ramachandran (US), the awardee of the Ramon y Cajal
Award, gave a lecture titled “Art and Brain.”
The topics of the lectures in the Fifth Congress were:
Vascular Dementia [M. Gaviria (US)]; Schizophrenia as Disorder of
Consciousness [C.R. Hojaij (Australia)]; Ethical Issues in Biological Psyc-
hiatry Research [A. Okasha (Egypt)]; Long-Term Outcome of Schizophrenia
[H.J. Möller (Germany)]; The Psychopathology of Fatigue [C. Shapiro (Canada)];
The Evolution of the Limbic System and Epilepsy [M. Trimble (UK)]; Art and
Brain [V.S. Ramachandran (US)]; Bipolar I and II Disorders [L. Judd (US)]; What
Causes the Onset of Psychosis? [R.M. Murray (UK)]; Can Stress Cause Depression?
[H.M. van Praag (the Netherlands)]; Catatonia [M. Fink (US)]; Neuropsychiatry of
Traumatic Brain Injury [R.G. Robinson (US)]; Brain Mechanisms of Cognitive
Processes [A. Georgopoulos (US)]; Towards New International Classification and
Diagnostic Systems [J.E. Mezzich (US)]; Biological Correlates of Obsessive
Compulsive Disorders [J.J. López-Ibor (Spain)]; Genetics of Mood Disorders
[J. Mendlewicz (Belgium)]; Agitated Depression in Bipolar Disorder [M. Maj
(Italy)]; Biological Perspectives in Psychiatric Prevention [G. Christodoulou
(Greece)]; Neuropsychiatric Aspects of Mental Disorders in Old Age [K. Miyoshi
(Japan)]; Impulsivity and Aggression [J.L. Ayuso-Gutiérrez (Spain)]; and Whither
Neuropsychiatry? [P.S. Sachdev (Australia)].
The topics of the symposia in the Fifth Congress were:
Cognitive Declines and Behavioral Changes in Neuropsychiatric Disorders,
Methodological Approaches in Neuropsychiatric Disorders, Psychopharmacology
for Children and Adolescents, Basic and Clinical Aspects on Hippocampus in
Depression, Management of Post Stroke Depression, ECT, Emerging Pharmacological
and Neuroimaging Strategies in the Evaluation and Treatment of Dementia,
Neuroimaging, Clinical and Experimental Europsychopharmacology, Clinical
Responses and Ethnopsychopharmacology, Neuropathological Vistas in
Neuropsychiatry, New Developments in Event-Related Potential Methodology,
Fig. 3 The INA President Dr. C. Soldatos (2006–2008)

310 K. Miyoshi
Prise en Charge au long cours dans la schizophrenie (in French), Neuropsychiatry

and Beyond, Updates from Clinical Research in Bipolar Disorders, Cognitive
Functional and Structural Changes in First-Episode Schizophrenic Children and
Adults, The Contribution of New Tools to the Comprehension of Schizophrenia,
Nuevos avances en la enfermedad de Alzheimer (in Spanish), Themes and Variations
in Neuropsychiatry, The Neuropsychiatry of Epilepsy, Neuroendocrinology of
Stress-Related Psychiatric Disorders, Genetics of Cognitive and Eye Tracking
Dysfunctions in Major Psychoses, Depression and Aging, Sleep Disorders in
Neuropsychiatry and Biological Psychiatry, Neuropsychiatric Disorders in
Intellectual and Developmental Disabilities, Alzheimer’s Disease and Lewy Body
Dementia, Biological Correlates of Learning Disabilities, Research in Neuroscience,
Evidence of Schizophrenia as a Systemic Disease, Depression and Late Life
Cognitive Disorders, Homocysteine and MTHFR Polymorphism in Psychiatry,
Thyroid–Brain Interaction Across the Life Cycle, Continuing Challenges in Bipolar
Disorders and Its Treatment, Neurobiology of Eating Disorders, Neuropsychiatric
Aspects of Traumatic Brain Injury, Psychopathology in the Era of Neuroscience,
Biological Aspects of Suicidal Behaviour, Animal Models of Schizophrenia,
Magnetoencephalography in Psychiatry, Cholinesterase Inhibitors in Neuropsychiatry,
The Link Between Experimental Studies and Clinical Practice, Neurocognitive
Functions in Schizophrenia, Decision-Making Process in Neuropsychiatric Disorders,
Utility of Quantitative EEG in Diagnosing and Treating Patients with Psychiatric
Disorders, Neuropsychiatric Topics in Mexican Clinical Practice, etc.
The Widening: The Sixth Congress in Sydney
The Sixth Congress was held in Sydney in 2006. Approximately 600 people
attended the congress. Neurobiological investigations of the endogenous psychoses
as well as the neuropsychiatric disorders were discussed in the congress. In this
congress, the realm of the neuropsychiatry was clearly widened by the impressive
presentations of the neurobiological bases of endogenous psychoses as well as
neuropsychiatric disorders. Dr. Perminder Sachdev, chair of the meeting, publicized
the core curriculum for the training of neuropsychiatrists.
In this meeting, Dr. Soldatos was elected the fourth INA president. Professor
Alvaro Pascual-Leone had been awarded the Ramon y Cajal award for his
outstanding contribution to the understanding of higher cognitive functions and the
treatment of neuropsychiatric disorders using transcranial magnetic stimulation.
The Lishman Award was awarded to Professor C. Edward Coffey, an accomplished
physician and healthcare leader recognized for developing highly successful
integrated mental health care systems and for his important contributions to
our understanding of brain–behavior relationships. As the Award Lectures,
Dr. A. Pascual-Leone presented a lecture entitled “The Right Side in Sigmund
Freud,” and Dr. C.E. Coffey gave a lecture on “Dramatically Improving the Quality
of Care in Neuropsychiatry” (Fig. 3).
Instead of the sessions of the plenary lectures, the symposia and workshops were
planned as the main sessions of the congress.
The topics of the symposia in the Sixth Congress were:
Neuropsychiatry as a Discipline for the Future (Presidential Symposium),
Transcranial Magnetic Stimulation, Neurophilosophy, Psychiatric Aspects of Epilepsy,
Traumatic Brain Injury (TBI), Neurology of Schizophrenia, Newer Antidepressants,
Delusional Belief, Developmental Neuropsychiatry, Neuropsychopharmacology,
Neuroimaging, Neurobiology of Consciousness, Movement Disorders and Catatonia,
Neurobiology of Hallucinations, Neuropsychiatry of Bipolar Disorder, Old Age
Psychiatry, Vitamins, Homocysteine and Omega 3 in Neuropsychiatry, Investigative
Applications, Genetics of Childhood-Onset Psychiatric Disorders, Brain Stimulation,
Neurobiology of Eating Disorders, Neuroimaging, Neurobiology of Melancholia,
Unusual and Uncommon Neuropsychiatric Syndromes, New Horizons in Epilepsy
and Behaviour, Brain Changes in Early Psychosis, Current Status of Vascular
Cognitive Impairment, An Update on ECT, Depression in Old Age, ADHD Across
the Lifespan, Catatonia and Cycloid Psychoses, Parkinson’s Disease, The Genetics of
Neuropsychiatric Disorders, Frontotemporal Dementia, Dementia, Controversies
about Mild Cognitive Impairment (MCI), Neuropsychiatry of Sleep, Brain Reserve,
and Traumatic Brain Injury.
Principal participants of the meeting in the program of the Sixth Congress were:
R.H. Belmaker (Israel), M. Bennett (Australia), S. Berkovic (Australia), H.
Brodaty (Australia), G.A. Broe (Australia), C.E. Coffey (US), D. Copolov (Australia),
A. David (UK), M. Gaviria (US), P. Hay (Australia), A. Jablensky (Australia), D.
Jeste (US), P. Joyce (New Zealand), E.S. Krishnamoorthy (India), H.S. Mayberg
(Canada), R. Meares (Australia), P. Mitchell (Australia), K. Miyoshi (Japan), C.
Pantelis (Australia), G. Parker (Australia), A. Pascual-Leone (US), G.C. Román
(US), M Ron (US), I. Skoog (Sweden), C. Shapiro (Canada), A. Snyder (US), C.R.
Soldatos (Greece), S.E. Starkstein (Australia), M. Trimble (UK), etc.
The Latest: The Seventh Congress in Cancun
The Seventh Congress took place in Hotel Fiesta Americano Condesa, Cancun,
Mexico, December 3–5, 2008. As a chairman of the Congress, Professor Ricardo
Colin-Piana and his colleagues organized the meeting very nicely. Scientific topics
covered the neuropsychiatric field widely. The awardee of Cajal’s award, Dr. M Marsel
Mesulam, presented a lecture on “Primary Progressive Aphasia.” The awardee of
Lishman’s award, Dr. German E. Berrios, gave a lecture on “Neuropsychiatry–
Clinical Epistemology and Hermeneutics”.
The topics of the plenary lectures in the Seventh Congress were:
Early Detection of Neurodegenerative and Vascular Dementia [A. Wallin (Sweden)];
Behavioral Disturbances in Dementia [M. Mendez (US)]; Thyroid Axis Functioning
and Psychosis [R. Bunevicius (Lithuania)]; Atypical Viral Brain Infections [J. Sotelo
(Mexico)]; The Mayan Heritage [J.D. Vos (Mexico)]; Atypical Antipsychotics and
312 K. Miyoshi
Neuroleptic Malignant Syndrome [J. Trollor (Australia)]; Neuropsychiatry and

Humanism [R. Alarcon (US)]; Psychotic Disorders After Temporal Lobectomy [E.S.
Krishnamoorthy (India)]; Conversion Disorders [B. Yeong (Singapore)]; Mirrors in the
Brain [P. Sachdev (Australia)]; and Dangerous Lives, War and the Emotional Health of
Journalists [A. Feinstein (Canada)].
The topics of the symposia in the Seventh Congress were:
Steroid Hormones in Mental Health and Disease, Cognitive Neuroscience,
Neuropsychiatry of Frontal Lobes, Neuropsychiatry of Multiple Sclerosis,
Neuropsychiatry and Addictions, Neuropsychiatry of Affective Disorders, Traumatic
Brain Injury, Brain Stimulation Therapies, Neurointegrative Mechanisms of
Psychological Trauma and Chronic Pain, History of Neuropsychiatry,
Neurodegeneration, Epidemiology of Vascular and Metabolic Factors in Mental
Disorders, and International Health.
Dr. Koho Miyoshi succeeded to the INA presidency, and Dr. I. Skoog (Sweden),
Dr. D. Arciniegas (US), Dr. K. Maeda (Japan), and Dr. E. Coffey (US) were elected
as the new members of the Executive Committee. Dr. M. Gaviria (Member of the
Advisory Council) was re-elected as a member of the Executive Committee.
Regional Activities
The Argentine Neuropsychiatric Association has held the Latin-American Congress

of Neuropsychiatry every year since 2003. The Indian Neuropsychiatric Group has
held the Indian Symposium of Neuropsychiatry biennially since 2004. The Greek
Neuropsychiatric Group hosted the European Congress of the INA every 2 years
since 2004. The Japan Neuropsychiatric Association held the Kobe Conference of
the INA in Kobe, Japan, September 12–13, 2009.
The Coming INA Meetings
The Eighth International Congress of Neuropsychiatry will be held in Chennai, India,

in 2011. Dr. Krishnamoorthy will chair the Congress. The Ninth Congress will be held
in Chicago. Dr. Moises Gaviria, one of the founders of the INA, is now organizing the
meeting. The Peruvian psychiatrist Dr. Gastelumendi is planning to hold a regional
congress of neuropsychiatry in Lima, Peru, June 18–19, 2010. The Third European INA
congress will take place in Thessaloniki, Greece, November 18–21, 2010.
Current Status of the INA
Officers and INA Office
Currently, Dr. K. Miyoshi holds the position of INA president. Dr. M. Kopelman
will succeed to the presidency in Chennai in the year 2011. Dr. J. Trollor is
secretary-general and treasurer until 2013. Ms. Angie Russell is the secretariat in
the INA office, located in Sydney. Dr. M. Mula edits the newsletter, and Mr. L.
Tortora is the webmaster of INA. The INA Secretariat Office, Neuropsychiatric
Institute, The Prince of Wales Hospital, Randwick, NSW 2031, Australia (email:
[email protected]).
Executive Committee
The names of the Members of the Executive Committee are as follows: Ignacio
Brusco (Argentina), Robertas Bunevicius (Lithuania), Ricardo Colin-Piana (Mexico),
Anthony David (UK), Valsamma Eapen (Australia), Ennapadam S. Krishnamoorthy
(India), Robert Belmaker (Israel), Kiyoshi Maeda (Japan), Edward Coffey (US),
Moises Gaviria (US), Ingmar Skoog (Sweden), and David Arciniegas (US).
Advisory Council
The past presidents, Colin M. Shapiro (Canada), Moises Gaviria (US), Constantin
R. Soldatos (Greece) and Perminder Sachdev (Australia), are the members of the
Advisory Council. The core business of this committee is to advise the Executive
Committee (EC) on future directions for INA to propose nominations for vacancies
of the EC. All members will continue to sit on the Executive.
International Committee
The members of the International Committee are expected to (1) contribute to the
life and direction of INA, (2) act as key contacts for local activities of INA,
including taking initiative to hold local or regional scientific meetings on behalf of
INA, (3) communicate closely and regularly with the INA secretariat, (4) contribute
articles regarding neuropsychiatry activities in their country to the newsletter every
2 years, and (5) recruit new INA members in their own countries by sharing e-mail
lists of individuals who may have an interest in joining INA.
The members of the International Committee are:
Ahmed Malalia Salah AlAnsari (Bahrain), Celso Arango (Spain), Gilberto
Brofman (Brazil), Alexandre Castro Caldas (Portugal), Vytenis Deltuva (Lithuania),
Greg Finucane (New Zealand), Simon Fleminger (UK), Eduardo Gastelumendi
(Peru), Andres M Kanner (US), Francis Krivoy (Venezuela), Mario Lipez-Gomez
(Mexico), Maximiliano Luna (Argentina), Olya Mikova (Bulgaria), Ming-Chyi Pai
(Taiwan), Kang Seob Oh (Korea), Ranan Rimon (Finland), Ilya Reznik (Israel),
Bernard Saletu (Austria), Surachai Kuasirkul (Thai), Thordur Sigmundsson
314 K. Miyoshi
(Iceland), Patrick Vuilleumier (Switzerland), Masahito Yamada (Japan), Beng

Yeong (Singapore), John Fayyad (Lebanon), Raben Rosenberg (Denmark), Anders
Wallin (Sweden), Zoltan Rihmer (Hungary), Xin Yu (China)*, Yongjin Wang
(China)* [*rotate-on-duty every 2 years].
Awards
The Lishman Award was established to honor William Alwyn Lishman of London,
UK, as the modern pioneer of neuropsychiatry. It is awarded to an individual who
has made a notable contribution to clinical neuropsychiatry at an international level.
By accepting the award, the recipient presents a lecture at the Biennial Congress.
The Cajal Award was established to honor the “Father of Neuroscience,”
Santiago Ramon Y Cajal, and is awarded to an individual who has made a
distinguished contribution to neuroscience with an application to neuropsychiatry.
Similarly to the Lishman award, the recipient presents a lecture at the INA Congress
held every 2 years. The inaugural Lishman and Cajal Awards were given at the
Congress held in Buenos Aires, Argentina, in 2002.
Journal
The official journal of the INA, Neuropsychiatric Disease and Treatment, is an

international peer-reviewed journal of clinical therapeutics and pharmacology
focusing on concise rapid reporting of clinical or preclinical studies on a range of
neuropsychiatric and neurological disorders.
This journal is published by Dove Press, and edited by Dr. Roger Pinder and
Dr. David Arciniegas.
Relationships to National Neuropsychiatric Associations
The neuropsychiatric associations in many countries communicate closely with

INA. Actually, almost all the presidents of these associations are the members of
the executive committee of INA.
The British Neuropsychiatry Association, established in 1987, is the oldest one
in the world, and the American Neuropsychiatric Association was established in
1988. There are neuropsychiatric associations in Japan (since 1995) and Argentina
(since 2002). The Argentina Neuropsychiatric Association had held the
Latin-American Congress of Neuropsychiatry every year since 2003.
In 2006, Slovak neuropsychiatrists established their association. The Indian
Neuropsychiatric Group has held the INA Indian Symposium regularly since 2004,
and the Greek Neuropsychiatric Group has hosted the European Congress of
Neuropsychiatry biennially since 2006. The Mexican Neuropsychiatric Association

held the International Congress of Neuropsychiatry in 2008.
The Chinese Neuropsychiatry Summit (CNS) became active in 2008. Beside
these associations, there are many neuropsychiatric groups playing important roles
in the INA.
Future Direction
Cerebral disorders almost always cause psychiatric symptoms. Therefore, integration

of neurology and psychiatry is necessary for clinical procedures to relieve the
distress of patients with brain disorders. In the aged society, the numbers of patients
with neuropsychiatric disorders is increasing. There are no doubt that neuropsychiatry
will be much more important as society continues to age. In the psychiatric field,
neuropsychiatry has been trying to deepen our understanding of psychiatric
disorders from the point of view of neurobiology. As you know, recent investigations
with current neuroscience have been widening the perspective of neuropsychiatry
by revealing the neurobiological bases of so-called functional psychiatric
disorders.
The INA welcomes any individuals who are interested in neuropsychiatry and
any neuropsychiatric groups to join the INA as regular members and/or affiliated
associations.
Core Curriculum in Neuropsychiatry
of the International Neuropsychiatric
Association*
Perminder Sachdev and The Curriculum Committee of the

International Neuropsychiatric Association
Abstract Neuropsychiatry (NP) and behavioral neurology (BN) are rapidly

emerging as superspecializations in the fields of psychiatry and neurology, respec-
tively. The International Neuropsychiatric Association (INA) set up a committee
to develop a curriculum for reference and guidance in the development of training
programs in different countries. The purpose of any training program in NP would
be to produce specialists who are competent in the diagnosis and management of
common neuropsychiatric disorders, who are able to utilize specialized neuropsy-
chiatric investigations in the evaluation of these disorders, who are able to provide
secondary and tertiary level consultations to general physicians, psychiatrists, and
neurologists, and who will be involved in teaching and research in relationship to
these disorders. It is recognized that this curriculum will need to be adapted to the
local needs and available resources in that setting. It is hoped that the curriculum,
through the aegis of the INA, will promote NP internationally and help provide the
best treatment for patients with neuropsychiatric disorders.
Keywords Behavioral฀neurology฀•฀Curriculum฀•฀Neuropsychiatry฀•฀Specialization฀
•฀Training
*฀The฀Curriculum฀Committee฀of฀the฀INA฀was฀composed฀of฀P.฀Sachdev฀(chair),฀M.฀Gaviria,฀
C.฀Soldatos,฀C.฀Shapiro,฀J.฀Trollor,฀and฀E.S.฀Krishnamoorthy.
P. Sachdev (*)
School of Psychiatry, University of New South Wales,
Sydney, NSW 2052, Australia
and
Neuropsychiatric฀Institute,฀Euroa฀Centre,฀Prince฀of฀Wales฀Hospital,
Barker Street, Randwick, NSW 2031, Australia

DOI 10.1007/978-4-431-53871-4_25, © Springer 2010
318 P. Sachdev et al.
Background
Neuropsychiatry (NP) is an old discipline with its origins in the mid-nineteenth

century, or perhaps even earlier to the seventeenth century, much before the birth of
modern psychiatry. For many decades, however, neurology and psychiatry
developed as separate disciplines, leading to a dearth of dialogue between the
disciplines. NP has remerged in the last two decades as a subdiscipline that bridges
the two established disciplines of neurology and psychiatry. In its broader role, NP
applies the principles of neuroscience to the understanding and treatment of
emotional, behavioral, and cognitive disorders. In its narrower and more practical
approach, NP is that branch of psychiatry that is concerned with the diagnosis and
management of the psychiatric and behavioral consequences of demonstrable brain
disturbance. As such, the practice of NP requires skills and knowledge that in part
traverse the traditional psychiatry/neurology boundary.
The discipline of NP must be considered in relation to behavioral neurology
(BN). In many respects, NP and BN are two slightly different approaches to the
same set of disorders and conditions, with the former being biased toward tradi-
tional psychiatry and the latter having its route through neurology. The core com-
petencies are similar, with perhaps differences in vemphasis. As this curriculum is
being developed under the aegis of the International Neuropsychiatric Association
(INA), the term NP is used. An effort is made to identify specific areas that are
particularly important to BN so that the curriculum can be readily adapted to it.
Currently฀there฀are฀few฀training฀programs฀worldwide฀that฀are฀exclusive฀to฀NP฀
and lead to a specific NP specialist accreditation. In most countries, trainees who
gain฀ experience฀ in฀ NP฀ do฀ so฀ within฀ general฀ adult฀ psychiatry,฀ old฀ age฀ psychiatry,฀
child psychiatry, or forensic psychiatry; this is true even for countries in which a
number฀ of฀ NP฀ specialist฀ positions฀ exist.฀ Some฀ countries฀ have฀ a฀ dual฀ training฀ in฀
neurology and psychiatry, with a certification in both disciplines. Although this
approach meets some of the requirements of training in NP, it is the position of the
INA that training in NP specifically, following basic training in psychiatry and
neurology, is necessary to meet the requirements of specialist NP training.
Goals of the Training Program
The purpose of a training program in NP is to produce specialists who will be com-

petent in the diagnosis and management of common neuropsychiatric disorders,
able to utilize specialized neuropsychiatric investigations in the evaluation of these
disorders, able to provide secondary and tertiary level consultations to general
physicians, psychiatrists and neurologists, and be involved in teaching and research
in relationship to these disorders. Although the range of disorders included in NP
is difficult to delineate, an attempt is made in the core competencies section of this
chapter to define this territory, with the acknowledgment that this is an evolving
process depending upon the knowledge base of the day.
Neuropsychiatric฀Core฀Curriculum฀of฀the฀INA 319
The following are the goals of the training program:

1. To develop a sound knowledge base of the neuroscientific principles underlying
neuropsychiatric practice, in relationship to neuroanatomy, neurophysiology,
neurochemistry, and neuropharmacology.
2.฀ To฀gain฀irst-hand฀experience฀of฀common฀neuropsychiatric฀disorders฀and฀become฀
competent in their diagnosis and management.
3.฀ To฀develop฀an฀expertise฀in฀the฀use฀and฀interpretation฀of฀specialized฀neuropsychiatric฀
investigations, in particular, neurophysiology (e.g. electroencephalography),
neuroimaging, and neuropsychology.
4. To be competent in the recognition and management of common psychiatric and
neurological disorders.
5. To develop specialized skills in the physical treatments in NP, but without ignoring
the principles of psychotherapeutic and rehabilitative approaches.
6. To develop skills in the critical evaluation of research evidence in the pathophys-
iology, phenomenology, and treatment of neuropsychiatric disorders.
7. To conduct research to improve the empirical basis of neuropsychiatric knowledge
and practice.
8. To act as advocates for sufferers of neuropsychiatric illnesses, and to contribute
to the development of the profession.
Structure of the NP Training Program
There is no one model that will suit all training programs in NP. An attempt is made
here to outline the basic tenets of such a program.
1. An NP training program shall endeavor to create specialists in NP who function
as secondary and tertiary level specialists. They shall provide consultations to
general psychiatrists, neurologists, and general physicians on a range of neurop-
sychiatric disorders.
2. An NP training program will generally comprise a 2-year fellowship program
that focuses on the core competencies detailed below. In some situations, only a
1-year fellowship in NP may be practicable. Full competency should not be
assumed฀ after฀ 1฀ year฀ of฀ training.฀ However,฀ if฀ the฀ trainee฀ works฀ for฀ a฀ further฀
2฀years฀in฀a฀largely฀or฀exclusively฀neuropsychiatric฀service฀(but฀not฀speciically฀
as a trainee), it would be considered likely that the training requirements would
have been met in this period.
3. The NP Fellow will have previously received training in psychiatry and/or neu-
rology. In general, this would have been a 3-year training program in a center
that฀offers฀training฀in฀both฀specialties.฀It฀is฀expected฀that฀the฀psychiatry฀trainee฀
would have received at least 6 months training in neurology, but the neurology
trainee would have at least 1 year of training in psychiatry. If this is not the case,
the Fellowship period would be used to remedy this with a clinical rotation in the
appropriate discipline.
4. The NP training will be in a neuropsychiatric center with two or more

neuropsychiatrists, one or more clinical neuropsychologists, a neurologist (part-
time or full-time), and a working relationship with psychiatric, clinical neurology,
and neurosurgical services. The center would be part of a general teaching hospital
and have easy access to a neurophysiology service and up-to-date neuroimaging,
which would include structural magnetic resonance imaging (MRI) and functional
imaging. It would also have a research program.
5. The training program will include a research project, which would preferably be
based on empirical research.
6. The training program will have an evaluation component, based on a formal
assessment and/or a series of informal assessments by the supervisors.
7. The program will prepare the trainee for a lifelong period of education and
professional enhancement.
8.฀ The฀program฀will฀instil฀by฀example฀the฀highest฀ethical฀standards฀of฀conduct฀in฀
clinical practice and scholarly work.
Objectives
Attitude Objectives
NP trainees should develop a positive attitude toward neuropsychiatric patients and

their carers. NP trainees will demonstrate this attitude by:
1. Being prepared to advocate for the needs of neuropsychiatric patients and their
carers.
2. Recognizing and dealing constructively with biased attitudes toward sufferers of
neuropsychiatric illness.
3. Developing an awareness of the impact of illness on carers and the wider com-
munity, and striving to balance the needs of neuropsychiatric patients with those
of carers and the wider community.
Knowledge Objectives
By the completion of training, NP trainees should be knowledgeable about the

following:
1. Normal biological, psychological, and social development of the brain and mind:
(a) Brain structure at the macroscopic and microscopic levels, in particular the
knowledge of neuronal networks, the limbic system, the neuroanatomical
substrates฀of฀memory,฀and฀the฀frontal฀executive฀system;
(b)฀ Central฀nervous฀system฀(CNS)฀structure–function฀correlations;
(c) Neurochemistry, especially neurotransmitter and receptor function;
(d)฀ A฀ basic฀ grasp฀ of฀ issues฀ related฀ to฀ the฀ mind–brain฀ debate,฀ the฀ biology฀ of฀
consciousness, and other neurophilosophical issues.
2. Basic neuroscience:
(a) The molecular biology of psychiatric disorders;
(b) The biochemical basis of neuropsychopharmacology;
(c) The basic principles of neurophysiology, and their application to diagnosis
and treatment of neuropsychiatric disorders;
(d)฀ The฀basic฀principles฀of฀genetics฀and฀immunology฀as฀they฀apply฀to฀the฀CNS;
(e) The basic principles of neuroimaging and their application to diagnosis and
assessment of neuropsychiatric disorders.
3. Neuropsychiatric disorders
epidemiology, etiology, psychopathology, clinical features (including complica-
tions), and natural history of neuropsychiatric disorders, including concepts of
impairment, disability, and handicap. A sound knowledge of the assessment and
care฀of฀these฀conditions฀is฀also฀expected.
(a) The incidence and prevalence of neuropsychiatric illnesses in various
populations;
(b) The phenomenology of organic brain syndromes, including nonspecific and
atypical presentations of illness such as “pseudodementia,” “masked”
depression, “conversion” disorders, and behavioral disorders;
(c) The criteria on which neuropsychiatric diagnoses are based, within the
framework of one of the widely accepted classification systems;
฀ (d)฀ Possible฀causative฀or฀exacerbating฀factors฀in฀neuropsychiatric฀disorders;
(e) The natural history of the disease process in neuropsychiatric disorders,
which enables identification of (1) the severity of the disease; (2) the
urgency of the need for treatment; (3) the stage of the illness; and (4)
the prognosis;
(f) The assessment of common neuropsychiatric disorders, including the
following:
฀ (i)฀ Cognitive฀disorders
(ii) Dementias and predementia syndromes
(iii) Nondementing cognitive disorders
(iv) Seizure disorders
(v) Movement disorders
(vi) Traumatic brain injury
(vii) Secondary psychiatric disorders, that is, psychosis, depression, mania,
and฀anxiety฀disorders฀secondary฀to฀“organic”฀brain฀disease
(viii) Substance-induced psychiatric disorders: alcohol, drugs of abuse, etc.
฀ (ix)฀ A฀ ttentional฀ disorders฀ [adult฀ attention฀ deficit฀ hyperactivity฀ disorder฀
(ADHD)฀and฀related฀syndromes]
฀ ฀฀(x)฀ General฀hospital฀liaison฀neuropsychiatry
฀ (xi)฀ Developmental฀disorders
฀฀(xii)฀ Sleep฀disorders
(g) Appropriate management plans for neuropsychiatric disorders including:
(i) Interpretation of medical, psychological, and neurodiagnostic investi-
gations and assessments
฀ ฀฀(ii)฀฀ T
฀ he฀ use฀ of฀ psychopharmacology,฀ electroconvulsive฀ therapy฀ (ECT),฀
and other physical treatments including the frequency and manage-
ment of side effects
(iii) Application of psychotherapies, including supportive, cognitive-behav-
ioral, group, and family therapies
(iv) The use of behavior modification, environmental adaptation, and pre-
ventive measures
(v) Situations in which referral to, or consultation with, colleagues in
psychiatry and other disciplines is appropriate
(vi) Programs involving changes in lifestyle
(vii) Rehabilitation programs
(viii) Management in forensic settings
฀ (ix)฀฀ Strategies฀that฀meet฀the฀needs฀of฀carers฀including฀the฀role฀of฀self-help฀
groups, including Alzheimer’s Association, Tourette Syndrome
Association, etc.
(h) The influence of specific factors on assessment and care of neuropsychiatric
disorders, including:
(i) Age
(ii) Intellectual capacity including intellectual disability
(iii) Medical illness and disability
฀ ฀(iv)฀ Sex
฀ ฀฀฀(v)฀ Culture
(vi) Spiritual beliefs
(vii) Socioeconomic status
(viii) Psychiatric comorbidity
฀ (ix)฀ Polypharmacy
฀฀ ฀฀(x)฀ Support฀factors
(i) The influence of factors that affect treatment outcome including other medi-
cal illnesses;
(j) The principles underlying the choice and integration of interventions
in neuropsychiatry, including the evidence base and relative cost-
effectiveness;
(k) The principles of medicolegal aspects to the practice of NP, with particular
emphasis on mental health and guardianship legislation, including its local
application, testamentary capacity, enduring power of attorney, informed
consent, assessment of older offenders, and fitness to plead;
(l) The community care system including the relevant welfare legislation that
affects the management of people with neuropsychiatric disorders, especially
dementia;
(m) Issues of aging and mental health in older people with intellectual and other
disabilities;
(n) Prevention and health promotion in NP;
(o) Issues specific to mental health promotion in relationship to neuropsychiatry;
(p) Risk factors for neuropsychiatric disorders that become apparent earlier in life.
4. Medicine in relationship to NP
By the completion of training, NP trainees should be knowledgeable about
medical฀ and฀ surgical฀ conditions฀ in฀ general.฀ Higher฀ levels฀ of฀ knowledge฀ are฀
expected฀in฀those฀areas฀of฀medicine฀that฀particularly฀relate฀to฀psychiatric฀prac-
tice, such as neurology, rehabilitation medicine, etc.
5. Research method
principles of scientific method in their practice and the use of this knowledge to
evaluate developments in neuropsychiatric research.
6. Service issues
organization and delivery of mental health care to neuropsychiatric patients,
including the ethical, economic, geographic, and political constraints within
which it operates.
7. Professional responsibility
principles of medical ethics, the development of professional attitudes, and
mechanisms for the development and maintenance of clinical competence,
acknowledging the need for professional and public accountability.
Skills Objectives
1.฀ Health฀promotion
•฀ By the completion of training, the NP trainee should be able to apply specific
knowledge of the principles and processes of health promotion and illness
prevention:
– Recognize and address risk factors for common neuropsychiatric prob-
lems in the community, in hospitals, and in long-term care, such as falls,
confusion, and depression;
– Recognize and address the needs of carers of neuropsychiatric patients.
2. Assessment of neuropsychiatric patients
•฀ By the completion of training, trainees should possess the skills necessary for
performing฀a฀comprehensive฀neuropsychiatric฀examination:
– Demonstrate interviewing skills adapted to the needs of neuropsychiatric

patients;
– With tact and respect, appropriately use and interpret cognitive tests and
document these accurately;
– Appropriately refer people for neuropsychological assessment and
effectively utilize the results;
– Conduct฀ assessments฀ in฀ a฀ range฀ of฀ hospital฀ and฀ community฀ settings,฀
including assessment of the environment;
– Perform a functional assessment including activities of daily living and
apply it to the determination of the most appropriate form of living
arrangements for the individual;
– Recognize฀and฀assess฀relevant฀features฀of฀the฀family฀context฀including฀the฀
family’s role as carers, carer stress, and elder abuse;
– Perform medicolegal assessments with particular emphasis on testamen-
tary capacity, guardianship, enduring power of attorney, competency, and
informed consent.
A Survey of Required Competencies in Neuropsychiatry
The curriculum below identifies some core competencies in the skill base and spe-
cific modules of the specialist knowledge base; these shall be acquired over 2 years.
The competencies are described as modules, but they are not necessarily indepen-
dent of each other. The importance of the core skills module is highlighted. The
aims and objectives of this module will normally be covered within the specific
clinical modules undertaken but should represent an additional and specific focus
of฀study฀within฀the฀individual฀clinical฀modules.฀The฀level฀of฀expertise฀in฀each฀of฀the฀
specific modules will vary, depending upon the facilities available, but a basic level
of฀competence฀in฀each฀module฀is฀expected฀in฀a฀2-year฀training฀program.
1.฀ Core฀skills฀module
1.1. Knowledge base in clinical neuroscience
1.2.฀ Clinical฀skills฀in฀neuropsychiatry
1.2.1.฀ ฀Neuropsychiatric฀diagnosis฀including฀history฀and฀examination,฀neu-
rophysiological investigations, neuroimaging, neuropsychology, and
other investigations;
1.2.2. Treatment, including pharmacology and other physical treatments
[ECT,฀transcranial฀magnetic฀stimulation฀(TMS),฀surgical฀interven-
tions],฀ without฀ neglecting฀ psychotherapeutic฀ and฀ rehabilitative฀
interventions.
1.3.฀ Critical฀thinking฀in฀neuropsychiatry:฀research฀and฀scholarship
2. Specific modules
2.1.฀ Cognitive฀disorders
2.1.1. Dementias and predementia syndromes

2.1.2. Nondementing cognitive disorders
2.2. Seizure disorders
2.3. Movement disorders
2.4. Traumatic brain injury
2.5. Secondary psychiatric disorders, that is, psychosis, depression, mania, and
anxiety฀disorders฀secondary฀to฀“organic”฀brain฀disease
2.6. Substance-induced psychiatric disorders: alcohol, drugs of abuse, etc.
฀ 2.7.฀ Attentional฀disorders฀(adult฀ADHD฀and฀related฀syndromes)
฀ 2.8.฀ General฀hospital฀liaison฀neuropsychiatry
2.9. Developmental neuropsychiatry
2.10. Sleep disorders
2.11. Neuropsychiatric rehabilitation
2.12. Forensic neuropsychiatry
Core Skills Module
Specific Competencies
Knowledge Base in Neuroscience
•฀ Knowledge of brain structure at the macroscopic and microscopic levels, in

particular the knowledge of neuronal networks, the limbic system, the neuroana-
tomical฀substrates฀of฀memory,฀and฀the฀frontal฀executive฀system.
•฀ A฀knowledge฀of฀CNS฀structure–function฀correlations.
•฀ Knowledge of neurochemistry, especially neurotransmitter and receptor function.
•฀ The biochemical basis of neuropsychopharmacology.
•฀ The basic principles of neurophysiology.
•฀ The฀basic฀principles฀of฀genetics฀and฀immunology฀as฀they฀apply฀to฀the฀CNS.
•฀ A฀ basic฀ grasp฀ of฀ issues฀ related฀ to฀ the฀ mind–brain฀ debate,฀ the฀ biology฀ of฀ con-
sciousness, and other neurophilosophical issues.
Clinical฀Skills฀in฀Neuropsychiatry
1. Undertake clinical assessment of patients with apparent or possible neuropsychi-

atric problems.
(a) Take a neuropsychiatric history; this includes all the information routinely
gathered as part of a psychiatric and medical history, but with special
emphasis on gathering information about:
•฀ Possible illnesses or injury to the central nervous system.
•฀ Sudden or gradual changes in intellectual functioning, level of conscious-
ness, personality, and judgment, as well as changes in motor and sensory
functions, which might indicate neurological disease.
(b) Perform a neuropsychiatric assessment; this will again involve and encom-
pass฀all฀the฀routine฀skills฀required฀to฀carry฀out฀a฀psychiatric฀examination,฀but฀
in addition will include:
•฀ Demonstration of the ability to elicit information relevant to possible
neuropsychiatric฀disorders฀and฀neurological฀conditions,฀for฀example,฀the฀
ability to list the history of stepwise cognitive decline or psychomotor
seizure activity.
(c)฀ Perform฀a฀cognitive฀examination฀(simple฀and฀extended):
•฀ A core skill in NP is the ability to carry out simple tests “at the bedside”
to determine a patient’s level of orientation, attention, concentration,
memory,฀etc.,฀and฀to฀do฀so฀in฀the฀context฀of฀a฀psychiatric฀examination.
•฀ A neuropsychiatrist, and in particular one from a neurological back-
ground,฀ would฀ be฀ competent฀ in฀ assessing฀ deficits฀ in฀ language,฀ praxis,฀
gnosis, visuo-spatial function, and other cognitive syndromes.
•฀ This competency would not require the ability to administer formal neu-
ropsychological tests, but may involve carrying out paper-and-pencil
tests and the use of simple materials such as word lists or pictures.
•฀ A neuropsychiatrist should have competency in interpreting results of
such฀an฀examination฀to฀determine฀whether฀the฀patient฀is฀suffering฀from฀a฀
dementing illness, a confusional state, or a specific cognitive deficit as
well as competency in diagnosing the range of adult psychiatric condi-
tions.฀Part฀of฀the฀skill฀would฀involve฀placing฀the฀results฀of฀the฀examina-
tion฀in฀the฀context฀of฀the฀patient’s฀educational฀and฀social฀background฀and฀
premorbid level of functioning.
(d)฀ Perform฀a฀neurological฀examination:
•฀ The trainee should be able to carry out a full and detailed neurological
examination,฀ if฀ necessary,฀ with฀ particular฀ emphasis฀ on฀ the฀ central฀ ner-
vous system and higher cortical functioning.
•฀ The trainee should be able to demonstrate the ability to interpret any
abnormal฀ signs฀ elicited฀ and฀ place฀ them฀ in฀ the฀ context฀ of฀ the฀ patient’s฀
presentation and a differential diagnosis; this may include eliciting signs,
which requires further specialist investigation, either within the realm of
NP or neurology or electrophysiology.
(e)฀ Construct฀a฀neuropsychiatric฀differential฀diagnosis:
•฀ The trainee neuropsychiatrist should be able to demonstrate familiarity
with฀multi-axial฀forms฀of฀classification.
•฀ The trainee should be able to arrange multiple diagnoses into a rational
hierarchy and be able to summarize the key elements of the history and
examination฀which฀support฀that฀differential฀diagnosis.
•฀ The฀ trainee฀ should฀ be฀ able฀ to฀ evaluate฀ the฀ extent฀ to฀ which฀ patterns฀ of฀
psychiatric symptomatology and presentation may be the result of under-
lying organic brain disease.
•฀ The trainee should be familiar with the range of organic disorders that
may account for particular presentations.
•฀ The trainee should be able to communicate this in a clear and concise
way to other health professionals as well as to patients and their carers.
2. Undertake and plan investigation of a patient with apparent or possible neuro-
psychiatric problems:
(a) Trainees should be familiar with the relevant hematological, metabolic,
฀bacteriological,฀virological,฀immunological,฀and฀toxicological฀investigations฀
of relevance to NP. This requirement includes:
•฀ Demonstrating knowledge and judgment that the relevant parameter is of
central importance to the neuropsychiatric presentation.
•฀ Knowing which investigations need to be pursued with further tests and
knowing which may be incidental or within normal limits.
•฀ Interpretation฀of฀examination฀of฀cerebrospinal฀fluid,฀nerve,฀muscle,฀and฀brain฀
biopsy will also be required, although detailed knowledge is not necessary.
(b) In contrast to many other specialities within psychiatry, NP requires familiarity
with฀EEG฀and฀other฀neurophysiological฀investigations฀and฀their฀interpretation:
•฀ The trainee should be able to discuss the advantages and limitations of
the฀routine฀EEG,฀sleep฀EEG,฀and฀longer-term฀EEG฀telemetry฀in฀patients฀
with possible neuropsychiatric problems.
•฀ Although฀ the฀ trainee฀ is฀ not฀ expected฀ to฀ be฀ competent฀ in฀ reading฀ EEGs฀
independently, she or he should have a working knowledge of the profiles
of฀normal฀and฀abnormal฀EEGs.
•฀ In addition, the trainee should understand the use and application of sen-
sory฀ evoked฀ potentials฀ and฀ nerve฀ conduction฀ studies฀ and฀ EMG฀ as฀ they฀
occur in neurological disorders with neuropsychiatric complications, and
also฀as฀a฀tool฀to฀exclude฀neurological฀causes฀of฀abnormal฀function฀that฀
may in fact have a psychological basis.
•฀ The trainee should be familiar with the settings in which these investiga-
tions are carried out, should be able to query the interpretation with a
consultant฀or฀experienced฀technician฀in฀the฀area,฀and฀to฀convey฀this฀infor-
mation to members of the multidiscipline team, carers, and patients alike.
(c) NP requires sound understanding of the indications for, and interpretations
of, the various forms of brain imaging, both structural and functional,
including฀magnetic฀resonance฀imaging฀(MRI),฀computed฀tomography฀(CT),฀
single-photon฀emission฀computed฀tomography฀(SPECT),฀and฀positron฀emis-
sion tomography (PET):
•฀ The trainee should have sufficient familiarity with these techniques to be
able to describe them to a patient and their family/carer and to be able to
interpret the results.
•฀ The trainee should know when such investigations are likely to alter
management or treatment decisions and should have some understanding
of their theoretical importance.
•฀ The฀trainee฀should฀have฀sufficient฀first-hand฀knowledge฀of฀CT฀and฀MRI฀
brain scans to be able to detect salient abnormalities and critically assess
an฀expert฀report.
3. Prescribe and oversee treatment of patients with neuropsychiatric disorders such
as฀those฀with฀psychiatric฀and฀behavioral฀symptoms฀and฀coexisting฀neurological฀
disorder. Be familiar with social, psychological, and biological interventions for
neuropsychiatric disorders:
(a)฀ ฀The฀trainee฀should฀have฀sufficient฀skill฀to฀explain฀the฀mode฀of฀action,฀ben-
efits, and side effects of these treatments to fellow health professionals,
patients, and their families;
•฀ Be familiar with the principles of treatment of major neurological disorders
and be familiar with neuropsychiatric complications of such treatment.
•฀ The neuropsychiatrist should also be aware of the neurological manifes-
tations and complications of psychiatric treatment and advise patients
and professionals on evaluating the importance of these and in minimiz-
ing their occurrence and severity.
(b) Be familiar with potential drug interactions between psychiatric and neuro-
logical medications and other treatments;
•฀ This requirement will include the awareness of the risks associated with
prescribing psychotropic drugs to patients with neurological and neuro-
surgical diseases.
(c) Be familiar with nonpharmacological treatments in neurological and
neuropsychiatric disorders;
•฀ The trainee will have competence in the assessment for and the adminis-
tration฀of฀ECT฀in฀its฀current฀form.
•฀ The trainee should have some understanding of the newer physical
treatments such as transcranial magnetic stimulation (TMS), vagus nerve
stimulation (VNS), deep brain stimulation (DBS), and other physical
treatments.
•฀ The trainee should also acquire knowledge of the principles of neurore-
habilitation and familiarity with the concepts of disability and handicap.
4.฀ To฀diagnose฀and฀treat฀patients฀with฀medically฀unexplained฀symptoms฀that฀present฀
as neurological and neuropsychiatric problems; this includes working with col-
leagues in other disciplines to determine which further tests and investigations
are necessary or not as the case may be;
(a) NP should involve competence in understanding the possible social, cultural,
and฀family฀inluences฀on฀unexplained฀neurological฀symptoms.
(b) The trainee should be able to develop a grasp of the principles behind cogni-
tive-behavioral treatments for such patients and be able to plan and oversee
such treatments carried out by another professional such as a trained nurse
or clinical psychologist.
(c) The trainee should be aware of the relationship between NP and allied psy-
chiatric subspecialties such as old age, child and learning disability psychiatry,
and which service patients might most appropriately be served by.
Critical฀Thinking฀in฀Neuropsychiatry:฀Research฀and฀Scholarship
A specialist training in NP will equip the trainee to think critically in the field. The
trainee should be able to critically assess the empirical evidence in support of any
clinical practice, including the ability to criticize published material. This skill can
be developed by means of journal clubs, attendance at research meetings, research
presentations, short-term courses, etc.
It฀ is฀ expected฀ that฀ in฀ the฀ second฀ year฀ of฀ training,฀ the฀ trainee฀ will฀ undertake฀ a฀
research project. This work should ideally involve all the steps in an empirical
project (background review, design of study, applying for ethics clearance, data
gathering,฀ analysis,฀ and฀ report฀ preparation).฀ However,฀ it฀ may฀ take฀ the฀ form฀ of฀ a฀
critical review of a current topic, or a case series. The trainee will produce a report
of a publishable standard, as judged by the supervisors, and will be encouraged to
publish in a peer-reviewed journal. The research report will be a mandatory com-
ponent of the second year of training.
Specific Modules
Module 2.1: Cognitive Disorders
Specific฀Competencies
I. Dementias and predementia syndromes

Be familiar with the diagnosis and investigation of dementias resulting from:
1. Alzheimer’s disease (AD)
2.฀ Vascular฀cognitive฀impairment฀(VCI)
3. Dementia with Lewy bodies (DLB)
4. Frontotemporal dementia (FTD), including semantic dementia, progressive
aphasia, etc.
5. Dementias related to Parkinsonism + syndromes (progressive supranuclear
palsy, corticobasal degeneration, multiple system atrophy)
6.฀ Prion฀diseases,฀especially฀Creutzfeldt–Jakob฀disease฀and฀variant฀CJD
7.฀ Huntington’s฀disease
8. Dementia resulting from head injury, alcohol use, and medical conditions includ-
ing฀human฀immunodeficiency฀virus฀(HIV),฀brain฀tumors,฀encephalitis,฀etc.
II. Other cognitive disorders
1. Be familiar with the diagnosis and investigation of specific memory disor-
ders (amnesic syndromes), in particular:
•฀ Alcoholic Korsakoff’s syndrome

•฀ Other causes of thiamine deficiency
•฀ Brain infection such as herpes encephalitis or other encephalopathies
•฀ Brain฀dysfunction฀resulting฀from฀cerebral฀hypoxia,฀for฀example,฀carbon฀
monoxide฀poisoning
•฀ Vascular disorders, such as thalamic infarction or subarachnoid hemorrhage
2.฀ Be฀ familiar฀ with฀ the฀ diagnosis฀ and฀ investigation฀ of฀ frontal/executive฀ syn-
dromes of disinhibitory and nonspontaneous types
3. Be familiar with the diagnosis and investigation of other, more “posterior”
cognitive disorders:
•฀ Including language disorders (anomias, and disorders of comprehension
or฀ expression),฀ reading฀ disorders฀ (surface฀ and฀ deep฀ dyslexia),฀ mental฀
฀calculation฀(whether฀or฀not฀part฀of฀Gerstmann’s฀syndrome),฀disorders฀of฀
visuo-spatial awareness, perception, construction, and the agnosias.
III. Be familiar with the diagnosis and investigation of psychologically based
cognitive impairments
•฀ Hysterical฀conditions,฀including฀psychogenic฀amnesias
•฀ Pseudo-dementias, as in depression
•฀ Cognitive฀ impairment฀ as฀ part฀ of฀ somatization,฀ factitious฀ or฀ malingering฀
syndromes
IV. Be familiar with the status and controversies regarding mild cognitive
impairment.
Diagnostic Techniques
1. Understand clinical assessment including neurological and clinical cognitive

examination.
2. Be familiar with the role, importance, and principles of neuropsychological testing.
3. Be familiar with the interpretation of occupational therapy and with speech and
language therapy assessments and reports.
4. Be familiar with the relevant investigations in a clinical blood screen.
5.฀ Be฀aware฀of฀when฀an฀EEG฀can฀be฀helpful฀or฀even฀crucial.
6.฀ Be฀familiar฀with฀the฀purpose฀and฀interpretation฀of฀CT฀and฀MRI฀brain฀scans.
7.฀ Be฀aware฀of฀the฀putative฀role฀of฀other฀forms฀of฀neuroimaging฀including฀SPECT,฀
PET, diffusion tensor imaging (DTI), and functional MRI (fMRI).
Be familiar with the main principles involved in the management and treatment of
cognitive disorders and of dementias
1. The work of a multidisciplinary team (MDT).

2. The contribution of cognitive behavior therapy and psychological counseling in
specific conditions.
3. The use of cognitive-enhancing drugs including cholinesterase inhibitors and

memantine.
4. The use of other medications in NP, including anticonvulsants and antidepressants.
5. The management of behavioral disturbances in dementia.
6. The use of outreach and community support services.
How฀Taught
1. Observation and modeling

2. Working as a team member
3. Supervised clinical practice
4.฀ Review฀of฀suitable฀texts฀and฀papers฀in฀scientiic฀publications,฀including฀review฀
articles
How฀Assessed
1.฀ Clinical฀supervision
2. Direct observation
3.฀ Clinical฀logbook
4.฀ Clinical฀audit
5.฀ Case฀presentations,฀etc.
Module 2.2: Seizure Disorders
1. Undertake a clinical assessment of patients with suspected epilepsy:

(a) Take a seizure history;
(b) Take a neuropsychiatric history focusing on eliciting impact of seizure dis-
order on the patient;
(c) Take a history from an informant;
(d)฀ Perform฀a฀neurological฀examination฀on฀patients฀with฀suspected฀epilepsy;
(e)฀ ฀Construct฀a฀formulation฀with฀differential฀diagnoses฀for฀the฀seizure฀type฀and฀
syndrome, along with discussion of etiology.
2. Assess patients suspected of having nonepileptic seizures (NEAD):
(a) Be familiar with the main features differentiating epilepsy and NEAD;
(b)฀ Be฀familiar฀with฀the฀coexistence฀of฀epilepsy฀and฀NEAD;
(c) Be familiar with the management of NEAD.
3. Undertake investigation of patients with suspected epilepsy:
(a)฀ ฀Be฀familiar฀with฀EEG฀recording฀and฀interpretation฀(including฀the฀limitations)฀
in people with epilepsy;
(b) Be familiar with the indications for and interpretation of structural and func-
tional neuroimaging in people with epilepsy.
4.฀ Prescribe฀treatment฀to฀patients฀with฀coexisting฀neurological฀disorder:
(a) Be familiar with social and psychological interventions for the treatment of
epilepsy฀ including฀ relaxation฀ techniques฀ and฀ other฀ behavioral฀ methods฀ of฀
controlling/inhibiting seizures;
(b) Be familiar with the principles of the medical treatment of the different
seizure and syndrome types;
(c) Be familiar with potential drug interactions between psychiatric medications
and anticonvulsants;
(d) Be aware of the risks associated with prescribing psychotropic agents to
patients with epilepsy;
(e) Be familiar with the surgical treatment of epilepsy including vagal nerve
stimulation.
5. Assess and manage special patient groups with epilepsy:
(a) Be familiar with the difficulties in assessing and managing seizure disor-
ders in children and adolescents with epilepsy, including issues around
puberty;
(b) Be familiar with the difficulties in assessing and managing seizure disor-
ders in women with epilepsy, including catamenial epilepsy, contracep-
tion, pregnancy, teratogenicity, polycystic ovarian syndrome, and
menopause;
(c) Be familiar with the difficulties in assessing and managing seizure disorders
in older age patients, including cognition and issues regarding concomitant
physical illnesses and medication;
(d) Be familiar with the difficulties in assessing and managing seizure disorders
in patients with learning disability including etiology, difficulty eliciting a
history, and cognitive and treatment issues.
6. Assess and manage psychiatric comorbidity in people with epilepsy: pre-ictal,
ctal, post-ictal, inter-ictal, and iatrogenic:
(a) Be familiar with the diagnosis and management of depression in people with
epilepsy, including the risk of suicide;
(b)฀ ฀Be฀familiar฀with฀the฀diagnosis฀and฀management฀of฀anxiety/panic฀attacks฀in฀
people with epilepsy, including the difficulties in differentiating between
panic attacks and ictal panic;
(c) Be familiar with the diagnosis and management of psychosis (post-ictal
psychosis, chronic inter-ictal psychosis, and forced normalization) in people
with epilepsy;
(d) Be familiar with the diagnosis and management of cognitive dysfunction in
people with epilepsy, resulting from seizures and anticonvulsant medication,
including the role of neuropsychological assessments;
(e)฀ ฀Be฀ familiar฀ with฀ the฀ diagnosis฀ and฀ management฀ of฀ sexual฀ dysfunction฀ in฀
people with epilepsy;
(f) Be familiar with the diagnosis and management of disorders of impulse

control (anger/irritability, drug/alcohol problems) in people with epilepsy;
(g) Be familiar with quality of life issues in people with epilepsy, such as
stigma, locus of control, and employment/relationship difficulties.
7. Be aware of the issues involved in the medicolegal aspects of epilepsy:
(a) Be aware of the driving license implications of having epilepsy;
(b) Be familiar with the concept of automatisms when used as a defense in court.
8. Liaison with Epilepsy Surgery Program:
In centers affiliated with Epilepsy Surgery programs, the trainee should become
familiar with the psychiatric issues involved in the assessment of candidates for
epilepsy surgery and be able to provide preoperative consultations and postop-
erative follow-up to such patients.
Module 2.3: Movement Disorders
1.฀ Clinical฀assessment
(a) Take a history of movement disorder
(b) Assess psychiatric history
(c) Assess neurological history
(d)฀ Perform฀psychiatric฀examination
(e)฀ Perform฀neurological฀examination
(f)฀ Construct฀differential฀diagnosis฀of฀movement฀disorder
2. Investigation
(a)฀ Review฀previous฀neurological฀examinations
(b) Review previous neurological treatment
(c) Review previous psychiatric treatment
(d) Order further relevant investigations
3. Treatment
(a) Review previous psychiatric treatment
(b) Review previous neurological treatment
(c) Recommend alterations to current treatment
(d) Prescribe new appropriate treatment
(e) Review effects of treatment
Suggested Learning Methods
1. Attend movement disorders clinic

2. Discuss neurological treatment of movement disorders with neurologist
Suggested฀Assessment฀Method:฀Clinic฀Logbook
1. Parkinson’s disease
2. Tourette’s syndrome: tics
3. Tremor
4. Dystonia
5.฀ Catatonia
6. Neuroleptic-induced movement disorders: tardive dyskinesia, tardive dystonia,
akathisia, NMS, drug-induced parkinsonism, etc.
7.฀ Hysterical฀conversion/somatization฀disorders
Module 2.4: Traumatic Brain Injury
Clinical฀Settings
1. Emergency services, with patient presenting with psychiatric disturbance fol-

lowing head injury
2. Medical or surgical ward, involving patients with neuropsychiatric disturbance
following head injury
3. Outpatient clinics
4. Neurorehabilitation settings
5. Medicolegal settings
1. To take a competent trauma history, including the assessment of posttraumatic

amnesia฀(PTA),฀administration฀of฀Glasgow฀Coma฀Score฀(GCS),฀etc.
2. To assess psychiatric morbidity related to head injury.
3. To assess the relative contributions of brain injury, posttraumatic epilepsy, physi-
cal disability, personality, and psychosocial and medicolegal factors contributing
to neuropsychiatric presentations.
4. To be able to assess cognitive disturbances following head injury, including the
interpretation of neuropsychological assessments.
5. To be able to manage neuropsychiatric disturbances in head-injured patients
using drug treatment, cognitive, and behavioral interventions.
1. Participate in emergency, medical, and surgical consultations with supervisor.

2. Assess patients in outpatient clinics and follow up these patients.
3. Attend rehabilitation rounds and participate in consultations.
Module 2.5: Secondary Psychiatric Syndromes and Delirium
Clinical฀Settings
1. Psychiatric wards
2. Neuropsychiatric outpatient clinics
3. Medical and surgical wards
1. Familiarity with common presentations of delirium and secondary psychiatric

syndromes, including secondary delusional disorder, secondary hallucinosis,
secondary฀ depression฀ or฀ mania,฀ secondary฀ anxiety฀ disorder,฀ secondary฀ obses-
sive-compulsive฀disorder฀(OCD),฀and฀organic฀personality฀disorders.
2. Knowledge of the common causes of these syndromes.
3.฀ Competency฀in฀the฀investigation฀of฀the฀etiology฀of฀secondary฀syndromes,฀and฀the฀
interpretation of the results of the investigations.
4.฀ Experience฀in฀the฀treatment฀of฀such฀syndromes,฀including฀the฀use฀of฀psychotro-
pic and neurotherapeutic drugs.
5. Knowledge of the pathophysiological mechanisms underlying the development
of secondary syndromes.
1. Review of published material

2. Neuropsychiatric clinic attendance
3.฀ Consultations฀on฀psychiatric,฀medical,฀and฀surgical฀wards
4.฀ Case฀discussions
Module 2.6: Substance-Induced Neuropsychiatric Syndromes
Clinical฀Settings
1. Drug dependence clinic

4. Medical and surgical wards
1. Familiarity with common presentations of alcohol- and substance-related neu-

ropsychiatric syndromes.
2.฀ Competency฀in฀the฀investigation฀of฀these฀syndromes,฀including฀biological฀and฀
psychosocial investigations.
pic drugs and psychosocial and rehabilitative interventions.
of these syndromes.

2.฀ Clinic฀attendance
Module 2.7: Attentional and Dysexecutive Syndromes

(Including Adult ADHD)
Clinical฀Settings
1.฀ Specialized฀adult฀ADHD฀clinic
1.฀ Familiarity฀with฀common฀presentations฀of฀ADHD฀in฀adults.
2.฀ Competency฀ in฀ the฀ investigation฀ of฀ attentional฀ and฀ frontal฀ dysexecutive฀ syn-
dromes, including biological and psychosocial investigations.
pic drugs and psychosocial and rehabilitative interventions.
of these syndromes.

2.฀ Clinic฀attendance
Module 2.8: General Hospital Liaison Neuropsychiatry
Key฀Competencies
Undertake฀assessment฀of฀patients฀with฀unexplained฀neurological฀symptoms:
1. Take an appropriate neuropsychiatric history.
2. Interpret previously performed investigations.
3.฀ Perform฀examination฀of฀mental฀and฀physical฀status.
4.฀ Assess฀the฀patients’฀function฀in฀the฀context฀of฀their฀disability.
5. Understand the concepts of conversion, somatization, and dissociation in a neu-
rological฀context.
6. Formulate appropriate management plans.
7.฀ Communicate฀information฀to฀the฀neurological฀team.
Learning and Assessment Methods
1. Take an appropriate neuropsychiatric history

(a) Interpret previously performed investigations
Suggested learning methods Suggested assessment methods
Observation/modeling Validated self-assessment
Supervised clinical practice Clinical฀supervision
Specific teaching from relevant health Case฀presentation
professionals (e.g., radiologist)
Perform฀examination฀of฀physical฀and฀mental฀status฀(see฀other฀sections)
(b)฀ Assess฀patients’฀function฀in฀the฀context฀of฀their฀disability
Specific teaching from relevant health Clinical฀logbook
professionals (e.g., occupational Case฀presentation
therapist)
(c) Understand the concepts of conversion, somatization, and dissociation

Reading฀relevant฀texts Clinical฀logbook
Peer group discussion Case฀presentation
(d) Formulate appropriate management plans (see other sections)

(e)฀ Communicate฀information฀to฀neurology฀team
Obervation/modeling Clinical฀supervision
Supervised clinical practice Direct observation
2. Undertake assessment of patients with delirium

(a) Take a relevant clinical history from patient and informants
(b)฀ Gather฀information฀from฀clinical฀staff
Observation/modeling Clinical฀supervision
Working as a team member
Perform฀examination฀of฀physical฀and฀mental฀status
(c)฀ ฀Construct฀an฀appropriate฀differential฀diagnosis฀(delirium฀vs.฀depression฀vs.฀
dementia)
Appropriate reading Case฀presentation
Clinical฀logbook
Validated self-assessment
(d) Perform investigation to ascertain etiology

Specific teaching from other health Clinical฀logbook
professionals Validated self-assessment
(e) Initiate and monitor treatment where appropriate
Module 2.9: Developmental Neuropsychiatry
Preamble
Developmental NP is that branch of psychiatry concerned with the diagnosis and man-
agement of emotional, behavioral, and learning disorders that are associated with
demonstrable or suspected organic brain dysfunction, and which manifest during
childhood. Because these disorders are primarily disruptive to normal developmental
attainments or adjustment, they are known as neurodevelopmental disorders. The prac-
tice of developmental NP requires skills and knowledge that encompass not only child
psychiatry, in broad terms, but also pediatric neurology and learning disabilities.
Currently,฀there฀is฀no฀formal฀training฀program฀leading฀to฀a฀specific฀accreditation฀
in developmental NP. In this respect, the subspecialty is in the same category as
adult฀ NP.฀ Few฀ child฀ psychiatric฀ training฀ programs฀ explicitly฀ include฀ training฀ in฀
developmental฀ NP.฀ However,฀ it฀ is฀ arguable฀ that฀ within฀ the฀ clinical฀ field฀ of฀ child฀
psychiatry, neurodevelopmental disorders are now the predominant reason for
specialist referral.
The competencies outlined below describe the minimum range of skills in devel-
opmental NP that should be acquired by consultant child psychiatrists in training.
We฀recommend฀that฀all฀trainees฀have฀at฀least฀1฀year฀of฀experience฀in฀this฀specialty,฀
but that those who intend to become specialists in this area may choose to spend
additional time gaining particular skills.
Skills in Developmental Neuropsychiatry
1. Undertake clinical assessment of patients with apparent neurodevelopmental
disorders
(a) Take a developmental neuropsychiatric history
Working as a team member In-training assessment
Focused training courses Direct observation of clinical work
Peer review
Clinical฀logbook
Clinical฀audit
Case฀presentations
Review of case notes and other records
Chart-stimulated฀recall
(b) Perform a neurobehavioral assessment;

฀ (c)฀ Arrange฀for,฀and฀interpret,฀a฀neurocognitive฀examination;
฀ (d)฀ Perform฀a฀neurological฀examination,฀and฀interpret฀signs;
฀ (e)฀ Construct฀a฀neurodevelopmental฀differential฀diagnosis.
2. Undertake investigation of patients with apparent developmental neuropsychiatric

disorders:
(a) Be familiar with relevant hematological and metabolic investigations;
฀ (b)฀ Be฀familiar฀with฀EEG฀recording฀and฀interpretation;
(c) Be familiar with indications for and interpretation of structural neuroimaging.
3. Prescribe treatment to patients on basis of clinical assessment:

(a) Be familiar with the evidence for the effectiveness of specific pharmacologi-
cal treatments of common neurodevelopmental disorders;
(b) Be familiar with the constraints on prescribing psychotropic medications to
children, the indications, “approval status,” and potential side effects;
(c) Be familiar with the need to undertake appropriate investigations before

prescription, and the need for monitoring of treatments prescribed, to min-
imize side effects and complications;
(d) Be familiar with indications for nonmedical treatments including behavioral
management techniques, educational interventions, skills, and training (e.g.,
motor, social, speech and language).
4. Work collaboratively with neuroscience colleagues:

(a) Obtain relevant information about patients’ behavior from neuroscience
staff;
(b) Advise neuroscience ward staff about interpretation and management of
abnormal mental states and behaviors;
(c) Work collaboratively with neuroscience clinicians to establish correct diag-
noses and treatment plans;
(d) Develop academic links within the neuroscience community.
1. Obtain relevant information about patients’ behavior from neuroscience staff

2. Advise staff about the interpretation and management of abnormal mental states
and behaviors
3. Work collaboratively with neuroscience colleagues to establish correct diagnosis

and treatment plans
4. Develop academic links with the neuroscience community

Supervised clinical practice Case฀presentation
5. Assess critically ill patients in a neuroscience setting

(a) Assess the mental states of patients who are in the postoperative period or in
a “neuro-critical care” setting
Working as a team member Direct observation
Supervised clinical practice Clinical฀logbook
Case฀presentation
(b) Produce a differential diagnosis and formulation for patients with mental
disorder in this setting
Clinical฀logbook
(c) Make assessments of capacity in critically ill patients

Observation/modeling Case฀presentation
(d) Advise on the management of disturbed behavior in critically ill patients

Working as a team member
Module 2.10: Sleep Disorders
Core฀competencies฀in฀assessment฀and฀management฀of฀patients฀with฀sleep฀disorders
Have฀knowledge฀of฀etiology,฀prevalence,฀diagnosis,฀categorization,฀and฀treatment฀
of sleep disorders:
1. Primary insomnia
2. Secondary insomnia
3.฀ Hypersomnias
4. Parasomnias
5. Neuropsychiatric consequences of sleep apnoea syndrome
Diagnostic Techniques
1. Take an appropriate history relevant to sleep problems.

2.฀ Perform฀appropriate฀examination฀of฀mental,฀neurological,฀and฀physical฀status.
3. Be able to relate history and clinical findings to relevant medical, neurological,
psychological, and social issues associated with etiology and treatment.
4.฀ Have฀knowledge฀of฀use,฀reliability,฀and฀validity฀of฀generally฀accepted฀techniques฀
and investigations for diagnostic assessment and the interpretation of results.
5.฀ Have฀a฀basic฀understanding฀of฀the฀EEG,฀polysomnogram,฀oximetry,฀and฀actigraphy.
6. Understand the major theories of sleep mechanisms.
7.฀ Have฀competence฀to฀form฀a฀differential฀diagnosis฀and฀to฀diagnose฀medical,฀neu-
rological, and psychiatric sleep disorders and those sleep problems associated
with medical, psychiatric, and neurological conditions.
8. Understand the biological, psychological, social, and economic factors that
influence evaluation and management of sleep disorders.
Management
1. Formulate appropriate management plans.

2.฀ Be฀familiar฀with฀therapies฀used฀[behavior฀therapy,฀psychotherapy,฀drug฀treatment,฀
and฀physical฀treatments฀such฀as฀continuous฀positive฀airway฀pressure฀(CPAP)].
3.฀ Have฀competence฀in฀being฀aware฀of฀when฀refer฀to฀a฀sleep฀disorders฀clinic.
4.฀ Have฀basic฀knowledge฀relating฀to฀ethical฀and฀legal฀aspects฀of฀sleep฀medicine.
1. Observation/modeling
2. Supervised clinical practice
3.฀ Reading฀relevant฀texts
4. Peer group discussion
5. Multidisciplinary case conferences, journal clubs
6.฀ Speciic฀ teaching฀ from฀ relevant฀ health฀ professionals฀ (e.g.,฀ EEG,฀ respiratory,฀
neurology)
7. Primary responsibility for diagnosis and treatment of a reasonable number and
adequate variety of patients with acute and chronic sleep disorders (e.g., at least
five hypersomnia, five parasomnia, ten insomnia, of a range of ages)
8. Attendance at a respiratory sleep disorder clinic for the diagnosis of sleep
apnea
9. Attendance at multidisciplinary national conferences
Suggested Assessment Methods
1. Validated self-assessment
2.฀ Clinical฀supervision฀and฀feedback
3.฀ Case฀presentation
4.฀ Clinical฀logbook
Module 2.11: Rehabilitation Neuropsychiatry
Clinical฀Settings
1. Rehabilitation units providing neurophysical rehabilitation; District and/or

Regional Rehabilitation Units.
2.฀ Neuropsychiatric/Cognitive-Behavioral฀ Rehabilitation฀ Units฀ for฀ people฀ with฀
brain injury.
3.฀ Neuropsychiatry/liaison฀psychiatry฀services฀to฀Clinical฀Neurosciences฀Centres,฀
General฀District฀Hospitals,฀and฀nursing฀homes฀and฀other฀residential฀units.
4. Neuropsychiatry/liaison psychiatry outpatient clinics.
Knowledge
1. Of the pathophysiology of common causes of acquired brain injury.

2.฀ Of฀brain–behavior฀relationships,฀in฀particular,฀following฀acquired฀focal฀lesions฀
to the brain and diffuse brain injury.
3. Of the neuropsychiatric sequelae of acquired brain injury, including etiology and
management of symptoms.
4. Of the principles of cognitive behavior therapy and behavior therapy for behav-
ioral problems and other symptoms following brain injury.
5.฀ Of฀ the฀ ICIDH฀ (International฀ Classiication฀ of฀ Impairments,฀ Disabilities,฀ and฀
Handicaps)฀model฀of฀impairment,฀disability,฀and฀handicap฀(impairment,฀activi-
ties, and participation).
6. Of outcome measures suitable for patients with acquired brain injury.
7. Of rehabilitation service provision, organization, and funding, including volun-
tary sector provision.
Skills
1. To undertake an assessment to understand the role of brain injury in neuropsy-

chiatric symptom formation.
2. To assess the role of psychological processes and mental illness in symptom
formation after acquired brain injury.
3. To use pharmacotherapy to manage neuropsychiatric symptoms after acquired
brain injury.
4. To work with the MDT, including psychologists and other therapists, to produce
an overall treatment strategy for symptoms.
5. To interpret neuropsychometric test results sufficiently to produce a neuropsy-
chiatric formulation.
6. To set up, in collaboration with the MDT, a program of therapy based on goal
planning.
7. To work alongside psychologists, behavioral nurse therapists, and others to
implement cognitive-behavioral treatments and behavioral treatments.
8. To set up effective aftercare following inpatient rehabilitation, based on good
communication across health services, social services, statutory services, and
voluntary sector.
9. To undertake a risk assessment for all commonly occurring risks following
acquired brain injury, and ensure that there are procedures in place to offer a
reasonable risk management strategy.
10. To understand the symptoms and signs of the post-concussion syndrome and pro-
vide advice to patients following a brain injury to minimize the risk of problems on
returning to work, and/or return to living in the community with family and/or carers.
11. To appreciate the psychodynamic processes that follow brain injury and other
forms of disability and provide appropriate psychotherapeutic support.
12. To manage the common sequelae of brain injury, including disturbances of
mood, psychotic disorders, personality change (especially associated with anti-
social behavior), and reduced initiation and motivation.
1. Attending neuropsychiatric clinics, liaison assessments in rehabilitation units,

general hospitals, etc.
2. Attachment to rehabilitation unit attending management rounds/ward rounds.
3. Attending postgraduate teaching programs/conferences on NP/brain injury.
4. Specific attachments to rehabilitation neuropsychologists and therapists.
5. Assessment methods: self-assessment, clinical supervision, and case presenta-
tion and clinical logbook.
Module 2.12: Forensic Neuropsychiatry
Key฀Competencies
1. Knowledge of organic basis of violence and of antisocial and criminal behavior.

2.฀ Competence฀ in฀ the฀ clinical฀ assessment฀ of฀ individuals฀ with฀ violent฀ or฀ criminal฀
behavior, from both biological and psychosocial perspectives.
3. Ability to intervene in the management of such behavior from a neuropsychiatric
perspective, including drug management and psychosocial interventions.
4. Awareness of the ethical and medicolegal aspects of such disorders.

5.฀ Ability฀to฀write฀an฀expert฀report฀for฀the฀court฀or฀other฀forensic฀settings.
1. Attending neuropsychiatric clinics in a forensic setting

2. Assessing patients referred for forensic reports
3. Preparation of reports under supervision
4. Attending court proceedings when medicolegal evidence presented
Acknowledgements We฀are฀grateful฀to฀the฀British฀Neuropsychiatric฀Association฀(H.฀Ring)฀and฀
the American Neuropsychiatric Association (D. Arciniegas) for making their curricula available
for use during the preparation of this document. Members of the Neuropsychiatric Section of the
RANZCP฀made฀useful฀contributions฀(P.฀Hay,฀S.฀Starkstein,฀M.฀Hopwood,฀D.฀Velakoulis).฀Lauren฀
Norton and Angie Russell assisted with manuscript preparation.
Recommended Reading
Neuropsychiatry Textbooks
฀ 1.฀ Yudofsky฀SC,฀Hales฀RE฀(2008)฀Textbook฀of฀neuropsychiatry฀and฀clinical฀neurosciences,฀5th฀
edn. American Psychiatric Publishing, Arlington, VA
2. David A, Fleminger S, Kopelman M, Lovestone S (2009) Lishman’s organic psychiatry: a
textbook฀of฀neuropsychiatry.฀Wiley-Blackwell,฀London
฀ 3.฀ Cummings฀ JL,฀ Mega฀ MS฀ (2003)฀ Neuropsychiatry฀ and฀ behavioral฀ neuroscience.฀ Oxford฀
University Press, New York
฀ 4.฀ Schiffer฀RB,฀Rao฀SM,฀Fogel฀BS฀(2003)฀Neuropsychiatry:฀a฀comprehensive฀textbook,฀2nd฀edn.฀
Lippincott Williams & Wilkins, Baltimore
฀ 5.฀ Coffey฀ CE,฀ Brumback฀ RA฀ (1998)฀ Textbook฀ of฀ pediatric฀ neuropsychiatry.฀ American฀
Psychiatric฀Publishing,฀Washington,฀DC
฀ 6.฀ Coffey฀CE,฀Cummings฀JL฀(2000)฀Textbook฀of฀geriatric฀neuropsychiatry,฀2nd฀edn.฀American฀
Psychiatric฀Publishing,฀Washington,฀DC
฀ 7.฀ Arciniegas฀DB,฀Beresford฀TP฀(2001)฀Neuropsychiatry:฀an฀introductory฀approach.฀Cambridge฀
University฀Press,฀Cambridge
฀ 8.฀ Sachdev฀P฀(with฀Keshavan฀M)฀(2010)฀Secondary฀schizophrenia.฀Cambridge฀University฀Press,฀
Cambridge
Behavioral Neurology
฀ 9.฀ M-Marsel฀ M฀ (2000)฀ Principles฀ of฀ behavioral฀ and฀ cognitive฀ neurology,฀ 2nd฀ edn.฀ Oxford฀
University Press, New York
10.฀ Pincus฀ JH,฀ Tucker฀ GJ฀ (2003)฀ Behavioral฀ neurology,฀ 4th฀ edn.฀ Oxford฀ University฀ Press,฀
New York
11.฀ Feinberg฀ TE,฀ Farah฀ MJ฀ (1997)฀ Behavioral฀ neurology฀ and฀ neuropsychology.฀ McGraw-Hill,฀
New York
12.฀ Kirshner฀ HS฀ (2002)฀ Behavioral฀ neurology:฀ practical฀ science฀ of฀ mind฀ and฀ brain,฀ 2nd฀ edn.฀
Butterworth-Heinemann,฀Boston
13.฀ Leon-Carrion฀J,฀Giannini฀MJ฀(2001)฀Behavioral฀neurology฀in฀the฀elderly.฀CRC,฀Boca฀Raton
14. Strub RL, Black FW (1981) Neurobehavioral disorders: a clinical approach, 2nd edn. Davis,
Philadelphia
15.฀ Cummings฀ JL,฀ Trimble฀ MR฀ (2002)฀ Concise฀ guide฀ to฀ neuropsychiatry฀ and฀ behavioral฀
neurology, 2nd edn. American Psychiatric Publishing, Arlington, VA
16.฀ Trimble฀MR,฀Cummings฀JL฀(1997)฀Contemporary฀behavioral฀neurology฀(blue฀books฀of฀prac-
tical฀neurology),฀vol฀16.฀Butterworth-Heinemann,฀Boston
Neuropsychology
17.฀ Lezak฀ MD,฀ Howieson฀ DB,฀ Loring฀ DW฀ (with฀ Hannay฀ HJ,฀ Fischer฀ JS)฀ (2004)฀ Neuro-
psychological฀assessment,฀4th฀edn.฀Oxford฀University฀Press,฀New฀York
18.฀ Walsh฀K,฀Darby฀D฀(1999)฀Neuropsychology:฀a฀clinical฀approach,฀4th฀edn.฀Churchill฀Living-
stone, Edinburgh
Neuroscience
19.฀ Kandel฀ER,฀Schwartz฀JH,฀Jessell฀TM฀(2000)฀Principles฀of฀neural฀sciences,฀4th฀edn.฀McGraw-
Hill,฀New฀York
20.฀ Squire฀LR,฀Bloom฀FE,฀Spitzer฀NC,฀du฀Lac฀S,฀Ghosh฀A,฀Berg฀D฀(2008)฀Fundamental฀neurosci-
ence, 3rd edn. Academic, Burlington
General Neuropsychiatric Education
21.฀ Sachdev฀P฀(2002)฀Neuropsychiatry:฀a฀discipline฀for฀the฀future.฀J฀Psychosom฀Res฀53:625–627฀
(Editorial)
22.฀ Sachdev฀P฀(2005)฀Whither฀neuropsychiatry?฀J฀Neuropsychiatry฀Clin฀Neurosci฀17:140–144
23.฀ Price฀BH,฀Adams฀RD,฀Coyle฀JT฀(2000)฀Neurology฀and฀psychiatry:฀closing฀the฀great฀divide.฀
Neurology฀54:8–14
24. ANPA Standards for Fellowship Training in Neuropsychiatry (2001) I. Definition of neurop-
sychiatry. http://www.neuropsychiatry.com/ANPA
25.฀ Accreditation฀ Council฀ on฀ Graduate฀ Medical฀ Education฀ (2001)฀ Program฀ requirements฀ for฀
training in psychiatry. http://www.acgme.org/RRC/Psy_Req2.asp
26.฀ Accreditation฀ Council฀ on฀ Graduate฀ Medical฀ Education฀ (2002)฀ Program฀ requirements฀ for฀
training in neurology. http://www.acgme.org/RRC/Psy_Req2.asp
27. American Board of Psychiatry and Neurology, Inc (2003) Information for applicants for
certification in the subspecialties of addiction psychiatry, clinical neurophysiology, forensic
psychiatry, geriatric psychiatry, and neurodevelopmental disabilities. http://www.abpn.com/
Downloads/2003subspec_ifa.pdf
28. Academy of Psychosomatic Medicine (1998) Standards for fellowship training in consulta-
tion-liaison psychiatry. http://www.apm.org/fellow.html
Index
A Body consciousness, 72
Activities of daily living (ADL), 39, 165 Body image, 100
Adoption studies, 289 Body schema, 72
Adult guardianship law, 232 Body-scheme disorders, 95
Age Gene/Environment Susceptibility- BPRS, 43
Reykjavik Study, 170 Brain-derived neurotrophic factor, 174
Alcohol dependence, 288 Brain Impairment Behavior
Allan–Herndon–Dudley syndrome, 24 Bother Scale, 172
Alpha synuclein, 248 Brain Impairment Behavior
Alzheimer’s dementia, 229 Inventory, 172
Alzheimer’s disease, 25, 26, 56, 150, Brain injury, 38
214, 236 Burden, 38
Alzheimer type pathology, 248
Amygdala, 113, 132
Angiotensin-converting enzyme, 293 C
Anosognosia, 34, 72 Capgras syndrome, 70
a1-Antichymotrypsin, 178, 194 Catechol-O-methyltransferase
Antidepressants, 28 (COMT), 291
Antiepileptic drugs, 104, 108, 109 CBT, 37
Anxiety, 10, 25 Cerebral white matter, 132
Apathy, 10, 132, 206 Chalder Fatigue Scale, 169
Apathy Scale, 166 Cingulate cortex, 132
Apolipoprotein E, 237 Cingulated, 36
Asomatognosia, 100 Clinical epileptology, 95
Attention-deficit disorder, 22 Cognitive impairment, 149–157, 170
Autoimmune thyroid disease, 20, 26 Complex partial seizure, 96
Ayahuasca, 281–285 Confabulation, 84
Confusion Assessment Protocol, 135–136
Consciousness, 283–285
B Consultations, 317–319, 333–336
BADS, 40 Contralateral release phenomenon, 165
BDI, 43 Copy number variant, 240
Behavioral and psychological symptoms of Corticobasal degeneration, 13
dementia, 233 C-reactive protein (CRP), 191, 192
Behavioral change, 12 Cretinism, 23
Behavioral dyscontrol, 132 Creutzfeldt-Jakob disease (CJD), 59
Behavioral neurology, 317, 318, 345 CT, 273, 274
Benzodiazepines, 166 Curriculum, 317, 318, 324
Bipolar disorder, 35, 109 Cytokines, 178
347
348 Index
D Frontal lobe, 36
Deiodinase, 20, 25, 26, 28 Frontal lobe syndrome, 173
Delirium, 12, 26 Frontotemporal lobar degeneration (FTLD),
Delirium Rating Scale-Revised-98, 135–136 236, 261
Delusion, 11 Fusiform area, 113
Delusional misidentification syndrome
(DMS), 70
Delusional perception, 66 G
Dementia, 12, 38, 149–157, 203, 235 Galveston Orientation and Amnesia Test
Dementia of the Alzheimer type, 13 (GOAT), 128
Dementias of non-Alzheimer type, 13 General physicians, 317–319
Dementia with Lewy bodies (DLB), 14, 52, Genetic biomarkers, 216
247–251, 256 Glasgow Coma Scale, 128
clinical features, 249–250 G-protein signaling 2 (RGS2), 293
Demyelination, 154 Grey matter, 36
Denial, 34 Guidelines for diagnoses and treatment of
Depression, 25–27, 103–110, 151, 153–154, dementia, 234
156–157, 202, 281, 283, 285, 288
Depressive disorder, 35
DEX, 34 H
Diagnosis, 317–319, 321, 324, 326, 329, 330, Hallucination, 11
332, 333, 338–342 Hashimoto’s encephalopathy, 27
Diffuse Lewy body disease, 256 Herpes encephalitis, 83–84
Diffuse neurofibrillary tangles with calcifica- Hippocampus, 132
tion, 271–277 Human rights, 233
clinical features, 274–275 Huntington’s disease, 58
pathological features, 275–276 Hypertension, 152–155
Dignity, 232 Hyperthyroidism, 21, 25
Discrepancy, 40 Hypothalamic-pituitary-adrenal
Dopamine transporter imaging, 251 (HPA) system, 290
Dorsolateral prefrontal cortex, 37, 132 Hypothyroidism, 21, 25
Dyssomnia, 167
I
E Ictal autoscopy hallucination, 99
Early detection, 228, 230 Ictal visual spatial distortions, 98
Early diagnosis, 215 Idiosyncratic auras, 97
Edelman’s Model, 73 Inferior (inferolatera) prefrontal cortex, 132
Emotional disinhibition syndrome, 171 Inflammation, 178, 179
Emotional Intensity Scale (EIS), 67 Informant, 40
Entorhinal-hippocampal complex, 132 Interictal dysphoric disorder, 103–110
Epilepsy, 96, 113 Interleukins, 178, 191–193
Epilepsy addendum for psychiatric International Index of Erectile Function, 169
assessment, 108 International Neuropsychiatric Association
Evaluation, 317–320, 342 (INA), 301–315, 317, 318
Executive function impairments, 132, 134 Advisory Council, 312
Alwyn Lishman Award, 314
executive committee, 313
F history, 301–312
Fahr-type calcification, 271, 273, 274, 277 INA Office, 312
Fluctuation, 249, 250 International Committee, 313
Forgetfulness, 229 Ramon Y. Cajal Award, 314
Frontal assessment battery, 136–137 The Fifth Congress, 308
Index 349
The First Congress, 302 Modules, 324, 329

The Fourth Congress, 307 Mood disorder, 10
The Mission Statement, 305 Mood stabilizer, 290
The Second Congress, 304 Motor neuron, 267
The Seventh Congress, 311 MRI, 36, 250
The Sixth Congress, 310 Multiple neuropsychiatric symptoms, 6
The Third Congress, 306 Multiple system atrophy, 56
International Organization of Neuropsychiatry
(ION), 301
Investigations N
cerebrospinal fluid markers, 250 National Neuropsychiatric Associations, 314
electrophysiological fluid markers, 250 Neuroimaging, 36
genotypic fluid markers, 250 Neuroleptic sensivity, 247, 251
neuroimaging, 250 Neurological disorders depression inventory
IQ, 36 for epilepsy, 109
IS, 34 Neurologists, 317–319
ITAQ, 34 Neuropsychiatric disorders, 4, 5, 317–319,
321–323, 326, 328, 329
Neuropsychiatric investigations, 317–319
J Neuropsychiatric symptoms, 4, 5
Japanese Psychogeriatric Society, 233 Neuropsychiatry, 317, 318, 321–325, 329,
337–339, 343–345
Neuropsychological profile, 251
K Neurotic complaint, 10
The Korsakoff syndrome, 81–83 NFTs, 273–275
NM scale, 229
Noradrenergic system, 287
L
Lead toxicity, 271, 276
Lewy body, 247, 248 O
Lewy body disease, 257 Odds ratio (OR), 291
Lewy body pathology, 277 OPRM, 291
Lewy neurite, 248 Orbitofrontal cortex, 132
Local needs, 317 Organic delusional syndrome, 65
Long-term care insurance, 228, 232 Organic mental disorders, 3, 4
Loss of consciousness, 132 Organic psychosis, 3
Low triiodothyronine syndrome, 26 Orientation Log (O-Log), 128, 136
Oxfordshire Community Stroke Project, 164
Oxidative stress, 179
M
a2-Macroglobulin, 178
Management, 317–319, 322, 327, 330–333, P
337, 338, 340–344 Parkinsonism, 250, 251
Mania, 25 Parkinson’s disease (PD), 54, 247–249, 251,
Medial prefrontal (cingulate) cortex, 132 256
Medial temporal areas, 132 Parkinson’s disease dementia (PDD), 248, 251
Medical Center for Dementia Disorders, 230, Parkinson’s disease with dementia, 256
231 Paroxysmal heautoscopy, 97
Memory deficits, 39 Paroxysmal visuo-spatial disorder, 96
Mild neuropsychiatric symptoms, 7 Pathological affect, 171
Mini-mental state examination, 136 Pathological Laughter and Crying Scale, 172
Mixed dementia, 150, 152 Patients, 317, 320, 323–325, 327–329,
Modularity, 39 331–334, 337–344
350 Index
PCRS, 34 R
Peri-ictal symptoms, 106 Rancho Los Amigo Scale (RLAS), 135–136
Persistent cognitive impairment, 12 Rankin Scale, 168
Persistent neurological memory disorders, REM sleep, 167
81–84 REM sleep behaviour disorder, 250, 251
Persistent psychogenic amnesia, 87–88 3-Repeat tau protein, 276
Personality change, 12 4-Repeat tau protein, 276
Perth Community Stroke Project, 164 Research, 317–320, 323, 324, 329
Pick bodies, 264 Restless leg syndrome, 168
Polymorphism, 290 Reticulocortical system, 132
Possible neuropsychiatric symptoms, 7 Reticulothalamic system, 132
Poststroke Risk factors of suicide, 289
agitation, 173
anxiety, 165
apathy, 166 S
cognitive performance, 170 SAI-E, 34
depression, 173 Schizophrenia, 26, 27, 34, 288
disturbance of the sleep-wake cycle, 167 Serotonergic system, 287
fatigue, 168 Serum amyloid A, 193
involuntary emotional expression disorder, Silent infarcts, 154
171 Single nucleotide polymorphism (SNP), 291
irritability, 172 Single-photon emission computed tomography
mania, 164 (SPECT), 165
psychosis, 172 Situation-specific amnesia, 86–87
sexual dysfunction, 169 Skin conductance responses (SCRs), 70
Posttraumatic amnesia (PTA) Somatoparaphrenia, 72
aggression, 132 Specialization, 317
definition, 132 Stroke, 152–154
Galveston Orientation and Amnesia Test Subcortical dementia, 13
(GOAT), 128, 136 Subtle neurological signs, 136
Orientation Log (O-Log), 128, 136 Suicide, 287
outcome prediction using PTA, 129 SUMD, 34
Posttraumatic coma, 132, 133 Symptomatic epilepsy, 96
Posttraumatic dysexecutive syndrome,
132–134
Posttraumatic encephalopathy, 132–134 T
Posttraumatic seizures, 139 TDP-43, 239, 266
Presenilin, 237 Teaching, 317, 318, 320, 337, 338, 342, 344
Prevalence, 248 Temporal cortices, anterior, 132
Primary care physicians, 229–231 Temporal lobe, 36
Probable neuropsychiatric symptoms, 6 Temporal lobe epilepsy, 96, 105
Programs, 317–319, 322, 333, 339, 344 Thyroid and brain development, 23, 28
Progranulin, 239 Thyroid and mood disorders, 27
Progressive supranuclear palsy, 13, 57 Thyroid and schizophrenia, 27
Prosopagnosia, 70 Thyroid hormones, 20, 28
Prostaglandin E receptor, 293 receptors, 21
Psychiatrists, 317–319, 339 transporters, 21, 25, 29
Psychiatry, 113 Thyrotropin-releasing hormone (TRH), 26, 28
Psychogenic fugue, 85–86 Training, 317–321, 323, 324, 329, 338–340
Psychotic disorders following traumatic brain Transcranial magnetic stimulation, 175
injury (PDFTBI), 66 Transient epileptic amnesia, 80
Psychotic symptoms, 151 Transient global amnesia, 79–80
Psychotropic, 282 Transient ischemic attack (TIA), 168
Index 351
Transient neurological amnesias, 79–80 posttraumatic amnesia (PTA), 128,

Transient psychogenic amnesia, 85–87 132–134
Traumatic brain injury posttraumatic coma, 132, 133
anticholinergic agents and, 140 posttraumatic delirium, 132
anticonvulsants and, 139–140 posttraumatic dysexecutive syndrome,
antidopaminergic agents and, 140 132–134
antihypertensive agents and, 140 posttraumatic encephalopathy, 132–134
benzodiazepines and, 140 posttraumatic seizures, 139
biomechanical injury, 130 secondary neurological and systemic
contact injury, 130 problems, 131
intertial injury, 130 seizure prophylaxis, 139
brain areas vulnerable to injury, 140 severity classification, 128
brain-behavior relationships, 131–132 American Congress of Rehabilitation
cholinergic disturbances, 131, 132 Medicine, 128
computed tomographic imaging, role of, Glasgow Coma Scale, 128
129, 138 mild
cytotoxic injury, 130 complicated, 129
definition, 127 uncomplicated, 129
diffuse axonal injury, 130 moderate, 128, 129
electroencephalography (EEG), 138 severe, 128, 129
epidemiology, 126 subtle neurological signs in, 136
excitatory amino acid disturbances, Treatment, 217
130–131 Tumour necrosis factor, 178
frontal assessment battery in, 136–137 Twin studies, 289
hospitalization rate, 126
laboratory assessment, 138–139
loss of consciousness, 132 V
magnetic resonance imaging, role of, 129 Vascular cognitive impairment, 14
medications and, 139 Vascular dementia, 152, 229
mini-mental state examination in, 136–137 VBM, 37
monoaminergic disturbances, 131 Ventral forebrain, 132
neurobehavioral assessment, 137 Ventral prefrontal cortex, 132
neuroendocrine disturbances, 139 Ventricular enlargement, 36
neuropsychiatric evaluation of, 135–140 Visual hallucinations, 249–251
neuropsychological assessment, 137–138
neurotransmitter disturbances, 130–131
opiates and, 140 W
outcome, 129 WCST, 36
penetrating vs. non-penetrating, 130 White matter lesions, 152, 154–156

Neuropsychiatric Disorders - Miyoshi, Koho (2010)

Uploaded by

Copyright:

Available Formats

Neuropsychiatric Disorders - Miyoshi, Koho (2010)

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Neuropsychiatric Disorders - Miyoshi, Koho (2010)

Uploaded by

Copyright:

Available Formats

Koho Miyoshi Yasushi Morimura

Kiyoshi Maeda, M.D., Ph.D.

ISBN 978-4-431-53870-7 e-ISBN 978-4-431-53871-4

Library of Congress Control Number: 2010924621

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Neuropsychiatry is an integrating neuroscience of neurology and psychiatry that

which originally appeared on the website of the International Neuropsychiatric

Clinical Manifestations of Neuropsychiatric Disorders .............................. 3

Part II Neuropsychiatric Syndromes

Thyroid–Brain Interactions in Neuropsychiatric Disorders ....................... 19

Lack of Insight and Awareness in Schizophrenia

Visual Hallucinations in Neurodegenerative Disorders............................... 51

Organic Delusional Syndrome: Tentative Neuropsychological

Neurological and Psychological Forms of Amnesia ..................................... 77

Part III Seizure Disorders

The Neuropsychological Aspect of Epilepsy ................................................. 95

The Interictal Dysphoric Disorder of Epilepsy ............................................ 103

Neuropsychiatric Symptoms of Seizure Disorders

Part IV Traumatic Brain Injury

Neuropsychiatric Assessment of Traumatic Brain Injury

Part V Vascular and Inflammatory Disorders

Neuropsychiatric Aspects of Vascular Cognitive Impairment.................... 149

Neuropsychiatric Complications of Cerebrovascular Disease .................... 163

Systemic Inflammation and Cognition in the Elderly ................................. 177

Part VI Neurodegenerative Disorders

Diagnosis and Clinical Relevance of Depression and Apathy

Cognitive Decline and Treatment of Alzheimer’s Disease ........................... 213

Alzheimer’s Disease in Japan: Current Situation

AD-FTLD Spectrum: New Understanding

Dementia with Lewy Bodies ........................................................................... 247

Dementia with Lewy Bodies and Parkinson Disease

Clinicopathological Characterization of Frontotemporal

Diffuse Neurofibrillary Tangles with Calcification ...................................... 271

Part VII Topics of Neuropsychiatric Disorders

Ayahuasca: Current Interest in an Ancient Ritual ...................................... 281

The Molecular Genetics of Suicide ................................................................ 287

Part VIII International Neuropsychiatric Association

Brief History and Current Status of the International

Core Curriculum in Neuropsychiatry of the International

Index ................................................................................................................. 347

Koho Miyoshi and Yasushi Morimura

Abstract Cerebral disorders commonly cause psychiatric symptoms. It is

Keywords Cognitive impairment • Dementia • Neuropsychiatric disorders

K. Miyoshi (*) and Y. Morimura

K. Miyoshi et al. (eds.), Neuropsychiatric Disorders, 3

endogenous psychiatric disorders, have been revealed by recent investigations, it

Neuropsychiatric Symptoms and Neuropsychiatric Disorders

Neuropsychiatric symptoms could be defined as psychiatric manifestations of

(dementias), movement disorders, stroke, epilepsy, multiple sclerosis, traumatic

Characteristics of Clinical Manifestations of Neuropsychiatric

Multiple Neuropsychiatric Symptoms Occur Simultaneously

Brain diseases commonly cause neurological, neuropsychological, and psychiatric

Neuropsychological Neurological Symptoms

Fig. 1 Structures of the clinical manifestations of cerebral disorders

Fig. 2 Structures of the neuropsychiatric symptoms of cerebral disorders

Probable and Possible Symptoms of Neuropsychiatric Disorders

Cognitive impairment is a core symptom of neuropsychiatric disorders. Almost

Probable and Possible Neuropsychiatric Symptoms