Clinical and Neuropathological Criteria For Frontotemporal Dementia

41646ournal of Neurology, Neurosurgery, and Psychiatry 1994;57:416-418
CONSENSUS STATEMENT
Clinical and neuropathological criteria for

frontotemporal dementia
The Lund and Manchester Groups
Clinical and neuropathological descriptions of
patients with non-Alzheimer's disease atrophy
of the frontotemporal lobes have emerged
chiefly from Lund, Sweden and Manchester,
UK. The nosology of both the clinical syndrome and the underlying histological change
is in danger of becoming confused in the medical literature and terminological distinctions
between clinical and pathological criteria are
not always strictly kept. Accordingly, the
workers in both centres have shared their clinical and pathological findings and have
decided upon commonly agreed criteria for
neuropsychiatric and pathological diagnosis.
These are based on clinical evaluation of
several hundreds of patients and upon pathological analysis of more than 60 brains.
Together these represent the largest series in
the world and have been the focus of interest in
the two international conferences on Frontotemporal Dementia held in Lund in 1986'
University Hospital,
Lund, Sweden,
Department of
Pathology
A Brun
B Englund
Department of
Psychogeriatrics
L Gustafson
U Passant
Department of
Pathological Sciences,
Division of Molecular
Pathology, University
of Manchester,
Manchester, UK
D M A Mann
Department of
Neurology, The Royal
Infirmary,
Manchester, UK
D Neary
J S Snowden
Correspondence to:
Professor D Neary,
Department of Neurology,
Manchester Royal Infirmary,
Manchester M13 9WL, UK.
Received 29 June 1993
and in revised form
13 September 1993.
Accepted 21 September 1993
and 19922.
Frontotemporal dementia is the prototypical behavioural disorder arising from frontotemporal cerebral atrophy and is associated
in a few cases with the clinical manifestations
of the amyotrophic form of motor neuron disease. Two types of histological change underlie
the atrophy and both share an identical
anatomical distribution in the frontal and
temporal lobes. The commonest pathology is
that of nerve cell loss and spongiform change
(microvacuolation), together with a mild or
moderately severe astrocytic gliosis in the
outer cortical layers, and is designated frontal
lobe degeneration. This is to distinguish it
from the typical Pick-type histology characterised by intense astrocytic gliosis in the presence of intraneuronal inclusion bodies and
inflated neurons in all cortical layers. Cases of
frontotemporal dementia with a similar level
of astrocytosis but without inclusions or
inflated neurons should be best included in
this Pick-type category pending a more definitive histological identification. When spinal
motor neuron degeneration occurs, the cerebral pathology is almost always that of frontal
lobe degeneration.
This formulation distinguishes the clinical
syndrome of frontotemporal dementia from
other disorders that may also affect frontotemporal structures, such as Alzheimer's
disease, Creutzfeldt-Jakob disease, subcortical
vascular disease and Huntington's disease
as well as affective and schizophreniform
psychoses.
The application of descriptive labels to the
three major histological patterns avoids the
imputation of aetiological significance. Future

studies may indicate that there is a spectrum
of non-specific histology involving both, or
alternatively, that each may reflect a distinct
process governed by different genetic or molecular mechanisms. To consider the Pick'stype of change as a histological variant of
frontotemporal atrophy, manifesting clinically
as frontotemporal dementia, avoids the vexed
clinical and pathological arguments as to what
constitutes, so-called "Pick's disease".
Frontotemporal dementia results from
bilateral and more or less symmetrical distribution of pathology in the frontotemporal
lobes.
Asymmetrical degeneration, however, may,
influence the clinical picture. Predominant
involvement of the language dominant frontal
and temporal lobes leads to linguistic rather
than behavioural symptoms.' 4 The clinical
entity of progressive aphasia and the link
between this condition and frontotemporal
dementia is essentially determined anatomically, both forming part of the clinical spectrum of lobar atrophy and sharing the same
spectrum of histology.5 The criteria for, and
the different forms of language breakdown in,
progressive aphasia are not discussed here.
We describe the clinical and pathological criteria for frontotemporal dementia.
Clinical diagnostic features of
frontotemporal dementia6-2
CORE DIAGNOSTIC FEATURES
Behavioural disorder
* Insidious onset and slow progression
* Early loss of personal awareness (neglect of
personal hygiene and grooming)
* Early loss of social awareness (lack of
social tact, misdemeanours such as
shoplifting)
* Early signs of disinhibition (such as
unrestrained sexuality, violent behaviour,
inappropriate jocularity, restless pacing)
* Mental rigidity and inflexibility
* Hyperorality (oral/dietary changes, overeating, food fads, excessive smoking and
alcohol consumption, oral exploration of
objects)
* Stereotyped and perservative behaviour
(wandering, mannerisms such as clapping,
singing, dancing, ritualistic preoccupation
such as hoarding, toileting, and dressing)

* Utilisation behaviour (unrestrained exploration of objects in the environment)
* Distractibility, impulsivity, and impersistence
Clinical and neuropathological criteria for frontotemporal dementia
* Early loss of insight into the fact that the

altered condition is due to a pathological
change of own mental state.
Affective symptoms
* Depression, anxiety, excessive sentimentality, suicidal and fixed ideation, delusion
(early and evanescent)
* Hypochondriasis, bizarre somatic preoccupation (early and evanescent)
* Emotional unconcern (emotional indifference and remoteness, lack of empathy and
sympathy, apathy)
* Amimia (inertia, aspontaneity).
Speech disorder
* Progressive reduction of speech (aspontaneity and economy of utterance)
- Stereotypy of speech (repetition of limited
repertoire of words, pharases, or themes)
* Echolalia and perseveration
* Late mutism.
Spatial orientation and praxis preserved

(intact abilities to negotiate the environment).
Physical signs
* Early primitive reflexes
* Early incontinence
* Late akinesia, rigidity, tremor
* Low and labile blood pressure.
Investigations
* Normal EEG despite clinically evident
dementia
* Brain imaging (structural or functional, or
both): predominant frontal or anterior
temporal abnormality, or both
* Neuropsychology (profound failure on
"frontal lobe" tests in the absence of severe
amnesia, aphasia, or perceptual spatial
disorder).
SUPPORTIVE DIAGNOSTIC FEATURES
* Onset before 65
* Positive family history of similar disorder
in a first degree relative
* Bulbar palsy, muscular weakness and wasting, fasciculations (motor neuron disease).
DIAGNOSTIC EXCLUSION FEATURES
*
*
*
*
*
*
*
*
*
*
*
*
0
Abrupt onset with ictal events

Head trauma related to onset
Early severe amnesia
Early spatial disorientation, lost in surroundings, defective localisation of objects
Early severe apraxia
Logoclonic speech with rapid loss of train
of thought
Myoclonus
Cortical bulbar and spinal deficits
Cerebellar ataxia
Choreo-athetosis
Early, severe, pathological EEG
Brain imaging (predominant post-central
structural or functional deficit. Multifocal
cerebral lesions on CT or MRI)
Laboratory tests indicating brain involvement or inflammatory disorder (such as
multiple sclerosis, syphilis, AIDS and
herpes simplex encephalitis).
417
RELATIVE DIAGNOSTIC EXCLUSION FEATURES
* Typical history of chronic alcoholism

* Sustained hypertension
* History of vascular disease (such as angina,
claudication).
Neuropathological diagnostic features of
fronto-temporal dementia
FRONTAL LOBE DEGENERATION TYPE5 13-17
Gross changes
These include slight symmetrical convolutional atrophy in frontal and anterior temporal
lobes, neither circumscribed nor of a knife
blade type; atrophy can be severe in a few
cases. The ventricular system is widened
frontally. Usually there is no gross atrophy of
the striatum, amygdala or hippocampus
although, in some instances, severe involvement of these regions can occur.
Distribution of microscopic changes

Changes are seen in the frontal convexity cortex, sometimes in the orbitofrontal cortex,
often in the anterior third of the temporal cortex, and the anterior, but rarely the posterior,
cingulate gyrus. The superior temporal gyrus
is conspicuously spared.
The parietal cortex is mildly involved in a
few patients, more so in rare, advanced cases.
In some patients with pronounced stereotypic behaviours, there is less neocortical
involvement, with mostly striatal, amygdala,
and hippocampal changes. These may represent a possible subtype.
Microscopic characteristics, grey matter

Microvacuolation and mild-to-moderate
astrocytic gliosis affecting chiefly laminae I-III
are seen, sometimes one or the other change
prevailing.
There is atrophy/loss of neurons in laminae
II and III, whereas those of lamina V are
mildly affected, being atrophic rather than lost.
Occasionally there are a few dystrophic neurites.
There are no Pick bodies, inflated neurons
or Lewy bodies. Immunohistochemistry for
tau or ubiquitin reveals no distinctive features.
In the substantia nigra of some patients, there
is mild-to-moderate loss of pigmented neurons.
Microscopic characteristics, white matter
White matter astrocytic gliosis, moderate to
mild, is seen in subcortical u-fibres. There is
very mild astrocytic gliosis in deeper white
matter, sometimes with slight attenuation and
loss of myelin. The distribution is related to
grey matter changes. Sometimes there is also
ischaemic white matter attenuation.
PICK-TYPE
Gross changes
These have the same topographic localisation
as frontal lobe degeneration, but generally
more intense and usually more circumscribed.
Asymmetry and striatal atrophy is common.
Distribution of microscopic changes

These are the same as frontal lobe degeneration, in agreement with the gross distribution.
418
The Lund and Manchester Groups
Microscopic characteristics, grey and white matter

The main characteristics are the same as
frontal lobe degeneration, but with intense
involvement of all cortical layers. Inflated
neurons and Pick bodies, which are silver
positive, tau and ubiquitin immunoreactive,
are present. There is more intense white matter
involvement. Patients with intense astrocytosis
but without inflated neurons or inclusions, or
both, may for the present be included.
MOTOR NEURON DISEASE TYPE'8
Gross changes
These are the same as frontal lobe degeneration, although usually less severe.
Distribution of microscopic changes and
microscopic characteristics in grey and white matter
These are the same as for frontal lobe degeneration. There is spinal motor neuron degeneration, affecting cervical and thoracic levels
more than lumbar or sacral. There is greater
cell loss in medial than lateral cell columns.
Motor neurons, layer II neurons in frontal and
temporal cortex, and hippocampal dentate
gyrus neurons show inclusions that are ubiquitin positive but not silver or tau reactive.
Nigral cell loss is severe in many patients.
There is also hypoglossal degeneration in some.
DIAGNOSTIC EXCLUSION FEATURES
There are senile plaques, diffuse amyloid

deposits, and amyloid angiopathy with anti-flprotein antibodies, tangles, and neuropil
threads, with anti-tau and ubiquitin antibodies, more than normal for age. Prion protein
are present with anti-prion antibodies.
1 Frontal lobe degeneration of non-Alzheimer type. Arch

Gerontol Geriatr 1987;6:Special issue:6.
2 The 2nd International Conference of Frontal Lobe
Degeneration of Non-Alzheimer Type. Dementia.
1993;4:4.
3 Snowden JS, Neary D, Mann DMA, et al. Progressive

language disorder due to lobar atrophy. Ann Neurol
1992;31: 174-83.
4 Neary D, Snowden JS, Mann DMA. Familial progressive
aphasia: its relationship to other forms of lobar atrophy.
J Neurol Neurosurg Psychiatry 1993;56: 1122-5.
5 Neary D, Snowden JS, Mann DMA. The clinical pathological correlates of lobar atrophy. A review. Dementia
1993;4: 154-9.
6 Gustafson L. Frontal lobe degeneration of non-Alzheimer
type. II. Clinical picture and differential diagnosis. Arch
Gerontol Geriatr 1987;6:209-23.
7 Risberg J. Frontal lobe degeneration of non-Alzheimer
type. III. Regional cerebral blood flow. Arch Gerontol
Geriatr 1987;6:225-33.
8 Neary D, Snowden JS, Shields RA, et al. Single photon
emission tomography using 99 mTc-HM-PAO in the
investigation of dementia. J Neurol Neurosurg Psychiatry
1987;50:1 101-9.
9 Neary D, Snowden JS, Northen B, Goulding PJ. Dementia
of frontal lobe type. J Neurol Neurosurg Psychiatry 1988;
51:353-61.
10 Gustafson L. Clinical picture of frontal lobe degeneration
of non-Alzheimer type. Dementia 1993;4:143-8.
11 Elfgren C, Passant U, Risberg J. Neuropsychological
findings in frontal lobe dementia. Dementia 1993;4:
214-9.
12 Risberg J, Passant U, Warkentin S, Gustafson L. Regional
cerebral blood flow in frontal lobe dementia of nonAlzheimer type. Dementia 1993;4: 186-7.
13 Brun A. Frontal lobe degeneration of non-Alzheimer
type I. Neuropathology. Arch Gerontol Geniatr 1987;6:
193-208.
14 Englund E, Brun A. Frontal lobe degeneration of nonAlzheimer type. IV. White matter changes. Arch Gerontol
Geriatr 1987;6:235-43.
15 Brun A. Frontal lobe degeneration of non-Alzheimer type.
Revisited. Dementia 1993;4:126-31.
16 Mann DMA, South PW, Snowden J, Neary D. Dementia of
frontal lobe type; neuropathology and immunohistochemistry. J Neurol Neurosurg Psychiatry 1993;56:
605-614.
17 Mann DMA, South PW. The topographic distribution of
brain atrophy in frontal lobe dementia. Acta Neuropathol
1993;85:334-40.
18 Neary D, Snowden JS, Mann DMA, et al. Frontal lobe

dementia and motor neuron disease. 7 Neurol Neurosurg
Psychiatry 1990;53:23-32.

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41646ournal of Neurology, Neurosurgery, and Psychiatry 1994;57:416-418

Clinical and neuropathological criteria for

imputation of aetiological significance. Future

singing, dancing, ritualistic preoccupation

such as hoarding, toileting, and dressing)

Clinical and neuropathological criteria for frontotemporal dementia

* Early loss of insight into the fact that the

Spatial orientation and praxis preserved

Abrupt onset with ictal events

* Typical history of chronic alcoholism

Neuropathological diagnostic features of

Distribution of microscopic changes

Microscopic characteristics, grey matter

Distribution of microscopic changes

The Lund and Manchester Groups

Microscopic characteristics, grey and white matter

There are senile plaques, diffuse amyloid

1 Frontal lobe degeneration of non-Alzheimer type. Arch

3 Snowden JS, Neary D, Mann DMA, et al. Progressive

18 Neary D, Snowden JS, Mann DMA, et al. Frontal lobe

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