DEGENERATIVE DISEASES OF THE NERVOUS SYSTEM:

DEMENTING DISORDERS

DEFINITION OF TERMS
ATROPHY:
A gradual wasting and a loss of a system of neurons, leaving on their wake, no degradative products and only a sparsely cellular fibrous gliosis

DEGENERATION:
A more rapid process of neuronal, myelin or tissue breakdown; degradative products evoke a more vigorous reaction of phagocytosis and cellular gliosis

APOPTOSIS
The naturally occurring cell death in the CNS during development

General Clinical Characteristics

1. Begin insidiously, after a long period of normal nervous system function and pursues a gradually progressive course that may continue for many years 2. Familial occurrence 3. Ceaselessly progressive course and with few exceptions are not influenced by any medical or surgical diseases 4. Bilateral symmetry of the clinical manifestations and lesions

General Pathologic Features

1. Selective involvement of anatomically and physiologically related systems of neurons (e.g., ALS motor neurons of the cerebral cortex; Progressive ataxia Purkinje cells of the cerebellum) Slow wasting and loss of neurons, not only of the cell bodies but also their dendrites, axons and myelin sheaths The cerebrospinal fluid shows little if any change at most a slight increase in protein count Radiologic examination shows either no change or a volumetric reduction (atrophy) with a corresponding enlargement of the CSF compartments

2.

3. 4.

ALZHEIMER DISEASE
The most common and important degenerative disease of the brain Epidemiology:
Majority of patients are in their 60s or older; small number in their late 50s or younger Makes up some 20% of all patients in psychiatric hospitals Incidence rate is similar throughout the world; 3 new cases per 100,000 persons below 60 and 125 new cases per 100.000 persons over 60 3X higher in women

ALZHEIMER DISEASE
Epidemiologic risk factors:
1. 2. 3. 4. Birth order Mothers age at birth Family history of Down syndrome Head injury
Familial occurrence (1%) - autosomal dominant inheritance Increased risk of sporadic Alzheimer disease among first-degree relatives of patients with AD

ALZHEIMER DISEASE
Clinical Features:
Gradual development of forgetfulness is the major symptom
Small day-to-day happenings are not remembered Appointments are forgotten; possessions misplaced Questions are repeated again and again Remote memories are preserved; recent ones are lost (Rivots law of memory)

ALZHEIMER DISEASE
Clinical Features:
Failures in cerebral function
Speech halts because of failure to recall the needed word Vocabulary becomes restricted; expressive language stereotyped and inflexible Patient could not carry out a complicated request Finally, a failure to speak in full sentences; little that is said or written is fully comprehended Echolalia (dramatic repetition of every spoken phrase)

ALZHEIMER DISEASE
Clinical Features:
Failures in cerebral function
Skill in arithmetic deteriorates; faults in balancing the checkbook; mistakes in figuring the price of items and in making the correct change Defective visuospatial orientation: car cannot be parked; arms do not find the correct sleeves; turns in the wrong direction on the way home or becomes lost; cannot understand given directions As the state worsens, the simplest of geometric forms and patterns cannot be copied

ALZHEIMER DISEASE
Clinical Features:
Motor incapacities
Forgets how to use common objects and tools while retaining the necessary motor power and coordination for these activities Only the most habitual and virtually automatic actions are preserved Tests of commanded and demonstrated actions cannot be executed or initiated (ideational and ideomotor apraxia)

ALZHEIMER DISEASE
Clinical Features:
Changes in behavior
Restlessness and agitation or inertia and placidity Dressing, shaving and bathing are neglected Anxieties and phobias of being left alone Disturbance of the normal day and night sleep patterns A poorly organized paranoid delusional state (jealousy) sometimes with hallucinations Infatuation with a younger person or sexual indiscretions

ALZHEIMER DISEASE
Clinical Features:
Movement abnormalities
Difficulty in locomotion with shortened steps nut with only slight motor weakness and rigidity Parkinsonian akinesia and rigidity with fine tremors in patients with advanced motor disability Ultimately loses the ability to stand and walk, being forced to lie inert in bed and having to be fed and bathed Legs may curl into a fixed posture of paraplegia in flexion

ALZHEIMER DISEASE
Diagnostic Criteria:
Dementia defined by clinical examination , the MiniMental State, the Blessed Dementia Scale, or similar mental status examination Age of patient (over 40 years) Deficits in two or more areas of cognition and progressive worsening of memory and other cognitive functions- language, perception and motor skills (praxis) Absence of disturbed consciousness Exclusion of other brain diseases

AZHEIMER DISEASE
Pathology
Brain in a diffusely atrophied appearance; brain weight reduced by 20% or more Cerebral convolutions narrowed; sulci widened Third and lateral ventricles symmetrically enlarged Atrophic frontal, temporal and parietal lobes Extreme atrophy of the hippocampus on MRI: diagnostic Microscopically, widespread loss of nerve cells in the cerebral cortex, hippocampus, entorhinal cortex, parahippocampal gyri, subiculum, anterior nuclei of the tahalamus, amygdala Residual neurons have lost volume and ribonucleoprotein; dendrites are diminished and crowd upon one another owing to loss of synapses

ALZHEIMER DISEASE
Pathology 3 microscopic changes:
Presence within the nerve cell cytoplasm of thick, fiber-like strands of silver-staining material, in the form of loops, coils or tangled masses (neurofibrillary tangles)
Hyperphosphorylated form of the microtubular protein, tau, appearing as pairs of helical filaments

Spherical deposits of amorphous material throughout the cerebral cortex, the core of the aggregates is the protein amyloid (senile or neuritic plaque) Granulovascular degeneration of neurons in the pyramidal layer of the hippocampus

ALZHEIMER DISEASE
Pathology
The neurofibrillary tangles correlate best with the severity of the dementia It is the hippocampus, particularly the CA1 and CA2 zones and the entorhinal cortex, subiculum and amygdala that are affected most These parts have abundant connections with other parts of the temporal lobe cortex and dentate nucleus of the hippocampus and account for the amnesic component of the dementia

Pathology of Alzheimer Disease

Beta-amyloid AB deposition is specific for AD; neurofibrillary change is also seen in other degenerative diseases AB is a 40-42 amino acid peptide, which is part of a larger protein, the amyloid precursor protein (APP) Accumulation of AB is thought to result from aberrant cleavage of APP AB is toxic to neurons; causes long term potentiation, damages synapses and kills neurons; spares cerebellar neurons Tau deposits interfere with cellular functions by displacing organelles, destabilizing the cytoskeleton; they also impair the axoplasmic flow and affect the nutrition of axon terminals and dendrites

Senile Plaque

Senile Plaque

Neurofibrillary Tangles

Neurofibrillary Tangles

ALZHEIMER DISEASE
Neurotransmitter Abnormalities:
Marked reduction in choline acetyl transferase (ChAT) and acetylcholine in the hippocampus and neocortex Loss of cholinergic capacity is attributed to the loss of cells in the nucleus basalis of Meynert Loss of monoaminergic neurons, diminution of noradrenergic, GABA-ergic and serotoninergic functions in the affected neocortex Reduced concentration of glutamate, substance P, somatostatin and cholecystokinin 30% reduction in cerebral glucose metabolism in the parietal lobes

ALZHEIMER DISEASE
Genetic aspect of Alzheimer Disease
Defective gene localized to a region of chromosome 21, near the B-amyloid gene that codes for an errant amyloid precursor protein Alzheimer changes characterize practically all patients with the trisomy 21 defect (Down syndrome) after their 20th year Familial Alzheimer disease linked to gene mutations of chromosome 14 (50%) and chromosome 1 (remaining) genes and protein products are termed presenilin 1 and presenelin 2, respectively Apolipoproyein E, a precursor of lipid metabolism that has an affinity for the B-amyloid protein in Alzheimers plaques is another genetic marker On of the isioforms of apolipoprotein E, the E4 (and its corresponding alelle E4 on chromosome 19) is associated with a tripling of the risk of developing sporadic Alzheimer disease

ALZHEIMER DISEASE
Diagnostic Studies
CT scan and MRI: enlarged third and lateral ventricles; disproportionate atrophy of the hippocampus with a corresponding enlargement of the temporal horns of the lateral ventricle EEG: diffuse slowing to the delta and theta range in the late course of the illness CSF: normal; occasionally, elevated CSF protein Neuropsychologic tests: deterioration in memory and verbal access skills No available histologic marker of Alzheimer disease

Alzheimer Disease

Alzheimer Disease

ALZHEIMER DISEASE
Differential Diagnosis
Neurosyphilis Normal pressure hydrocephalus Chronic subdural hematoma Nutritional deficiencies (Wernicke, Korsakoff, Vit B12 deficiency) Frontal and temporal lobe tumors Cerebral vasculitis Creutzfeld Jacob disease

Treatment
Cholinergic precursors, agonists and acetylcholinesterase inhibitors: Taurine and Donepezil Trazodone, Haloperidol, Thioridazine to suppress aberrant behavior Benzodiazepines (Lorazepam- Ativan)

LOBAR ATROPHY (PICK DISEASE)

Atrophy is circumscribed (most often in the frontal and/or temporal lobes), with involvement of both gray and white matter Pathologic change is more circumscribed and sometimes asymmetrical; atrophy may extend to the island of Reil and the amygdaloid-hippocampal structures Affected gyri become paper-thin; white matter volume is reduced; corpus callosum and anterior commissure share in the atrophy Disease essentially involves the association areas; thalamus, subthalamic nucleus, substantia nigra and globus pallidus may also be affected

LOBAR ATROPHY (PICK DISEASE)

Salient histologic features: loss of neurons, most marked in the first three cortical layers Surviving neurons are swollen and some contain argentophilic (Pick) bodies within the cytoplasm Pick bodies are straight fibrils (differ from the paired helical filaments in Alzheimer disease) These bodies predominate in the medial parts of the temporal lobes and in the atrophic hippocampus Loss of myelinated fibers in the white matter beneath the atrophic cortex Granulovascular degeneration of neurons in the hippocampus

Pick Disease (Lobar Atrophy)

Pick Disease (Lobar Atrophy)

LOBAR ATROPHY (PICK DISEASE)

Clinical Features:
Gradual onset of mental confusion with respect to place and time; anomia, slowness of comprehension; inability to cope with unaccustomed problems Loss of tact, deterioration of work habits; neglect of personal hygiene and grooming; apathy and alterations of personality and behavior Inability to perform sequences of motor tasks, motor perseveration, abulia, impairment of gait and upward stance; prominent grasp and suck reflexes Focal disturbances (aphasia and apraxia) Early language disorder: speaks less, forgets and misuses words, fails to understand what is heard or read Verbal perseveration and echolalia; bulimia and alterations in sexual behavior

LOBAR ATROPHY (PICK DISEASE)

Talkative, lighthearted, cheerful or anxious, constantly on the move and sensitive to every passing incident Taciturn, inert, emotionally dull and lacking in initiative and impulse Cause of Pick disease is unknown; probably transmitted as a dominant trait with polygenic modification Women seem to be more affected; no chemical, vascular, traumatic as causative factor Course of the illness is usually 2-5 years, occasionally longer Good nursing care

FRONTOTEMPORAL DEMENTIA
Degeneration of the frontal and temporal lobes Identical clinically and in their gross pathology (gyral atrophy) to Alzheimer and Pick types but do not show the characteristic histologic changes Exhibits tau-staining material in neurons of the affected regions One source of an abnormal (i.e., hyperphosphorylation) tau is from a mutation of the tau gene on chromosome 17 Personality and behavioral changes: apathy, perseveration, poor judgement and abstraction, bizarre affect and a general disengagement

FRONTOTEMPORAL DEMENTIA
An initial diagnosis of depression is common; sociopathic and disinhibited behavior with aspects of hyperorality and hyperphagia Alternatively, aphasic or word-finding syndrome (lateral temporal lobe degeneration) Most cases are sporadic (only tau-staining material in neurons) Main distinction from Pick disease is the presence or absence of Pick bodies or tau-staining material in neurons of the affected regions and the greater affection of the white matter in Pick disease

LEWY BODY DISEASE

Cortical neurons contain Lewy bodies; neurofibrillary changes and senile plaques less conspicuous Progressive dementia with late onset of parkinsonian signs (limb and axial rigidity) Orthostatic hypotension due to cell loss and Lewy bodies in the intermediolateral cell column of the spinal cord Most characteristic feature besides the movement disorder: intermittent psychosis and delirious behavior Episodic increases in confusion, hallucinations and paranoid delusions (generally uncharacteristic of Alzheimer and lobar dementias) Deterioration in other mental functions does not differ from Alzheimer

 Diffuse Cerebral Atrophy of Non-Alzheimer Type

Clinical picture indistinguishable from that of Alzheimer disease Has none of the pathologic features of Alzheimer or Pick disease Diffuse neuronal loss, slight glial proliferation, secondary demyelination of the white matter

Thalamic Dementia
Relatively pure degeneration of the thalamic neurons Dementia relatively rapid and associated with choreoathetosis; features may be similar to Creutzfeldt-Jacob disease

MOTOR SYSTEM DISEASE

A progressive degenerative disorder of neurons in the spinal cord, brainstem and motor cortex manifested clinically by muscular weakness, atrophy and corticospinal signs in varying combinations A disease of middle life and progresses to death in a matter of 2-6 years or longer in exceptional cases

Types of Motor System Disease

1. Amyotrophic Lateral Sclerosis (ALS)
The most frequent form in which amyotrophy (denervation atrophy and waekness of muscle) and hyperreflexia are combined More in men; more than 50 years old No sensory manifestations Triad: atrophic weakness of the hands and forearms, slight spasticity of the arms and legs, generalized hyperreflexia Coarse fasciculations Early involvement of the thoracic, abdominal or posterior neck muscles and early diaphragmatic weakness

 Amyotrophic Lateral Sclerosis

Awkwardness in tasks requiring fine finger movements (difficulty with buttons and keys), stiffness of the fingers and slight weakness or wasting of the hand muscles Cramping and fasciculations of the forearm, upper arm and shoulder girdles Abductors, adductors and extensors of fingers and thumb become weak before the flexors; dorsal interosseous spaces become hallowed cadaveric or skeletal hand Atrophic weakness spreads to the neck, tongue, pharyngeal and laryngeal muscles Coarse fasciculations are almost never the sole presenting feature of ALS

Types of Motor System Disease

2. Progressive Muscular Atrophy
Weakness and atrophy alone without corticospinal changes More in men Symmetrical wasting of intrinsic hand muscles up to the more proximal parts of the arms Slower pace and more benign than ALS Patients survive for 15 years or longer

3. Progressive Bulbar Palsy

Weakness of muscles innervated by the motor nuclei of the lower brainstem (muscles of the jaw, face, tongue, pharynx and larynx) Early defect in articulation: difficulty pronouncing lingual (r, n, l), labial (b, m, p, f) and palatal (k, g) consonants Exaggerated jaw jerk; Bulldog reflex: with attempts to open the mouth, jaws snap shut involuntarily

Types of Motor System Disease

3.Progressive Bulbar Palsy
Ocular muscles always escape Inexorably progressive; patient dies of inanition and aspiration pneumonia within 2-3 years of onset The earlier the onset of the bulbar involvement in the course of ALS, the shorter the course of the illness

4. Primary Lateral Sclerosis

Restricted bilateral signs of motor neuron disease Begins with a pure spastic paraparesis; later on, the arms and the oropharyngeal muscles become involved 5th or 6th decade Progression for about 3 years without evidence of lower motor dysfunction

Types of Motor System Disease

4. Primary Lateral Sclerosis
About half the patients have spasticity of the bladder Begins with stiffness of the legs with spasticity predominating over weakness as the years go on Pathology: decreased numbers of Betz cells in the frontal and prefrontal motor cortex, degeneration of the corticospinal tract. Preservation of neurons in the brainstem and spinal cord Attempts to reduce the spasticity with medications as baclofen or tizanidine

Laboratory Features of Motor Neuron Disease

Elctromyography (EMG) displays widespread fibrillations and fasciculations (active denervation and reinnervation) Nerve Conduction Velocity (NCV) studies show evidence of denervation of many somatic segments (at least 3); widespread denervation of paraspinal neurons, ganglionic or facial muscles Normal sensory nerve potential CSF protein normal or slightly elevated; serum creatine kinase slightly or moderately elevated MRI may show slight atrophy of the motor cortices and wallerian degeneration of motor tracts

Pathology of Motor Neuron Disease

Principal finding is a loss of nerve cells in the anterior horns of the spinal cord and motor nuclei of the lower brainstem; lost cells are replaced by fibrous astrocytes Surviving cells are small, shrunken and filled with lipofuscin Anterior horn cells are thin with disproportionate loss of large myelinated fibers in motor neurons Muscle show typical denervation atrophy of different ages Depletion of muscarinic, cholinergic, glycinergic and benzodiazepine receptors in the spinal cord where motor neurons had disappeared

Pathology of Motor Neuron Disease

Loss of Betz cells in the motor cortex (frontal lobe atrophy on the MRI in primary lateral sclerosis but not in most cases of ALS) Other fibers in the ventral and lateral funiculi are depleted (characteristic pallor on myelin stains) Extensive neuronal loss, gliosis and vacuolation involving the premotor area (superior frontal gyri and the anterolateral cortex of the temporal lobes) No histologic changes of Alzheimer or Pick disease but neurofibrillary degeneration has been observed

Diagnosis of Motor Neuron Disease (Differential Diagnosis)

Central spondylotic bar or ruptured cervical disc
Pain in the neck and shoulders, limitation of neck movements and sensory changes; lower motor neuron affection restricted to 1 or 2 spinal segments

Multiple sclerosis
Mild hemiparesis or monoparesis difficult to distinguish from early ALS

Peroneal muscular atrophy (Charcot-Marie-Tooth neuropathy)

May be differentiated from progressive spinal muscular atrophy lack of family history, complete lack of sensory change, and different EMG patterns

Diagnosis of Motor Neuron Disease (Differential Diagnosis)

Myasthenia gravis, polymyositis, muscular dystrophy
Main consideration in relation to progressive bulbar palsy

Lacunar infarct (pseudobulbar palsy)

Spastic form of bulbar palsy

Chronic motor polyneuropathy with or without multifocal block GM2 gangliosidosis (Tay-Sachs Disease)

Pathogenesis of Motor Neuron Disease

Not known Discovery of a mutant gene that codes for the enzyme Cu-Zn superoxide dismutase (SOD) in some familial cases of ALS and of an abnormality of the gene for a subunit of the neurofilament protein in others 20 to 50% reduction in SOD enzyme activity in affected patients leads to speculation that an excess of free radicals attributed to the enzyme deficiency allows a slow destruction of neurons Enhancement of glutaminergic activity due to the SOD defect an alternative explanation No causative relationship between ALS and trauma, paraproteinemia, disordered immune function and intoxication with heavy metals (lead, mercury, aluminum)

Treatment of Motor Neuron Disease

No specific treatment; only supportive measures Give medication of some type to try to slow the progress of the disease, though none is known to be definitely effective Guanidine hydrochloride, gangliosides, interferons, high-dose iv cyclophosphamide. thyrotropin-releasing hormone

Treatment of Motor Neuron Disease

Antiglutamate agent riluzole appears to slow the progression of ALS and improve survival in patients, but add, at best only 3 months to life expectancy Gabapentin, also a glutamate inhibitor, has slight beneficial effects Respiratory support; food and nutrition; treatment of spasticity