Neurology: Degenerative Diseases of the Nervous System-Dementing Disorders

DEGENERATIVE DISEASES OF THE NERVOUS SYSTEM: DEMENTING DISORDERSDr. OronceNeurology

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 Begin insidiously, after a long period

of normal nervous system function and pursues a gradually progressive course that may continue for many years

Familial occurrence Ceaselessly progressive course and

with few exceptions are not influenced by any medical or surgical diseases

Bilateral symmetry of the clinical manifestations and lesions

General Pathologic Features 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

ALZHEIMER DISEASE

The most common and important degenerative disease of the brain

Epidemiology:o Majority of patients are in

their 60s or older; small number in their late 50s or younger

o Makes up some 20% of all patients in psychiatric hospitals

o 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

o 3X higher in women Epidemiologic risk factors:

1. Birth order2. Mother’s age at birth3. Family history of Down

syndrome4. Head injury

Familial occurrence (1%) - autosomal dominant inheritance

Increased risk of sporadic Alzheimer disease among first-degree relatives of patients with AD

Clinical Features: Gradual development of

forgetfulness is the major symptomo Small day-to-day happenings

are not rememberedo Appointments are forgotten;

possessions misplacedo Questions are repeated again

and againo Remote memories are

preserved; recent ones are lost (Rivot’s law of memory)

Failures in cerebral function o Speech halts because of

failure to recall the needed word

o Vocabulary becomes restricted; expressive language stereotyped and inflexible

o Patient could not carry out a complicated request

o Finally, a failure to speak in full sentences; little that is

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said or written is fully comprehended

o Echolalia (dramatic repetition of every spoken phrase)

o Skill in arithmetic deteriorates; faults in balancing the checkbook; mistakes in figuring the price of items and in making the correct change

o 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

o As the state worsens, the simplest of geometric forms and patterns cannot be copied

Motor incapacities o Forgets how to use common

objects and tools while retaining the necessary motor power and coordination for these activities

o Only the most habitual and virtually automatic actions are preserved

o Tests of commanded and demonstrated actions cannot be executed or initiated (ideational and ideomotor apraxia)

Changes in behavior o Restlessness and agitation or

inertia and placidityo Dressing, shaving and bathing

are neglectedo Anxieties and phobias of

being left aloneo Disturbance of the normal day

and night sleep patternso A poorly organized paranoid

delusional state (jealousy) sometimes with hallucinations

o Infatuation with a younger person or sexual indiscretions

Movement abnormalities o Difficulty in locomotion with

shortened steps nut with only slight motor weakness and rigidity

o Parkinsonian akinesia and rigidity with fine tremors in patients with advanced motor disability

o Ultimately loses the ability to stand and walk, being forced to lie inert in bed and having to be fed and bathed

o Legs may curl into a fixed posture of paraplegia in flexion

Diagnostic Criteria: Dementia defined by clinical

examination, the Mini-Mental 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

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

• 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

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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

• 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

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

Neurofibrillary Tangles

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

Genetic aspect of Alzheimer Disease

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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 Alzheimer’s 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

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

Differential Diagnosiso Neurosyphiliso Normal pressure hydrocephaluso Chronic subdural hematomao Nutritional deficiencies (Wernicke,

Korsakoff, Vit B12 deficiency)o Frontal and temporal lobe tumorso Cerebral vasculitiso 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

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)

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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)

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

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

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

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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 Disease1. 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

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

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

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Exaggerated jaw jerk; Bulldog reflex: with attempts to open the mouth, jaws snap shut involuntarily

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

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

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

o 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 sclerosiso Mild hemiparesis or

monoparesis difficult to distinguish from early ALS

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Peroneal muscular atrophy (Charcot-Marie-Tooth neuropathy)

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

Myasthenia gravis, polymyositis, muscular dystrophy

o Main consideration in relation to progressive bulbar palsy

Lacunar infarct (pseudobulbar palsy)

o Spastic form of bulbar palsy Chronic motor polyneuropathy

with or without multifocal block

o 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

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

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Neurology: Degenerative Diseases of the Nervous System-Dementing Disorders

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