CENTRAL NERVOUS SYSTEM :
DEGENERATIVE AND METABOLIC DISEASES
References: Kumar, Cotran & Robbins, 6th edition, pg. 738-742
Rubin & Farber, 2nd edition, pg. 1425-1436
Cotran, Kumar and Collins, 6th Edition, pg.1329-1343;1275-1280
It is estimated that 47% of the population over age 85 is afflicted. This represents a major social and public health concern. Symptoms are those of slowly progressive global mental deterioration.
There is a 2:1 female predominance
Duration is about 5 years, but some patients live 10-20 years. In the terminal phase, there is complete or nearly complete loss of memory, loss of speech, incontinence and cachexia.
The clinical diagnosis is made by excluding treatable causes of dementia. Thyroid deficiency, B12 deficiency, drug reaction, depression, tumor, subdural hematoma, cardivascular disease, and other primary degenerative neurologic diseases such as Parkinson’s disease, Huntington’s disease, Creutzfeldt-Jakob disease and Pick’s disease.
Risk factors are a family history of dementia, head trauma, hematologic malignancies, Down’s syndrome and the apolipoproteinE allele, ApoE4.
There are autosomal dominant forms of early onset disease. In rare families, there is a mutation in the amyloid precursor protein on chromosome 21. The most common familial form is due to a mutation in the presenilin 1 on chromosome 14. A few families have a mutation on chromosome 1, presenilin 2.
Late onset familial and sporadic AD is associated with the apolipoprotein E allele ApoE4 on chromosome 19. This accounts for 45% of cases in all populations.
Gross pathologic features are nonspecific. There is cortical atrophy and ventricular dilatation.
Definitive diagnosis requires histologic examination and demonstration of "senile" or "neuritic" plaques amd neurofibrillary tangles. Also seen, but not required for diagnosis are varying degrees of amyloid angiopathy, granulovacuolar generation, Hirano bodies and spongiform change.
Plaques are formed by abnormal neurites, extracellular amyloid, microglia and astrocytes.
Tangles are intracellular inclusions formed by bundles of twisted filaments. Microtubule-associated proteins (tau, MAP-2), amyloid and some neurofilament-related proteins are contained in tangles.
The role of vascular or b -amyloid in the pathogenesis of Alzheimer’s disease is controversial, but certain facts are known: The gene is on chromosome 21; mutations are rarely associated with early onset familial AD. There are increased vascular amyloid deposits on persons who inherit the ApoE4 gene
In general, Alzheimer’s disease affects principally the large neurons of the neocortex and of the hippocampal formation. Many neurotransmitter systems are affected, especially acetylcholine (from the nucleus basalis of Meynert). The only pharmacological therapies currently available are choloinergic agonits which are effective in a few patients.
There is an increased incidence of Parkinsonism in Alzheimer’s patients, Affecting approximately 20% of AD patients. Diagnostic criteria for this subgroup have recently been established, which is now known as "Dementia with Lewy Bodies". Recent research has shown that this group may be linked to a gene on Chromosome 12.
Autopsy findings in patients with clinical diagnosis of Probable AD:
AD alone 60%
Dementia with Lewy Bodies 20%
AD + Vascular 10%
Vascular alone 5%
Frontotemporal Dementia (Pick’s) 5%
Other including CJD <1%.
Age of onset is usually after 60 years.
Symptoms reflect the involvement of the extrapyramidal motor system: resting tremor, rigidity, akinesia. Disturbances of posture, equilibrium, and autonomic function may occur. Intention tremor is called benign and does not imply PD.
Approximately 20% of patients will develop a dementia which is usually mild but may be severe. This is typically a "subcortical" dementia. It may antedate the motor findings.
Duration is about 5-15 years.
The underlying pathologic defect is damage and death of the dopaminergic pigmented neurons of the substantia nigra, the cells of origin of the nigrostriatal pathway.
Grossly, there is loss of pigmentation in substantia nigra.
Microscopically, the substantia nigra shows neuronal loss and gliosis. In addition, cytoplasmic inclusions are usually present:
Most cases of "idiopathic" Parkinson’s disease have Lewy bodies.
Postencephalitic Parkinson’s disease is characterized by tangles in patients recovering from 1918 flu pandemic.
Other pigmented neurons of the brainstem are also affected.
Rare cases of Parkinson’s disease are due to ingestion of neurotoxins (MPTP in contaminated heroin).
Treatment includes levodopa and anticholinergic drugs.
Experimental transplants of fetal brain tissue or autologous adrenal tissue have been tried in some cases, but overall the results are not promising.
PICK’S DISEASE – FRONTOTEMPORAL DEMENTIA
Clinically frequently indistinguishable from AD, although there is a slightly earlier onset. Signs of frontal or temporal lobe degeneration as well as behavioral abnormalities and extrapyramidal symptoms may be present.
Pathologically characterized by "knife-blade" atrophy of the frontal and temporal lobes.
Very marked neuronal loss and gliosis in areas with ballooned neurons and intracytoplasmic Pick bodies.
Recent research has uncovered mutations in microtubule associated protein (tau) on Chromosome 17 in some families
Age at onset is usually 35-45 years.
Symptoms reflect the involvement of the basal ganglia and the neocortex.
Mild personality changes (irritability, impulsivity, depression) may be the earliest changes. Cognitive changes begin with mild impairments in judgements and usually progress to severe global dementia. Many patients show psychotic behavior.
Chorea occurs in about 90% of patients and usually begins insidiously with jerkiness and clumsiness. Chorea is worsened by emotional stress. Chorea may precede or follow the changes in personality and intellect. Other motor findings are increased tone, dysarthria, gait abnormalities, and problems with eye movements (saccades).
The duration of the disease is about 15 years.
Huntington’s disease is autosomal dominant with virtually 100% penetrance. The "huntington" gene is on the short arm of chromosome 4 associated with variable numbers of CAG trinucleotide repeats.
Grossly, the brain in Huntington’s disease is characterized by atrophy of the caudate nucleus which is visible on CT scans. The normally rounded head of the caudate becomes flattened, then concave.
Microscopically, there is loss of the small and medium-sized neurons of the caudate and putamen with corresponding gliosis. Milder changes occur in the cortex, thalamus, substantia nigram, brainstem and spinal cord.
Some investigators believe that GAPDH, a chemical that occurs naturally in the brain, may be an "excitotoxin" that produces the neuronal degeneration of Huntington’s disease by activating a receptor for the excitatory neurotransmitter glutamic acid. Glutamine is encoded by CAG.
AMYOTROPHIC LATERAL SCLEROSIS (ALS: LOU GEHRIG’S DISEASE)
Age of onset is usually mid to late life.
Males are affected twice as often as females.
Symptoms are related to progressive degeneration of the corticospinal tracts (upper motor neurons) and the alpha motor neurons of the spinal cord and brainstem (lower motor neurons). Gait disorder, limb weakness, dysarthria or dysphagia, and loss of muscle bulk are common initial complaints.
Duration is about 3-5 years, although some patients live 10-20 years. The immediate cause of death is often respiratory failurre.
Early on, the symptoms may mimic those of a treatable spinal cord lesion.
About 5% of cases are familial, some of which are due to superoxide dismutase gene mutation on Chromsome 21. These may have "extra" features such as sensory loss, dementia, or Parkinsonism.
Gross pathologic findings include atrophy of the ventral (motor) roots of the spinal cord and grey discoloration of the lateral cortical spinal tracts due to loss of myelinated axons.
Microscopically, there is axonal loss and loss of myelin staining in the lateral corticospinal tracts, neuronal loss and gliosis in the affected areas of the ventral horn of the spinal cord and the motor nuclei in the brainstem (nucleus ambiguus, hypoglossal nucleus). There may be focal swellings of the axons and dendrites of affected neurons. Bunina bodies in lower motor neurons.
ALS-Parkinsonism-Dementia complex of Guam has been linked to a plant excitant neurotoxin from the cycad plant, but the cause of classic ALS is unknown.
Inherited Metabolic Disorders
Variant A (Derry's disease)
Galactosidase isoenzymes A, B, C
b-Galactosidase isoenzymes B, C
Variant B (type I)
Variant O (type III)
Hexosaminidases A and B
(Austin's disease), variant O
Arylsulfatases A, B, and C
Less polarized lipids
(a -lipoprotein deficiency)
(b -lipoprotein deficiency)
METABOLIC NEURONAL DISEASES
Phenylketonuria due to a deficiency in phenylalanine hydroxylase; mental retardation if not treated with a diet low in phenylalanine.
Cretinism - hypothyroidism in infancy; reversible if treated with thyroxine. Still common in Third World Countries in areas of heavy rainfall.
Wilson Disease - hepatolenticular degeneration due to a defect in copper metabolism. Kayser-Fleischer ring in cornea.
Kernicterus - degeneration of basal ganglia due to hyperbilirubinemia in infancy.
Wernicke Syndrome - altered consciousness with nystagmus and opthalmoplegia progresses rapidly to death if not treated with thiamine. Coma in alcoholics.
Subaute combined degeneration of spinal cord - B12 deficiency due to pernicious anemia, gastric resection.
Atrophy superior cerebellar vermis - ataxia