NPEL: Degenerative Disorders of the CNS

NEUROPATHOLOGY- DEGENERATIVE DISEASES

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I. DEGENERATIVE DISEASES OF THE CNS
II. MOTOR NEURON DISEASE
III. PARKINSON'S DISEASE
IV. HUNTINGTON'S DISEASE (HD)

VOCABULARY:
Terms you should be familiar with:

Degenerative diseases
Cell sclerosis
Lewy body
Parkinson's disease
Motor neuron disease
Amyotrophic lateral sclerosis
Lou Gehrig disease
Lower motor neuron
Upper motor neuron
Atrophy
Fasciculations
Spasticity
Hyperreflexia
Babinski sign
Progressive muscular atrophy
Primary lateral sclerosis
Progressive bulbar palsy
Substantia nigra
Dopamine
Acetylcholine
Bradykinesia
Extrapyramidal
Pyramidal
Huntington's disease

OBJECTIVES: The objectives of this hour are to understand the meaning of the term degenerative disease, and to become familiar with its three most common forms.

I. DEGENERATIVE DISEASES OF THE CNS

These are a heterogeneous group of disorders that are of unknown etiology and pathogenesis. Frequently, they take the form of a systems degeneration in which a particular subset of neurons with a particular functional significance undergoes atrophy and ultimately is lost. The pathologic process involving these neurons is given the generic term cell sclerosis. This neuronal loss is frequently accompanied by astrocytosis and gliosis so that brain sections obtained at autopsy may show only a gliotic tombstone for what was once a vital neuronal center. Specific neuropathologic markers (e.g., the Lewy body of Parkinson's disease) are found in some of these disorders. Practically speaking, there are only three degenerative diseases with which I would like you to be familiar.

II. MOTOR NEURON DISEASE

This is also known as amyotrophic lateral sclerosis or Lou Gehrig's disease (MND).

As the term implies, this is a disease in which the anterior horn cells (lower motor neuron) of the spinal cord degenerate. In theory, the upper motor neuron contained within the cerebral cortex is involved as well; however, cell loss of cortical motor neurons may be difficult to detect in routine tissue sections.
Clinical variants of MND
- Sporadic
  - Worldwide incidence is 1.6/100,000
  - 4th-6th decades of life
  - Slight male predominance, 3:2
  - Mean survival after diagnosis: 5 years
  - Death usually results from respiratory failure due to involvement of cervical levels 3, 4, and 5.
- Familial: accounts for about 10% of cases of MND. Similar clinically and pathologically to sporadic, but earlier age of onset and more rapidly progressive.
- Guamanian form: high incidence focus in the western Pacific. Epidemiologic evidence suggests environmental or toxic etiology, and a better understanding of this form may provide clues for the etiology of the sporadic form.
- Amyotrophy may be associated with a wide variety of other neurologic conditions.
Signs and Symptoms: the classic form of MND is amyotrophic lateral sclerosis (ALS). Because both the upper and lower motor neurons are involved pathologically, the signs and symptoms are a mixture of upper and lower motor signs and symptoms.
- Lower: progressive weakness beginning distally associated with atrophy and fasciculations.
- Upper: spasticity associated with hyperreflexia and Babinski signs.
- The mixture of upper and lower motor neuron manifestations varies from case to case based on the relative involvement of each level.
- Occasionally, the disease process is limited to either the upper or the lower motor neuron.
  - Lower: called progressive muscular atrophy.
  - Upper: called primary lateral sclerosis.
- Occasionally, the disease process is limited to involvement of the cranial nerve nuclei (lower motor neuron) of the medulla and called progressive bulbar palsy.
Pathology
- Loss of anterior horn cells and/or cells in cranial nerve nuclei of the medulla associated with astrocytosis and gliosis.
- Wallerian degeneration in the lateral corticospinal tract that is a reflection of the loss of the upper motor neuron.
- Muscle biopsy: denervation with reinnervation that is a reflection of loss of anterior horn cells.
With regard to etiology, several genes have been implicated in MND. As noted above in section B2, approximately 10% of cases of adult onset ALS are familial and show autosomal dominant inheritance associated with age dependent penetrance. In > 20 families with early onset familial ALS, there is linkage to markers on chromosome 21. The affected individuals in these families show missense mutations in the superoxide dismutase 1 (SOD1) gene. In concert, the SOD family act as free radical scavengers that catalyze the formation of hydrogen peroxide through the dismutation of superoxide anions. In addition, SOD1 may function as a metal buffering protein, suggesting that mutations may alter this function and, in some way, cause toxic injury to motor neurons.

III. PARKINSON'S DISEASE

This disease (PD) is an expression of cell loss and degeneration involving the substantia nigra. Dopaminergic neurons of this structure project principally to the striatum (caudate and putamen), and their death thus leads to a loss of dopaminergic innervation to the striatum. The resulting imbalance of dopamine and acetylcholine within the extrapyramidal system is the biochemical basis for the signs and symptoms of PD.
Clinical Features: PD is presently the most common neurodegenerative disease affecting the elderly.
- Onset usually after the 6th decade
- Progressive deterioration marked by tremors, bradykinesia, abnormal gait, and loss of postural reflexes. All of these symptoms can be thought of as a manifestation of the extrapyramidal (involuntary) motor system. The pyramidal (voluntary) motor system remains intact.
- Relentlessly progressive, although the pace differs from one patient to another
- Treatment is pharmacologic and directed at dealing with the dopamine/acetylcholine imbalance.
  - Dopaminergic agents to increase CNS dopamine
  - Anticholinergic agents
  - Dopamine receptor agents
Pathology
- Grossly, depigmentation of the substantia nigra may be present.
- Microscopic features include cell loss, depigmentation, astrocytosis and gliosis of the substantia nigra.
- The characteristic microscopic feature is the Lewy body. In cases of PD, this is also found in the nucleus basalis of Meynert, locus ceruleus, and dorsal motor nucleus of the vagus.
Experiments of nature that may provide clues for the etiology of PD.
- Intoxication with MPTP
- Guamanian focus of parkinsonism-dementia

IV. HUNTINGTON'S DISEASE (HD)

This disease is caused by a degeneration of the striatum (caudate and putamen). Loss of neurons is accompanied by astrocytosis and gliosis.
Clinical Features
- Autosomal dominant inheritance. The genetic defect resides on chromosome 4 and is characterized as a "trinucleotide repeat". There is a correlation between the number of repeats and the age of onset of the disease.
- Movement disorder (chorea)
- Personality change characterized as depression followed by dementia
Pathology
- Grossly, atrophy of the caudate may be marked
- Microscopic, as above
Major issue of this disorder is that it is not expressed phenotypically until between the ages of 35 and 55 years, after the child bearing years. However, recently molecular genetic techniques have localized the genetic defect of HD to chromosome 4, and it is now possible for individuals within large pedigrees to be detected as carriers of this dominant genetic defect.
From a neurobiologic perspective, HD can be defined as a genetic disorder characterized by programmed premature death of localized nerve cells.

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