Neurodegenerative Diseases

Dementias

Motor Neuron Diseases

Extrapyramidal Diseases

Cerebellar and Spinocerebellar Degenerations

Multiple System Atrophy

The progressive deterioration and ultimate death of the neurons within selective anatomic regions characterize the neurodegenerative diseases. Notably, the group encompasses common and less common but important dementing diseases and movement disorders. Some diseases present only with dementia, some only with motor disorder, and some with both.

Neurodegenerative diseases affect all ages from infancy on, but they occur chiefly during midlife or later. The clinical symptoms and signs indicate the anatomic regions involved in the disease process. The course is slowly progressive over several years, leading inevitably to severe mental and neurologic disabilities and, among long-time survivors, to a terminal vegetative state. As yet, no therapy is curative.

The etiology of neurodegenerative diseases remains elusive. Some diseases are sporadic, some inherited, and some both. A vast amount of information has accumulated on the genetic basis of several diseases. In an increasing number, the gene or its chromosomal locus has been identified. It is noteworthy that the genetic mechanism, in one group of inherited diseases, differs from that of classical Mendelian genetics. These diseases result from the expansion of trinucleotide repeats encoding for polyglutamine tracts and are referred to as polyglutamine diseases. Genetic testing is gaining wide use to confirm the diagnosis in symptomatic patients suspected of suffering from an inheritable neurode-generative disease.

The degeneration of the neurons is confined to definite anatomic regions: in dementias, to the cerebral cortex; in movement disorders, to anatomically and functionally related structures within the motor, extrapyramidal, or cerebellar systems (multisystem degenerations).

The presence of inclusion bodies, derived from abnormal aggregations of proteins in the cytoplasms or nuclei of the neurons and glial cells (astrocytes, oligodendrocytes), characterizes the pathology of a number of dementias and movement disorders. Hence the concept that disturbances in protein metabolism play a fundamental role in the pathogenesis of neurodegenerative diseases. The molecular components of these inclusions have been identified using immunohistochem-ical technics. Two kinds of inclusions are those that stain positively for tau protein, a microtubule-associated protein involved in microtubule assembly, and those that stain positively for a-synuclein, a presynaptic protein involved in synaptic function. Diseases that display tau protein or a-synuclein-positive inclusions are classified as tauopathies or synucleinopathies, respectively. Furthermore, cytoplasmic and nuclear inclusions in several diseases display immunoreactivity for ubiquitin, a stress protein involved in protein degradation. An emerging trend is to link certain clinical phenotypes to particular protein abnormalities. Such correlations, based on neu-ropathologic studies, enhance diagnostic accuracy and may suggest therapeutic strategies.

The neurons in degenerative diseases die generally by apoptosis (programmed cell death). A failure of the neurons to cope with oxidative stress likely promotes apoptosis. A slow, chronic form of excitotoxic neurodegeneration is an alternative mechanism. Oxidative stress renders the neurons vulnerable to the slowly evolving effects of excitatory neurotransmitters. Persistent over-excitation of the neurons ultimately leads to their deaths.

For presentation, neurodegenerative diseases are classified into five categories based on their chief clinical features and the anatomic distribution of the lesions:

• Motor neuron diseases

• Extrapyramidal diseases

• Cerebellar and spinocerebellar degenerations

• Multiple system atrophy

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