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Neurodegenerative disorders are characterized by progressive and irreversible loss of neurons from specific regions of the brain. Prototypical neurodegenerative disorders include Parkinson disease (PD) and Huntington's disease (HD), where loss of neurons from structures of the basal ganglia results in abnormalities in the control of movement; Alzheimer's disease (AD), where the loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability; and amyotrophic lateral sclerosis (ALS), where muscular weakness results from the degeneration of spinal, bulbar, and cortical motor neurons.


As a group, these disorders are relatively common and represent a substantial medical and societal problem. They are primarily disorders of later life, developing in individuals who are neurologically normal, although childhood-onset forms of each of the disorders are recognized. PD is observed in more than 1% of individuals over the age of 65 (Tanner, 1992), whereas AD affects as many as 10% of the same population (Evans et al., 1989). HD, which is a genetically determined autosomal dominant disorder, is less frequent in the population as a whole but affects, on average, 50% of each generation in families carrying the gene. ALS also is relatively rare but often leads rapidly to disability and death (Kurtzke, 1982).


Currently available therapies for neurodegenerative disorders alleviate the disease symptoms but do not alter the underlying neurodegenerative process. Symptomatic treatment for PD, where the neurochemical deficit produced by the disease is well defined, is, in general, relatively successful, and a number of effective agents are available. The available symptomatic treatments for AD, HD, and ALS are much more limited in effectiveness. On the horizon are pharmacological treatments aimed at preventing or retarding progression of neurodegeneration. A wide range of such disease-modifying approaches hold the promise to transform the approach to both the diagnosis and the treatment of neurodegenerative disorders.




Selective Vulnerability. A striking feature of neurodegenerative disorders is the exquisite specificity of the disease processes for particular types of neurons. For example, in PD there is extensive destruction of the dopaminergic neurons of the substantia nigra, whereas neurons in the cortex and many other areas of the brain are unaffected. In contrast, neural injury in AD is most severe in the hippocampus and neocortex, and even within the cortex, the loss of neurons is not uniform but varies dramatically in different functional regions (Arnold et al., 1991). Even more striking is the observation that in HD the mutant gene responsible for the disorder is expressed throughout the brain and in many other organs, yet the pathological changes are most prominent in the neostriatum (Landwehrmeyer et al., 1995). In ALS, there is loss of spinal motor neurons and the cortical neurons that provide their descending input (Tandan and Bradley, 1985). The diversity of these patterns of neural degeneration suggests that the process ...

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