We propose the extension of existing knowledge on the functional and biochemical characterization of neurologic disease through the use of new radiotracer techniques involving positron emission tomography. We will continue the development of new radiotracer techniques for the study of important biochemical hypotheses of the pathophysiologic mechanisms underlying degenerative brain diseases. Our focus in this area is on the introduction of noninvasive methods for assessment of mitochondrial oxidative capacity, permitting the future testing of hypotheses on the role of oxidative toxicity in the progression of neuronal loss in disorders such as Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. Clinical aspects of the program will focus on the neuropharmacologic characterization of neurodegenerative movement disorders, including olivopontocerebellar atrophy, multiple system atrophy, Alzheimer's disease with extrapyramidal symptoms, Parkinson's disease, essential tremor, Huntington's disease, Tourette's syndrome, and dystonia. The proposed studies will elucidate features of these disorders which will advance understanding of the neuronal elements affected in symptomatic patients, as well as characterization of the relationships between the stage and progression of disease and the severity and distribution of altered neurochemical markers. We will focus attention on new methods for quantitative evaluation of synaptic binding sites for acetylcholine, dopamine and benzodiazepines, and on the novel determination of presynaptic monoaminergic and cholinergic vesicles as an indicator of presynaptic integrity. Results of the proposed studies will not only permit better taxonomic distinctions among the extrapyramidal movement disorders, but may yield important information for the introduction of new therapeutic strategies on the basis of rational pharmacologic design. These neurochemical data will permit development of better symptomatic therapies, as well as the evaluation of potential disease-modifying (neuroprotective) approaches.
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