Research Plan: Parkinson's disease (PD) and Huntington's disease (HD) may be viewed respectively as prototypic examples of degenerative hypokinetic and hyperkinetic movement disorders. Great strides have been made in understanding the pathophysiologic mechanisms underlying the neurodegenerative processes in both PD and HD, prompting clinical trials of new therapies aimed at slowing or halting the progression of these diseases. To assess these new therapies, reliable invivo markers of neuronal loss are needed. The research plan of the original Mentored Clinical Scientist Development Award was to perform longitudinal metabolic and neurochemical PET studies in subjects with PD and HD, and to perform a comprehensive clinicopathological analysis of the degenerative processes in an effort to developing imaging markers for potential use as outcome measures for clinical trials. This basic plan has remained unchanged in this continuation application. Much progress has been made toward the completion of the originally proposed studies, but followup data will continue to be collected over the next 2 years. While performing these ongoing studies, the applicant has performed thorough analyses of the baseline data, and some of the followup data. Furthermore, the work has been expanded to include an assessment of the utility of neuroimaging methods in the evaluation of symptomatic therapies for PD, and HD. Specifically, the applicant has completed a series of studies evaluating the effects of levodopa therapy on brain metabolism and blood flow in PD patients, as well as studies to further characterize brain networks in HD. These studies have led to 2 new Specific Aims: 1) To use PET in conjunction with levodopa infusion and deep brain stimulation (DBS) to identify the functional networks that mediate levodopainduced dyskinesia, and 2) to use novel methods of PET imaging during induced sleep to identify the specific brain networks that mediate the hyperkinetic manifestations of HD. The extension of this career development award will allow the applicant to complete the original research plan as well as the newly proposed studies. Educational Plan. By performing multiple neuroimaging studies involving PET, SPECT, and MRI over the past 3 years, the applicant has become familiar with aspects of imaging study design, implementation, quantitative analysis, and presentation. The extension of the award for an additional 2 years will allow the applicant to gain additional experience by focusing on important aspects of neuroimaging in neurodegenerative disorders not specifically addressed over the last 3 years, including: 1) MRI atrophy correction methods, 2) issues related to the conduct of multicenter imaging studies, and 3) applications of fMRI techniques to the study of therapeutics. The extension of this career development award will allow the candidate to become a fully independent and productive clinical scientist.
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