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The specific aims Of this study will include quantifying longitudinal changes in the tone Of the dopaminergic nervous system with neuroimaging techniques in patients with Parkinson's disease who are treated with adjunctive subthalamic nucleus (STN) stimulation. The findings will be compared to outcome in patients treated with pallidotomy Or conventional medications alone. Long-term outcome in each of these groups will be assessed with neuropsychological tests, clinical rating scales administered by research neurologists, and repeated measurements of dopamine transporter concentrations. Transporter concentrations will be estimated with an award-winning, technetium-99m labeled imaging agent that can accurately distinguish patients with Parkinson's disease from matched controls. Appropriate asymmetries can be detected in young, recently diagnosed patients with Hami-Parkinson's. At a cost of only pennies per milliCurie, the data clearly demonstrate that the uptake values of [Tc-99m]TRODAT-1 are significantly related to several neuropsychological task performance scores that are known to be partially mediated by dopamine in both patients and controls. The study has been designed as a multi-arm clinical trial. In patients, simultaneous measurements of transporter concentrations and neuropsychological test performance will be performed by blinded investigators two weeks before surgery, and then repeated at six (6) month intervals over the next three (3) years. In matched controls, the same protocol will be performed at two-week intervals once each year for three years. Both fully automated statistical parametric mapping and rigorous MRI coregistration image analysis techniques will be used to correlate physiology with behavior while controlling f9r aging as a confounding covariate. The results may be clinically relevant for several reasons. Parkinson's disease remains a relatively common and potentially devastating problem. Subthalamic nucleus stimulation seems to be a particularly promising approach in some patients. Chronic inhibition of the glutaminergic neurons projecting from the subthalamus may protect, if not actually rescue, dopaminergic neurons. While there is already some strong support for its effectiveness, it is not risk-free, and an objective measure of relevant physiology that reflects the response of the human brain to chronic subthalamic nucleus stimulation has not been reported. This study will provide that data while pursuing a long-term goal of developing a more effective and economical method for objectively assessing the outcome of an new treatment.
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