ON-OFF MOOD CHANGE IN PARKINSONS DISEASE

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The proposed career development plan will form a bridge from the applicant's past clinical and research experience to a productive research career focused on the functional neuroanatomy of movement disorders. This is seen as a natural extension of the applicant's prior research experience, and his longstanding clinical interests in movement disorders and neuropsychiatry. Short-term career goals include (1) continued development of an in vivo test of dopamine-mediated pathway function, and application of this test to a suitable clinical population. (2) This will provide important new research skills leading to independent research with positron emission tomography (PET). (3) Further clinical expertise with movement disorders is another short-term goal. Long-term goals include the application of this PET technique or similar methods to other neuropsychiatric illnesses with abnormal dopaminergic function; the proposed research provides a natural stepping stone to these goals. Additional elements of the career development plan include limited, focused clinical work, and regular seminars in PET methods, movement disorders, and neuropharmacology. The environment in which this will occur is unparalleled. This laboratory is internationally recognized as a leader in PET methodology and applications, and is fully equipped. Also literally under the same roof are major research and clinical MRI facilities. The mentor has extensive experience both in clinical aspects of movement disorders and in the application of PET to their study. He has also contributed substantially to the development and application of basic PET methods. In addition, significant opportunities for informal and formal collaboration exist with other independent investigators in this laboratory and elsewhere on campus, especially within the departments of neurology, neurobiology, psychiatry and radiology. The goal of the proposed animal research is to further develop an in vivo test of the sensitivity of specific dopamine-mediated pathways. The localized effects of specific dopamine agonists on cerebral blood flow (rCBF) measured with PET will be used to indicate changes in neuronal activity. Although a fairly novel application of PET, this is analogous to the well-known "activation " of rCBF by visual stimuli or memory tasks, and autoradiographic animal studies of metabolic changes due to dopamine agonists support its validity and utility. Preliminary data, both in patients with Parkinson's disease (PD) and baboons, demonstrate athe feasibility of this approach. The proposed clinical PET study will examine the effects of L-DOPA and specific dopamine agonists on rCBF in a group of PD patients with marked dopamine-related changes in mood (off-period depression), as compared to a carefully matched group of PD patients without off-period depression. Localized, pharmacologically specific group differences are hypothesized. This research potentially has wide applicability, not only to the many PD patients with off-period depression, but also to other clinically-defined subgroups of patients with PD, as well as patients affected by idiopathic major depression, dystonia, schizophrenia, and Tourette syndrome.