PARKINSON DISEASE PATHOPHYSIOLOGY--CSF MARKERS

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Though its clinical picture and brain pathology (loss of nigrostriatal dopaminergic projections) are distinctive, Parkinson Disease (PD) is associated with few biological markers that can be studied in life. Several abnormalities in PD have been found in cerebrospinal fluid (CSF) constituents, among them, monoamine neurotransmitter metabolites (HVA, 5- HIAA, and MHPG), GABA and other amino compounds, pteridines, copper, specific proteins on 2-dimensional gel electrophoresis, and immunoreactivities recognizing CCK, somatostatin, beta-endorphin, and met- enkephalin. In addition, antibodies against mesencephalic neurons will be analyzed and characterized. This study will systematically investigate these neurochemical clues, in correlation with an intensive PD assessment database collected from 150 unmedicated subjects, aged 30-70 and in early stages of PD. CSF will be obtained on 2 occasions up to 25 months apart; specimens will also be collected and studies from normals matched to the parkinsonians' 5 decade age-span. The utility of these substances in differentiating PD from controls, and milder from more severe parkinsonism will be investigated. Analyses will also be focused on correlations between these constituents and specific features (clinical, demographic, and neuropsychological) of PD and its sub-types, as well as to rate of progression and other clinical outcomes of the unmedicated disorder. These CSF markers represent a diversity of neurochemical clues whose significance in the natural history of the disorder remains to be determined. Certain of these CSF substances may be correlated of severity or specific clinical features of PD (and so might have prognostic applications), while others might prove to be markers of risk or lifelong trait of PD (which would be extremely valuable for studying familial patterns or pre-clinical stages of this disorder). If these study goals are achieved, there would also be important implications for an ongoing study of deprenyl and tocopherol in PD. Should this 800 patient therapeutic trial (the source of CSF specimens and the clinical database for the proposed study) provide evidence that anti- oxidative therapy can avert further development of parkinsonism, then those CSF traits or state markers which are altered in the treatment- responsive group might provide insight into the mechanism(s) for initiation and progression of PD.