Identification of the earliest stage of Parkinson's disease (PD) is critical to understanding its etiology. The idea that the substantia nigra is the primary site of pathology in PD is challenged by the anatomical staging for Lewy body disease (LBD) proposed by Braak and co-workers, in which substantia nigra LBs are detected at mid-stage and neuronal loss at some undefined later stage. If the LBD staging scheme is validated, the implications are clear. Non-motor manifestations are the earliest signs of PD (i.e. preclinical PD), not the extrapyramidal signs that are currently used to diagnose PD. The aim of this proposal is to validate the LBD staging scheme using clinicopathologic approaches and the Mayo Medical Records Linkage System (MMRLS). Medical records of cases determined to have incidental LBs will be screened for clinical, demographic and environmental risk factors that have been implicated in PD and compared to matched cases without LBs. The LBD staging scheme predicts several non-motor features of preclinical PD, including anosmia, autonomic dysfunction, sleep disorders and depression. The MMRLS will be queried for cases that have come to autopsy meeting these clinical descriptors and their brains and matched controls will be studied for LBs. The proposed LBD staging scheme does not include estimates of severity or neuronal loss, but these will be assessed with quantitative methods. Specifically, in brains found to have incidental LBs and those with more advanced stages, neuronal counts and gliosis will be measured in brainstem and basal forebrain nuclei that are vulnerable at the earliest stages. In collaboration with Project by Yen, biochemical measures of abnormal alpha-synuclein species will be measured in multiple brain regions to compare biochemical with histopathologic staging. To validate LBD staging in an independent pathologic cohort, a large series of progressive supranuclear palsy (PSP) brains will be screened for LBs, and the distribution will be compared to staging in non-PSP cases. The applicability of the LBD staging scheme will also be assessed in LBD cases acquired through various resources available to the Neuropathology Core, including cases of dementia with LBs, PD with later developing dementia and familial LBD cases studied by the Clinical and Genetic Cores. Finally, the possible contribution of tau pathology to LBD will be assessed since studies by the Genetic Core implicate TAU in PD.