Background: Parkinson's Disease (PD) is an enormous burden on the Veterans Health Administration (VHA) and disease prevalence expected to double by 2030. Our understanding is very limited about the first two decades of PD progression before diagnosis, called the prodromal period, because this stage involves vague under-recognized symptoms such as non-motor disorders of the skin. Previous studies of skin tissue pathology are limited but have implicated pathologic features associated with prodromal-stage PD, particularly neuronal synuclein accumulation and aggregation. The knowledge gap about early PD and lack of tissue studies is a major obstacle toward understanding pathogenesis, identifying subtypes, and ultimately disease-modifying therapies. Significance: This proposal will map the early pathologic features of prodromal PD in peripheral skin tissues and link these pathologic features to clinical and genetic “big data” available at the VHA. Understanding the timing and diagnostic utility of early peripheral pathology in PD is of high importance for the VA healthcare system as the VA has an older average age, males are more likely to acquire the disease, PD is recognized as a service-connected disease, and veterans with PD are more likely to rely solely on the VA for their health care than veterans without PD. Innovation: This proposal is innovative by creating curating a novel dataset measuring twenty years of prodromal disorders in nationwide PD cases and 4:1 matched controls and cataloguing the presence of archival biopsies spanning 1-20 years before PD diagnosis. In addition, this study for the first time integrates histopathology, clinical data, and genetic data from the VA mega-biobank, called the Million Veterans Program (MVP). Finally, this study is novel in comparing two leading biomarker assays, immunofluorescence and real- time quaking induced conversion (RT-QuIC). Specific Aims: 1) Determine the presence of neuronal synuclein accumulation and seeded synuclein aggregation in skin preceding a diagnosis of PD and association with clinical disorders, 2) Determine the association of genetic variants with prodromal clinical disorders and a cluster of disorders that co-segregate with synuclein. Methods: All PD patients and 4:1 matched controls are identified in the VA medical database (n=1.5 million) and skin biopsies are identified before PD diagnosis or equivalent age controls. Tissue blocks will be collected initially from the Portland pathology service and if needed scaled to tissue collaborators at Phoenix and Palo Alto VAMC. Using immunofluorescent microscopy, we will measure neuronal α-synuclein and using RT-QuIC we will measure synuclein seeded aggregation. Genome association analysis will be performed between prodromal clinical disorders and variant allele frequencies from the MVP. Next Steps: By understanding the earliest features of PD, this project can lead to targeted study of the earliest causes of PD, relate complementary but...