Project Summary/Abstract The accurate clinical diagnosis of Lewy body diseases (LBD: Parkinson’s disease (PD), dementia with Lewy bodies (DLB)), and Alzheimer’s disease (AD) is challenged by overlapping clinical features. Novel biofluid biomarkers including real time quaking induced conversion (RT-QuIC) offer the ability to diagnose patients with greater accuracy during life by identifying pathologic α-synuclein (a-syn) or tau seeds. However, in LBD, approximately 50% of cases will harbor significant AD pathology, and in AD up to 50% harbor limbic a-syn which can complicate interpretation of biomarker signatures. Therefore, comprehensive pathological validation studies are essential to understand the utility of these new assays and their association with histopathologic burden and clinical correlations. If RT-QuIC metrics relate to pathological burden or cognitive outcomes, they could be used as an objective biomarker in LBD, an ongoing critical need. The aims of this proposal are to test whether a-syn and tau RT-QuIC is associated with 1) histopathological features and 2) cognitive outcomes in LBD and AD. The hypotheses are that a-syn and tau RT-QuIC will be able to predict primary and co-pathologies in LBD and AD and that higher degrees of RT-QuIC activity will associate with greater neuropathological burden and worse cognitive outcomes. The proposed experiments will leverage pre-existing autopsy cohorts with antemortem CSF and cognitive testing collected at the University of California San Diego (UCSD) and the University of Pennsylvania with the RT-QuIC expertise of the NIH/NIAID Rocky Mountain Laboratories. The K23 candidate is an Assistant Professor of Neurosciences at the UCSD, having previously completed movement disorders fellowship and a NIH TL1-supported Masters of Translational Research. He has a history of productivity, having conducted translational and clinical research in neuroscience, recently focusing on the neuropathology of PD, DLB, and AD. The candidate is committed to a career in translational research and proposes a comprehensive five year plan of mentorship, formal training, self-directed learning, and research. This K23 career development award will support Dr. Coughlin’s short-term goals, including 1) developing a detailed understanding of RT-QuIC and its association with histopathological and cognitive outcomes, 2) acquisition of skills for multimodal tissue characterization using immunohistochemistry and Western blotting techniques, 3) learning the neuropsychology of dementia with a focus on LBD and AD, and 4) learning the statistical methods to carry out these and future studies. Dr. Coughlin will meet these objectives under the guidance of a mentorship team, including Dr. Douglas Galasko, an expert in biofluid biomarkers, Dr. Robert Rissman PhD, an expert in the molecular pathology of neurodegenerative disease and Dr. David Salmon PhD expert neuropsychologist with a long research track record in LBD and AD. This awa...