Project Summary/Abstract Parkinson disease (PD) is the second most common neurodegenerative disorder and causes a combination of motor, cognitive, and psychiatric symptoms. The clinical manifestations of PD are highly variable, and the underlying neurobiological mechanisms that drive this variability remain unknown. Dementia in PD is associated with neocortical accumulation of alpha- synuclein in Lewy bodies, which likely contributes to impaired function of cortical neurons. However, PD also affects a number of subcortical nuclei including noradrenergic (NA) neurons, which have diffuse projections to cortical and limbic regions. Thus impaired function and degeneration of both cortical neurons and subcortical NA neurons may contribute to nonmotor symptoms in PD, including dementia. We hypothesize that levels of synaptic and noradrenergic proteins in cerebrospinal fluid (CSF) are lower in PD. The loss of cortical synaptic terminals and cortical noradrenergic neurons in PD brain tissue would likely correspond to reduced levels of cerebrospinal fluid (CSF) analytes derived from cortical synapses and noradrenergic neurons. Thus, such CSF analytes would be useful as biomarkers reflecting either disease progression or therapeutic targets and have the potential to act as indicators for the effectiveness of disease-modifying therapies. Our preliminary data from cross-sectional analysis of CSF and post-mortem brain tissue samples supports our strategy to utilize these CSF analytes as indicators of PD disease progression. The primary objective of the proposed study will determine whether CSF analytes derived from cortical synaptic terminals (aim 1) and noradrenergic neurons (aim 2) differ between PD and control participants and whether levels change longitudinally as disease progresses. We will use both traditional and single-molecule immunoassays and liquid chromatography to quantitate CSF analytes of interest. The second objective is to determine whether levels of the CSF analytes correlate to motor, cognitive, and psychiatric features of PD (aim 3). The final objective for the candidate is to continue authoring manuscripts and generate preliminary data towards a K23 application, where the candidate would continue to develop and validate CSF biomarkers. Although with independent aims, the present study leverages existing data collected as a part of multiple large-scale longitudinal studies with established funding. Scientifically, we envision a combination of CSF biomarkers that may be used to track the progression of motor, cognitive, and psychiatric symptoms in Parkinson disease. These CSF biomarkers will provide information on disease prognosis and can be used to monitor the effectiveness of novel disease-modifying therapeutics.