Project abstract/summary The need to develop better biomarkers and more effective therapies in Parkinson's disease (PD) is a priority. This proposed research project applies novel molecular neuroimaging methods to directly investigate synapses and the dopamine transporter (DAT) in PD by using positron emission tomography (PET) imaging with newly developed tracers,11C-UCB-J for synaptic density and 18FE-PE2I for DAT. The study will perform a detailed comparison with 60 total PD subjects, 20 subjects each in different clinical stages (Hoehn and Yahr stages 1-3) with 11C-UCB-J (Aim 1). We hypothesize that there will be a regional pattern of synaptic deficits in PD patients in primary regions-of-interest in the brain that will first include subcortical nuclei and then spread to prefrontal and motor cortices, occurring in the cortex earlier than predicted from a caudal-to-rostral evolution model. Using a subset of subjects from the first aim, 15 PD subjects in different clinical stages of the disease will be examined two years later for longitudinal changes (Aim 2). We expect that the tracer will be sensitive to changes in each clinical stage, with cortical synaptic density decreases more pronounced later in the disease process. We will also examine these changes with 18FE-PE2I compared to 11C-UCB-J binding, giving direct evaluations of sensitivity in different stages of the disease as well as longitudinally (Aim 3). Exploratory aims will have a subset of subjects repeat clinical examinations three years from the initial PET scans to investigate whether synaptic density and DAT were predictive of symptom change (Sub-Aim 1.) We also study cognitively normal PD patients vs. PD with mild cognitive impairment (PD-MCI) to observe possible differences in cortical areas (Sub-Aim 2). Finally, we will investigate body-first vs. brain-first onset of symptoms in this important developing area of research (Sub-Aim 3). The study will last a total of four years. PD subjects will be recruited from the Yale Movement Disorders Clinic and local PD support groups. PD subjects will have clinical confirmation of diagnosis (e.g., MDS-Unified Parkinson's Disease Rating Scale). All subjects will include examinations (including ECG and blood work) to determine study eligibility. Subjects eligible to participate will also receive an anatomical MRI for co-registration (and partial volume corrections) and the highest resolution human brain PET scanner available with the radiotracers 11C-UCB-J and 18FE-PE2I. This project is a highly innovative study to investigate novel PET imaging agents in PD. This is important for several reasons. First, it combines two cutting edge tracers that have been found to be significantly decreased in PD. Secondly, it is a crucial step to validate exciting initial work by including larger, more clinical advanced cohorts. Thirdly, it examines longitudinal follow up periods within subjects, providing needed data on the sensitivity of these markers. Last...