In vivo synaptic and dopamine transporter imaging in Parkinson's disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions worldwide, with a pressing need for improved biomarkers to guide diagnosis and therapy. This research project aims to advance understanding of PD by directly imaging synaptic density and dopamine transporter (DAT) function in the living brain, using cutting-edge positron emission tomography (PET) techniques and novel radiotracers. The study addresses key questions about how synaptic loss and DAT dysfunction evolve across different clinical stages of PD, whether these changes can be detected early and tracked over time, and how they relate to symptom progression and cognitive decline. To accomplish this, researchers will recruit 60 individuals with clinically confirmed PD, representing early to moderate stages of the disease, from the Yale Movement Disorders Clinic and local support groups. Participants will undergo PET scans with two innovative tracers: 11C-UCB-J, which measures synaptic density, and 18FE-PE2I, which assesses DAT availability. The team will compare regional patterns of synaptic deficits across disease stages, testing the hypothesis that synaptic loss extends from subcortical nuclei to the cortex earlier than previously thought. A subset of participants will be followed longitudinally, with repeat imaging after two years, to evaluate the sensitivity of these markers to disease progression. Exploratory aims include assessing whether synaptic density and DAT imaging can predict changes in motor and cognitive symptoms, distinguishing cognitively normal PD patients from those with mild cognitive impairment, and investigating whether symptom onset patterns—body-first versus brain-first—correlate with imaging findings. All subjects will also receive anatomical MRI scans to enhance PET image accuracy and will be screened for study eligibility using standardized clinical assessments. By integrating advanced imaging technology, rigorous clinical evaluation, and longitudinal follow-up, this project seeks to validate and refine PET-based biomarkers for PD. The anticipated outcomes include a deeper understanding of PD pathophysiology, improved tools for tracking disease progression, and insights into the relationship between synaptic and dopaminergic changes and clinical symptoms. Ultimately, the findings could inform future clinical trials, support the development of personalized treatment strategies, and guide the next generation of neuroimaging approaches for PD and related disorders.