Project Summary/Abstract Parkinson's disease (PD) is the second most common neurodegenerative disorder which poses an enormous individual and public health burden. Current treatments help transiently with symptoms, but are not curative. There is thus an urgent need for therapies to delay or even reverse the neurodegeneration of the dopaminergic system, which is the main pathological process underlying PD. Randomized clinical trials have shown that exercise improves the symptoms of PD. There is preclinical and preliminary human evidence that exercise directly affects the dopaminergic system. However, it is largely unknown whether exercise also shows neuroprotective effects in humans with PD. We aim to fill this knowledge gap by investigating the effects of exercise on the dopaminergic system in vivo in humans with PD using neuroimaging. We will use dynamic quantitative positron emission tomography (PET) to measure striatal dopamine transporters (DAT). As DAT expression is regulated by ligand-availability, higher DAT levels are observed after interventions that increase synaptic dopamine levels. Using DAT-PET we will investigate the exercise-related changes in dopaminergic neuronal functioning. We will also use a novel magnetic resonance imaging (MRI) sequence to measure neuronal loss from the substantia nigra. Using MRI we will investigate the exercise- induced changes in the rate of dopaminergic neuronal loss. We have an established collaboration with a PD-specific exercise program “Beat PD Today”. We will enroll 13 participants for this study from the large pool of Beat PD applicants about to begin exercise. DAT-PET, MRI, and clinical assessments will be performed before and after six months of the sustained high-intensity program. Using rigorous neuroimaging biomarkers, our goal is to demonstrate that high-intensity exercise has measurable effects on the dopaminergic neurons.