How genes and exercise may affect Parkinson’s progression

The proposed multi-site, Genetics and Aerobic Exercise to Slow PD (GEARS) Trial will, for the first time, determine the interplay between genetics and exercise in altering PD progression. In sum, 200 PD patients will be recruited from the Cleveland and Salt Lake City metro areas to participate in the Pedaling for Parkinson's (PFP) community-based exercise program. Participants will exercise at community-based sites 3x/week for 12 months. All participants will undergo genotyping using an array that includes the genome backbone and common risk variants associated to increase risk for multiple neurological disorders including PD.

A long-standing unmet need in the treatment of Parkinson's disease (PD) is the identification of a disease-modifying intervention (e.g. pharmaceutical, surgical or behavioral). A growing body of evidence indicates that high-intensity aerobic exercise, when delivered in a highly supervised, well-controlled laboratory setting, improves PD symptomology. Two fundamental gaps remain related to the widespread utilization of exercise to slow PD: 1) are community-based exercise programs effective in altering disease progression and 2) what is the role of genetics in modulating the disease altering effects of high-intensity aerobic exercise? Our underlying hypothesis is that high-intensity, community-based exercise slows disease progression in PD and does so more effectively in individuals with a lower genetic/biological burden. Genetic burden for PD will be determined through the calculation of a PD polygenic risk score (PRS). Total study duration is \~12.5 months to accommodate data collection sessions and enrollment in PFP class. The study consists of five in-person assessments at the Cleveland Clinic or the University of Utah: informed consent, enrollment (On- and Off-medication separated by at least 24 hrs), 6 months (Off-medication), and 12 months (Off-medication). Asking participants to withhold medication for Off-state examinations imposes a burden, but the Off-state (12 hours off meds) will increase insight into the direct effect of exercise on PD and provides more reliable, less confounded time comparisons. Antiparkinsonian medication will be reconciled at Baseline, 6- and 12-month timepoints. Outcome metrics are provided in Table 1. Notably, all outcome metrics will be collected at each time point after the consent appointment (baseline on, baseline off, 6 month and 12 month) with the exception of the quality of life metrics (Neuro-QoL and MDS-UPDRS I, II, IV) which will be collected at one of the two baseline assessments (instead of both baseline assessments), 6 month, and 12 month; the quality of life questionnaires ask questions about one's quality of life over the previous 7 days and are non-specific to medication state. Genetic data and demographics will be gathered at the first enrollment assessment visit. Following the two enrollment visits, the participant will begin attending PFP classes 3x/wk at the community center most convenient to them. Participants will be recruited and enrolled on a continuous basis.