Partnered Dance Aerobic Exercise as a neuroprotective, motor and cognitive intervention in Parkinson's disease

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Parkinson’s disease (PD), an intractable condition impairing motor and cognitive function, is imperfectly treated by drugs and surgery. Two priority issues for a majority of people with PD are OFF-time and Cognitive impairment. Even under best medical management, 74% of people with PD experience “OFF-time” related to medication-related motor fluctuations, which severely impacts both quality of life and cognition 1. Cognitive deficits are found even in newly diagnosed people with PD and are very difficult to treat 2. However, our strong preliminary data demonstrate that partnered dance-aerobic exercise reduces OFF-time (Cohens standardized d=1.09), on the Movement Disorders Society Unified Parkinson Disease Rating Scale-IV, MDS-UPDRS-IV) and ameliorates other disease features 5-8, with retention of benefits for at least one month post-PDAE. These data motivate this proposal. PDAE provides AE during an improvisational, cognitively-engaging rehabilitative physical activity. Cognitive engagement is a critical component of PDAE, which has benefitted spatial cognition (d=.76). Consistent with these findings, we have strong preliminary evidence, obtained via functional magnetic resonance imaging (fMRI), that biweekly PDAE training increases activity in brain regions implicated in cognition. Although exercise benefits motor and cognitive symptoms and may be neuroprotective for PD, 3,4 studies using robust biomarkers of neuroprotection in humans are quite rare. We propose to perform a randomized, controlled trial in veterans and non-veterans with diagnosed PD to compare the efficacy of PDAE versus walking AE (WAE) for OFF-time, cognition, and neuroprotection. Importantly, we will assess neuroprotection with novel neuromelanin- sensitive MRI (NM-MRI) and iron-sensitive (R2*) MRI sequences to quantify neuromelanin loss and iron accumulation in substantia nigra pars compacta (SNc) 3,8 9. We will use these biomarkers, neuromelanin loss and iron accumulation, as tools to chart the course of neurodegeneration in patients with PD who have undergone long-term (16 months) intervention. Our overall hypothesis is that PDAE – a cognitively engaging AE – is more effective at reducing OFF-time and improving cognition than WAE. However, similar to WAE, we believe PDAE is neuroprotective in PD. We will randomly assign 102 veterans with mild-moderate PD to 16 months of PDAE or WAE. The 16-month observation period is required to robustly assess neuroprotection with imaging outcomes. The innovative 16-month intervention period will consist of previously established Training (3 months of biweekly sessions) and novel Maintenance (13 months of weekly sessions) phases. We will assess participants at baseline, 3 months (immediately post-Training), and 16 months (immediately post-Maintenance) for OFF-time and behaviorally and physiologically measured cognition. We will acquire NM-MRI and R2* imaging data at baseline and 16 months to assess neuroprotection. We will: 1. examine effects of Training and Maintenance phases of PDAE vs. WAE on OFF-time; 2. compare PDAE vs WAE at 3 and 16 months on behavioral and fMRI measures of spatial cognition; and 3. compare PDAE vs. WAE for effects on rates of neurodegeneration. The primary outcome measure of Aim 1 will be the Movement Disorders Society Unified Parkinson Disease Rating Scale Part IV score, which assays MRMF. The primary outcome measure for spatial cognition of Aim 2 will be the Corsi blocks. For the first time, we will use promising, cutting edge imaging techniques to reveal whether PDAE, used as long-term exercise, slows neurodegeneration in PD more than walking. Understanding the relationships between drug efficacy and exercise modalities will allow clinicians to better treat PD. Understanding the mechanisms for improving cognition via PDAE will determine whether PDAE, a scalable, readily available treatment, is a robust model of concurrent physical/mental training to address CI in PD. This project combines patient-centered, clinical science and mechanistic aims to improve veteran health care.