Slow wave sleep as a biomarker of rehabilitation-induced cognitive improvement in Parkinson's disease

ABSTRACT Parkinson’s disease (PD) is a neurodegenerative disorder associated with Lewy Body pathology that can lead to progressive cognitive decline and Parkinson’s disease dementia (PDD), a form of Lewy Body Dementia. Cognitive dysfunction in PD is common, affecting up to 80% of persons with PD (PwP) over the disease course. PD-associated cognitive decline has devastating consequences, including quality of life impairment, increase in caregiver burden, loss of independence and productivity, and increased risk of institutionalization. This results in significant public health and societal burden. Pharmacologic treatments for cognitive dysfunction in PD are often ineffective and none prevent progression to PDD. Exercise has promise for improving cognition in PD, but the best exercise prescription for individual PwP is unknown. Slow wave sleep (SWS) is important for cognitive function due to its involvement in synaptic plasticity, cortical reorganization, and glymphatic function. The PI’s preliminary data show that SWS is important for cognitive performance in PwP. Further, the PI found that exercise increases SWS in PD and only PwP with increased SWS had improvement in executive function. This interindividual response heterogeneity provides an opportunity to tailor exercise prescriptions to individual PwP. The hypothesis is that exercise will improve cognitive function in PD and that changes in SWS will serve as a biomarker and mediator of rehabilitation-induced cognitive response. Our exploratory hypothesis is that efficiency of glymphatic function may underlie these effects. Using an innovative Sequential Multiple Assignment Randomized Trial (SMART) design, the PI will test these hypotheses in a randomized, controlled trial of 120 PwP to investigate 1) the effects of exercise rehabilitation versus delayed-exercise control on cognition in PwP (Aim 1); 2) determine if changes in SWS due to exercise mediate the exercise-induced changes in executive function in PwP (Aim 2); and 3) determine if glymphatic function predicts exercise-induced changes in cognition (Exploratory Aim). Study design: In the first phase of the trial, participants will be randomized to 12-weeks of progressive resistance training rehabilitation (PRT) or delayed-exercise control (1:1). Arm assignment in the 2nd 12-week phase of the trial will be determined by individual response in the first 12 weeks. Specifically, responders (those with increases in SWS) will continue PRT for the 2nd 12 weeks of the trial while non-responders (no sufficient increase in SWS) will transition to endurance training (ET) for the 2nd 12 weeks. After the 1st 12 weeks of the trial, participants in the delayed-exercise group will perform PRT for the 2nd 12 weeks of the trial. The study addresses priority areas of NCMRR by investigating 1) an objective marker (SWS) that may predict individual rehabilitation treatment response and 2) treatment for secondary conditions (cognitive impairment) associated with physical impairment (Parkinson’s disease).