Parkinson's disease (PD) is the second most common neurodegenerative disorder. An estimated 1,200,000 United States residents will be living with PD by 2030 creating a profound health and economic burden. While the disorder is commonly known as a movement disorder, there are a host of non-motor symptoms, such as cognitive dysfunction, that occur frequently and can be just as debilitating as the motor impairments. Cognitive dysfunction is rapidly becoming one of the domains in PD with the greatest need for therapeutic intervention. Cognitive dysfunction can affect up to ~40% patients early in disease, with as many as 80% of patients affected when disease duration exceeds 20 years. Examples of common cognitive complaints involve trouble sustaining attention, easily distracted, problems finishing tasks, problems with naming, and forgetting recent events. These symptoms can worsen as the disease progresses and lead to dementia, severely diminishing the quality of life for patients. Unfortunately, there are currently no symptomatic treatments specific to cognitive dysfunction and no treatments to slow or stop the progression of PD. Thus, research focused on determining the pathology and progression of cognitive dysfunction is an important goal in PD. Therefore, in Aim 1 we will develop and compare three models of PD with varying degrees of alpha-synuclein pathology (the pathological hallmark of PD) in the cortex and basal forebrain, brain regions implicated in cognitive dysfunction in PD. We will measure multiple aspects of cognitive function, alpha-synuclein pathology, and neurodegeneration. In addition, we will determine changes in genes involved in cell communication in cortical neurons with and without alpha-synuclein pathology.

Physical exercise has been proposed as a nonpharmacological therapeutic intervention for PD and is typically recommended to facilitate and maintain mobility. However, exercise is also known to have broad effects on multiple aspects of behavior including cognitive function. Aerobic exercise, in general, has been shown to improve attention, executive function, and memory in healthy adults. All these aspects of cognition can be impaired in PD suggesting aerobic exercise may have therapeutic potential for cognitive dysfunction in the disorder. Therefore, in Aim 2 we will test the effect of exercise in our animal model of PD with cognitive dysfunction. We will measure how treadmill exercise affects executive function, attention, and memory in addition to alpha-synuclein pathology and neurodegeneration. Similar to Aim 1, we will measure changes in genes involved in cell communication in the exercise and no exercise groups.

This proposed research addresses two of the Fiscal Year 2022 Parkinson's Research Program Synergistic Idea Award Focus Areas "Biological mechanisms or biomarkers of non-motor symptoms that could lead to the development of treatments for PD" and "Biological mechanisms or biomarkers associated with non-pharmacological interventions for non-motor symptoms of PD." Work from this proposal will determine the effect of synucleinopathy in brain regions implicated in cognitive decline in PD. It will also test the effect of treadmill exercise on cognitive function and neurodegeneration in the rat model.

Results from this research could help individuals afflicted by PD. An understanding of the most important pathological mechanisms associated with cognitive dysfunction in PD is required to identify targeted therapeutics that can lessen cognitive dysfunction and combat PD pathology. If exercise can reduce cognitive symptoms and/or slow disease progression then it would provide a much needed, non-invasive, non-pharmacological, low-cost therapeutic strategy for PD patients and at-risk populations, including military Veterans. Exercise therapy could be made readily available through hospitals and VA systems across the country.