Background and Rationale: Parkinson's disease (PD) is a chronic progressive neurodegenerative brain disorder that disrupts connections in the brain responsible for normal cognition (thinking) and movement (walking and balance). Currently, there are no cures for PD. Studies from our research group and others have shown that exercise is an important component in the care of PD. Exercise has been shown to improve quality of life and may alter disease progression through enhancing neuroplasticity, which is defined as the ability of the brain to modify and improve brain connections, especially those lost in PD. However, while exercise is a promising therapy for patients with PD, the underlying mechanisms driving exercise benefits remain relatively unknown. Elucidating such mechanisms may provide insight toward new treatments to further extend the ways in which exercise leads to improved movement and cognition in patients with PD and slows disease progression.

Objectives/Study Question: This study will examine two mechanisms -- metabolism and immune response -- that are mediated by non-neuronal cells (astrocytes and microglia, respectively), how they are impacted by exercise, and how these relate to neuroplasticity and improved movement and cognition in PD patients and animal models.

Aims: The goal of our research is to elucidate the underlying mechanisms by which exercise leads to improved motor and cognitive behavior both in patients with PD and in animal models of this disorder. Specifically, we will examine (i) the role of brain metabolism and (ii) the role of anti-inflammatory activity, and their respective impact on neuroplasticity. The first question will be asked in an animal model of PD while the second question will be asked in both an animal model of PD and individuals with PD. To first address brain metabolism, we will examine whether exercise increases uptake of glucose into the brain and how that relates to astrocyte reactivity (a cell type in the brain responsible for coordinating blood flow and maintaining neuronal function). We will further investigate the specific metabolism of astrocytes following exercise and then block metabolic coordination between astrocytes and neurons and subsequently diminish exercise effects on neuroplasticity. To address anti-inflammatory activity following exercise, we will first use an animal model of PD. First, we will explore whether exercise (i) activates anti-inflammatory microglia (the brain resident immune cells) and (ii) increases the recruitment of immune cells from peripheral blood. Next, we will block the ability for peripheral immune cells to cross into the brain and study the subsequent impact on the formation of synapses (the building blocks of brain communication and neuroplasticity) and recovery of movement and cognition. Finally, we will extend our laboratory studies to the clinic by studying how the presence of anti- or pro-inflammatory markers in human serum are associated with exercise intensity, fitness, and cognitive function in individuals with PD. Taken together, these studies will examine whether exercise modifies a coordinated brain-body metabolic and immune response to improve neuroplasticity and movement and cognitive recovery in PD.

Study Approach: Exercise has been increasingly studied for its protective and restorative applications, especially in neurodegenerative diseases such as PD. However, the contributing mechanisms to such benefits remain significant gaps in our understanding. For this study, we will utilize a dual approach to better understand two potential mechanisms that we believe are important for exercise effects on neuroplasticity and behavioral recovery based on published and preliminary results from our labs. This study leverages the utility of a well-established and accepted animal model of dopamine depletion (using the neurotoxin 6-OHDA), which shares many features with PD. Metabolic and immune studies will be carried out in this animal model to deeply investigate changes in genes, proteins, and neuronal structures following intensive treadmill exercise that strengthen brain connections and function. We will additionally explore the longitudinal connection between immune biomarkers and cognitive function in patients with PD over an 18-month period to understand how exercise modulates immune responses to improve brain function.

Relationship to the Program Announcement: This study aims to look at the impact of exercise on two potential mechanisms – metabolism and the immune system – and how they influence neuroplasticity in brain regions injured in PD.

Applicability of Research: Findings from this study will have far-reaching scientific and clinical impact. Scientific insights in the role of glia (astrocytes and microglia) will support an important and new approach to understanding the mechanisms of PD including how exercise impacts specific regions of the brain to promote benefits involving behavior and synaptogenesis.

Clinical Applications, Benefits, and Risks: The clinical application will include the identification of serum biomarkers with cognitive recovery before, during, and after exercise treatments. An advantage of this study is that the overall benefits are potentially large, patients with PD are enrolled in an existing DoD research project, and the risk of exercise and serum collection are low and easily translated to a community setting.