PROJECT SUMMARY This is an application for a Mentored Patient-Oriented Research Career Development Award (K23) by Dr. Nijee Luthra, a neurologist specializing in movement disorders. As the number of people with Parkinson’s disease (PD) is expected to grow to pandemic proportions, cognitive deterioration associated with PD will prevail in a majority of this population. The integrated career development and research plan proposed for this K23 award is motivated by an increasing awareness of the urgent need to identify pathways that target cognitive impairment in PD. Exercise has potent anti-aging effects and can influence cognitive outcomes in PD but its underlying mechanisms remain unclear. Identifying biomarkers that respond to exercise, and how they associate with cognition and underlying disease pathology may elucidate key mechanisms for countering cognitive decline. This proposal focuses on longevity hormone klotho as a biomarker that may mediate exercise-induced benefits and contribute to cognitive resilience. Klotho has been shown to enhance cognition, synaptic plasticity, and brain volumes in mouse models of aging and neurodegeneration. Dr. Luthra and her team have also recently shown that klotho associates with better cognitive function in PD patients. While klotho levels decrease with aging and in PD, physical exercise robustly increases klotho levels in healthy adults. Whether exercise increases klotho in PD and protects against cognitive decline is not yet known. To this end, the aims of this research proposal are: 1) knowing its positive link with cognition, to now investigate whether klotho modifies underlying markers of PD pathology, and 2) in parallel, design a pilot study to determine if klotho increases in response to exercise in PD and correlates with improved cognitive abilities. Answers to these questions would highlight the potential of klotho as an exercise-related biomarker and as a new pathway for targeting cognitive dysfunction. The research plan is complemented by didactic and practical training in design and conduct of clinical trials, advanced biostatistical methods, and analysis and interpretation of multimodal biomarkers and cognitive assessments. To accomplish the goals of this research and training, the candidate has assembled a mentoring team with decades of experience in clinical trials and exercise interventions, along with expertise in biomarkers and cognitive impairment in PD. Completion of this research plan and training objectives will allow the candidate to advance her career in becoming an independent clinical investigator focused on investigating strategies such as exercise and multiple related biomarkers that mediate cognitive resilience in PD.