Cortical mechanisms of cognitive-motor interactions in mild cognitive impairment
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Identifying the role of neurovascular health and brain oxidative stress in walking impairment in amnestic mild cognitive impairment (aMCI) will allow for early identification of interventions for those who are highly likely to convert to dementia / Alzheimer's disease. Mobility declines in older adults are evident 6 to 10 years before cognitive symptoms appear in MCI, and reduced physical function predicts increased odds of dementia for older individuals. However, the neural mechanism of walking decline in aMCI is poorly understood. Recent interest in dementia and Alzheimer’s disease points to the ‘vascular two-hit hypothesis’: cerebrovascular damage triggers neurodegeneration (first hit), while reduced vascular health leads to increased neurotoxins and oxidative stress, advancing Alzheimer’s disease pathology (second hit). The overall objective of this project is to determine the role of the brain’s oxidative state and neurovascular health on walking and cognition decline in aMCI. The training goal is to acquire complementary expertise in magnetic resonance spectroscopy (MRS), functional near-infrared spectroscopy (fNIRS), and clinical neuroscience to prepare for an independent research career. My overall hypothesis is that lower glutathione (GSH) contributes to the pathogenesis of aMCI, manifesting early on as walking dysfunction, and that reduced cerebral blood flow in the prefrontal cortex reflects the early change in neurovascular health that influences the pathogenesis. The K99 project will be a cross-sectional study quantifying GSH with edited-MRS and hemodynamic response during walking with fNIRS in people with aMCI. Aim 1(K99) will identify the role of sensorimotor cortical GSH in cognitive function in healthy aging and aMCI. Aim 2 (K99) will determine the association between cognition and hemodynamic response during walking in individuals with aMCI. Aim 3 (R00) will be a clinical trial identifying whether cortical GSH levels play a role in the effect of acute exercise on the hemodynamic response during walking in aMCI. The candidate will undergo training at the University of Florida under the primary mentorship of Dr. Rachael Seidler. The research support and extensive career development opportunities of the training environment will provide the candidate with the skills, resources, and collaborative support needed to become an independent investigator. This project will identify brain biomarkers linked to walking in mild cognitive impairment, which will enable early detection and targeted interventions to help preserve mobility in cognitively impaired individuals.
