The overall objective of this proposal is to test the hypothesis that cerebrovasular function is impaired in patients with mild cognitive impairment (MCI) leading to brain hypoperfusion, brain atrophy, white matter lesions and cognitive impairment. Importantly, we will determine whether endurance exercise training improves cerebrovascular function and brain perfusion, thus ameliorating brain atrophy, white matter lesions and cognitive decline in patients with MCI. To accomplish these objectives, we will complete the following specific aims.
Specific aim 1 a: to determine whether baroreflex function is impaired, leading to enhanced blood pressure instability and thus hemodynamic challenges for brain perfusion in patients with MCI.
Specific aim 1 b: To determine whether cerebral autoregulation and cerebral vasomotor reactivity to CO2 are impaired in patients with MCI and whether cerebrovascular dysfunction is associated with atherosclerosis and arterial stiffness.
Specific aim 2 : To determine whether enhanced blood pressure instability in conjunction with cerebrovascular dysfunction leads to brain atrophy, white matter lesions and cognitive impairment.
Specific aim 3 : To determine whether exercise training improves cerebrovascular function, brain perfusion and ameliorates brain atrophy, white matter lesions and cognitive decline in patients with MCI and whether exercise training upregulates brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF). Cerebrovascualr function, brain perfusion, brain tissue volume and white matter lesions will be measured using magnetic resonance imaging (MRI) and transcranial Doppler (TCD). Cognitive function will be assessed using a comprehensive battery of neuropsychological tests focused on the executive and memory function. Multiple linear regression models will be used for statistical data analysis.

Public Health Relevance

Alzheimer's disease (AD) is a devastating brain disorder imposing heavy burdens on the society with aging population. Existing therapies are at best, symptomatic and do not prevent or slow the progression of the disease. Mild cognitive impairment (MCI) is likely to be a transitional state between normal aging and AD, suitable for therapeutic interventions. The outcome of this project will provide in-depth understanding of important pathophysiological mechanisms for the control of brain perfusion in patients with MCI. Most importantly, this project will determine whether exercise training improves cerebrovascular function leading to improvement in brain structure and function in patients with MCI. The new knowledge will have significant impact on prevention or treatment of AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Ryan, Laurie M
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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