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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033106-03
Application #
8130588
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Ryan, Laurie M
Project Start
2009-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$874,381
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Stowe, Ann M; Ireland, Sara J; Ortega, Sterling B et al. (2017) Adaptive lymphocyte profiles correlate to brain A? burden in patients with mild cognitive impairment. J Neuroinflammation 14:149
Chapman, Sandra B; Spence, Jeffrey S; Aslan, Sina et al. (2017) Enhancing Innovation and Underlying Neural Mechanisms Via Cognitive Training in Healthy Older Adults. Front Aging Neurosci 9:314
Xing, Chang-Yang; Tarumi, Takashi; Meijers, Rutger L et al. (2017) Arterial Pressure, Heart Rate, and Cerebral Hemodynamics Across the Adult Life Span. Hypertension 69:712-720
Marmarelis, Vasilis Z; Shin, Dae C; Tarumi, Takashi et al. (2017) Comparison of Model-Based Indices of Cerebral Autoregulation and Vasomotor Reactivity Using Transcranial Doppler versus Near-Infrared Spectroscopy in Patients with Amnestic Mild Cognitive Impairment. J Alzheimers Dis 56:89-105
Krishnamurthy, Lisa C; Mao, Deng; King, Kevin S et al. (2016) Correction and optimization of a T2-based approach to map blood oxygenation in small cerebral veins. Magn Reson Med 75:1100-9
Marmarelis, V Z; Mitsis, G D; Shin, D C et al. (2016) Multiple-input nonlinear modelling of cerebral haemodynamics using spontaneous arterial blood pressure, end-tidal CO2 and heart rate measurements. Philos Trans A Math Phys Eng Sci 374:
Liu, Jie; Tseng, Benjamin Y; Khan, Muhammad Ayaz et al. (2016) Individual variability of cerebral autoregulation, posterior cerebral circulation and white matter hyperintensity. J Physiol 594:3141-55
Chapman, Sandra B; Aslan, Sina; Spence, Jeffrey S et al. (2016) Distinct Brain and Behavioral Benefits from Cognitive vs. Physical Training: A Randomized Trial in Aging Adults. Front Hum Neurosci 10:338
Chapman, Sandra B; Aslan, Sina; Spence, Jeffrey S et al. (2015) Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. Cereb Cortex 25:396-405
Tarumi, Takashi; Harris, Thomas S; Hill, Candace et al. (2015) Amyloid burden and sleep blood pressure in amnestic mild cognitive impairment. Neurology 85:1922-9

Showing the most recent 10 out of 42 publications