Mild Cognitive Impairment: Cerebrovascular Dysfunction and Exercise Training

描述（由申请人提供）：本提案的总体目标是验证轻度认知障碍（MCI）患者脑血管功能受损导致脑灌注不足、脑萎缩、白质病变和认知障碍的假设。重要的是，我们将确定耐力运动训练是否能改善脑血管功能和脑灌注，从而改善MCI患者的脑萎缩、白质病变和认知能力下降。为实现这些目标，我们将完成以下具体目标：具体目的1a：确定轻度认知损伤患者的压反射功能是否受损，从而导致血压不稳定加剧，从而对脑灌注造成血流动力学挑战。具体目的1b：确定MCI患者的大脑自我调节和脑血管运动对CO2的反应性是否受损，以及脑血管功能障碍是否与动脉粥样硬化和动脉僵硬相关。具体目的2：确定血压不稳定升高合并脑血管功能障碍是否会导致脑萎缩、白质病变和认知障碍。具体目的3：确定运动训练是否改善MCI患者的脑血管功能、脑灌注、改善脑萎缩、白质病变和认知能力下降，以及运动训练是否上调脑源性神经营养因子（BDNF）、胰岛素样生长因子-1 （IGF-1）和血管内皮生长因子（VEGF）。使用磁共振成像（MRI）和经颅多普勒（TCD）测量脑血管功能、脑灌注、脑组织体积和白质病变。认知功能将通过以执行和记忆功能为重点的综合神经心理学测试来评估。多元线性回归模型将用于统计数据分析。公共卫生相关性：阿尔茨海默病（AD）是一种破坏性的脑部疾病，给人口老龄化的社会带来了沉重的负担。现有的治疗方法充其量是对症治疗，不能预防或减缓疾病的进展。轻度认知障碍（Mild cognitive impairment， MCI）可能是介于正常衰老和AD之间的过渡状态，适合进行治疗干预。本项目的结果将为MCI患者脑灌注控制的重要病理生理机制提供深入的认识。最重要的是，该项目将确定运动训练是否能改善脑血管功能，从而改善MCI患者的大脑结构和功能。这一新知识将对阿尔茨海默病的预防或治疗产生重大影响。

DESCRIPTION (provided by applicant): 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 1a: 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 1b: 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.