Brain Vasodilator Responses in Healthy and Cognitively Impaired Humans

描述（由申请人提供）：本申请的总体目标是研究年轻人和老年人的大脑微血管血管舒张剂功能，并测试与微血管功能和认知广泛相关的假设。该项目将作为申请人在心血管老化方面的培训的载体，并结合与轻度认知障碍（MCI）和阿尔茨海默病相关的脑血管变化。最近的证据表明微血管功能障碍是MCI的主要促成因素，MCI是正常衰老与痴呆或阿尔茨海默病之间的过渡阶段。由于阿尔茨海默病患者表现出全身内皮功能障碍和内皮祖细胞（EPCs）减少，MCI患者可能具有类似的表型。为了实现我们的总体目标，我们将系统地评估患有和不患有轻度认知损伤的人的微血管扩张剂功能。在目的1中，我们将通过比较三组中大脑中动脉（MCA）二氧化碳介导的血管舒张和前臂血流对反应性充血的反应，来确定MCI患者的大脑和周围血管舒张反应是否减弱：1)年轻健康成人；2)认知完好的老年人；3)老年轻度认知障碍患者。在Aim 2中，我们将通过比较吲哚美辛对相同3组中mca中CO2介导的血管扩张的影响，确定血管舒张性前列腺素的缺失是否解释了MCA血管舒张剂对CO2反应的降低。我们预计前列腺素介导的血管扩张剂机制在完整的老年受试者和轻度认知损伤患者中都将丧失。在目标3中，我们将确定EPC再生能力减弱是否伴随着脑血管舒张剂对二氧化碳反应的降低。我们将利用人类EPCs移植后颈动脉损伤小鼠模型，通过评估再内皮化来确定再生能力：1)年轻健康成人；2)认知完整的老年人；3)老年轻度认知障碍患者。我们预计EPC再生能力在年轻人中最大，在老年人中居中，在MCI患者中降低，并与二氧化碳介导的脑血管舒张相关。总之，我们有一个全面的计划来研究人类的脑血管舒张功能，以及它是如何随着年龄或认知状态而改变的。阶梯式高碳酸血症通气方案的使用将使我们能够以一种非侵入性但概念上类似于前臂和心脏血管功能测试的方式评估MCA血管扩张剂的分级反应，这种方法为心血管疾病的微血管病理提供了很大的机制理解。研究吲哚美辛将允许我们测试血管舒张前列腺素在血管舒张功能丧失与年龄和轻度认知损伤中的作用。EPC再生能力的研究进一步探讨了微血管功能障碍是MCI的潜在因素。总之，这种方法将为微血管功能障碍在认知障碍中的作用提供重要的见解，并允许候选人在脑血流调节机制方面发展翻译专业知识。

DESCRIPTION (provided by applicant): The overall goal of this application is to study cerebral microvascular vasodilator function in young and old humans and test hypotheses broadly related to microvascular function and cognition. This project will serve as a vehicle to build upon the applicant's training in cardiovascular aging and integrate with the cerebrovascular changes associated with Mild Cognitive Impairment (MCI) and Alzheimer's disease. Recent evidence suggests that microvascular dysfunction is a major contributing factor to MCI, the transitional stage between normal aging and dementia or Alzheimer's disease. Because Alzheimer's patients demonstrate systemic endothelial dysfunction and reduced endothelial progenitor cells (EPCs), it is likely that MCI patients have a similar phenotype. To address our overall goal we will systematically evaluate microvascular vasodilator function in humans with and without MCI. In Aim 1 we will determine if cerebral and peripheral vasodilator responses are blunted in MCI patients by comparing CO2-mediated vasodilation in the middle cerebral artery (MCA) and the forearm blood flow response to reactive hyperemia in 3 groups: 1) young healthy adults; 2) cognitively intact older adults; and 3) older adults with MCI. In Aim 2 we will determine if a loss of vasodilating prostaglandins explains the reduction in MCA vasodilator responses to CO2 by comparing the effects of indomethacin on CO2-mediated vasodilation in the MCA in the same 3 groups. We expect a loss of prostaglandin-mediated vasodilator mechanisms in both the intact older subjects and MCI patients. In Aim 3 we will determine if blunted EPC regenerative capacity accompanies the reduction in cerebral vasodilator responses to CO2. We will determine the regenerative capacity by assessing reendothelialization using a carotid artery injury mouse model after transplantation of human EPCs from 3 groups: 1) young healthy adults; 2) older cognitively intact adults; 3) older adults with MCI. We expect that EPC regenerative capacity is greatest in young subjects, intermediate in older adults and reduced in MCI patients and correlated with CO2-mediated cerebral vasodilation. In summary, we have a comprehensive plan to investigate cerebral vasodilator function in humans and how it is altered by age or cognitive status. The use of a stepped hypercapnic ventilatory protocol will permit us to assess graded vasodilator responses in the MCA in a way that is non-invasive yet conceptually similar to the tests of vascular function in the forearm and heart that have provided great mechanistic understanding of microvascular pathology in cardiovascular disease. The studies with indomethacin will permit us to test the role of vasodilating prostaglandins in the loss of vasodilator function with aging and MCI. The examination of EPC regenerative capacity further explores the notion that microvascular dysfunction is an underlying factor in MCI. Together this approach will provide significant insight into the role of microvascular dysfunction in cognitive impairment and permit the candidate to develop translational expertise in the mechanisms of cerebral blood flow regulation. PUBLIC HEALTH RELEVANCE: With an aging population, early identification of debilitating diseases like dementia and Alzheimer's is crucial for adequate prevention and treatment. Microvascular dysfunction in the cerebral circulation is likely an under-recognized mechanism contributing to mild cognitive impairment and the associated dementia. We aim to use a physiological test of cerebral vasodilator function as a method to identify potential mechanisms related to cognitive decline. Our human studies will be complemented by translational studies in endothelial progenitor cells to explore cellular mechanisms that might contribute to altered physiology.