Brain Vasodilator Responses in Healthy and Cognitively Impaired Humans

描述(申请人提供)：本申请的总体目标是研究年轻人和老年人的脑微血管扩张剂功能，并测试与微血管功能和认知广泛相关的假说。该项目将作为一种工具，以申请者在心血管老化方面的培训为基础，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的一个主要因素，MCI是从正常衰老到痴呆或阿尔茨海默病的过渡阶段。由于阿尔茨海默病患者表现出全身性内皮功能障碍和内皮祖细胞(EPC)减少，因此MCI患者很可能具有类似的表型。为了达到我们的总体目标，我们将系统地评估患有和不患有MCI的人类的微血管扩张剂功能。在目标1中，我们将通过比较3组患者大脑中动脉(MCA)的CO2介导的血管扩张反应和前臂对反应性充血的血流反应来确定MCI患者的大脑和外周血管扩张反应是否减弱：1)年轻的健康成年人；2)认知正常的老年人；3)患有MCI的老年人。在目标2中，我们将通过比较相同三组中吲哚美辛对二氧化碳介导的MCA血管扩张的影响，来确定血管扩张剂前列腺素的丧失是否解释了MCA对CO2的血管扩张反应的降低。我们预计在完好的老年受试者和MCI患者中都会失去前列腺素介导的血管扩张机制。在目标3中，我们将确定钝化的EPC再生能力是否伴随着脑血管扩张剂对二氧化碳反应的减少。我们将通过使用颈动脉损伤小鼠模型评估来自3组人内皮祖细胞移植后的再生能力：1)年轻的健康成年人；2)认知正常的老年人；3)患有MCI的老年人。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扩张相关。总而言之，我们有一个全面的计划来研究人类的脑血管扩张剂功能，以及它是如何随着年龄或认知状态的变化而改变的。阶梯式高碳酸血症呼吸方案的使用将使我们能够以一种非侵入性的方式评估大脑中动脉的分级血管扩张反应，但在概念上类似于前臂和心脏的血管功能测试，后者提供了对心血管疾病微血管病理的巨大机械理解。对吲哚美辛的研究将使我们能够测试血管扩张前列腺素在随着年龄和MCI而丧失血管扩张功能方面的作用。EPC再生能力的检测进一步探索了微血管功能障碍是MCI的潜在因素这一概念。总之，这种方法将对微血管功能障碍在认知障碍中的作用提供重要的见解，并使应聘者能够在脑血流调节机制方面发展翻译专业知识。 公共卫生相关性：随着人口老龄化，及早识别痴呆症和阿尔茨海默氏症等衰弱疾病对于充分预防和治疗至关重要。脑循环中的微血管功能障碍可能是导致轻度认知障碍和相关痴呆的一种未被认识的机制。我们的目标是使用脑血管扩张剂功能的生理测试作为一种方法来确定与认知能力下降相关的潜在机制。我们的人体研究将得到对内皮祖细胞的翻译研究的补充，以探索可能有助于改变生理的细胞机制。

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.