Mechanisms of Cerebrovascular Reactivity in Health and Disease

摘要 脑血管反应性(CVR)是临床上衡量脑血管功能受微血管因素影响的指标 大血管效应包括血液到达时间延迟、组织反应延迟和慢性血管扩张。 利用时间延迟分别和同时测定血流延迟、CVR幅度和CVR延迟 我们开发的分析方法将产生更丰富和更具体的潜在信息 血管病理学比目前可用的更多。在健康组织中，血管扩张调节血管对血流的阻力， 并根据不断变化的对氧气和营养的需求来调节大脑的灌注量；这种能力是 在许多形式的脑血管病理中减少或缺失。脑血管反应性(CVR)，以及 相关数量脑血管储备，是衡量脑血管扩张能力的指标， 可为有脑缺血风险的患者提供有用的临床信息 脑血管闭塞。传统的CVR分析方法，将修改后的计划关联起来 用BOLD fMRI信号对吸入气体中的二氧化碳变化进行体素分析，会导致系统性低估CVR 响应相对于燃气管理时间表延迟的地区的震级。我们有 验证了一种检测和量化血流到达的局部延迟并得出校正的CVR的方法 等值图。即使在知道CVR的真实规模之后，问题仍然是 CVR延迟是由于血液延迟到达感兴趣组织(上游病理)，或延迟 受损组织的血管扩张(局部病理)，或两者兼而有之。因此，我们建议同时使用 血管舒张性和非血管舒张性气体手法结合近红外光谱在 功能磁共振成像分别评估每个延迟源。这项建议充分利用了 麦克莱恩医院/哈佛医院提供的资源和范德比尔特医院提供的独特临床资源 大学医学中心开发、实施和评估无创治疗的临床方案 不仅评估真实的CVR大小，而且评估CVR和血液循环的个体贡献者 时间，因为它们与潜在的循环生理学有关。 我们将首先用校准的CVR方法研究70名20岁至70岁的健康对照受试者 分别确定CVR幅度和延迟时间(目标1)，并分别评估 CVR延迟：血液到达时间和组织反应时间(目标2)。然后，我们将在 30名颅内动脉粥样硬化性狭窄患者和15名年龄匹配的对照组，以测试 假设血液到达时间延迟增加，CVR幅度在受影响的区域减少 狭窄(目标3)。以前的工作有力地表明，这两个因素的相对贡献将有所帮助。 辨别不同病因的不同病理类型。

Summary Cerebrovascular reactivity (CVR) is clinical measure of cerebrovascular function influenced by micro- and macrovascular effects including delay in blood arrival time, delay in tissue reponse, and chronic vasodilation. Individually and simultaneously determing blood flow delay, CVR magnitude and CVR delay using time delay analysis methods we have developed will yield much richer and more specific information about underlying vascular pathology than is currently available. In healthy tissue, vasodilation adjusts vessels' resistance to flow, and modulates cerebral perfusion in response to changing demands for oxygen and nutrients; this ability is reduced or absent in many forms of cerebrovascular pathology. Cerebrovascular reactivity (CVR), and the related quantity cerebrovascular reserve, are measures of brain blood vessels' capacity for vasodilation, which may offer useful clinical information in patients at risk for cerebral ischemia associated with chronic stenosis or occlusion of cerebral blood vessels. Traditional methods of CVR analysis, which correlate a modified schedule of CO2 changes in inhaled gases voxelwise with BOLD fMRI signal, lead to systematic underestimation of CVR magnitude in regions where the response is delayed with respect to the gas administration schedule. We have validated a method to detect and quantify local delays in blood flow arrival, and to derive corrected CVR magnitude maps. Even after the true magnitude of the CVR is known, questions remain regarding whether the delay in CVR is due to delayed arrival of blood in the tissue of interest (upstream pathology), or delayed vasodilation in impaired tissue (local pathology), or a combination of both. Therefore, we propose to use both vasodilatory and nonvasodilatory gas manipulations in combination with near-infrared spectroscopy during fMRI imaging to evaluate each source of delay separately. This proposal capitalizes on the technical resources available at McLean Hospital / Harvard and the unique clinical resources available at the Vanderbilt University Medical Center to develop, implement, and evaluate a clinical protocol for the noninvasive assessment of not only true CVR magnitude, but also the individual contributors to CVR and blood circulation times as they relate to underlying circulatory physiology. We will first study 70 healthy control subjects between 20 and 70 years old with the calibrated CVR method to separately determine CVR magnitude and delay time (Aim 1), and separately evaluate two components of CVR delay: blood arrival time, and tissue reactivity time (Aim 2). We will then perform the same measures in a population of 30 patients with intracranial atherosclerotic stenosis, and 15 age-matched controls, to test the hypothesis that blood arrival time delay is increased and CVR magnitude is decreased in areas affected by stenosis (Aim 3). Previous work strongly suggests that the relative contribution of these two factors will help differentiate different types of pathology with different etiologies.