Mechanisms of Cerebrovascular Reactivity in Health and Disease

总结 脑血管反应性（CVR）是脑血管功能的临床指标， 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舒张。 使用时间延迟单独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信息， 血管病理学比目前可用的。在健康的组织中，血管舒张调节血管对流动的阻力， 并调节脑灌注以响应对氧气和营养物的需求变化;这种能力是 在许多形式的脑血管病变中减少或不存在。脑血管反应性（CVR），以及 相关量脑血管储备，是脑血管舒张能力的量度， 可能为慢性狭窄相关脑缺血风险患者提供有用的临床信息， 脑血管闭塞。传统的CVR分析方法，将修改后的时间表与 BOLD fMRI信号的CO2变化，导致系统性低估CVR 在响应相对于气体施用时间表延迟的区域中的幅度。我们有 验证了一种检测和量化血流到达局部延迟的方法，并推导出校正的CVR 星等图即使知道了CVR的真实大小，关于CVR是否存在的问题仍然存在。 CVR延迟是由于血液延迟到达感兴趣的组织（上游病理学），或延迟 受损组织中的血管舒张（局部病理学），或两者的组合。因此，我们建议同时使用 血管舒张和非血管舒张气体操作与近红外光谱法相结合， fMRI成像来分别评估每个延迟源。该提案利用了技术 姆克林医院/哈佛的可用资源和范德比尔特的独特临床资源 大学医学中心开发，实施和评估非侵入性的临床协议 不仅评估真实的CVR幅度，而且评估CVR和血液循环的个体贡献者 时间，因为他们涉及到潜在的循环生理学。 我们将首先使用校准的CVR方法研究70名20至70岁之间的健康对照受试者， 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（目的2）。然后，我们将在一个 30名颅内动脉粥样硬化性狭窄患者和15名年龄匹配的对照人群， 假设血液到达时间延迟增加，CVR幅度降低， 狭窄（Aim 3）。以前的工作强烈表明，这两个因素的相对贡献将有助于 区分不同类型的病理与不同的病因。

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.