Development of a clinically-relevant test for assessment of cerebral vascular function

开发用于评估脑血管功能的临床相关测试

• 批准号: 10227260
• 负责人: Alexander Rosenberg
• 金额: $ 2.24万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227260
• 关键词: Address; Adult; Affect; Aging; Area Under Curve; Arteries; Atherosclerosis; Blood Vessels; Brain; Buffers; Caliber; Carbon Dioxide; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Chronic; Cigarette; Clinical; Communities; Data; Detection; Deterioration; Development; Disease; Distal; Doppler Ultrasound; Elderly; Elements; Endothelium; Ensure; Event; Functional disorder; Future; Glycopyrrolate; Goals; Health; Homeostasis; Human; Hyperemia; Impaired cognition; Impairment; Individual; Internal carotid artery structure; Investigation; Ischemia; Knowledge; Lead; Left; Lower Body Negative Pressure; Measures; Mediating; Medical; Metabolic; Methodology; Nicardipine; Organ; Outcome; Pathogenesis; Perfusion; Peripheral; Pharmaceutical Preparations; Pharmacology; Phentolamine; Play; Process; Protocols documentation; Quality of life; Regulation; Reperfusion Therapy; Research; Research Project Grants; Resistance; Risk; Risk Assessment; Smoker; Stimulus; Stress; Stroke; Techniques; Testing; Therapeutic Intervention; Tissue Viability; Tissues; Transcranial Doppler Ultrasonography; Vascular Endothelium; Vasodilation; arterial stiffness; brachial artery; cerebral hemodynamics; cerebrovascular; cerebrovascular health; cholinergic; clinically relevant; cognitive disability; endothelial dysfunction; femoral artery; human subject; improved; indexing; innovation; insight; middle age; middle cerebral artery; neurovascular coupling; novel; pre-clinical; pressure; prognostic; reactive hyperemia; recruit; response; shear stress; therapeutic development; tobacco smokers; tool; vasoconstriction; vasomotion

PROJECT SUMMARY The overall goal of this research project is to develop a test of cerebral vascular function, and provide mechanistic insight into the extent to which the myogenic, neurogenic, and shear-mediated responses contribute to the regulation of the cerebral vasculature. Cerebrovascular disease is the 5th leading cause of death, as well as being a major cause of cognitive impairment and disability in middle-aged to older adults. Understanding the relationship between aging and cerebrovascular function is essential to the development of therapeutic interventions that will improve quality of life and reduce the risk of cerebrovascular events. There are currently no preclinical tools for prediction of future cerebrovascular disease/events in healthy humans; the proposed study aims to address this knowledge gap. The central hypothesis is that our test of “Cerebral-Vascular Function” will elicit a vasodilatory stimulus, which will be reduced in healthy older subjects, and chronic smokers, and that impairment in these responses will be associated with impaired peripheral vascular regulation and with reduced cerebral vascular reactivity to CO2. A secondary hypothesis is that that blockade of myogenic and neurogenic responses to the “Cerebral-Vascular Function” test will facilitate assessment of the endothelial shear- stress dependent mechanism of cerebral blood flow regulation. We will address these hypotheses in two broad Specific Aims: 1) assess the responses to the Cerebral-Vascular Function test , and compare responses with a classic test of Cerebral Vascular Reactivity to CO2, and the Peripheral-Vascular Reactivity tests in healthy young subjects, and subjects known to have impaired systemic vascular function, (older healthy subjects, and chronic smokers), and; 2) determine the relative contribution of endothelial-mediated hyperemia from myogenic and neurogenic control of cerebral blood flow. Human subjects will be recruited to address these aims, by adapting the peripheral flow-mediated dilation (FMD) approach of ischemia-reperfusion to the cerebral vasculature by use of lower body negative pressure (LBNP). LBNP (-60 mmHg) will be applied to induce an “ischemic” stress to the cerebral tissue; rapid release of this stress will elicit shear stress induced cerebral vasodilation. Reactive hyperemia in the intracranial and extracranial arteries will be assessed via calculation of the peak and area under the curve for each response as an index of resistance vessel function. Independently, FMD in the brachial and femoral arteries will be assessed. The rationale for the proposed research is to develop a clinically-relevant test for assessment of cerebral vascular function and identify a mechanism for the previously observed increase in cerebral blood flow to simulated “ischemia-reperfusion” stress. The approach is innovative as it may provide evidence that cerebral reactive hyperemia is a novel methodological approach and a valid stimulus to assess cerebrovascular function. This contribution is significant as it will provide insight into the detrimental cerebrovascular adaptations that occur with aging, and the overall contribution that endothelial dysfunction may play within this process.

项目概要 该研究项目的总体目标是开发脑血管功能测试，并提供 从机制上洞察肌源性、神经源性和剪切介导的反应的贡献程度 脑血管系统的调节脑血管疾病也是第五大死亡原因。 是中老年人认知障碍和残疾的主要原因。 衰老与脑血管功能之间的关系对于治疗的发展至关重要 目前有一些干预措施可以改善生活质量并降低脑血管事件的风险。 没有临床前工具来预测健康的未来人类脑血管疾病/事件； 研究旨在解决这一知识差距，其核心假设是我们对“脑血管”的测试。 功能”将引起血管舒张刺激，这种刺激在健康的老年受试者和长期吸烟者中会减少， 这些反应的损害将与周围血管调节受损以及 降低脑血管对 CO2 的反应性 第二个假设是阻断肌源性和 对“脑血管功能”测试的神经源性反应将有助于评估内皮剪切力 我们将从两个方面来阐述这些假设。 具体目标： 1) 评估对脑血管功能测试的反应，并将反应与 脑血管对 CO2 反应性的经典测试以及健康人群的外周血管反应性测试 年轻受试者和已知全身血管功能受损的受试者（老年健康受试者和 慢性吸烟者），以及；2）确定肌源性内皮介导的充血的相对贡献 将招募人类受试者来实现这些目标。 将缺血再灌注的外周血流介导的扩张（FMD）方法应用于脑 将使用下半身负压 (LBNP) (-60 mmHg) 来诱导血管系统。 对脑组织的“缺血”应激；这种应激的快速释放会引起脑剪切应激 颅内和颅外动脉的反应性充血将通过计算进行评估。 每个响应的峰值和曲线下面积独立地作为阻力血管函数的指数。 将评估肱动脉和股动脉的 FMD 拟议研究的基本原理是开发。 用于评估脑血管功能的临床相关测试并确定先前的机制 观察到脑血流量增加以模拟“缺血再灌注”应激，该方法是创新的。 因为它可能提供证据表明脑反应性充血是一种新的方法学方法和有效的方法 评估脑血管功能的刺激这一贡献非常重要，因为它将提供对脑血管功能的深入了解。 随着衰老而发生的痛苦的脑血管适应，以及内皮细胞的总体贡献 功能障碍可能会在此过程中发挥作用。