Improving Human Cerebrovascular Function Using Acute Intermittent Hypoxia

项目总结 血管功能障碍是许多神经疾病的病理基础，尽管目前 解决这些因素的治疗选择不足。该项目的总体目标是测试 一种新的干预措施的潜力，以改善大脑的血液供应，从而减轻血管贡献 神经退行性变和功能障碍。急性间歇性低氧(AIH)正在成为一种强有力的 改善整体心血管健康和促进神经可塑性的治疗，但其对人类的影响 脑血管功能尚不清楚。众所周知，缺氧通常会影响血管生成和血液流动，并且 暴露在短暂的低氧刺激下，可以使其他器官的血管系统更具弹性 严重的低氧威胁。这项研究测试了这样的假设，即每天3周的AIH干预将带来好处 人类大脑中的血管可塑性。健康的参与者将被招募来完成一项随机模拟- 对照交叉试验，评估每日AIH与假干预的影响。这项研究采用了一种 高度创新的磁共振成像(MRI)方案，以评估AIH对区域和地区的有益影响 人类脑血管生理学，使用先进的灌注成像和前瞻性靶向气体 激发血管扩张反应的挑战。AIH对脑生理的影响将通过以下方式确定 比较干预前后两个特定目标的MRI扫描结果。1)位相对比MRI和多后处理 将进行标记延迟伪连续动脉自旋标记磁共振成像，以量化全脑和 静息状态下局部组织灌注量和血管通过时间。2)吸入性低氧和高二氧化碳气体挑战 将在MRI扫描期间应用，以测量脑血管反应性(CVR)， 血管对扩张的刺激。与以前使用大体指标(例如经颅多普勒)的研究不同 B超)，动脉自旋标记MRI提供的区域洞察力将对追踪 AIH在未来患者研究中的有效性和安全性。成像协议还提供了定量的 为特定的队列或个人优化AIH“剂量”的框架。最后，提出的研究具有重要意义。 因为我们的结果可能表明AIH是一种强大而实用的工具，可以改善老年人的健康 大脑的血管系统。这对患者来说尤其重要，因为在患者身上有其他修改血管的方法 风险因素(例如，有氧运动)可能由于认知或运动障碍而难以应用。如果这个 概念验证研究成功，AIH将成为促进脑血管疾病的令人兴奋的新干预措施 在众多神经疾病中的可塑性和开辟新的治疗机会 涉及血管功能障碍，包括多发性硬化症、帕金森氏病和几种形式的 痴呆症。通过有益地改善这些患者的脑血管生理学，AIH有可能 探讨导致神经损伤进展的血管和神经血管病变。

PROJECT SUMMARY Vascular dysfunction contributes to the pathology of numerous neurological conditions, however current treatment options to address these factors are insufficient. The overall objective of this project is to test the potential of a novel intervention to improve the brain’s blood supply, thereby mitigating the vascular contributions to neurodegeneration and functional impairment. Acute Intermittent Hypoxia (AIH) is emerging as a powerful therapy to improve overall cardiovascular health and facilitate neural plasticity, however its impact on human cerebrovascular function is unclear. Hypoxia is known to generally influence angiogenesis and blood flow, and exposures to brief hypoxic stimuli can “precondition” the vasculature of other organs to be more resilient to severe hypoxic threat. This study tests the hypothesis that a 3-week daily AIH intervention will drive beneficial vascular plasticity in the human brain. Healthy participants will be recruited to complete a randomized sham- controlled crossover trial to assess the impact of daily AIH versus a sham intervention. This study employs a highly innovative magnetic resonance imaging (MRI) protocol to assess the beneficial effects of AIH on regional human cerebrovascular physiology, using advanced perfusion imaging and prospectively-targeted gas challenges to evoke vasodilatory responses. The impact of AIH on brain physiology will be determined through comparison of pre- and post-intervention MRI scans in two specific aims. 1) Phase-contrast MRI and multi-post- label-delay pseudo-continuous Arterial Spin Labeling MRI will be performed to quantify both whole-brain and regional tissue perfusion and vascular transit times at rest. 2) Inhaled hypoxia and hypercapnia gas challenges will be administered during MRI scanning to measure cerebrovascular reactivity (CVR), the responsiveness of blood vessels to a dilatory stimulus. Unlike previous studies that use gross metrics (e.g., transcranial Doppler ultrasonography), the regional insight provided by Arterial Spin Labeling MRI will be important for tracking the effectiveness and safety of AIH in future patient studies. The imaging protocol also provides a quantitative framework to optimize the AIH “dose” for a given cohort or individual. Finally, the proposed research is significant because our results may demonstrate that AIH is a powerful and practical tool for improving the health of the brain’s vasculature. This is of particular importance in patients where other approaches for modifying vascular risk factors (e.g., aerobic exercise) may be challenging to apply due to cognitive or motor impairment. If this proof-of concept study is successful, AIH will become an exciting new intervention for facilitating cerebrovascular plasticity and opening up new therapeutic treatment opportunities in the numerous neurological disorders where vascular dysfunction is implicated, including Multiple Sclerosis, Parkinson’s Disease, and several forms of dementia. By beneficially modifying cerebrovascular physiology in these patients, AIH has the potential to address the vascular and neurovascular pathologies that contribute to the progression of neurologic impairment.