Improving Human Cerebrovascular Function Using Acute Intermittent Hypoxia

项目摘要 血管功能障碍导致许多神经系统疾病的病理学，但目前 解决这些因素的治疗方案不足。本项目的总体目标是测试 一种新的干预措施，以改善大脑的血液供应，从而减轻血管的贡献的潜力 神经退化和功能损伤急性间歇性缺氧（AIH）正在成为一种强大的 治疗，以改善整体心血管健康和促进神经可塑性，但其对人类的影响， 脑血管功能尚不清楚。已知缺氧通常影响血管生成和血流，并且 暴露于短暂的缺氧刺激可以“预处理”其他器官的脉管系统，使其对缺氧更有弹性。 严重缺氧威胁这项研究验证了一个假设，即为期3周的每日AIH干预将推动有益的 人类大脑血管的可塑性。将招募健康受试者完成随机化假手术- 对照交叉试验，以评估每日AIH与假干预的影响。这项研究采用了 高度创新的磁共振成像（MRI）方案，以评估AIH对区域性 人体脑血管生理学，使用先进的灌注成像和前瞻性靶向气体 激发血管舒张反应的挑战。AIH对大脑生理学的影响将通过以下方式确定： 在两个特定目标中比较干预前后的MRI扫描。1)相位对比MRI和多后 将进行标记延迟伪连续动脉自旋标记MRI，以定量全脑和 区域组织灌注和静止时的血管通过时间。2)吸入性低氧和高碳酸血症气体挑战 将在MRI扫描期间给药，以测量脑血管反应性（CVR）， 血管扩张刺激。与以前使用总指标的研究不同（例如，经颅多普勒 超声检查），动脉自旋标记MRI提供的区域洞察力对于跟踪 在未来的患者研究中评估AIH的有效性和安全性。成像协议还提供了定量的 该框架旨在为给定的队列或个体优化AIH“剂量”。最后，提出了本文的研究意义 因为我们的研究结果可能表明，AIH是一个强大的和实用的工具，以改善健康的 大脑的脉管系统这在患者中是特别重要的，其中其他用于修饰血管的方法 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 概念验证研究是成功的，AIH将成为促进脑血管疾病的令人兴奋的新干预措施。 可塑性和开辟新的治疗机会，在许多神经系统疾病， 涉及血管功能障碍，包括多发性硬化症、帕金森病和几种形式的 痴呆通过有益地改变这些患者的脑血管生理学，AIH有可能 解决导致神经功能缺损进展的血管和神经血管病理。

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.