Molecular and Physiological Mechanisms of Hypertensive Cerebral Microangiopathy

项目摘要 大脑的小血管疾病不仅导致缺血性中风和出血性中风，而且 血管认知障碍和痴呆症是老年人残疾和死亡的主要来源。尽管 高血压脑小血管病(HTN-cSVD)是最常见的脑部疾病 微血管病变，将这种情况与脑组织损伤和认知障碍联系起来的机制是 未知，因此不存在针对生理病理过程的具体预防或治疗方法。 我们建议对HTN-cSVD的相关机制进行系统的、多学科的分析。 脑血管功能障碍、血管周围清除功能受损及其与脑损伤的关系包括 病理性淀粉样蛋白/tau蛋白堆积。独特的患者队列由非痴呆症患者组成 高血压脑出血幸存者(HTN-ICH)是严重HTN的典型指标-- CSVD。设计了具体的实验，以比较先进的血管生理学MRI测量方法 HTN-ICH患者与健康老年人的反应性和血管顺应性 血管功能障碍与已建立的HTN-cSVD标志物的关系[特异性靶(SA)] 1a及1b]。这些实验旨在验证HTN-cSVD导致血管病变的假设 功能障碍，进而可能导致更大规模的脑组织损伤。第二组实验将测试 HTN-cSVD对脑内淀粉样蛋白和tau蛋白蓄积的潜在影响，回答了关键 与小血管功能障碍相关的清除能力降低是否可能导致 阿尔茨海默病的这些病理特征的积累(SA 2a和2b)。第三组研究 我将分析血管、结构和分子变化对认知的影响，使用横截面 和纵向评估(SA3a和3b)。这项提议建立在广泛的尖端技术基础上 7T超高场功能磁共振多模式生理成像等方法学进展， 分子Aü和tau PET成像，以及使用最先进的HTN-cSVD结构成像标记物。 成功完成拟议的高度平移实验将决定生理和 HTN-cSVD相关脑组织损伤的分子机制及其对脑损伤的影响 认知力。这些结果将代表着朝着理解MOST的贡献迈出的重要一步 常见的脑血管病(HTN-cSVD)到痴呆症，从而允许设计旨在 使用经过验证的血管生理学成像标记物保护或增强血管功能。

Project Summary The small vessel diseases of the brain are responsible not only for ischemic and hemorrhagic strokes but also vascular cognitive impairment and dementia, major sources of disability and death in older adults. Despite the fact that hypertensive cerebral small vessel disease (HTN-cSVD) is the most common type of brain microangiopathy, the mechanisms linking this condition to brain tissue injury and cognitive impairment are unknown, therefore no specific preventive or therapeutic method targeting physiopathological processes exist. We propose a systematic, multidisciplinary analysis of the mechanisms underlying HTN-cSVD related cerebrovascular dysfunction, impaired perivascular clearance and their connections to brain damage including pathological amyloid/tau protein accumulations. The unique patient cohort is composed of nondemented survivors of a hypertensive intracerebral hemorrhage (HTN-ICH), a well-characterized indicator of severe HTN- cSVD. Specific experiments are designed to compare advanced physiological MRI measures of vascular reactivity and vascular compliance between patients with HTN-ICH and healthy older adults in addition to delineating the relationship of vascular dysfunction with established markers of HTN-cSVD [Specific Aim (SA) 1a and 1b]. These experiments are geared towards testing the hypothesis that HTN-cSVD causes vascular dysfunction which in turn might mediate larger-scale brain tissue injury. The second set of experiments will test the potential effects of HTN-cSVD on accumulation of amyloid and tau proteins in the brain, answering the key question of whether decreased clearance related to small vessel dysfunction might contribute to the accumulation of these pathological hallmarks of Alzheimer’s Disease (SA 2a and 2b). The third set of studies will analyze the effects of vascular, structural and molecular changes on cognition using both cross-sectional and longitudinal assessments (SA 3a and 3b). The proposal builds on a wide range of cutting-edge methodologic advances such as multimodal physiological imaging with 7T ultrahigh field functional MRI, molecular Aß and tau PET imaging, and the use of state-of-the-art structural imaging markers of HTN-cSVD. Successful completion of the proposed highly translational experiments will determine the physiological and molecular mechanisms of brain tissue damage related to HTN-cSVD and the impact of these processes on cognition. These results will represent a major step towards understanding the contributions of the most common vascular brain disease (HTN-cSVD) to dementia, thereby allowing design of clinical trials aimed at preserving or enhancing vascular function using validated imaging markers of the vascular physiology.