Microvascular mechanisms underlying white matter lesions in older adults

项目摘要 本提案提出了一个计划，为候选人的职业发展，重点是研究血流动力学 阿尔茨海默病（AD）风险背景下的白色病变（WML）病因学。目标是 揭示生理机制，可能为开发减少WML相关的治疗提供信息 AD风险升高的老年人认知能力下降。 候选人：候选人是哈佛医学院和马萨诸塞州的放射学讲师 综合医院他的研究兴趣是探索微血管生理学和AD之间的关系 通过开发新的方法来成像微血管功能作为疾病的标志。候选人的 学术培训为磁共振成像（MRI）方法提供了基础，重点是 血管疾病到目前为止，他的研究成果已经发表了一项记录， 奖项，并成功获得资金，证明他的强大潜力，发展成为一个成功的 调查员然而，候选人在MRI方法开发方面的背景与 他目前的兴趣是老年和痴呆症中的小血管疾病。候选人的职业规划 通过在老龄化和痴呆症、小血管疾病和人类疾病方面的培训， 研究设计.这门课程将与利用他的背景的实验培训相补充 微血管功能的核磁共振成像，以连接他的过渡到独立。 研究：到2050年，AD预计将影响1380万美国人，需要更完整的 了解病因学和发展诊断和进展的标志物。淀粉样 斑块和神经纤维缠结是AD病理学的特征，但假定的小血管起源的WML是AD病理学的特征。 是AD患者认知能力下降的独立因素。AD患者中WML的高患病率 提示脑血管病在AD的病理生理过程中可能起重要作用。但 促进WML发展的生理机制仍不清楚。更好地了解 与这些白色病变的形成相关的微血管生理学可以告知 开发旨在预防或延迟AD患者相关认知功能下降的治疗方法。一个关键 理解相关生理学的障碍是缺乏灵敏的非侵入性测量方法 白色物质中的微血管功能。这项工作的目标是在7特斯拉下应用敏感的MRI协议 用于测量白色物质血液动力学，以回答有关血液动力学的重点问题 在AD风险升高的老年人中发挥作用。结果也将为纵向人体研究的设计提供信息 检查有希望的微血管标记物在对高危个体进行预防性分层中的作用， 旨在减轻WML负担相关认知功能下降的治疗。

PROJECT SUMMARY This proposal presents a plan for the candidate’s career enhancement that focuses on studying hemodynamic etiology of white matter lesions (WML) in the context of risk for Alzheimer’s disease (AD). The goal is to uncover physiological mechanisms that may inform development of therapies for reducing WML-related cognitive decline in older adults at elevated risk for AD. Candidate: The candidate is an Instructor of Radiology at Harvard Medical School and Massachusetts General Hospital. His research interests are to explore relationships between microvascular physiology and AD by developing novel methods for imaging microvascular function as markers of disease. The candidate’s academic training has provided a foundation in magnetic resonance imaging (MRI) methods, with a focus in cerebrovascular diseases. His research efforts thus far have resulted in a publication record, conference awards, and success in obtaining funding that demonstrate his strong potential to develop into a successful investigator. However, there are gaps between the candidate’s background in MRI methods development and his current interests in small vessel disease in aging and dementia. The candidate’s plan for career enhancement addresses these gaps with training in aging and dementia, small vessel disease, and human study design. This coursework will be complemented with experimental training that leverages his background in MRI of microvascular function to bridge his transition to independence. Research: AD is expected to impact 13.8 million Americans by 2050, necessitating a more complete understanding of the etiology and the development of markers for diagnosis and progression. Beta-amyloid plaques and neurofibrillary tangles characterize AD pathology, but WMLs of presumed small vessel origin are an independent contributor to cognitive decline in AD patients. The high prevalence of WML in patients with AD suggests that cerebrovascular disease may play an important role in the pathophysiology of AD. However, the physiological mechanisms contributing to the development of WML remain unclear. A better understanding of the microvascular physiology associated with the formation of these white matter lesions may inform the development of therapies aimed at preventing or delaying associated cognitive decline in AD patients. A critical barrier to understanding relevant physiology is the lack of sensitive methods for noninvasively measuring microvascular function in white matter. The objective of this work is to apply sensitive MRI protocols at 7 Tesla for measuring white matter hemodynamics towards answering focused questions regarding hemodynamic function in older adults at elevated risk for AD. Results will also inform the design of longitudinal human studies examining the role of promising microvascular markers in stratifying high risk individuals for preventative therapies aimed at reducing the burden of WML burden-related cognitive decline.