Microvascular mechanisms underlying white matter lesions in older adults

项目总结 这项建议为求职者的职业发展提供了一个计划，重点是学习血流动力学 在阿尔茨海默病(AD)风险的背景下，白质损害(WML)的病因学。我们的目标是 揭示可能有助于开发减少WML相关疗法的生理机制 阿尔茨海默病风险较高的老年人认知能力下降。 应聘者：求职者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与阿尔茨海默病之间的关系 通过开发新的方法成像微血管功能作为疾病的标志。候选人的 学术培训提供了磁共振成像(MRI)方法的基础，重点是 脑血管疾病。到目前为止，他的研究努力已经产生了出版记录，会议 获奖，并成功获得资金，表明他有很强的潜力发展成为成功的 调查员。然而，候选人在核磁共振方法开发方面的背景与 他目前对衰老和痴呆症中的小血管疾病感兴趣。候选人的职业生涯规划 增强通过在衰老和痴呆、小血管疾病和人类方面的培训来解决这些差距 研究设计。本课程将辅以利用他的背景进行的实验培训 在核磁共振微血管功能的桥梁上他过渡到独立。 研究：到2050年，广告预计将影响1380万美国人，需要更完整的 了解病因以及诊断和进展的标记物的发展。β-淀粉样蛋白 斑块和神经原纤维缠结是AD的病理特征，但推测小血管起源的WML是 是AD患者认知功能下降的独立因素。阿尔茨海默病患者白细胞性白血病的高患病率 提示脑血管疾病可能在AD的病理生理机制中起重要作用。然而， WML发生发展的生理机制尚不清楚。更好地理解 与这些白质病变的形成相关的微血管生理学可能会告知 旨在预防或延缓AD患者相关认知功能下降的治疗方法的发展。一位批评者 理解相关生理学的障碍是缺乏敏感的非侵入性测量方法 脑白质的微血管功能。这项工作的目标是在7特斯拉上应用敏感的MRI方案 用于测量白质血流动力学以回答有关血流动力学的焦点问题 阿尔茨海默病风险增加的老年人的功能。结果也将为纵向人体研究的设计提供参考 检测有希望的微血管标志物在预防高危人群分层中的作用 旨在减轻WML负担相关认知功能下降的负担的治疗方法。

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.