Understanding the mechanistic link between vascular dysfunction and Alzheimers disease-related protein accumulation in the medial temporal lobe

项目摘要/摘要 标题：了解血管功能障碍和阿尔茨海默病相关蛋白之间的机制联系 积聚在内侧颞叶。 脑部小血管疾病(CSVD)，以大脑淀粉样蛋白的形式影响大脑的小血管 血管病变(CAA)或动脉硬化，是导致或显著促进 阿尔茨海默病和相关痴呆(AD/ADRD)。然而，目前尚不清楚血管病理是否 与AD相关的病理独立地促成痴呆或相互因果作用。功能障碍 在血管周围清除中，负责处理来自 脑和血脑屏障(BBB)渗漏，都发生在CSVD病理存在时，并且是候选的 可以解释这种相互作用的机制。拟议研究的目标是确定 CSVD和AD相关病理之间的相互作用，以推断其潜在的 机械装置。重点将放在内侧颞叶(MTL)，这是大脑发育的关键区域 AD/ADRD，因为它是认知的基础，是多种AD相关病理的场所 共存(例如，β斑块、神经原纤维tau缠结、TARDNA结合蛋白43和神经元丢失)，一些 在疾病的非常早期阶段(例如缠绕)。首先，申请人将调查CSVD是否在 MTL加重了AD相关的病理(假设1)。其次，她将推断出 血管周围清除功能障碍和BBB渗漏到这些相互作用(假设2)，目的是创建 并在MTL中验证微血管健康的神经成像标记物(假设3)。它的创新之处在于 建议使用定量神经成像和神经病理学方法，包括超高 分辨率体外核磁共振、偏振敏感光学相干断层扫描和基于深度学习的措施 核磁共振和系列组织学的结果。拟议的调查解决了一个重大的知识差距，与 AD和CSVD之间的复杂相互作用，这一直是NIH强调的研究重点。 成功完成AIMS将产生组织学证实的微血管神经成像标志物 MTL的健康状况，可用于活体研究，以了解疾病修改的影响 干预措施。这项建议充分利用了候选人现有的技能和在血管方面的专业知识 并将提供宝贵的培训机会，以获得新的技能和分析方法。这 获奖将有助于成功过渡到独立调查员。重要的是，支持 在人类CSVD和AD方面拥有一支国际公认的(共同)导师团队，以及独特的资源 马萨诸塞州总医院和哈佛医学院提供的药物是确保有效的关键成分 结果。

Project Summary/Abstract Title: Understanding the mechanistic link between vascular dysfunction and Alzheimer’s disease-related protein accumulation in the medial temporal lobe. Cerebral small vessel disease (CSVD), which affects small vessels of the brain in the form of cerebral amyloid angiopathy (CAA) or arteriolosclerosis, is either primarily responsible or a significantly contributing factor to Alzheimer’s disease and related dementias (AD/ADRD). However, it remains unclear whether vascular pathology and AD-related pathology independently contribute to dementia or causally interact with each other. Dysfunction in perivascular clearance, one of the systems responsible for the disposal of metabolic waste products from the brain, and blood-brain barrier (BBB) leakage, both occur when CSVD pathology is present and are candidate mechanisms that could explain this interaction. The objective of the proposed research is to pinpoint the reciprocal interaction between CSVD and AD-related pathology, in order to infer its underlying mechanisms. The focus will be on the medial temporal lobe (MTL), a critical brain region for the development of AD/ADRD, because it is fundamental for cognition and it is a site where a multiplicity of AD-related pathologies coexist (e.g. Aβ-plaques, neurofibrillary tau tangles, TAR DNA binding protein 43, and neuronal loss), some of which in very early stages of the disease (e.g. tangles). Firstly, the applicant will investigate whether CSVD in the MTL worsens AD-related pathology (Hypothesis 1). Secondly, she will infer the contributing role of perivascular clearance dysfunction and BBB-leakage to these interactions (Hypothesis 2) and aims to create and validate neuroimaging markers of microvascular health in the MTL (Hypothesis 3). The innovation of this proposal lies in the use of quantitative neuroimaging and neuropathological methods, including ultra-high resolution ex vivo MRI, polarization-sensitive optical coherence tomography, and deep-learning based measures of MRI and serial histology. The proposed investigations address a significant knowledge gap, related to the complex interactions between AD and CSVD, which has been emphasized as a research priority by the NIH. Successful completion of the aims will result in histologically validated neuroimaging markers of microvascular health of the MTL, which can be applied to in vivo studies to understand the impact of disease-modifying interventions. This proposal leverages the candidate’s existing skillset and demonstrated expertise in vascular pathology and will provide an invaluable training opportunity to acquire new skills and analytic methods. This award will be instrumental for a successful transition into an independent investigator. Importantly, the support of an internationally recognized team of (co-)mentors in human CSVD and AD and the unique resources available at Massachusetts General Hospital and Harvard Medical School are key ingredients to ensure impactful results.