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

了解血管功能障碍与内侧颞叶阿尔茨海默病相关蛋白积累之间的机制联系

• 批准号: 10736523
• 负责人: Valentina Perosa
• 金额: $ 12.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736523
• 关键词: 3-Dimensional; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid; Area; Arterioloscleroses; Autopsy; Award; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Brain region; Cerebral Amyloid Angiopathy; Cerebral small vessel disease; Cerebrovascular Disorders; Clinical; Cognition; Complex; Contrast Media; Dementia; Development; Disease; Disease Marker; Ensure; Etiology; Excision; Extravasation; Fibrin; Functional disorder; General Hospitals; Goals; Health; Healthcare; Hippocampus; Histologic; Histology; Human; Impaired cognition; Impairment; International; Intervention; Investigation; Knowledge; Link; Magnetic Resonance Imaging; Maps; Massachusetts; Measures; Medial; Memory; Mentors; Metabolic; Methods; Monitor; Morphology; Neurofibrillary Tangles; Optical Coherence Tomography; Pathologic; Pathology; Pattern; Penetration; Phase; Predisposition; Proteins; Research; Research Personnel; Research Priority; Resources; Role; Senile Plaques; Site; System; Temporal Lobe; Training Programs; United States National Institutes of Health; Vascular Diseases; Visualization; Waste Products; Work; analytical method; arteriole; brain tissue; burden of illness; crosslink; deep learning; early detection biomarkers; entorhinal cortex; global health; imaging modality; in vivo; innovation; magnetic resonance imaging biomarker; medical schools; neuroimaging; neuroimaging marker; neuron loss; neuropathology; novel; protein TDP-43; quantitative imaging; skills; spatial relationship; tau Proteins; tau aggregation; training opportunity; ultra high resolution

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.

项目概要/摘要 标题：了解血管功能障碍与阿尔茨海默病相关蛋白之间的机制联系 聚集在内侧颞叶。 脑小血管病 (CSVD)，以脑淀粉样蛋白的形式影响大脑小血管 血管病 (CAA) 或动脉粥样硬化是导致血管病变的主要原因或显着因素 然而，目前尚不清楚阿尔茨海默氏病和相关痴呆（AD/ADRD）是否与血管病理有关。 和 AD 相关病理学独立地导致痴呆或彼此因果相互作用。 在血管周围清除中，负责处理来自血管的代谢废物的系统之一 脑和血脑屏障 (BBB) 渗漏，均发生在 CSVD 病理存在且为候选的情况下 可以解释这种相互作用的机制。拟议研究的目的是查明这种相互作用。 CSVD 和 AD 相关病理学之间的相互作用，以推断其潜在的 重点将放在内侧颞叶（MTL），这是发育的关键大脑区域。 AD/ADRD，因为它是认知的基础，并且是多种 AD 相关病理的发生地 共存（例如 Aβ 斑块、神经原纤维 tau 缠结、TAR DNA 结合蛋白 43 和神经元丢失），其中一些 在疾病的早期阶段（例如缠结），申请人首先要调查是否患有脑小血管病。 MTL 使 AD 相关病理恶化（假设 1）。 血管周围清除功能障碍和 BBB 渗漏导致这些相互作用（假设 2），旨在创建 并验证 MTL 中微血管健康的神经影像标记（假设 3）。 提案在于使用定量神经影像和神经病理学方法，包括超高 分辨率离体 MRI、偏振敏感光学相干断层扫描和基于深度学习的测量 所提出的解决方案调查了与 MRI 和系列组织学相关的重大知识差距。 AD 和 CSVD 之间复杂的相互作用，已被 NIH 强调为研究重点。 成功完成这些目标将产生经组织学验证的微血管神经影像标记物 MTL 的健康状况，可应用于体内研究以了解疾病缓解的影响 该提案利用了候选人现有的技能和在血管方面表现出的专业知识。 病理学并将提供宝贵的培训机会来获得新的技能和分析方法。 该奖项将有助于成功过渡为独立调查员，重要的是，支持。 由国际公认的人类 CSVD 和 AD 领域的（联合）导师团队以及独特的资源组成 马萨诸塞州总医院和哈佛医学院的可用资源是确保影响力的关键要素 结果。