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.

项目摘要/摘要 标题：了解血管功能障碍与阿尔茨海默氏病与疾病相关的蛋白质之间的机械联系 中位叶片中间积聚。 脑小血管疾病（CSVD），它以脑淀粉样蛋白的形式影响大脑的小血管 血管病（CAA）或小动脉粥样硬化，是主要负责人，要么是显着促成因素 阿尔茨海默氏病和相关痴呆症（AD/ADRD）。但是，尚不清楚是否血管病理 与广告相关的病理独立促进痴呆或随便相互作用。功能障碍 在血管周围清除中，负责从事代谢废物产品的系统之一 大脑和血脑屏障（BBB）泄漏，两者都在存在CSVD病理时发生并且是候选者 可以解释这种相互作用的机制。拟议研究的目的是确定 为了推断其基础 机制。重点将放在内侧临时叶（MTL）上，该叶子是开发的关键大脑区域 AD/ADRD，因为它是认知的基础，并且是多种与AD相关的病理的部位 共存（例如Aβ-Plaques，神经原纤维tau缠结，TAR DNA结合蛋白43和神经元损失），其中一些 在疾病的早期阶段（例如缠结）。首先，适用的将调查CSVD是否在 MTL恶化了与AD相关的病理（假设1）。其次，她将推断出 对这些相互作用的血管清除功能障碍和BBB裂解（假设2），旨在创建 并验证MTL中微血管健康的神经影像学标记（假设3）。这个创新 建议在于使用定量神经影像学和神经病理学方法，包括超高 分辨率离体MRI，极化敏感的光学相干断层扫描和基于深度学习的措施 MRI和序列组织学。拟议的调查解决了与 AD和CSVD之间的复杂相互作用，已被NIH强调为研究的优先级。 成功完成目标将导致组织学验证的微血管神经影像学标记 MTL的健康，可以应用于体内研究，以了解调整疾病的影响 干预措施。该建议利用候选人的现有技能，并在血管方面具有专业知识 病理学，将为获得新技能和分析方法提供宝贵的培训机会。这 奖项将为成功过渡到独立调查员而发挥作用。重要的是，支持 人类CSVD和AD中的（共同）导师的国际认可团队以及独特的资源 马萨诸塞州综合医院和哈佛医学院可用是确保影响力的关键要素 结果。