Multimodal investigation of tau-related vasculopathy in prodromal Alzheimer's disease

阿尔茨海默病前驱期 tau 相关血管病变的多模式研究

• 批准号: 10398920
• 负责人: Hesamoddin Jahanian
• 金额: $ 12.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398920
• 关键词: Accounting; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; American; Amyloid beta-42; Amyloid beta-Protein; Anatomy; Automobile Driving; Award; Blood; Blood Vessels; Blood flow; Brain; Carbon Dioxide; Cause of Death; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Characteristics; Clinical; Cognitive; Custom; Deposition; Development; Disease; Disease Marker; Ensure; Environment; Evolution; Functional disorder; Future; Gases; Generations; Goals; Impaired cognition; Individual; Investigation; K-Series Research Career Programs; Knowledge; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mentored Research Scientist Development Award; Mentors; Metabolic; Methods; Modeling; Nerve Degeneration; Neurons; Pathogenesis; Pathologic; Pathology; Pattern; Play; Positron-Emission Tomography; Process; Regulation; Reporting; Research; Research Personnel; Resources; Role; Severity of illness; Site; Statistical Models; Tauopathies; Testing; Therapeutic; Tracer; Training; United States National Institutes of Health; Universities; Vascular Cognitive Impairment; Vascular Diseases; Vascular System; Vasodilation; Washington; Waste Products; Work; arterial spin labeling; base; blood flow measurement; brain tissue; capillary bed; cerebral microvasculature; cerebrovascular; cerebrovascular health; effective therapy; fluorodeoxyglucose positron emission tomography; follow-up; glucose metabolism; imaging approach; imaging modality; imaging study; indexing; individualized medicine; multimodality; neuroimaging; novel; prodromal Alzheimer' s disease; prospective; protein biomarkers; response; senior faculty; skills; tau Proteins; tau aggregation; tau-1; tool; uptake; vascular contributions

Abstract Research: Amyloid-beta (Ab) and tau represent the key pathological protein markers of Alzheimer’s Disease (AD). Compared with Aβ, tau co-localizes more with sites of neurodegeneration and is more closely associated with cognitive impairment. However, despite its pivotal clinical importance, mechanistic understanding of the role of tauopathy in AD, including the associated pathophysiological effects leading to cognitive impairment, has been elusive. Particularly, little is known about its relationship with the cerebrovascular dysfunction which is a critical component in AD pathogenesis and neurodegeneration. This is especially true in prodromal AD patients. Leveraging a state-of-the-art multimodal MRI/PET imaging approach, our proposal aims to address this gap and disentangle the neuronal and vascular effects associated with tauopathy in prodromal AD. We propose to investigate the regional association between tau deposition (measured using tau-PET) and two complementary MRI markers of vascular system function: cerebral blood flow (CBF), and cerebrovascular reactivity (CVR). To disentangle the vascular from the neuronal effects, we will also measure the regional glucose metabolism using FDG-PET. We will then repeat the CBF and CVR measurements after 18-24 months to determine the relationship between tau deposition and the temporal changes in CBF and CVR. The significance of this work is that it will provide much richer and more specific information about underlying vascular pathology in prodromal AD than is currently available and may emphasize for further developments of vasoprotective treatments. Our future work will focus on identifying vascular mechanisms linking tauopathy to cognitive impairment and predicting the pathological and cognitive trajectories of individual AD patients. Candidate: My long-term goal is to become an independent investigator focused on neuroimaging research to create knowledge and tools for developing effective therapies tailored to the individual characteristics of each AD patient. I have a strong technical background in a wide range of MRI-based neuroimaging methods. Through this award, I will gain complementary conceptual (pathophysiology and clinical aspects of AD) and technical (PET imaging, statistical modeling) skills, which will enable me to formulate and test well-informed hypotheses for AD mechanisms. My short-term goals are to 1) acquire in-depth knowledge about the pathology and biomolecular basis of AD, 2) acquire clinical perspectives of AD, 3) develop proficiency in PET imaging and PET-based AD biomarkers, and 4) enhance my skills in statistical longitudinal modeling. Environment: The unparalleled clinical and technical resources available at the University of Washington Alzheimer’s Disease Research Center provide the ideal environment for me to attain these goals. My exceptional mentoring team is comprised of senior faculty who are experts in AD neuroimaging and have successfully mentored multiple trainees through NIH K awards.

抽象的 研究：β 淀粉样蛋白 (Ab) 和 tau 蛋白是阿尔茨海默病的关键病理蛋白标记物 （广告）。与 Aβ 相比，tau 蛋白与神经退行性变部位的共定位更多，且关联性更密切 患有认知障碍。然而，尽管其具有至关重要的临床重要性，但对其作用的机制理解 AD 中的 tau 蛋白病，包括导致认知障碍的相关病理生理学效应，已被 难以捉摸。特别是，人们对其与脑血管功能障碍的关系知之甚少，而脑血管功能障碍是一个关键的疾病。 AD 发病机制和神经变性的组成部分。对于前驱 AD 患者尤其如此。 我们的提案旨在利用最先进的多模态 MRI/PET 成像方法来解决这一差距并 解开 AD 前驱期 tau 蛋白病相关的神经元和血管效应。我们建议 研究 tau 沉积（使用 tau-PET 测量）与两种互补性之间的区域关联 血管系统功能的 MRI 标志物：脑血流量 (CBF) 和脑血管反应性 (CVR)。到 将血管与神经元的影响分开，我们还将使用以下方法测量区域葡萄糖代谢 FDG-PET。然后，我们将在 18-24 个月后重复 CBF 和 CVR 测量，以确定关系 tau 沉积与 CBF 和 CVR 的时间变化之间的关系。这项工作的意义在于它将 提供了比 AD 前驱期基础血管病理学更丰富、更具体的信息 目前可用，并可能强调血管保护治疗的进一步发展。我们未来的工作 将重点确定将 tau 蛋白病与认知障碍联系起来的血管机制并预测 AD 患者个体的病理和认知轨迹。候选人：我的长期目标是成为一名 独立研究者专注于神经影像学研究，以创造知识和工具来开发 根据每位 AD 患者的个体特征量身定制有效的治疗方法。我有很强的技术 具有广泛的基于 MRI 的神经影像方法的背景。通过这个奖项，我将获得互补 概念（AD 的病理生理学和临床方面）和技术（PET 成像、统计建模）技能， 这将使我能够制定和测试 AD 机制的消息灵通的假设。我的短期目标 1) 深入了解 AD 的病理学和生物分子基础，2) 获得临床 AD 的观点，3) 提高 PET 成像和基于 PET 的 AD 生物标志物的熟练程度，4) 增强我的能力 统计纵向建模技能。环境：无与伦比的临床和技术资源 华盛顿大学阿尔茨海默病研究中心提供了理想的环境 为了我实现这些目标。我杰出的指导团队由资深教师组成，他们是以下领域的专家 AD 神经影像学并已成功指导多名学员获得 NIH K 奖项。