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: 10188424
• 负责人: Hesamoddin Jahanian
• 金额: $ 12.16万
• 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/10188424
• 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; Spin Labels; Statistical Models; Structure; Tauopathies; Testing; Therapeutic; Tracer; Training; United States National Institutes of Health; Universities; Vascular Cognitive Impairment; Vascular Diseases; Vascular System; Vasodilation; Washington; Waste Products; Work; 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：淀粉样蛋白β（AB）和TAU抑制阿尔茨海默氏病的关键病理蛋白质标志物 （AD）与Aβ相比，Tau与神经退行性部位共同定位 但是，尽管其临床重要性 AD中的tauopathy的包括导致认知障碍的相关病理生理作用 尤其难以捉摸，对脑血管功能障碍的关系知之甚少 AD发病机理和神经退行性的成分尤其如此。 利用最先进的多模式MRI/PET成像方法，我们的建议旨在增加此差距和 我们建议使用的神经元和血管作用 研究tau沉积（使用tau-pet测量）和两个互补的区域关联 血管系统功能的MRI标记：脑血流（CBF）和脑血管重新效率（CVR） 血管与神经元效应的血管症状，我们还将测量使用使用使用的区域葡萄糖代谢。 FDG-PET。我们将在18-24个月后重复CBR测量 在CBF和CVR中的时间变化之间。 提供有关前序广告中血管病理学的更丰富和越来越多的特定信息，而不是IS is is is is is is as as as as as as as as as as is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is is as is is as is is is is is is as is is is is is is is is is is is is is is is as as is of。 目前可用，并可能强调我们未来的工作 将重点介绍将倍痛与认知障碍和预测联系起来的障碍机制 个体AD专业的病理和认知轨迹：我的长期目标是成为一个 独立研究者致力于神经影像学研究，以创建知识和工具来开发 为每个AD的个人特征量身定制的有效疗法。 通过此奖项，我将获得各种基于MRI的神经成像方法。 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， 这将使我能够为我的短期目标制定和测试知识渊博的假设 要1）获得有关AD的病理和生物分子基础的深入knoledge，2）获取临床 AD的观点，3）在PET成像和基于PET的AD生物标志物中发展利润，4）增强我 统计纵向建模的技能。 华盛顿大学疾病研究中心可用 我要实现这些目标。 AD神经影像学，并通过NIH K奖成功地指导了多位学员。