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

摘要 研究：淀粉样蛋白β（Ab）和tau代表阿尔茨海默病的关键病理蛋白标志物 （AD）。与Aβ相比，tau蛋白更多地与神经退行性变的部位共定位， 有认知障碍然而，尽管其关键的临床重要性，机械的理解的作用， AD中的tau蛋白病，包括导致认知障碍的相关病理生理学作用， 难以捉摸。特别是，很少有人知道它与脑血管功能障碍的关系，这是一个关键的 AD发病机制和神经退行性变的组成部分。这在前驱AD患者中尤其如此。 利用最先进的多模态MRI/PET成像方法，我们的提案旨在解决这一差距， 解开前驱AD中与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）与两种互补的 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 为了将血管效应与神经效应分开，我们还将使用 FDG-PET然后，我们将在18-24个月后重复CBF和CVR测量，以确定 tau蛋白沉积与CBF和CVR的时间变化之间的关系。这项工作的意义在于， 提供了更丰富和更具体的信息，潜在的血管病理学前驱AD比 目前可用，并可能强调血管保护治疗的进一步发展。我们今后工作 将专注于识别将tau蛋白病与认知障碍联系起来的血管机制，并预测 个体AD患者的病理和认知轨迹。应聘者：我的长期目标是成为一名 独立调查员专注于神经影像学研究，为开发 根据每位AD患者的个体特征量身定制的有效疗法。我有很强的技术 在广泛的基于MRI的神经成像方法的背景。通过这个奖项，我将获得补充 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机制的充分知情的假设。我的短期目标 是1）获得关于AD的病理学和生物分子基础的深入知识，2）获得临床 3）熟练掌握PET成像和基于PET的AD生物标志物，4）提高我的 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 来实现这些目标。我杰出的指导团队由资深教师组成，他们是 AD神经成像，并已成功地指导多名学员通过NIH K奖。

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.