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

摘要 研究：淀粉样β蛋白和tau代表阿尔茨海默病的关键病理蛋白标记物 (Ad)。与Aβ相比，tau更多地与神经变性部位共定位，并且与神经退行性变的关系更密切 有认知障碍。然而，尽管它具有关键的临床重要性，但对其作用的机械性理解 阿尔茨海默病的相互作用，包括导致认知障碍的相关病理生理效应，已经被 难以捉摸。特别是，它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种关键 参与AD的发病机制和神经退行性变。这在先兆性AD患者中尤其如此。 利用最先进的多模式MRI/PET成像方法，我们的提案旨在解决这一差距，并 解开与前驱阿尔茨海默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)和两个互补的 血管系统功能的MRI指标：脑血流量(CBF)和脑血管反应性(CVR)。至 将血管从神经元的影响中分离出来，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，以确定这种关系 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 提供比IS更丰富和更具体的有关先兆AD的潜在血管病理的信息 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 将专注于确定牵张症与认知障碍之间的血管机制，并预测 阿尔茨海默病患者的病理和认知轨迹。候选人：我的长期目标是成为一名 独立调查员专注于神经成像研究，以创造知识和工具来开发 针对每个AD患者的个体特征量身定做的有效治疗方法。我有很强的技术力量 研究背景基于磁共振成像的神经成像方法种类繁多。通过这个奖项，我将获得补充 概念性(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AD机制制定和测试消息灵通的假设。我的短期目标 1)深入了解阿尔茨海默病的病理和生物分子基础；2)了解临床 AD的前景，3)精通PET成像和基于PET的AD生物标记物，4)提高我的 具备统计纵向建模的技能。环境：无与伦比的临床和技术资源 可在华盛顿大学阿尔茨海默病研究中心提供理想的环境 对于我来说，要实现这些目标。我杰出的指导团队由资深教员组成，他们都是 AD神经成像，并通过NIH K奖项成功指导了多名实习生。

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.