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

点击翻译按钮获取中文摘要

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.