Microvascular Neuroimaging in Age-related Alzheimer's Disease and Tauopathies

项目总结/摘要 Ning Hua博士是一名MRI科学家，其首要职业目标是成为一名独立的研究者， 微血管功能障碍领域及其与阿尔茨海默病（AD）和脑老化的关系。的 提出的K 01研究结合了先进的体内动态对比增强（DCE）-MRI和新的离体 激光烧蚀电感耦合等离子体质谱（LA-ICP-MS），旨在探索创伤- 诱导的海马微血管损伤加速记忆缺陷、AD相关病理和白色物质 退化候选人：华博士是波士顿大学放射学系的助理教授 (BU)Chobanian & Avedisian医学院她获得了生物物理学博士学位， 主要研究心血管MRI和动脉粥样硬化。K 01提案将建立在她以前的 MRI、编程和血管生物学培训，有4个培训目标，以促进她过渡到 神经影像学和神经退行性疾病和走向职业独立：1）学习生物学和 AD的病理学基础; 2）学习神经创伤和AD小鼠模型的相关实验技能; 3） 提高她在神经影像学方面的技能; 4）为独立研究和职业发展做好准备。 导师/环境：华博士和她的主要导师Lee E. Goldstein，MD，PhD，已经组建了一个强大的 导师/咨询团队指导她完成K 01培训和研究活动。拟议的计划将 利用新成立的转化神经影像学中心（BU）和NIH-NIA的资源 支持BU阿尔茨海默病中心。BU和放射科致力于支持 初级教师通过内部资金，行政援助和结构化的机会。调研： 目前尚不清楚血脑屏障（BBB）功能障碍是否是加速AD的机制驱动因素 在神经创伤后我假设海马体易受神经创伤的影响， 微血管渗漏将加速淀粉样蛋白β和磷酸化tau蛋白的局部积聚， 加速白色物质变性，最终导致AD中加速的记忆缺陷。实验 将在良好表征的AD转基因小鼠模型（3xTg-AD）中进行， 创伤性脑损伤体内MRI测量的海马渗漏将与记忆缺陷相关 通过巴恩斯迷宫测试（Aim 1）测量。离体LA-ICP-MS测量海马中的次区域BBB渗漏 将与淀粉样蛋白和tau病理学的区域积累相关（目的2）。最后，离体扩散 MRI将用于评估海马损伤如何加速白色物质变性，特别是在 白色物质束连接到海马体并在记忆和学习中起重要作用（目的 3）。总结：该K 01提案利用先进的成像技术检测海马BBB渗漏， 及其与AD加速的关系。这将有助于华博士的职业过渡到独立， 神经影像学与AD的研究

PROJECT SUMMARY / ABSTRACT Ning Hua, PhD, is an MRI scientist whose overarching career goal is to become an independent investigator in the field of microvascular dysfunction and its relationship to Alzheimer’s disease (AD) and aging brain. The proposed K01 research combines advanced in vivo dynamic contrast enhanced (DCE)-MRI and novel ex vivo Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS), and aims to explore how trauma- induced hippocampal microvascular injury accelerates memory deficits, AD-related pathology, and white matter degeneration. Candidate: Dr. Hua is an Assistant Professor at the Department of Radiology of Boston University (BU), Chobanian & Avedisian School of Medicine. She gained her PhD in Biophysics, and her previous training was focused on cardiovascular MRI and arterial atherosclerosis. This K01 proposal will build on her previous training in MRI, programming, and vascular biology, with 4 training goals to facilitate her transition into neuroimaging and neurodegenerative diseases and towards career independence: 1) Learn the biology and pathology underlying AD; 2) Learn relevant experimental skills in neurotrauma and AD mouse models; 3) Advance her skills in neuroimaging; 4) Prepare for independent research and career track. Mentors/Environment: Dr. Hua and her primary mentor, Lee E. Goldstein, MD, PhD, have assembled a strong mentor/advisory team to guide her through the K01 training and research activity. The proposed plan will leverage resources of the newly established Center for Translational Neuroimaging (BU) and the NIH-NIA supported BU Alzheimer’s Disease Center. BU and the Department of Radiology are committed to supporting junior faculty through internal funding, administrative assistance, and structured opportunities. Research: Currently, it is unclear if blood-brain-barrier (BBB) dysfunction is a mechanistic driver for the acceleration of AD after neurotrauma. I hypothesize that hippocampus is vulnerable to neurotrauma, and that resulting hippocampal microvascular leakage will accelerate local accumulation of amyloid-β and phosphorylated-tau, as well as accelerate white matter degeneration, ultimately leading to accelerated memory deficits in AD. The experiments will be carried in a well-characterized transgenic mouse model of AD (3xTg-AD) with and without well-calibrated traumatic brain impacts. In vivo MRI measured hippocampal leakage will be correlated with memory deficits measured by Barnes Maze test (Aim 1). Ex vivo LA-ICP-MS measured subregional BBB leakage in hippocampus will be correlated with regional accumulations of amyloid and tau pathology (Aim 2). Finally, ex vivo diffusion MRI will be used to assess how hippocampal injury accelerates white matter degeneration, especially in the white matter bundles connecting to the hippocampus and playing an important role in memory and learning (Aim 3). Summary: This K01 proposal utilizes advanced imaging techniques to detect hippocampal BBB leakage, and its relation to the acceleration of AD. It will facilitate Dr. Hua’s career transition to independence in the research of neuroimaging and AD.