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

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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.