Map Paravascular Fluid Dynamic Signatures of Key Aging and AD Processes Using Dynamics Diffusion-Weighted Imaging

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Abstract Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) and tau pathologies. Mounting evidence from preclinical studies suggests that disruption of the paravascular cerebrospinal fluid (pCSF) clearance pathway (glymphatic system) contributes to Aβ and tau aggregation. These studies further highlighted a reliance of pCSF circulation on vascular functions, where spontaneous hypertension led to reduced pCSF flow. However, it is unclear whether similar phenomena exist in humans and how pCSF dynamics change with aging, essential hypertension, and AD. Human studies of the glymphatic system have proven to be challenging due to the lack of safe tracer-free imaging approaches. Recently, a novel clinically feasible imaging technique, dynamic diffusion-weighted imaging (dDWI), has been developed by the PI, which yields reproducible quantitative metrics of pCSF movement within the glymphatic system. The quantitative metrics can simultaneously assess the volume and dynamics of pCSF near the major and pial arteries – the influx of the glymphatic flow. As one of the early human studies in this glymphatic pathway, our results of a cohort aged 18 to 82 revealed significantly enlarged paravascular space and remarkably altered pCSF pumping in the older brain, the extent of which is associated with cognitive decline. Built upon the novel technique, intriguing preliminary results, and our team’s strong expertise in AD research, the overall goal of the proposal is to map pCSF signatures of key aging and AD processes. Our central hypothesis is that although aging and hypertension are two culprits of compromised pCSF, AD show disease-specific pCSF abnormalities related to pathogenesis. We will leverage the state-of-the-art neuroimaging techniques (e.g., dDWI, Aβ/tau positron emission tomography [PET]) and our large longitudinal clinical database of the Indiana Alzheimer’s Disease Research Center (IADRC) to achieve the following aims: (1) Map pCSF signatures of healthy aging. (2) Map pCSF signatures of aging with hypertension. (3) Map pCSF signatures of AD and determine their associations with Aβ/tau aggregation. The success of the three aims will determine whether fluid clearance function shows similar or distinct alterations in healthy aging, hypertension, and AD. Such knowledge is critical for identifying disease pathways and developing novel therapeutics. The new imaging technique is expected to provide valuable and translational imaging biomarkers for detecting and monitoring dysfunctional fluid clearance in AD and be applied to study other neurodegenerative diseases of high clinical impact.