Quantitative Endogenous MRI Imaging of Neuroinflammation in AD

PROJECT SUMMARY/ABSTRACT Neuroinflammation plays a central role in the pathogenesis of Alzheimer’s disease (AD) and links strongly with AD’s neuropathological hallmarks, including amyloid plaques and neurofibrillary tangles. While there have been tremendous strides over the last decade in the development of novel cerebrospinal fluid, blood-based assays, positron emission tomography (PET), and magnetic resonance imaging (MRI) techniques, there still is a desperate need for a clinical imaging modality that can reliably image and quantify neuroinflammation in the aging brain and facilitate the identification of the key pathological players in different stages of AD. To address this unmet need and response to FOA “PAR-21-038”, we propose a new research direction to develop and establish a brand-new diffusion MRI (dMRI) technique, Diffusion Dictionary Imaging (DDI), as a safe, specific endogenous, and economical solution for the neuroinflammation imaging in AD. By tracking the random walk of water molecules using FDA-approved diffusion MRI sequence and compressed sensing technique, DDI measures and specifically extracts the microstructural changes associated with the activation and infiltration of the microglia and astrocyte in AD. Moreover, the previously collected dMRI data can be retrospectively analyzed with this new technique. Therefore, we are in a unique position to cost-effectively develop DDI by leveraging the longitudinal data-rich studies from the Knight Alzheimer’s Disease Research Center (ADRC) at Washington University (>800 Sporadic AD participants) and the multi-site international Dominantly Inherited Alzheimer Network (DIAN) observational study (>500 autosomal-dominant AD [ADAD] participants). In this project, we will develop the DDI technique and evaluate its capability of imaging neuroinflammation in the postmortem AD brains (Aim 1). We will examine the associations between the DDI neuroinflammation index and CSF and plasma inflammation biomarkers (YKL-40, sTREM2, and GFAP) in the Knight ADRC and DIAN cohorts (Aim 2). We will also cross-sectionally and longitudinally quantify the neuroinflammation using DDI in the Knight ADRC and DIAN cohorts and examine its connections with amyloid deposition and tauopathy measured by PET tracers and clinical outcomes (cognitive and progression) (Aim 3). The successful development of a quantitative endogenous DDI imaging biomarker of neuroinflammation will represent an important technological leap forward. The integration of DDI neuroinflammation biomarker into the DIAN and other clinical trial studies will provide clinically feasible neuroimaging surrogates that can significantly improve our understanding of the role of neuroinflammation in AD pathogenesis.