Repository Core

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PROJECT SUMMARY – Repository Core The overarching goal of the Clinical significance of INciDEntal white matter lEsions on MRI in a Diverse population with cognitive complaints (INDEED) is to identify anatomic and biologic modulators of progressive white matter (WM) injury that drive cognitive impairment using a precision medicine approach in a large and diverse clinical population. To achieve this goal, three essential biological datasets will be acquired: 1) harmonized neuroimaging data to document the degree, location, and amount of WM injury; 2) fluid biomarker data to evaluate risk modifiers including inflammation, endothelial dysfunction, and co-morbid neurodegenerative conditions; and 3) genetic data to measure intrinsic genetic susceptibility using polygenic risk scores for Alzheimer's disease (AD) and WM hyperintensities (WMH) and known sequence variants (e.g. APOE4 and NOTCH3). The goal of the Repository Core (RC), therefore, is to use harmonized approaches to collect, process, store, track, analyze, and share neuroimaging, biospecimens and associated genetic data. Centralized core services are needed to effectively support the research mission and enable the scientific synergy necessary for a project of this scale, in which samples and data will be obtained from 2,250 diverse subjects nationwide at three time points, for a total of up to 6,750 data/sample sets. Collecting data/samples from multiple sites over 5 years will require standardized quality control (QC) checks, data tracking, and coordination with research staff at participating clinic sites. The RC, with its leadership and investigators experienced in managing similar tasks in the NINDS MarkVCID Consortium and ADRC Cores, will provide the technical, professional, and physical infrastructure to effectively implement the core mission by executing four specific aims. In Aim 1, the RC will work with NINDS, the Administrative Core (AC), and the collaborating clinic sites to develop and implement standardized operating procedures for blood collection, processing, sub- aliquoting, freezing, shipping, long-term storage, and distribution, by leveraging the existing AD Centers Program, MarkVCID Consortium, and DISCOVERY Network protocols. In Aim 2, we will generate, store, analyze, and distribute blood biomarker and genetic data relevant to WM injury and co-morbid neurodegenerative pathologies. In Aim 3, we will oversee acquisition, analysis, QC, and distribution of harmonized neuroimaging data that will directly inform the rate of progression and anatomic features of WM injury to their role in cognitive impairment. In Aim 4, we will work with the AC and the Statistical Core to export data and sample information, thus contributing to the sharing of data and specimens broadly with the research community. The RC will ensure consistent integrity of data and samples that will deliver a high level of scientific rigor and the reproducibility of results. The deposited data and biospecimens will create a rich and high-quality resource for future analyses, novel biomarker discovery, and identification of therapeutically significant pathways that underlie the contribution of WM injury to cognitive decline and dementia.