ARIA Pathophysiology Characterized by in vivo Neuroimaging, Plasma Biomarkers and Post-Mortem Proteomics

New York University School Of Medicine, New York NY

Investigators

Abstract

PROJECT SUMMARY There is an urgent and crucial unmet need for tools and resources developed to understand the vascular pathophysiology of in vivo neuroimaging findings in amyloid-related imaging abnormalities (ARIA). We propose to develop and validate a comprehensive set of in vivo and ex vivo post-mortem MR imaging protocols, along with analytical tools focusing on vascular pathogenesis and pathophysiology. These resources will help link MR imaging findings with clinical symptoms, cognitive functions, plasma biomarkers, and histopathological findings in a cohort that will be longitudinally followed with both ante-mortem and post-mortem data. We have assembled a multi-disciplinary research team with leading experts in several key aspects of the proposed study to achieve the following specific aims. Specific Aim 1. Characterize the vascular pathology contributing to ARIA using advanced MRI techniques in a prospective cohort of patients developing ARIA following anti-amyloid antibody treatment, compared to controls. Utilizing multi-modal vascular imaging protocols including the widely applied MarkVCID 3T imaging protocol with high reproducibility, we will assess water permeability across a vessel wall, cerebrovascular reactivity (CVR), and cerebral blood flow (CBF) before and after anti- amyloid treatment. Additionally, free water (FW) imaging, peak width of Skeletonized Mean Diffusivity (PSMD), and cerebral oxygen metabolism will be used to assess neuronal/axonal injury associated with ARIA. Specific Aim 2. Characterize longitudinal changes of plasma biomarkers before and after ARIA is identified and correlate these changes with the imaging findings described in Aim 1 and clinical performance in patients with and without ARIA. The plasma biomarkers include markers of neurodegeneration, neuroinflammation, and vascular pathology used in studies of Alzheimer's disease (AD) and AD-related dementias (ADRD) to better understand disease mechanisms and identify ARIA risk factors. Specific Aim 3. Conduct histopathology and proteomics studies on patients with ARIA who have participated in Aims 1 and 2 as well as utilizing available post-mortem brains from other patients with ARIA, to provide mechanistic insights and potentially identify novel ARIA-associated biomarkers. Specific Aim 4. Develop in vivo and postmortem tools and resources, along with relevant biomaterials of ARIA, to be shared with the research community from the above studies. We will leverage the synergy between the current project and two other large ongoing studies, which focus on in vivo clinical biomarkers and vascular pathophysiology, alongside postmortem tools and resource development for AD/ADRD. This unique synergetic effort will greatly enhance the success of our initiatives. Together, we aim to build a comprehensive schema for capturing metadata in prospectively designed in vivo and ex vivo studies. This schema will aid in determining the cause, impact, and prognosis of ARIA, ultimately informing future clinical guidance.