Defining Mechanisms of Cognitive Dysfunction in Central Nervous System Autoimmunity

Stanford University, Stanford CA

Investigators

Abstract

Project Summary Cumulative evidence indicates neuromyelitis optica (NMO) patients suffer from disabling cognitive decline (CD) despite effective immune therapies. We must therefore identify modifiable risk and protective factors to prevent neurologic disability from CD. Indeed, there is high interest among people living with CD if immune therapy preserves cognitive function. We have shown in our longitudinal, multi-center study using Montreal Cognitive Assessment (MoCA) that up to a third of NMO patients suffer CD, independent of clinical relapse. This R21 will evaluate the pathogenic NMO-IgG as a mediator of CD in NMO. Distinct patterns of CD among NMO patients exist, but the underlying mechanism is unknown. Others have shown brain atrophy occurs in NMO even in the absence of cerebral syndromes, while we have linked the NMO-IgG index titers with brain atrophy, which informed our hypothesis that NMO-IgG is a mediator of CD by targeting the blood- brain barrier (BBB) astrocytes with resultant gray and white matter dysfunction. Using NMO as an experimental model of immune-mediated CD, this study will leverage two distinct pre-existing cohorts with rich clinical and imaging data accompanied by biospecimens. The first is CIRCLES (Collaborative International Research in Clinical and Longitudinal Experience Study) cohort comprised of >1000 NMO patients from 2013-2020. This current proposal will link in-depth cognitive analyses with high-resolution, state-of the-art imaging data and cutting-edge proteomic blood biomarker studies, while mining over 8 years of follow-up data. The second is a prospective, ongoing biorepository, Project BIG (Stanford Brain, Immune and Gut Initiative), accessing data from >100 NMO patients, which will provide additional information on treatment effects on cognition over time. Specific aims are designed to test the hypothesis that NMO-IgG expression is directly linked to BBB deficiency and white matter pathology, leading to CD (aim 1), and that astrocyte damage from the NMO-IgG attack leads to gray matter dysfunction and CD (aim 2). Detailed data on clinical and socio-demographic modifiers of cognitive function will be accounted for in all analyses. The immediate impact of this study is to stop subclinical, relapse-independent progression and enhance productivity and quality of life, eagerly sought by patients living with NMO. In broader terms, this proposal has a high potential for advancing our understanding of the pathophysiology of immune-mediated CD and development of therapies targeting neurotoxic immune responses.