snRNA-seq stratifies multiple sclerosis patients into distinct white matter glial responses.

Poor understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. To address this gap, we analyzed 632,000 single-nucleus RNA sequencing profiles from 156 brain tissue samples of MS and control donors to examine inter- and intra-donor heterogeneity. We found distinct cell type-specific gene expression changes between MS gray and white matter, highlighting clear pathology differences. MS lesion subtypes had different cellular compositions but surprisingly similar cell-type gene expression patterns both within and across patients, suggesting global changes. Most gene expression variability was instead explained by patient effects, allowing us to stratify patients and describe the different pathological processes occurring between patient subgroups. Future mapping of these brain molecular profiles with blood and/or CSF profiles from living MS patients will allow precision medicine approaches anchored in patient-specific pathological processes.