Large scale cerebrospinal fluid proteomics reveals biomarkers of Multiple Sclerosis

Cerebrospinal fluid (CSF) plays critical roles in clinical diagnostics, offers a window into neuropathological mechanisms and is available at scale. To enable its large-scale proteomics characterization, we developed a high-throughput mass spectrometry-based workflow based on the Orbitrap Astral. This workflow quantifies about 2100 proteins per sample at a throughput of 100 samples per day. We measured 2600 CSF samples across a discovery and replication cohort from patients with multiple sclerosis and related inflammatory CNS conditions as well as neurological controls. Analysis of CSF proteomes yielded a panel of 29 protein biomarkers to identify MS with better diagnostic performance than established clinical CSF markers (QIgG, QAlb, leukocyte count) amongst patients presenting with MS-like symptoms but without CSF-specific oligoclonal bands.