Proteomics Reveals Age as Major Modifier of Inflammatory CSF Signatures in Multiple Sclerosis.

Background and objectives: Multiple sclerosis (MS) can start as relapsing or progressive. While their clinical features and treatment responses are distinct, it has remained uncertain whether their pathomechanisms differ. A notable age-related effect on MS phenotype and response to immunotherapies is well acknowledged, but the underlying pathophysiologic reasons are yet to be fully elucidated. We aimed to identify disease-specific and age-related proteomic signatures using a comprehensive targeted proteomic analysis.

Methods: In our retrospective cohort study, we analyzed the CSF and serum proteome of age-matched individuals with treatment-naïve relapsing-remitting and primary progressive MS, neurologic controls (NC), and individuals with neuroborreliosis using targeted proteomics and validated findings in an independent cohort. Proteomic results were integrated with clinical and laboratory covariates.

Results: Among 2,500 proteins, 47 CSF proteins were distinct between individuals with MS (n = 60) and NC (n = 20), with a subset also differing from those with neuroborreliosis (n = 8). We identified MS-associated proteins, including novel candidate biomarkers such as LY9 and JCHAIN, and putative treatment targets, such as SLAMF7, BCMA, and IL5RA, for which drugs are already licensed in other indications. The CSF proteome differences between relapsing and progressive MS were minimal, but major changes were noted in individuals older than 50 years, indicating a shift from MS-associated inflammatory to age-related protein signature. NEFL was the only serum protein that differed between individuals with MS and controls.

Discussion: This study unveils a unique CSF proteomic signature in MS, providing new pathophysiologic insights and identifying novel biomarker candidates and potential therapeutic targets. Our findings highlight similar immunologic mechanisms in relapsing and progressive MS and underscore aging's profound effect on the intrathecal immune response. This aligns with the observed lower efficacy of immunotherapies in the elderly, thus emphasizing the necessity for alternative therapeutic approaches in treating individuals with MS beyond the age of 50.