Age Is a Major Modifier of Inflammatory CSF Signatures in MS

Novel and promising age-informed multiple sclerosis (MS) cerebrospinal fluid (CSF) biomarkers and targets for therapeutic intervention were identified in a retrospective cohort study published in Neurology: Neuroimmunology & Neuroinflammation.

Using a comprehensive targeted proteomic approach, researchers aimed to identify and analyze disease course-specific and age-related CSF protein signatures in MS.

The discovery cohort in which CSF samples were analyzed comprised patients with relapsing-remitting MS (n=30), primary progressive MS (n=30), Lyme neuroborreliosis (n=8), and neurologic controls (n=20). Findings were replicated in a validation cohort, which included 20 patients with MS and 8 neurologic control patients. All individuals with MS were newly diagnosed and naïve to treatment.

To explore the effect of CSF diagnostic parameters, demographics, and clinical variables on protein abundance, linear regression was used. Gene set enrichment analysis was used to identify molecular pathways altered in MS.

In the proteomics analysis, albumin quotient, age, immunoglobulin G (IgG) synthesis in CSF, cell count, sex, and CD19+ B-cells in CSF were found to explain some of the variability in protein levels.

In the discovery cohort, 42 proteins were significantly more abundant and 5 were significantly less abundant in patients with MS vs control patients. In general, CSF protein profiles were differentiated by lymphocyte activation and humoral immune response.

A total of 43 of the differentially expressed proteins were confirmed in the validation cohort. Of proteins validated, 33 reached statistical significance after adjusting for multiple testing. The gene set enrichment analysis identified lymphocyte signaling and interaction, adaptive immune system, cytokine signaling in immune system, and interleukin 10 signaling as the most significant functions related with altered protein expression in MS.

To identify MS-specific changes, the 47 differentially expressed proteins identified in the discovery cohort were compared with patients with Lyme neuroborreliosis. Patients with MS vs Lyme neuroborreliosis had 7 proteins expressed at a higher level and 3 proteins expressed at a lower level.

The proteomics analysis was repeated with serum samples and only 1 protein, neurofilament light chain (NEFL), was replicated.

Among patients with MS, 10 of the validated proteins were more abundant and 1 was less abundant in relapse-remitting MS vs primary progressive MS. These differences were suggestive of increased B-cell- and T-cell-related inflammation in active relapse-remitting MS.

In the age-stratified analysis, patients with MS aged older than 50 had fewer inflammation-related differentially expressed proteins and more differentially expressed proteins involved in aging, tissue repair, and neurodegeneration.

Study limitations include the small and unbalanced cohort sample sizes, absence of a neurodegenerative control cohort, and cross-sectional study design.

“Future studies should include large neuroinflammatory and neurodegenerative control cohorts to understand the general age-dependent effects on CSF protein abundance across different cohorts,” the study authors concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.