Dimethyl fumarate treatment in relapsing remitting MS changes the inflammatory CSF protein profile by a prominent decrease in T-helper 1 immunity

Background: Dimethyl fumarate (DMF) is a widely used treatment for multiple sclerosis (MS), nevertheless, the precise mechanisms of action remain poorly understood. Notably, limited attention has been given to investigating alterations in the protein composition of plasma and cerebrospinal fluid (CSF). Analyzing the modifications in inflammation- and neurodegeneration-associated proteins in the CSF and plasma of persons with MS (pwMS) undergoing DMF treatment, is a potential tool to unravel the impacts of DMF treatment and monitor the response to this therapy. Methods: Using the proximity extension assay (PEA), a technique that provides high sensitivity and specificity, we measured the levels of 182 inflammation and neuro-associated proteins in paired samples of plasma (n=28) and cerebrospinal fluid (n=12) of pwMS both before and after one year of treatment with DMF. Disease activity and progression were evaluated through clinical examination and magnetic resonance imaging. To uncover drug-induced effects on the protein profile and identify potential biomarkers for predicting treatment response, we employed non-parametric statistical tests, STRING network analysis, and logistic regression models. Results: Levels of 21 plasma proteins and 10 CSF proteins significantly changed during one year of treatment with DMF (p<0.01). T-helper 1 (Th1)-associated proteins (CXCL10, CXCL11, granzyme A, IL-12p70, lymphotoxin-alpha) consistently decreased in CSF, while IL-7 increased, in line with a reduction in the pro-inflammatory and presumed disease promoting Th1 immunity. The changes in plasma protein levels did not follow the same pattern as in CSF. Levels of 10 proteins in CSF and 1 protein in plasma differed among responders and non-responders (p<0.01), and logistic regression models showed proteins (including plexins and neurotrophins) as potential biomarker candidates for prediction of treatment response. Conclusions: DMF treatment induced prominent changes of CSF protein levels, with a consistent decrease in Th1-associated pro-inflammatory proteins. Several proteins in CSF related to neurodegeneration showed a potential to predict response to treatment, suggesting the use of protein biomarkers as a tool for personalized medicine.