Sex-Specific Differences in Amino Acids and Neurotransmitters in Multiple Sclerosis Patients Compared to Non-Neuroinflammatory Controls: A Retrospective Case-Control Study.

Multiple sclerosis (MS) is an immune-mediated chronic neuroinflammatory and neurodegenerative disorder. Inflammation in MS disrupts the barriers between blood and central nervous system and affects transport and diffusion of metabolites between blood and cerebrospinal fluid (CSF). In this exploratory retrospective case-control study, we used targeted metabolomics to evaluate differences in serum and CSF amino acid and neurotransmitter levels between patients with MS (n = 73) and non-neuroinflammatory controls (n = 78). The influence of patient characteristics, including sex, age, disease duration, severity and treatment status, was also analzyed. Although no significant differences in serum and CSF metabolite levels were found between MS and control patients, a stratification by sex uncovered significantly reduced metabolites in male MS patients compared to male controls in CSF but not in serum. While in male MS patients CSF histidine levels were decreased, female MS patients showed increased levels. Further, sex-specific associations of amino acids and neurotransmitters with disease duration and disability were observed. MS patients exhibited enhanced positive correlations between CSF and serum analyte levels. In serum, only a few amino acids, along with serotonin and glutathione, were associated with MS disease duration. Overall, this study suggests that targeted metabolomics of selected analytes in matched CSF and serum samples is a valuable approach for assessing alterations in CSF-serum metabolite associations in MS, as well as sex-specific imbalances between excitatory and inhibitory neurotransmitters across disease duration. Our findings further highlight the importance of considering sex as a key biological factor in MS.