Proteomic analysis of cerebrospinal fluid from females with multiple sclerosis highlights elevated microglial function and impaired neurogenesis

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that is characterized by demyelination, inflammation, and neurological damage. MS is the most common neurological disorder of young adults, negatively impacting their quality of life. Recent population-based estimates have determined that the prevalence of MS in the United States is growing and can be up to 3 times higher in females. While the etiology of MS is complex, involving genetics, immune dysregulation, and environmental triggers, the factors elevating MS risk in women are relatively unexplored. Hence, there is a major need for studies that further our understanding of the pathophysiology of MS in women and identify potential biomarkers and therapeutic targets. To this end, we used highly sensitive and untargeted liquid chromatography-mass spectrometry (LC-MS) to identify proteins in the cerebrospinal fluid (CSF) of age-matched females who were either diagnosed with MS or headache (HA). We found that the CSF of female individuals with MS was enriched in proteins involved in macrophage and microglia function yet depleted in proteins involved in neurogenesis and neuronal function. Overall, our findings support recently identified therapeutic targets (e.g., FABP5), as well as highlighting potential targets that may predict or promote MS neuropathogenesis in females (e.g., CD99, APOC3), which should be studied in larger cohorts going forward.