Longitudinal proteomic profiling of cerebrospinal fluid in untreated multiple sclerosis defines evolving disease biology

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, but the molecular mechanisms underlying its course remain incompletely understood. We measured 4789 cerebrospinal fluid proteins in 1040 samples from 438 individuals with MS and controls followed longitudinally. To isolate disease-related biology, we adjusted for normal aging, sex, while also measuring residual effects of demographic and genetic covariates. Here we show that 3714 proteins are significantly associated with twelve clinical and imaging outcomes, highlighting processes linked to viral infection, disruption of epithelial barriers, stromal cell-mediated tissue remodeling, demyelination, and synaptic and neuronal loss. We also find strong sex-related differences: men show greater activation of pathways associated with tissue injury and disability accumulation, whereas women upregulate neurodevelopmental programs that may promote resilience or repair. These molecular maps of MS natural history provide a framework for understanding disease mechanisms and a resource for future drug development.