Serum proteome characterizes sequence of CNS injury in pre-symptomatic multiple sclerosis

The timing of the biological onset of multiple sclerosis (MS) is unclear. We utilized high-throughput discovery proteomics and samples from pre-symptomatic individuals with MS (pwMS) and matched healthy controls (HC) to define the biological neurological onset and characterize involved mechanisms. Remarkably, myelin injury was seen 7-8 years before the symptomatic onset and preceded evidence of axonal injury by 1-2 years. By contrast, astrocyte involvement became evident only at clinical onset. Numerous changes in the serum proteome indicate the involvement of interleukin 3 and nuclear factor kappa B pathways during the pre-symptomatic stage. A protein biomarker panel identified pre-symptomatic pwMS from HC with 95% sensitivity. Additionally, pwMS with a distinct autoantibody signature showed increased immune cell activity compared to those without. Our findings can help decipher the pathophysiology of MS as well as the cascade of CNS injury and facilitate early detection of MS in high-risk individuals.