A large proteomic analysis found that signs of myelin damage were present about 7 years prior to the first neurologic symptoms of multiple sclerosis. Axonal injury followed roughly 1 year later, while astrocytic involvement appeared only at clinical onset.
Serum levels of myelin oligodendrocyte glycoprotein (MOG) and neurofilament light chain (NEFL) were elevated years before symptom onset, whereas glial fibrillary acidic protein elevated close to diagnosis. In presymptomatic stages, pathways linked to interleukin (IL)-3 and nuclear factor (NF) kappa-B were activated, indicating early immune activity.
Among more than 5,000 proteins analyzed, 38 differed prior to symptom onset and 18 remained distinct afterward. A 21-protein panel identified presymptomatic multiple sclerosis (MS) with 91% sensitivity and 65% specificity (area under the curve = 0.81).
Network analyses showed higher connectivity among B cells and natural killer cells, with emerging activity in oligodendrocyte precursors. Patients with a previously described MS-specific autoantibody immunological cluster (IC) displayed stronger B-cell, T-cell, and plasma-cell connectivity following symptom onset compared with those without IC, underscoring heterogeneity in immune response profiles.
Investigators examined 315 serum samples from 134 patients with MS and 79 matched controls from the US Department of Defense Serum Repository (DODSR) as well as 26 patients from the University of California, San Francisco ORIGINS cohort. Samples taken a median of 4 years prior to symptom onset were analyzed using the Olink Explore HT assay, which quantified over 5,000 proteins per sample.
Data were obtained from the Defense Medical Surveillance System and Defense Health Agency (1987 to 2007 and released 2010). Analyses were adjusted for age and sex. Mixed-effects models estimated when protein levels diverged between MS and controls, while pathway and network analyses mapped immune and cellular processes associated with early disease. Machine-learning models (random forest and logistic regression) were used to train and test the biomarker panel’s accuracy.
Investigators noted that the DODSR cohort was predominantly male, differing from the general MS population. Long-term serum storage could have affected protein stability, and detailed genetic and therapy information was unavailable for several participants. The classifier hasn't been validated in independent presymptomatic cohorts, and data set-specific biases may remain.
The results demonstrated that biological processes leading to MS may begin long before symptoms manifestation. The early appearance of MOG, NEFL, IL-3, and NF–kappa-B activity defined a preclinical immune-activation phase that preceded the inflammation seen following onset.
Full disclosures can be found in the published study.
Source: Nature Medicine
