With the availability of more powerful treatments for multiple sclerosis (MS), prognostic biomarkers are badly needed.
Our objective was to evaluate the long-term prognostic value of 4 protiens in paired serum and CSF samples obtained early-on following MS diagnosis.
In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) and more than 15 years of routine clinical follow-up. Neurofilament light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Tau and UCHL-1 were quantified in paired serum (s) and CSF (c) samples from patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Outcomes of biomarker performance included conversion to progressive MS phenotype and reaching an EDSS ≥4.
67 patients had a median follow-up of 17.4 years (range:15.1-26.1), by which time 10/67 had been classified as PPMS, 16 SPMS and 41 RRMS. 29 had developed EDSS ≥4. Baseline CSF levels 3 of the candidate markers were higher than MS patients compared to controls: cNfL (Mann Whitney p=0.0001, median 624 vs. 277pg/mL), cGFAP (p<0.0001, 6900 vs. 694pg/mL) and cTau (p=0.0001, 15.4 vs. 8.12pg/mL) but not UCH-L1. Patient-control differences were less marked in serum: sNfL (p= 0.0037, 10.1 vs. 7.3pg/mL), sGFAP (p=0.0011, 68 vs 51pg/mL), no difference in sTau and sUCH-L1. Positive correlations existed between paired serum and CSF samples only for NfL (Spearman r=0.71, p<0.0001) and GFAP (r=0,4, p=0.003). ROC curve analysis showed cUCH-L1 was most predictive of developing EDSS ≥4 after 15 years of follow-up (AUC 0.72, p=0.003) followed by sNfL (AUC 0.70, p=0.012) and cGFAP (AUC 0.66, p=0.03). Similarly, cUCH-L1 was most predictive of developing a progressive phenotype (PP/SPMS, AUC 0.69, p=0.0097), followed by cGFAP (AUC 0.66, p=0.024) and barely by sNfL (AUC 0.64,p=0.057). cNfL (AUC 0.60,p=0.17), sGFAP, sTau, cTau and sUCH-L1 were not predictive of either reaching EDSS ≥4 or converting to a progressive phenotype (PP/SPMS).
This is the first study to report and association of baseline CSF UCH-L1 levels with long term clinical outcomes in MS. This marker was more predictive of EDSS worsening and conversion to a progressive phenotype than well-established markers NfL and GFAP. More generally, CSF biomarker levels better segregating MS patients from controls at baseline compaired to levels in paired serum samples.