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Objective  This study aimed to identify long-term prognostic protein biomarkers associated with disease progression in patients with progressive multiple sclerosis (MS).    Methods  CSF samples were collected from a discovery cohort of 28 patients with progressive MS who participated in a clinical trial with interferon beta. Patients were classified into high and low disability progression phenotypes according to numeric progression rates (NPR) and step-based progression rates (SPR) after a mean follow-up time of 12 years. Protein abundance was measured by shotgun proteomics. Selected proteins from the discovery cohort were quantified by parallel reaction monitoring in CSF samples from an independent validation cohort of 41 patients with progressive MS classified also into high and low disability progression phenotypes after a mean follow-up time of 7 years.    Results  Of 2,548 CSF proteins identified in the discovery cohort, 10 were selected for validation based on their association with long-term disability progression: SPATS2-like protein, chitinase 3–like 2 (CHI3L2), plasma serine protease inhibitor, metallothionein-3, phospholipase D4, beta-hexosaminidase, neurexophilin-1, adipocyte enhancer-binding protein 1, cathepsin L1, and lipopolysaccharide-binding protein. Only CHI3L2 was validated, and patients with high disability progression exhibited significantly higher CSF protein levels compared with patients with low disability progression ( p  = 0.03 for NPR and  p  = 0.02 for SPR). CHI3L2 levels showed good performance to discriminate between high and low disability progression in patients with progressive MS (area under the curve 0.73; sensitivity 90% and specificity 63%).    Conclusions  Although further confirmatory studies are needed, we propose CSF CHI3L2 as a prognostic protein biomarker associated with long-term disability progression in patients with progressive MS.    Classification of Evidence  This study provides Class II evidence that high CSF CHI3L2 levels identified higher disability progression in patients with progressive MS.

CSF Chitinase 3–Like 2 Is Associated With Long-term Disability Progression in Patients With Progressive Multiple Sclerosis