Abstract
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.
Glossary
- AEBP1=
- adipocyte enhancer-binding protein 1;
- AGC=
- auto gain control;
- CHI3L2=
- chitinase 3–like 2;
- CIS=
- clinically isolated syndrome;
- CTSL=
- cathepsin L1;
- EDSS=
- Expanded Disability Status Scale;
- HEXB=
- hexosaminidase;
- IFNβ=
- interferon beta-1b;
- MS=
- multiple sclerosis;
- MT3=
- metallothionein-3;
- NFL=
- neurofilament light chain;
- NPR=
- numeric progression rates;
- NXPH1=
- neurexophilin-1;
- PLD4=
- phospholipase D4;
- PPMS=
- progressive MS;
- PRM=
- parallel reaction monitoring;
- ROC=
- receiver operating characteristic;
- RRMS=
- relapsing-remitting course;
- SERPINA5=
- plasma serine protease inhibitor;
- SPATS2L=
- SPATS2-like protein;
- SPR=
- step progression rates;
- UPLC=
- ultra-performance liquid chromatography
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
The authors report no conflict of interest.
- Received February 26, 2021.
- Accepted in final form July 15, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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