Neurodegeneration and humoral response proteins in cerebrospinal fluid associate with pediatric-onset multiple sclerosis and not monophasic demyelinating syndromes in childhood

Arlette L. Bruijstens*, Christoph Stingl, Dutch Pediatric MS and ADEM Study Group, Canadian Pediatric Demyelinating Diseases Network, Coskun Güzel, Marcel P. Stoop, Yu Yi M. Wong, E. Danielle van Pelt, Brenda L. Banwell, Amit Bar-Or, Theo M. Luider, Rinze F. Neuteboom

*Corresponding author for this work

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Abstract

Background: Pediatric-onset multiple sclerosis (POMS) represents the earliest stage of disease pathogenesis. Investigating the cerebrospinal fluid (CSF) proteome in POMS may provide novel insights into early MS processes. Objective: To analyze CSF obtained from children at time of initial central nervous system (CNS) acquired demyelinating syndrome (ADS), to compare CSF proteome of those subsequently ascertained as having POMS versus monophasic acquired demyelinating syndrome (mADS). Methods: Patients were selected from two prospective pediatric ADS studies. Liquid chromatography-mass spectrometry (LC-MS) was performed in a Dutch discovery cohort (POMS n = 28; mADS n = 39). Parallel reaction monitoring-mass spectrometry (PRM-MS) was performed on selected proteins more abundant in POMS in a combined Dutch and Canadian validation cohort (POMS n = 48; mADS n = 106). Results: Discovery identified 5580 peptides belonging to 576 proteins; 58 proteins were differentially abundant with > 2 peptides between POMS and mADS, of which 28 more abundant in POMS. Fourteen had increased abundance in POMS with > 8 unique peptides. Five selected proteins were all confirmed within validation. Adjusted for age, 2 out of 5 proteins remained more abundant in POMS, that is, Carboxypeptidase E (CPE) and Semaphorin-7A (SEMA7A). Conclusion: This exploratory study identified several CSF proteins associated with POMS and not mADS, potentially reflecting neurodegeneration, compensatory neuroprotection, and humoral response in POMS. The proteins associated with POMS highly correlated with age at CSF sampling.

Original languageEnglish
Pages (from-to)52-62
Number of pages11
JournalMultiple Sclerosis Journal
Volume29
Issue number1
Early online date24 Sept 2022
DOIs
Publication statusPublished - Jan 2023

Bibliographical note

Funding Information:
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.L.B., C.S., C.G., M.P.S., Y.Y.M.W., E.D.vP. B.L.B., T.M.L., and R.F.N. declared no conflicts of interest. A.B-O. has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme.

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported in part by the Dutch MS Research Foundation and the Canadian Multiple Sclerosis Scientific Research Foundation. This study was not industry sponsored.

Funding Information:
The authors thank the patients and their families for their participation in this study as well as members of the Dutch Pediatric MS and ADEM Study Group and the Canadian Pediatric Demyelinating Disease Network for their contributions. Furthermore, the authors would like to dedicate this manuscript to the memory of Prof. Rogier Q. Hintzen, who was actively involved in the original concept of the study and in the first analyses, but unexpectedly passed away on 15 May 2019. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported in part by the Dutch MS Research Foundation and the Canadian Multiple Sclerosis Scientific Research Foundation. This study was not industry sponsored.

Publisher Copyright:
© The Author(s), 2022.

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