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Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach
Accurate determination of relapses in multiple sclerosis is important for diagnosis, classification of clinical course and therapeutic decision making. The identification of biofluid markers for multiple sclerosis relapses would add to our current diagnostic armamentarium and increase our understand...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568847/ https://www.ncbi.nlm.nih.gov/pubmed/34755110 http://dx.doi.org/10.1093/braincomms/fcab240 |
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author | Yeo, Tianrong Probert, Fay Sealey, Megan Saldana, Luisa Geraldes, Ruth Höckner, Sebastian Schiffer, Eric Claridge, Timothy D W Leppert, David DeLuca, Gabriele Kuhle, Jens Palace, Jacqueline Anthony, Daniel C |
author_facet | Yeo, Tianrong Probert, Fay Sealey, Megan Saldana, Luisa Geraldes, Ruth Höckner, Sebastian Schiffer, Eric Claridge, Timothy D W Leppert, David DeLuca, Gabriele Kuhle, Jens Palace, Jacqueline Anthony, Daniel C |
author_sort | Yeo, Tianrong |
collection | PubMed |
description | Accurate determination of relapses in multiple sclerosis is important for diagnosis, classification of clinical course and therapeutic decision making. The identification of biofluid markers for multiple sclerosis relapses would add to our current diagnostic armamentarium and increase our understanding of the biology underlying the clinical expression of inflammation in multiple sclerosis. However, there is presently no biofluid marker capable of objectively determining multiple sclerosis relapses although some, in particular neurofilament-light chain, have shown promise. In this study, we sought to determine if metabolic perturbations are present during multiple sclerosis relapses, and, if so, identify candidate metabolite biomarkers and evaluate their discriminatory abilities at both group and individual levels, in comparison with neurofilament-light chain. High-resolution global and targeted (1)H nuclear magnetic resonance metabolomics as well as neurofilament-light chain measurements were performed on the serum in four groups of relapsing-remitting multiple sclerosis patients, stratified by time since relapse onset: (i) in relapse (R); (ii) last relapse (LR) ≥ 1 month (M) to < 6 M ago; (iii) LR ≥ 6 M to < 24 M ago; and (iv) LR ≥ 24 M ago. Two hundred and one relapsing-remitting multiple sclerosis patients were recruited: R (n = 38), LR 1–6 M (n = 28), LR 6–24 M (n = 34), LR ≥ 24 M (n = 101). Using supervised multivariate analysis, we found that the global metabolomics profile of R patients was significantly perturbed compared to LR ≥ 24 M patients. Identified discriminatory metabolites were then quantified using targeted metabolomics. Lysine and asparagine (higher in R), as well as, isoleucine and leucine (lower in R), were shortlisted as potential metabolite biomarkers. ANOVA of these metabolites revealed significant differences across the four patient groups, with a clear trend with time since relapse onset. Multivariable receiver operating characteristics analysis of these four metabolites in discriminating R versus LR ≥ 24 M showed an area under the curve of 0.758, while the area under the curve for serum neurofilament-light chain was 0.575. Within individual patients with paired relapse–remission samples, all four metabolites were significantly different in relapse versus remission, with the direction of change consistent with that observed at group level, while neurofilament-light chain was not discriminatory. The perturbations in the identified metabolites point towards energy deficiency and immune activation in multiple sclerosis relapses, and the measurement of these metabolites, either singly or in combination, are useful as biomarkers to differentiate relapse from remission at both group and individual levels. |
format | Online Article Text |
id | pubmed-8568847 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-85688472021-11-08 Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach Yeo, Tianrong Probert, Fay Sealey, Megan Saldana, Luisa Geraldes, Ruth Höckner, Sebastian Schiffer, Eric Claridge, Timothy D W Leppert, David DeLuca, Gabriele Kuhle, Jens Palace, Jacqueline Anthony, Daniel C Brain Commun Original Article Accurate determination of relapses in multiple sclerosis is important for diagnosis, classification of clinical course and therapeutic decision making. The identification of biofluid markers for multiple sclerosis relapses would add to our current diagnostic armamentarium and increase our understanding of the biology underlying the clinical expression of inflammation in multiple sclerosis. However, there is presently no biofluid marker capable of objectively determining multiple sclerosis relapses although some, in particular neurofilament-light chain, have shown promise. In this study, we sought to determine if metabolic perturbations are present during multiple sclerosis relapses, and, if so, identify candidate metabolite biomarkers and evaluate their discriminatory abilities at both group and individual levels, in comparison with neurofilament-light chain. High-resolution global and targeted (1)H nuclear magnetic resonance metabolomics as well as neurofilament-light chain measurements were performed on the serum in four groups of relapsing-remitting multiple sclerosis patients, stratified by time since relapse onset: (i) in relapse (R); (ii) last relapse (LR) ≥ 1 month (M) to < 6 M ago; (iii) LR ≥ 6 M to < 24 M ago; and (iv) LR ≥ 24 M ago. Two hundred and one relapsing-remitting multiple sclerosis patients were recruited: R (n = 38), LR 1–6 M (n = 28), LR 6–24 M (n = 34), LR ≥ 24 M (n = 101). Using supervised multivariate analysis, we found that the global metabolomics profile of R patients was significantly perturbed compared to LR ≥ 24 M patients. Identified discriminatory metabolites were then quantified using targeted metabolomics. Lysine and asparagine (higher in R), as well as, isoleucine and leucine (lower in R), were shortlisted as potential metabolite biomarkers. ANOVA of these metabolites revealed significant differences across the four patient groups, with a clear trend with time since relapse onset. Multivariable receiver operating characteristics analysis of these four metabolites in discriminating R versus LR ≥ 24 M showed an area under the curve of 0.758, while the area under the curve for serum neurofilament-light chain was 0.575. Within individual patients with paired relapse–remission samples, all four metabolites were significantly different in relapse versus remission, with the direction of change consistent with that observed at group level, while neurofilament-light chain was not discriminatory. The perturbations in the identified metabolites point towards energy deficiency and immune activation in multiple sclerosis relapses, and the measurement of these metabolites, either singly or in combination, are useful as biomarkers to differentiate relapse from remission at both group and individual levels. Oxford University Press 2021-10-12 /pmc/articles/PMC8568847/ /pubmed/34755110 http://dx.doi.org/10.1093/braincomms/fcab240 Text en © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article Yeo, Tianrong Probert, Fay Sealey, Megan Saldana, Luisa Geraldes, Ruth Höckner, Sebastian Schiffer, Eric Claridge, Timothy D W Leppert, David DeLuca, Gabriele Kuhle, Jens Palace, Jacqueline Anthony, Daniel C Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach |
title | Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach |
title_full | Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach |
title_fullStr | Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach |
title_full_unstemmed | Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach |
title_short | Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach |
title_sort | objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568847/ https://www.ncbi.nlm.nih.gov/pubmed/34755110 http://dx.doi.org/10.1093/braincomms/fcab240 |
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