Dynamics and heterogeneity of brain damage in multiple sclerosis

Kotelnikova, Ekaterina; Kiani, Narsis A.; Abad Adan, Elena; Martínez Lapiscina, Elena H.; Andorrà, Magí; Zubizarreta, Irati; Pulido Valdeolivas, Irene; Pertsovskaya, Inna; Alexopoulos, Leonidas G.; Olsson, Tomas; Martin, Roland; Paul, Friedemann; Tegnér, Jesper; García Ojalvo, Jordi; Villoslada, Pablo

Dynamics and heterogeneity of brain damage in multiple sclerosis

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dc.contributor.author Kotelnikova, Ekaterinaca
dc.contributor.author Kiani, Narsis A.ca
dc.contributor.author Abad Adan, Elenaca
dc.contributor.author Martínez Lapiscina, Elena H.ca
dc.contributor.author Andorrà, Magíca
dc.contributor.author Zubizarreta, Iratica
dc.contributor.author Pulido Valdeolivas, Ireneca
dc.contributor.author Pertsovskaya, Innaca
dc.contributor.author Alexopoulos, Leonidas G.ca
dc.contributor.author Olsson, Tomasca
dc.contributor.author Martin, Rolandca
dc.contributor.author Paul, Friedemannca
dc.contributor.author Tegnér, Jesperca
dc.contributor.author García Ojalvo, Jordica
dc.contributor.author Villoslada, Pabloca
dc.date.accessioned 2018-03-21T08:06:17Z
dc.date.available 2018-03-21T08:06:17Z
dc.date.issued 2017
dc.description.abstract Multiple Sclerosis (MS) is an autoimmune disease driving inflammatory and degenerative processes that damage the central nervous system (CNS). However, it is not well understood how these events interact and evolve to evoke such a highly dynamic and heterogeneous disease. We established a hypothesis whereby the variability in the course of MS is driven by the very same pathogenic mechanisms responsible for the disease, the autoimmune attack on the CNS that leads to chronic inflammation, neuroaxonal degeneration and remyelination. We propose that each of these processes acts more or less severely and at different times in each of the clinical subgroups. To test this hypothesis, we developed a mathematical model that was constrained by experimental data (the expanded disability status scale [EDSS] time series) obtained from a retrospective longitudinal cohort of 66 MS patients with a long-term follow-up (up to 20 years). Moreover, we validated this model in a second prospective cohort of 120 MS patients with a three-year follow-up, for which EDSS data and brain volume time series were available. The clinical heterogeneity in the datasets was reduced by grouping the EDSS time series using an unsupervised clustering analysis. We found that by adjusting certain parameters, albeit within their biological range, the mathematical model reproduced the different disease courses, supporting the dynamic CNS damage hypothesis to explain MS heterogeneity. Our analysis suggests that the irreversible axon degeneration produced in the early stages of progressive MS is mainly due to the higher rate of myelinated axon degeneration, coupled to the lower capacity for remyelination. However, and in agreement with recent pathological studies, degeneration of chronically demyelinated axons is not a key feature that distinguishes this phenotype. Moreover, the model reveals that lower rates of axon degeneration and more rapid remyelination make relapsing MS more resilient than the progressive subtype. Therefore, our results support the hypothesis of a common pathogenesis for the different MS subtypes, even in the presence of genetic and environmental heterogeneity. Hence, MS can be considered as a single disease in which specific dynamics can provoke a variety of clinical outcomes in different patient groups. These results have important implications for the design of therapeutic interventions for MS at different stages of the disease.
dc.description.sponsorship The European Union Seventh Framework Program (HEALTH-F4-2012-305397): “CombiMS”, grant agreement No 30539; the Horizon 2020 program ERACOSYSMED: Sys4MS grant, and the Spanish Ministry of Economy and Competitiveness and FEDER (project FIS2015-66503-C3-1-P), and the Swedish Research Council (3R).
dc.format.mimetype application/pdf
dc.identifier.citation Kotelnikova E, Kiani NA, Abad E, Martinez-Lapiscina EH, Andorra M, Zubizarreta I et al. Dynamics and heterogeneity of brain damage in multiple sclerosis. PLoS Comput Biol. 2017 Oct 26;13(10):e1005757. DOI: 10.1371/journal.pcbi.1005757
dc.identifier.doi http://dx.doi.org/10.1371/journal.pcbi.1005757
dc.identifier.issn 1553-734X
dc.identifier.uri http://hdl.handle.net/10230/34222
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)ca
dc.relation.ispartof PLOS Computational Biology. 2017 Oct 26;13(10):e1005757
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305397
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/643271
dc.rights © 2017 Kotelnikova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Multiple sclerosis
dc.subject.keyword Inflammation
dc.subject.keyword Brain damage
dc.title Dynamics and heterogeneity of brain damage in multiple sclerosisca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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