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dc.contributor.authorKotelnikova, Ekaterina
dc.contributor.authorKiani, Narsis A.
dc.contributor.authorAbad, Elena
dc.contributor.authorMartinez-Lapiscina, Elena H.
dc.contributor.authorAndorra, Magi
dc.contributor.authorZubizarreta, Irati
dc.contributor.authorPulido-Valdeolivas, Irene
dc.contributor.authorPertsovskaya, Inna
dc.contributor.authorAlexopoulos, Leonidas G.
dc.contributor.authorOlsson, Tomas
dc.contributor.authorMartin, Roland
dc.contributor.authorPaul, Friedemann
dc.contributor.authorTegner, Jesper
dc.contributor.authorGarcia-Ojalvo, Jordi
dc.contributor.authorVilloslada, Pablo
dc.date.accessioned2017-10-30T07:55:29Z
dc.date.available2017-10-30T07:55:29Z
dc.date.issued2017-10-26
dc.identifier.citationKotelnikova E, Kiani NA, Abad E, Martinez-Lapiscina EH, Andorra M, et al. (2017) Dynamics and heterogeneity of brain damage in multiple sclerosis. PLOS Computational Biology 13: e1005757. Available: http://dx.doi.org/10.1371/journal.pcbi.1005757.
dc.identifier.issn1553-7358
dc.identifier.pmid29073203
dc.identifier.doi10.1371/journal.pcbi.1005757
dc.identifier.urihttp://hdl.handle.net/10754/625966
dc.description.abstractMultiple 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.sponsorshipFunding support: 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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.publisherPublic Library of Science (PLoS)
dc.relation.urlhttp://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1005757
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleDynamics and heterogeneity of brain damage in multiple sclerosis
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
dc.identifier.journalPLOS Computational Biology
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionCenter for Neuroimmunology, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
dc.contributor.institutionUnit of Computational Medicine, Department of Medicine & Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
dc.contributor.institutionUniversitat Pompeu Fabra, Barcelona, Spain.
dc.contributor.institutionNational Technical University of Athens, Athens, Greece.
dc.contributor.institutionUnit of Neuroimmunology, Karolinska Institute, Stockholm, Sweden.
dc.contributor.institutionNeuroimmunology and MS Research, Neurology Clinic, University Hospital, University Zurich, Zurich, Switzerland.
dc.contributor.institutionNeuroCure Clinical Research Center, and the Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine Berlin, Berlin, Germany.
dc.contributor.institutionUniversity of California, San Francisco, United States of America.
kaust.personTegner, Jesper
refterms.dateFOA2018-06-14T03:34:55Z


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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.