dc.contributor.author
Kotelnikova, Ekaterina
dc.contributor.author
Kiani, Narsis A.
dc.contributor.author
Abad, Elena
dc.contributor.author
Martinez-Lapiscina, Elena H.
dc.contributor.author
Andorra, Magi
dc.contributor.author
Paul, Friedemann
dc.date.accessioned
2018-06-08T11:03:21Z
dc.date.available
2017-11-30T12:13:08.572Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/21539
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-24829
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.
en
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit
dc.title
Dynamics and heterogeneity of brain damage in multiple sclerosis
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
PLoS Comput Biol. - 13 (2017), 10, Artikel Nr. e1005757
dcterms.bibliographicCitation.doi
10.1371/journal.pcbi.1005757
dcterms.bibliographicCitation.url
http://doi.org/10.1371/journal.pcbi.1005757
refubium.affiliation
Charité - Universitätsmedizin Berlin
de
refubium.mycore.fudocsId
FUDOCS_document_000000028580
refubium.note.author
Der Artikel wurde in einer reinen Open-Access-Zeitschrift publiziert.
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000009187
dcterms.accessRights.openaire
open access