TY - JOUR
T1 - The sequence of structural, functional and cognitive changes in multiple sclerosis
AU - Dekker, Iris
AU - Schoonheim, Menno M.
AU - Venkatraghavan, Vikram
AU - Eijlers, Anand J. C.
AU - Brouwer, Iman
AU - Bron, Esther E.
AU - Klein, Stefan
AU - Wattjes, Mike P.
AU - Wink, Alle Meije
AU - Geurts, Jeroen J. G.
AU - Uitdehaag, Bernard M. J.
AU - Oxtoby, Neil P.
AU - Alexander, Daniel C.
AU - Vrenken, Hugo
AU - Killestein, Joep
AU - Barkhof, Frederik
AU - Wottschel, Viktor
N1 - Funding Information: Dekker received speaking honoraria from Roche. M.M. Schoonheim serves on the editorial board of Frontiers of Neurology and has received compensation for consulting services or speaker honoraria from ExceMed, Genzyme and Biogen. V. Venkatraghavan reports no disclosures. A.J.C. Eijlers reports no disclosures. I. Brouwer reports no disclosures. E.E. Bron reports no disclosures. S. Klein reports no disclosures. M.P. Wattjes reports personal consulting/speaking fees from Biogen, Novartis, Roche, Celgene, IXICO, Sanofi Genzyme, Bayer Healthcare, Biologix, Genilac, Merck Serono. A.M. Wink reports no disclosures. J.J.G. Geurts is an editor of MS journal and serves on the editorial boards of Neurology and Frontiers of Neurology and is president of the Netherlands organization for health research and innovation and has served as a consultant for Merck-Serono, Biogen, Novartis, Genzyme and Teva Pharmaceuticals. B.M.J. Uitdehaag reports personal fees from Genzyme, Biogen Idec, TEVA, Merck Serono, Roche, outside the submitted work. N.P. Oxtoby reports no disclosures. D.C. Alexander reports no disclosures. H. Vrenken has received research grants from MerckSerono, Teva and Novartis, consulting fees from MerckSerono, and speaker honoraria from Novartis; all paid directly to his institution. J. Killestein reports grants and personal fees from Biogen Idec, Novartis, Merck Serono, TEVA, Genzyme, grants and other from Biogen Idec, Novartis, TEVA, Bayer Schering Pharma, Glaxo Smith Kline, Merck Serono. F. Barkhof reports grants and personal fees from Roche, Biogen Idec, Novartis, Merck Serono, TEVA, IXICO, grants and other support from Biogen Idec, Novartis, GE healthcare and Merck Serono. V. Wottschel reports no disclosures. Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 666992 , and was sponsored by the Dutch MS Research Foundation , grant numbers 08-650 , 13-820 and 14-358e . FB, DCA, and NPO are supported by the NIHR Biomedical Research Centre at UCLH . Funding Information: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 666992, and was sponsored by the Dutch MS Research Foundation, grant numbers 08-650, 13-820 and 14-358e. FB, DCA, and NPO are supported by the NIHR Biomedical Research Centre at UCLH. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - Background: As disease progression remains poorly understood in multiple sclerosis (MS), we aim to investigate the sequence in which different disease milestones occur using a novel data-driven approach. Methods: We analysed a cohort of 295 relapse-onset MS patients and 96 healthy controls, and considered 28 features, capturing information on T2-lesion load, regional brain and spinal cord volumes, resting-state functional centrality (“hubness”), microstructural tissue integrity of major white matter (WM) tracts and performance on multiple cognitive tests. We used a discriminative event-based model to estimate the sequence of biomarker abnormality in MS progression in general, as well as specific models for worsening physical disability and cognitive impairment. Results: We demonstrated that grey matter (GM) atrophy of the cerebellum, thalamus, and changes in corticospinal tracts are early events in MS pathology, whereas other WM tracts as well as the cognitive domains of working memory, attention, and executive function are consistently late events. The models for disability and cognition show early functional changes of the default-mode network and earlier changes in spinal cord volume compared to the general MS population. Overall, GM atrophy seems crucial due to its early involvement in the disease course, whereas WM tract integrity appears to be affected relatively late despite the early onset of WM lesions. Conclusion: Data-driven modelling revealed the relative occurrence of both imaging and non-imaging events as MS progresses, providing insights into disease propagation mechanisms, and allowing fine-grained staging of patients for monitoring purposes
AB - Background: As disease progression remains poorly understood in multiple sclerosis (MS), we aim to investigate the sequence in which different disease milestones occur using a novel data-driven approach. Methods: We analysed a cohort of 295 relapse-onset MS patients and 96 healthy controls, and considered 28 features, capturing information on T2-lesion load, regional brain and spinal cord volumes, resting-state functional centrality (“hubness”), microstructural tissue integrity of major white matter (WM) tracts and performance on multiple cognitive tests. We used a discriminative event-based model to estimate the sequence of biomarker abnormality in MS progression in general, as well as specific models for worsening physical disability and cognitive impairment. Results: We demonstrated that grey matter (GM) atrophy of the cerebellum, thalamus, and changes in corticospinal tracts are early events in MS pathology, whereas other WM tracts as well as the cognitive domains of working memory, attention, and executive function are consistently late events. The models for disability and cognition show early functional changes of the default-mode network and earlier changes in spinal cord volume compared to the general MS population. Overall, GM atrophy seems crucial due to its early involvement in the disease course, whereas WM tract integrity appears to be affected relatively late despite the early onset of WM lesions. Conclusion: Data-driven modelling revealed the relative occurrence of both imaging and non-imaging events as MS progresses, providing insights into disease propagation mechanisms, and allowing fine-grained staging of patients for monitoring purposes
KW - Cognition
KW - Disability
KW - Disease progression
KW - Event-based modelling
KW - MRI
KW - Multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=85098935511&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.nicl.2020.102550
DO - https://doi.org/10.1016/j.nicl.2020.102550
M3 - Article
C2 - 33418173
SN - 2213-1582
VL - 29
JO - NeuroImage: Clinical
JF - NeuroImage: Clinical
M1 - 102550
ER -