Diffusion-based structural connectivity patterns of multiple sclerosis phenotypes

Background We aimed to describe the severity of the changes in brain diffusion-based connectivity as multiple sclerosis (MS) progresses and the microstructural characteristics of these networks that are associated with distinct MS phenotypes. Methods Clinical information and brain magnetic resonance images were collected from 221 healthy individuals and 823 people with MS at eight MAGNIMS centers. The patients were divided into four clinical phenotypes: clinically isolated syndrome, relapsing-remitting, secondary-progressive, and primary-progressive. Advanced tractography methods were used to obtain connectivity matrices. Then, differences in whole-brain and nodal graph-derived measures, and in the fractional anisotropy of connections between groups were analyzed. Support vector machine algorithms were used to classify groups. Results Clinically isolated syndrome and relapsing-remitting patients shared similar network changes relative to controls. However, most global and local network properties differed in secondary progressive patients compared with the other groups, with lower fractional anisotropy in most connections. Primary progressive participants had fewer differences in global and local graph measures compared to clinically isolated syndrome and relapsing-remitting patients, and reductions in fractional anisotropy were only evident for a few connections. The accuracy of support vector machine to discriminate patients from healthy controls based on connection was 81%, and ranged between 64% and 74% in distinguishing among the clinical phenotypes. Conclusions In conclusion, brain connectivity is disrupted in MS and has differential patterns according to the phenotype. Secondary progressive is associated with more widespread changes in connectivity. Additionally, classification tasks can distinguish between MS types, with subcortical connections being the most important factor. What is already known on this topic What this study adds How this study might affect research, practice or policy ### Competing Interest Statement The authors declare the following potential conflicts of interest: E.Martinez-Heras, F.Vivo, S.Alba-Arbalat, E.Strijbis, E. Pagani, S.Groppa, V.Fleischer, R.Dineen, D.Pareto, S.Collorone and F.Prados have nothing to disclose; E.Solana and E.Lopez-Soley received travel reimbursement from Sanofi and ECTRIMS; A. Calvi received support from the ECTRIMS-MAGNIMS fellowship (2018) and, was granted a postdoctoral fellowship from ECTRIMS in 2022; A. Saiz received compensation for consulting services and speaker honoraria from Merck, Biogen-Idec, Sanofi, Novartis, Roche, Janssen and Horizon Therapeutics; Y.Blanco received speaking honoraria from Biogen, Novartis and Genzyme; S.Llufriu received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, TEVA, Genzyme, Sanofi and Merck. M.M. Schoonheim serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck. H. Vrenken has received research grants from Pfizer, Merck Serono, Novartis. and Teva; speaker honoraria from Novartis; and consulting fees from Merck Serono, all paid directly to his institution. F. Barkhof: Steering committee and iDMC member for Biogen, Merck, Roche, EISAI. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Novartis, Merck, Biogen, GE, Roche. Co-founder and share holder of Queen Square Analytics LTD. MA.Rocca received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva and research support from the Canadian MS Society and Fondazione Italiana Sclerosi Multipla. M. Filippi is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). B. Bellenberg received financial support by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I. C. Lukas received a research grant by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I, has received consulting and speaker honoraria from Biogen Idec, Bayer Schering, Daiichi Sanykyo, Merck Serono, Novartis, Sanofi, Genzyme and TEVA. A. Rovira serves on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, Biogen, and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen. J. Sastre-Garriga serves as co-Editor for Europe on the editorial board of Multiple Sclerosis Journal and as Editor-in-Chief in Revista de Neurologia, receives research support from Fondo de Investigaciones Sanitarias (19/950) and has served as a consultant / speaker for Biogen, Celgene/Bristol Meyers Squibb, Genzyme, Novartis, Merck and Roche. A. Toosy has been supported by grants from MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079), has had meeting expenses from Merck, Biomedia and Biogen Idec and was UK PI for two clinical trials sponsored by MEDDAY (MS-ON - [NCT02220244][1] and MS-SPI2 - [NCT02220244][1]). O. Ciccarelli acts as a consultant for Novartis and Merck, and has received research funding from: NIHR, UK MS Society, NIHR UCLH BRC, MRC, Rosetrees Trust. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethical review board at the Hospital Clinic in Barcelona approved the study and all the participants gave their written consent for their data to be used. Data transfer agreements were established with the participating centres in order to allow sharing of pseudonymized images and clinical information governed by a central MAGNIMS collaboration framework agreement. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02220244&atom=%2Fmedrxiv%2Fearly%2F2023%2F03%2F24%2F2023.03.21.23287029.atom