Disentangling neurodegeneration from ageing in multiple sclerosis: the brain-predicted disease duration gap

Disentangling brain ageing from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. Here, we statistically modelled disease duration (DD) in PwMS as a function of brain MRI scans and evaluated whether the brain-predicted DD gap (i.e., the difference between predicted and actual duration) could complement the brain-age gap as a DD-adjusted global measure of multiple sclerosis-specific brain damage. In this retrospective study, we used 3D T1-weighted brain MRI scans of PwMS (i) from a large multicentric dataset (n = 4,392) for age and DD modelling, and (ii) from a monocentric longitudinal cohort of patients with early multiple sclerosis (n = 252 patients, 749 sessions) for clinical validation. We trained and tested a deep learning model based on a 3D DenseNet architecture to predict DD from minimally pre-processed brain MRI scans, while age predictions were obtained with the previously validated DeepBrainNet algorithm. Model predictions were scrutinised to assess the influence of lesions and brain volumes, while the DD gap metric was biologically and clinically validated within a linear model framework assessing its relationship with brain-age gap values and with physical disability measured with the Expanded Disability Status Scale (EDSS). Our model predicted DD better than chance (mean absolute error = 5.63 years, R2 = 0.34) and was nearly orthogonal to the brain-age model, as suggested by the very weak correlation between DD gap and brain-age gap values ( r = 0.06). DD predictions were influenced by spatially distributed variations in brain volume, and, unlike brain-predicted age, were sensitive to the presence of lesions (mean difference between unfilled and filled scans: 0.55 ± 0.57 years, p < 0.001). The DD gap metric significantly explained EDSS scores (β = 0.060, p < 0.001), adding to brain-age gap values (ΔR2 = 0.012, p < 0.001). Longitudinally, increasing annualised DD gap was associated with greater annualised EDSS changes ( r = 0.50, p < 0.001), with a significant incremental contribution in explaining disability worsening compared to changes of the brain-age gap alone (ΔR2 = 0.064, p < 0.001). The brain-predicted DD gap metric appears to be sensitive to multiple sclerosis-related lesions and brain atrophy, adding to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally. Potentially, it may be used as a multiple sclerosis-specific biomarker of disease severity and progression. ### Competing Interest Statement G.P. received research grants from ECTRIMS-MAGNIMS and ESNR. M.C. received speaker honoraria from Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, and Roche and receives research support from the Progressive MS Alliance and Italian Minister of Health. R.S. was awarded a MAGNIMS-ECTRIMS fellowship in 2019. Si.Co. discloses honoraria for advisory board participation from Amicus and research grants from Fondazione Italiana Sclerosi Multipla and Telethon. R.C. received speaker honoraria and travel support from Roche, Merck, Sanofi-Genzyme, Novartis and Janssen. She was awarded a MAGNIMS-ECTRIMS fellowship in 2019. M.F. is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. M.A.F. has received speaker honoraria from Merck. Cl.Ga. has received speaker honoraria and/or travel expenses for attending meeting from Bayer Schering Pharma, Sanofi-Aventis, Merck, Biogen, Novartis, Almirall, Bristol Myers Squibb. The University Hospital Basel (USB), as the employer of Cr.Gr., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; (iii) research support from Siemens, GeNeuro, Roche. C.G. is supported by the Swiss National Science Foundation (SNSF) grant PP00P3_176984, the Stiftung zur Forderung der gastroenterologischen und allgemeinen klinischen Forschung and the EUROSTAR E!113682 HORIZON2020. E.A.H. received honoraria for lecturing and advisory board activity from Biogen, Merck and Sanofi-Genzyme and unrestricted research grant from Merck. E.A.H. received honoraria for lecturing and advisory board activity from Biogen, Merck and Sanofi-Genzyme and unrestricted research grant from Merck. S.L. received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, TEVA, Genzyme, Sanofi and Merck. S.M. received honoraria for lecturing and advisory board activity from UCB and Biogen, and travel grant from Roche and Merck. M.M. has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck, and honoraria from Biogen, BMS Celgene, Ipsen, Merck, Novartis and Roche. J.P. has received support for scientific meetings and honorariums for advisory work From Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, Vitaccess, UCB, Mitsubishi, Amplo, Janssen. Grants from Alexion, Argenx, Roche, Medimmune, Amplo biotechnology. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZenica. Her group has been awarded an ECTRIMS fellowship and a Sumaira Foundation grant to start later this year. A Charcot fellow worked in Oxford 2019-2021. She acknowledges partial funding to the trust by Highly specialised services NHS England. She is on the medical advisory boards of the Sumaira Foundation and MOG project charities, is a member of the Guthy Jackon Foundation Charity and is on the Board of the European Charcot Foundation and the steering committee of MAGNIMS and the UK NHSE IVIG Committee and chairman of the NHSE neuroimmunology patient pathway and ECTRIMS Council member on the educational committee since June 2023. On the ABN advisory groups for MS and neuroinflammation. M.P. discloses meeting expenses from Novartis, Janssen, Roche and Merck, speaking honoraria from HEALTH&LIFE S.r.l., AIM Education S.r.l., Biogen, Novartis and FARECOMUNICAZIONE E20, honoraria for consulting services and for advisory board participation from Biogen and research grants from Italian MS Foundation, Baroni Foundation and Italian Ministry of University and Research. D.P. has received funding for travel from Merck, Genzyme/Sanofi-Aventis and Biogen, as well as speaking honoraria from Biogen, Novartis and Merck. M.A.R. received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. M.V. received speaker honoraria, consultant fees and travel expenses from Biogen Idec, Novartis, Roche, Merck and Teva and has been supported by the Czech Ministry of Education - project Cooperatio LF1, research area Neuroscience, and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107) - funded by the European Union-Next Generation EU and Czech Ministry of Health - the institutional support of the research RVO VFN 64165. A.R. serves/ed on scientific advisory boards for BMS, Novartis, Sanofi-Genzyme, Synthetic MR, Tensor Medical, Roche, Biogen, and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, BMS and Biogen. S.R. has received honoraria from Biogen, Merck Serono, Novartis, Bristol Myers Squibb and Sanofi as consulting services, speaking and/or travel support. A.T. has received speaker honoraria from Merck, Biomedia, Sereno Symposia International Foundation, Bayer and At the Limits and meeting expenses from Merck, Biogen Idec and Novartis He was the UK PI for two clinical trials sponsored by MEDDAY pharmaceutical company (MD1003 in optic neuropathy [MS-ON - [NCT02220244][1]] and progressive MS [MS-SPI2 - [NCT02936037][2]]). He has been supported by recent grants from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079). He is an associate editor for Frontiers in Neurology - Neuro-ophthalmology section and on the editorial board for Neurology and Multiple Sclerosis Journal. P.V. received speaker honoraria from Biogen Idec. M.M.S. 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. O.C. is an NIHR Research Professor (RP-2017-08-ST2-004); acts as a consultant for Biogen, Merck, Novartis, Roche, and Teva; and has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society, and the NIHR-HTA. J.H.C. is a scientific advisor to and shareholder in BrainKey and Claritas HealthTech PTE. F.B.: 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. The remaining authors report no competing interests. ### Funding Statement G.P. was supported by the ESNR Research Fellowship Programme (2021). F.P. and B.K. are supported by the UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at UCLH and UCL. A.C. is supported by EUROSTAR E!113682 HORIZON2020. Sa.Co. is supported by a Rosetrees Trust Grant (PGL21/10079). M.A.F. is supported by a grant from the MRC (MR/S026088/1). S.G. and G.G.E. receive support from the German Research Foundation (Deutsche Forschungsgemeinschaft, 'DFG': Priority Programme SPP2177; grants GR 4590/3-1 and GO 3493/1-1). The contribution of data from Oslo (H.F.H., E.A.H., and G.O.N.) was supported by grants from The Research Council of Norway (NFR, grant number 240102) and the South-Eastern Health Authorities of Norway (grant number 257955). The contribution of data from Prague (T.U. and M.V.) was supported by the Ministry of Health of the Czech Republic within the conceptual development of a research organization (00064165) at the General University Hospital in Prague, by the project National Institute for Neurological Research and by the European Union-Next Generation EU (Programme EXCELES, ID project No LX22NPO5107) and by Roche ([NCT03706118][3]). ### 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: Ethics committee of University College London gave ethical approval for this work. 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 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02220244&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F03%2F2024.01.02.23300497.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02936037&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F03%2F2024.01.02.23300497.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03706118&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F03%2F2024.01.02.23300497.atom