Contributions
Abstract: 189
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 21 Imaging
Grey matter (GM) atrophy is present from the earliest clinical stages of multiple sclerosis (MS), and progresses steadily, affecting some regions more extensively than others. We aimed to determine the sequence in which GM regions become atrophic in MS, and its association with disability accumulation.
In this retrospective, longitudinal study, we included 1417 subjects: 253 with clinically-isolated syndrome (CIS), 708 relapsing-remitting MS, 128 secondary-progressive MS (SPMS), 125 primary-progressive MS (PPMS), and 203 healthy controls (HCs) from 7 MAGNIMS centres. Subjects underwent repeated MRI scanning, with T1- and T2/FLAIR MRI. Mean follow-up for patients was 2.41yrs (SD±1.97). Disability was scored using the Expanded Disability Status Scale(EDSS). We calculated volumes of GM regions, white matter, and brainstem with Geodesic Information Flows software in an unbiased within-subject template. We used an event-based model (EBM) to determine the sequence of atrophy, and its uncertainty. We assigned each subject to a specific EBM stage, based on their number of atrophic regions. We used nested linear mixed-effects regression models to explore associations between the rate of increase in EBM stages over time with disease duration and annual rate of EDSS gain.
First regions to become atrophic in CIS and relapse-onset MS patients were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was observed in PPMS with early involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. Patients with SPMS showed the highest EBM stages (highest number of atrophic regions, p< 0.001) at study entry. Rates of increase in EBM stages were significant in all MS phenotypes, but not in CIS or HCs. Every unit increase in the EBM stage corresponded to 4.76yrs increase in disease duration (p < 0.001). EBM stage was associated with disability accumulation in PPMS and SPMS (p< 0.001).
This data-driven staging of atrophy progression demonstrates that GM atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across MS phenotypes and is associated with disease duration and disability accumulation in progressive MS. EBM provides new insights into the evolution of GM atrophy in MS and has potential clinical utility for staging of individual patients.
Disclosure:
A Eshaghi has received ECTRIMS-MAGNIMS and MSIF McDonald Fellowships (www.msif.org).
C. Tur has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from Teva Pharmaceuticals Europe and Ismar Healthcare.
F Prados has received a Guarantors of Brain fellowship.
N De Stefano has received honoraria from Biogen-Idec, Genzyme, Merck Serono, Novartis, Roche and Teva for consulting services, speaking and travel support. He serves on advisory boards for Merck Serono, Novartis, Biogen-Idec, Roche, and Genzyme, he has received research grant support from the Italian MS Society.
C Enzinger received funding for traveling and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./sanofi-aventis; received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./sanofi-aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./sanofi- Aventis.
A. Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Sanofi-Genzyme, and OLEA Medical, has received speaker honoraria from Bayer, Sanofi-Genzyme, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis and Biogen Idec, and has research agreements with Siemens AG and Icometrix.
M.A. Rocca received speaker's honoraria from Biogen Idec, Novartis, TEVA, Genzyme and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla.
M. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA).
F Barkhof acts as a consultant to Biogen-Idec, Janssen Alzheimer Immunotherapy, Bayer-Schering, Merck-Serono, Roche, Novartis, Genzyme, and Sanofi-aventis. He has received sponsorship from EU-H2020, NWO, SMSR, EU-FP7, TEVA, Novartis, Toshiba. He is on the editorial board of Radiology, Brain, Neuroradiology, MSJ, Neurology.
B Uitdehaag has received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA.
H. Vrenken has received research grants from Pfizer, MerckSerono, Novartis and Teva, and speaker honoraria from Novartis and MerckSerono; all funds were paid directly to his institution.
CAM Gandini Wheeler-Kingshott receives research grants (PI and co-applicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis.
Declan Chard has received honoraria (paid to his employer) from Ismar Healthcare NV, Swiss MS Society, Excemed (previously Serono Symposia International Foundation), Merck, Bayer and Teva for faculty-led education work; Teva for advisory board work; meeting expenses from Merck, Teva, Novartis, the MS Trust and National MS Society; and has previously held stock in GlaxoSmithKline.
D. Alexander has received funding for this work from EPSRC (M020533, M006093, J020990) as well as the European Union's Horizon 2020 research and innovation programme under grant agreement Nos 634541 and 666992.
AJ Thompson receives grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, and has received honoraria/support for travel for consultancy from Eisai, Biogen (Optum Insight), and Excemed. He received support for travel from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and the National MS Society (USA) as member of their Research Programs Advisory Committee, and receives an honorarium from SAGE Publishers as Editor-in-Chief of Multiple Sclerosis Journal.
O Ciccarelli receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre; she is a consultant for Teva, Roche, Novartis, Biogen, Genzyme and GE. She is an Associate Editor for Neurology, for which she receives an honorarium.
Abstract: 189
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 21 Imaging
Grey matter (GM) atrophy is present from the earliest clinical stages of multiple sclerosis (MS), and progresses steadily, affecting some regions more extensively than others. We aimed to determine the sequence in which GM regions become atrophic in MS, and its association with disability accumulation.
In this retrospective, longitudinal study, we included 1417 subjects: 253 with clinically-isolated syndrome (CIS), 708 relapsing-remitting MS, 128 secondary-progressive MS (SPMS), 125 primary-progressive MS (PPMS), and 203 healthy controls (HCs) from 7 MAGNIMS centres. Subjects underwent repeated MRI scanning, with T1- and T2/FLAIR MRI. Mean follow-up for patients was 2.41yrs (SD±1.97). Disability was scored using the Expanded Disability Status Scale(EDSS). We calculated volumes of GM regions, white matter, and brainstem with Geodesic Information Flows software in an unbiased within-subject template. We used an event-based model (EBM) to determine the sequence of atrophy, and its uncertainty. We assigned each subject to a specific EBM stage, based on their number of atrophic regions. We used nested linear mixed-effects regression models to explore associations between the rate of increase in EBM stages over time with disease duration and annual rate of EDSS gain.
First regions to become atrophic in CIS and relapse-onset MS patients were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was observed in PPMS with early involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. Patients with SPMS showed the highest EBM stages (highest number of atrophic regions, p< 0.001) at study entry. Rates of increase in EBM stages were significant in all MS phenotypes, but not in CIS or HCs. Every unit increase in the EBM stage corresponded to 4.76yrs increase in disease duration (p < 0.001). EBM stage was associated with disability accumulation in PPMS and SPMS (p< 0.001).
This data-driven staging of atrophy progression demonstrates that GM atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across MS phenotypes and is associated with disease duration and disability accumulation in progressive MS. EBM provides new insights into the evolution of GM atrophy in MS and has potential clinical utility for staging of individual patients.
Disclosure:
A Eshaghi has received ECTRIMS-MAGNIMS and MSIF McDonald Fellowships (www.msif.org).
C. Tur has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from Teva Pharmaceuticals Europe and Ismar Healthcare.
F Prados has received a Guarantors of Brain fellowship.
N De Stefano has received honoraria from Biogen-Idec, Genzyme, Merck Serono, Novartis, Roche and Teva for consulting services, speaking and travel support. He serves on advisory boards for Merck Serono, Novartis, Biogen-Idec, Roche, and Genzyme, he has received research grant support from the Italian MS Society.
C Enzinger received funding for traveling and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./sanofi-aventis; received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./sanofi-aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./sanofi- Aventis.
A. Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Sanofi-Genzyme, and OLEA Medical, has received speaker honoraria from Bayer, Sanofi-Genzyme, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis and Biogen Idec, and has research agreements with Siemens AG and Icometrix.
M.A. Rocca received speaker's honoraria from Biogen Idec, Novartis, TEVA, Genzyme and ExceMed and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla.
M. Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer´s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA).
F Barkhof acts as a consultant to Biogen-Idec, Janssen Alzheimer Immunotherapy, Bayer-Schering, Merck-Serono, Roche, Novartis, Genzyme, and Sanofi-aventis. He has received sponsorship from EU-H2020, NWO, SMSR, EU-FP7, TEVA, Novartis, Toshiba. He is on the editorial board of Radiology, Brain, Neuroradiology, MSJ, Neurology.
B Uitdehaag has received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA.
H. Vrenken has received research grants from Pfizer, MerckSerono, Novartis and Teva, and speaker honoraria from Novartis and MerckSerono; all funds were paid directly to his institution.
CAM Gandini Wheeler-Kingshott receives research grants (PI and co-applicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis.
Declan Chard has received honoraria (paid to his employer) from Ismar Healthcare NV, Swiss MS Society, Excemed (previously Serono Symposia International Foundation), Merck, Bayer and Teva for faculty-led education work; Teva for advisory board work; meeting expenses from Merck, Teva, Novartis, the MS Trust and National MS Society; and has previously held stock in GlaxoSmithKline.
D. Alexander has received funding for this work from EPSRC (M020533, M006093, J020990) as well as the European Union's Horizon 2020 research and innovation programme under grant agreement Nos 634541 and 666992.
AJ Thompson receives grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, and has received honoraria/support for travel for consultancy from Eisai, Biogen (Optum Insight), and Excemed. He received support for travel from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and the National MS Society (USA) as member of their Research Programs Advisory Committee, and receives an honorarium from SAGE Publishers as Editor-in-Chief of Multiple Sclerosis Journal.
O Ciccarelli receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre; she is a consultant for Teva, Roche, Novartis, Biogen, Genzyme and GE. She is an Associate Editor for Neurology, for which she receives an honorarium.