Alessandro Cagol1,2, Sabine Schaedelin3, Muhamed Barakovic1,2, Pascal Benkert3, Ramona-Alexandra Todea1,2,4, Reza Rahmanzadeh1,2, Riccardo Galbusera1,2, Po-Jui Lu1,2, Matthias Weigel1,2,5, Lester Melie-Garcia1,2, Esther Ruberte1,2,6, Nina Siebenborn1,2, Marco Battaglini7, Ernst-Wilhelm Radue1, Özgür Yaldizli1,2, Johanna Oechtering2, Tim Sinnecker1,2,6, Johannes Lorscheider2, Bettina Fischer-Barnicol2, Stefanie Müller8, Lutz Achtnichts9, Jochen Vehoff8, Giulio Disanto10, Oliver Findling9, Andrew Chan11, Anke Salmen11, Caroline Pot12, Claire Bridel13, Chiara Zecca10,14, Tobias Derfuss2, Johanna M Lieb4, Luca Remonda15, Franca Wagner16, Maria I Vargas17, Renaud Du Pasquier12,18, Patrice H Lalive13, Emanuele Pravatà10,19, Johannes Weber20, Philippe C Cattin21, Claudio Gobbi10,14, David Leppert2, Ludwig Kappos1,2, Jens Kuhle2, Cristina Granziera1,2. 1. Translational Imaging in Neurology (ThINK) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel, University of Basel, Basel, Switzerland. 2. Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland. 3. Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. 4. Division of Diagnostic and Interventional Neuroradiology, Clinic for Radiology and Nuclear Medicine, University Hospital Basel, University of Basel, Basel, Switzerland. 5. Division of Radiological Physics, Department of Radiology, University Hospital Basel, Basel, Switzerland. 6. Medical Image Analysis Center (MIAC) and Quantitative Biomedical Imaging Group, Department of Biomedical Engineering, University of Basel, Basel, Switzerland. 7. Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy. 8. Department of Neurology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. 9. Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland. 10. Neurology Department, Neurocenter of Southern Switzerland, Lugano, Switzerland. 11. Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 12. Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland. 13. Division of Neurology, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland. 14. Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland. 15. Department of Radiology, Cantonal Hospital Aarau, Aarau, Switzerland. 16. Department of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 17. Department of Radiology, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland. 18. Division of Radiology, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland. 19. Department of Neuroradiology, Neurocenter of Southern Switzerland, Lugano, Switzerland. 20. Department of Radiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. 21. Center for Medical Image, Analysis, and Navigation, Department of Biomedical Engineering, University of Basel, Allschwil, Switzerland.
Abstract
Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.
Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.
Authors: Maria A Rocca; Marco Battaglini; Ralph H B Benedict; Nicola De Stefano; Jeroen J G Geurts; Roland G Henry; Mark A Horsfield; Mark Jenkinson; Elisabetta Pagani; Massimo Filippi Journal: Neurology Date: 2016-12-16 Impact factor: 9.910
Authors: Antonio Scalfari; Chiara Romualdi; Richard S Nicholas; Miriam Mattoscio; Roberta Magliozzi; Aldo Morra; Salvatore Monaco; Paolo A Muraro; Massimiliano Calabrese Journal: Neurology Date: 2018-05-16 Impact factor: 9.910
Authors: Ernst-Wilhelm Radue; Frederik Barkhof; Ludwig Kappos; Till Sprenger; Dieter A Häring; Ana de Vera; Philipp von Rosenstiel; Jeremy R Bright; Gordon Francis; Jeffrey A Cohen Journal: Neurology Date: 2015-01-28 Impact factor: 9.910
Authors: Ludwig Kappos; Helmut Butzkueven; Heinz Wiendl; Timothy Spelman; Fabio Pellegrini; Yi Chen; Qunming Dong; Harold Koendgen; Shibeshih Belachew; Maria Trojano Journal: Mult Scler Date: 2017-05-30 Impact factor: 6.312
Authors: Bruce A C Cree; Jill A Hollenbach; Riley Bove; Gina Kirkish; Simone Sacco; Eduardo Caverzasi; Antje Bischof; Tristan Gundel; Alyssa H Zhu; Nico Papinutto; William A Stern; Carolyn Bevan; Andrew Romeo; Douglas S Goodin; Jeffrey M Gelfand; Jennifer Graves; Ari J Green; Michael R Wilson; Scott S Zamvil; Chao Zhao; Refujia Gomez; Nicholas R Ragan; Gillian Q Rush; Patrick Barba; Adam Santaniello; Sergio E Baranzini; Jorge R Oksenberg; Roland G Henry; Stephen L Hauser Journal: Ann Neurol Date: 2019-03-30 Impact factor: 10.422
Authors: Antje Bischof; Nico Papinutto; Anisha Keshavan; Anand Rajesh; Gina Kirkish; Xinheng Zhang; Jacob M Mallott; Carlo Asteggiano; Simone Sacco; Tristan J Gundel; Chao Zhao; William A Stern; Eduardo Caverzasi; Yifan Zhou; Refujia Gomez; Nicholas R Ragan; Adam Santaniello; Alyssa H Zhu; Jeremy Juwono; Carolyn J Bevan; Riley M Bove; Elizabeth Crabtree; Jeffrey M Gelfand; Douglas S Goodin; Jennifer S Graves; Ari J Green; Jorge R Oksenberg; Emmanuelle Waubant; Michael R Wilson; Scott S Zamvil; Bruce A C Cree; Stephen L Hauser; Roland G Henry Journal: Ann Neurol Date: 2022-01-04 Impact factor: 11.274