Iris Dekker1, Menno M Schoonheim2, Vikram Venkatraghavan3, Anand J C Eijlers2, Iman Brouwer4, Esther E Bron3, Stefan Klein3, Mike P Wattjes5, Alle Meije Wink4, Jeroen J G Geurts2, Bernard M J Uitdehaag6, Neil P Oxtoby7, Daniel C Alexander7, Hugo Vrenken4, Joep Killestein6, Frederik Barkhof8, Viktor Wottschel9. 1. Amsterdam UMC, Location VUmc, Departments of Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands; Neurology, MS Center Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands. 2. Anatomy and Neurosciences, MS Center Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands. 3. Biomedical Imaging Group Rotterdam, Departments of Medical Informatics and Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 4. Amsterdam UMC, Location VUmc, Departments of Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands. 5. Dept. of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany. 6. Neurology, MS Center Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands. 7. Centre for Medical Image Computing, Department of Computer Science, UCL, London, UK. 8. Amsterdam UMC, Location VUmc, Departments of Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands; Centre for Medical Image Computing, Department of Computer Science, UCL, London, UK; Institute of Neurology, UCL, London, UK. 9. Amsterdam UMC, Location VUmc, Departments of Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands. Electronic address: v.wottschel@amsterdamumc.nl.
Abstract
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.
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.
Authors: Brian M Sandroff; Robert W Motl; Cristina A F Román; Glenn R Wylie; John DeLuca; Gary R Cutter; Ralph H B Benedict; Michael G Dwyer; Robert Zivadinov Journal: J Neurol Date: 2022-06-19 Impact factor: 6.682
Authors: Emma L van der Ende; Esther E Bron; Jackie M Poos; Lize C Jiskoot; Jessica L Panman; Janne M Papma; Lieke H Meeter; Elise G P Dopper; Carlo Wilke; Matthis Synofzik; Carolin Heller; Imogen J Swift; Aitana Sogorb-Esteve; Arabella Bouzigues; Barbara Borroni; Raquel Sanchez-Valle; Fermin Moreno; Caroline Graff; Robert Laforce; Daniela Galimberti; Mario Masellis; Maria Carmela Tartaglia; Elizabeth Finger; Rik Vandenberghe; James B Rowe; Alexandre de Mendonça; Fabrizio Tagliavini; Isabel Santana; Simon Ducharme; Christopher R Butler; Alexander Gerhard; Johannes Levin; Adrian Danek; Markus Otto; Yolande A L Pijnenburg; Sandro Sorbi; Henrik Zetterberg; Wiro J Niessen; Jonathan D Rohrer; Stefan Klein; John C van Swieten; Vikram Venkatraghavan; Harro Seelaar Journal: Brain Date: 2022-06-03 Impact factor: 15.255
Authors: Neil P Oxtoby; Colin Birkenbihl; Sepehr Golriz Khatami; Yasamin Salimi; Martin Hofmann-Apitius Journal: Alzheimers Res Ther Date: 2022-04-20 Impact factor: 8.823
Authors: Seymour M Lopez; Leon M Aksman; Neil P Oxtoby; Sjoerd B Vos; Jun Rao; Erik Kaestner; Saud Alhusaini; Marina Alvim; Benjamin Bender; Andrea Bernasconi; Neda Bernasconi; Boris Bernhardt; Leonardo Bonilha; Lorenzo Caciagli; Benoit Caldairou; Maria Eugenia Caligiuri; Angels Calvet; Fernando Cendes; Luis Concha; Estefania Conde-Blanco; Esmaeil Davoodi-Bojd; Christophe de Bézenac; Norman Delanty; Patricia M Desmond; Orrin Devinsky; Martin Domin; John S Duncan; Niels K Focke; Sonya Foley; Francesco Fortunato; Marian Galovic; Antonio Gambardella; Ezequiel Gleichgerrcht; Renzo Guerrini; Khalid Hamandi; Victoria Ives-Deliperi; Graeme D Jackson; Neda Jahanshad; Simon S Keller; Peter Kochunov; Raviteja Kotikalapudi; Barbara A K Kreilkamp; Angelo Labate; Sara Larivière; Matteo Lenge; Elaine Lui; Charles Malpas; Pascal Martin; Mario Mascalchi; Sarah E Medland; Stefano Meletti; Marcia E Morita-Sherman; Thomas W Owen; Mark Richardson; Antonella Riva; Theodor Rüber; Ben Sinclair; Hamid Soltanian-Zadeh; Dan J Stein; Pasquale Striano; Peter N Taylor; Sophia I Thomopoulos; Paul M Thompson; Manuela Tondelli; Anna Elisabetta Vaudano; Lucy Vivash; Yujiang Wang; Bernd Weber; Christopher D Whelan; Roland Wiest; Gavin P Winston; Clarissa Lin Yasuda; Carrie R McDonald; Daniel C Alexander; Sanjay M Sisodiya; Andre Altmann Journal: Epilepsia Date: 2022-06-25 Impact factor: 6.740