학술논문
Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial.
Document Type
Academic Journal
Author
Rocca MA; Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy rocca.mara@hsr.it.; Neurology Unit, IRCCS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy.; Valsasina P; Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.; Romanò F; Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.; Tedone N; Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.; Amato MP; Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy.; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.; Brichetto G; Scientific Research Area, Italian Multiple Sclerosis Foundation (FISM), Genoa, Italy.; AISM Rehabilitation Service, Italian Multiple Sclerosis Society, Genoa, Italy.; Boccia VD; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.; Chataway J; Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK.; National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK.; Chiaravalloti ND; Kessler Foundation, West Orange, NJ, USA.; Department of Physical Medicine & Rehabilitation, Rutgers New Jersey Medical School, Newark, New Jersey, USA.; Cutter G; Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.; Dalgas U; Exercise Biology, Department of Public Health, Aarhus University, Aarhus, Denmark.; DeLuca J; Kessler Foundation, West Orange, NJ, USA.; Department of Physical Medicine & Rehabilitation, Rutgers New Jersey Medical School, Newark, New Jersey, USA.; Farrell RA; Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK.; Feys P; REVAL, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium.; University MS Center, Hasselt University, Pelt, Belgium.; Freeman J; Faculty of Health, School of Health Professions, University of Plymouth, Plymouth, Devon, UK.; Inglese M; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.; Meza C; Department of Psychiatry, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.; Motl RW; Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, Illinois, USA.; Salter A; Department of Neurology, Section on Statistical Planning and Analysis, UT Southwestern Medical Center, Dallas, Texas, USA.; Sandroff BM; Kessler Foundation, West Orange, NJ, USA.; Department of Physical Medicine & Rehabilitation, Rutgers New Jersey Medical School, Newark, New Jersey, USA.; Feinstein A; Department of Psychiatry, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.; Filippi M; Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.; Neurology Unit, IRCCS Ospedale San Raffaele, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy.; Neurorehabilitation Unit, IRCCS Ospedale San Raffaele, Milan, Italy.; Neurophysiology Service, IRCCS Ospedale San Raffaele, Milan, Italy.
Source
Publisher: BMJ Publishing Group Country of Publication: England NLM ID: 2985191R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-330X (Electronic) Linking ISSN: 00223050 NLM ISO Abbreviation: J Neurol Neurosurg Psychiatry Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings.
Methods: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task).
Results: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula.
Conclusions: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements.
Trial Registration Number: NCT03679468.
Competing Interests: Competing interests: MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche, and speaker honoraria from AstraZeneca, 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. PV received speaker honoraria from Biogen Idec. FR has nothing to disclose. NT has nothing to disclose. MPA received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Roche, Pharmaceutical Industries and Fondazione Italiana Sclerosi Multipla. GB has been awarded and receives research support from Roche, Fondazione Italiana Sclerosi Multipla, ARSEP, H2020 EU Call. VDB has nothing to disclose. In the last 3 years, JC has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust, he is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK, he has been a local principal investigator for a trial in MS funded by the Canadian MS society, a local principal investigator for commercial trials funded by: Ionis, Novartis and Roche, and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. NC is on an Advisory Board for Akili Interactive and is a member of the Editorial Boards of Multiple Sclerosis Journal and Frontiers in NeuroTrauma. GC is a member of Data and Safety Monitoring Boards for AstraZeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi Aventis, Reata Pharmaceuticals, Teva pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee), he is on Consulting or Advisory Boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics, he is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc, a private consulting company located in Birmingham AL. UD has received research support, travel grants and/or teaching honorary from Biogen Idec, Merck-Serono, Novartis, Bayer Schering and Sanofi Aventis as well as honoraria from serving on scientific advisory boards of Biogen Idec and Genzyme. JD is an Associate Editor of the Archives of Physical Medicine and Rehabilitation, and Neuropsychology Review, received compensation for consulting services and/or speaking activities from Biogen Idec, Celgene, MedRhythms and Novartis, and receives research support from Biogen Idec, National Multiple Sclerosis Society, Consortium of Multiple Sclerosis Centers and National Institutes of Health. RAF has received honoraria and served on advisory panels for Merck, TEVA, Novartis, Genzyme, GW pharma (Jazz pharmaceuticals), Allergan, Merz, Ipsen and Biogen, she is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. PF is editorial board member of NNR, MSJ and Frontiers in Rehabilitation Sciences (section ‘Strengthening Health Systems’), provides consultancy to NeuroCompass and was board of advisory board meetings for BIOGEN. JF has been awarded research grants from the NIHR, UK. MI is Co-Editor for Controversies for Multiple Sclerosis Journal, received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and received research support from NIH, NMSS, the MS Society of Canada, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, H2020 EU Call. CM has nothing to disclose. RWM has nothing to disclose. AS receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the US Department of Defense and is a member of editorial board for Neurology. BMS has nothing to disclose. AF is on Advisory Boards for Akili Interactive and Roche, and reports grants from the MS Society of Canada, book royalties from Johns Hopkins University Press, Cambridge University Press, Amadeus Press and Glitterati Editions, and speaker’s honoraria from Novartis, Biogen, Roche and Sanofi Genzyme. MF 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.
(© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Methods: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task).
Results: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula.
Conclusions: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements.
Trial Registration Number: NCT03679468.
Competing Interests: Competing interests: MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche, and speaker honoraria from AstraZeneca, 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. PV received speaker honoraria from Biogen Idec. FR has nothing to disclose. NT has nothing to disclose. MPA received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Roche, Pharmaceutical Industries and Fondazione Italiana Sclerosi Multipla. GB has been awarded and receives research support from Roche, Fondazione Italiana Sclerosi Multipla, ARSEP, H2020 EU Call. VDB has nothing to disclose. In the last 3 years, JC has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust, he is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK, he has been a local principal investigator for a trial in MS funded by the Canadian MS society, a local principal investigator for commercial trials funded by: Ionis, Novartis and Roche, and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. NC is on an Advisory Board for Akili Interactive and is a member of the Editorial Boards of Multiple Sclerosis Journal and Frontiers in NeuroTrauma. GC is a member of Data and Safety Monitoring Boards for AstraZeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi Aventis, Reata Pharmaceuticals, Teva pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee), he is on Consulting or Advisory Boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics, he is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc, a private consulting company located in Birmingham AL. UD has received research support, travel grants and/or teaching honorary from Biogen Idec, Merck-Serono, Novartis, Bayer Schering and Sanofi Aventis as well as honoraria from serving on scientific advisory boards of Biogen Idec and Genzyme. JD is an Associate Editor of the Archives of Physical Medicine and Rehabilitation, and Neuropsychology Review, received compensation for consulting services and/or speaking activities from Biogen Idec, Celgene, MedRhythms and Novartis, and receives research support from Biogen Idec, National Multiple Sclerosis Society, Consortium of Multiple Sclerosis Centers and National Institutes of Health. RAF has received honoraria and served on advisory panels for Merck, TEVA, Novartis, Genzyme, GW pharma (Jazz pharmaceuticals), Allergan, Merz, Ipsen and Biogen, she is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. PF is editorial board member of NNR, MSJ and Frontiers in Rehabilitation Sciences (section ‘Strengthening Health Systems’), provides consultancy to NeuroCompass and was board of advisory board meetings for BIOGEN. JF has been awarded research grants from the NIHR, UK. MI is Co-Editor for Controversies for Multiple Sclerosis Journal, received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and received research support from NIH, NMSS, the MS Society of Canada, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, H2020 EU Call. CM has nothing to disclose. RWM has nothing to disclose. AS receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the US Department of Defense and is a member of editorial board for Neurology. BMS has nothing to disclose. AF is on Advisory Boards for Akili Interactive and Roche, and reports grants from the MS Society of Canada, book royalties from Johns Hopkins University Press, Cambridge University Press, Amadeus Press and Glitterati Editions, and speaker’s honoraria from Novartis, Biogen, Roche and Sanofi Genzyme. MF 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.
(© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)