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Randomized Controlled Trial
. 2024 Nov 18;95(12):1139-1149.
doi: 10.1136/jnnp-2024-333460.

Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial

Maria A Rocca  1   2   3 , Paola Valsasina  4 , Francesco Romanò  4 , Nicolò Tedone  4 , Maria Pia Amato  5   6 , Giampaolo Brichetto  7   8 , Vincenzo Daniele Boccia  9 , Jeremy Chataway  10   11 , Nancy D Chiaravalloti  12   13 , Gary Cutter  14 , Ulrik Dalgas  15 , John DeLuca  12   13 , Rachel A Farrell  10 , Peter Feys  16   17 , Jennifer Freeman  18 , Matilde Inglese  9   19 , Cecilia Meza  20 , Robert W Motl  21 , Amber Salter  22 , Brian M Sandroff  12   13 , Anthony Feinstein  20 , Massimo Filippi  4   2   3   23   24 ; Cogex Research Team
Collaborators, Affiliations
Randomized Controlled Trial

Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial

Maria A Rocca et al. J Neurol Neurosurg Psychiatry. .

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.

Keywords: COGNITION; MRI; MULTIPLE SCLEROSIS; REHABILITATION.

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Conflict of interest statement

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.

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