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Ann Neurol. 2018 Feb;83(2):210-222. doi: 10.1002/ana.25145. Epub 2018 Feb 6.

Deep gray matter volume loss drives disability worsening in multiple sclerosis.

Author information

Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, Faculty of Brain Sciences, University College London.
Centre for Medical Image Computing (CMIC), Department of Computer Science, University College London, London, United Kingdom.
Translational Imaging Group, Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, University College London, London, United Kingdom.
National Institute for Health Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre (BRC), London, United Kingdom.
Medical Statistics Department, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
Department of Neurosciences, S Camillo Forlanini Hospital, Rome, Italy.
Department of Neurology and Psychiatry, University of Rome Sapienza, Rome, Italy.
Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
MR Unit and Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Department of Neurology/Neuroimmunology, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, The Netherlands.
Department of Neurology, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Department of Neurology, Medical University of Graz, Graz, Austria.
Division of Neuroradiology, Vascular & Interventional Radiology, Department of Radiology, Medical University of Graz, Graz, Austria.
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
Brain MRI 3T Mondino Research Center, C. Mondino National Neurological Institute, Pavia, Italy.



Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.


We analyzed 3,604 brain high-resolution T1-weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing-remitting [RRMS], 128 secondary-progressive [SPMS], and 125 primary-progressive [PPMS]), over an average follow-up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow-up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression.


SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001).


This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210-222.

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