Deep gray matter volume loss drives disability worsening in multiple sclerosis

Arman Eshaghi, Ferran Prados, Wallace J. Brownlee, Daniel R. Altmann, Carmen Tur, M. Jorge Cardoso, Floriana De Angelis, Steven H. van de Pavert, Niamh Cawley, Nicola De Stefano, M. Laura Stromillo, Marco Battaglini, Serena Ruggieri, Claudio Gasperini, Massimo Filippi, Maria A. Rocca, Alex Rovira, Jaume Sastre-Garriga, Hugo Vrenken, Cyra E. Leurs & 11 others Joep Killestein, Lukas Pirpamer, Christian Enzinger, Sebastien Ourselin, Claudia A.M.Gandini Wheeler-Kingshott, Declan Chard, Alan J. Thompson, Daniel C. Alexander, Frederik Barkhof, Olga Ciccarelli, on behalf of the MAGNIMS study group

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective: 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. Methods: 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. Results: 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). Interpretation: 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.

Original languageEnglish
Pages (from-to)210-222
Number of pages13
JournalAnnals of Neurology
Volume83
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Cite this

Eshaghi, A., Prados, F., Brownlee, W. J., Altmann, D. R., Tur, C., Cardoso, M. J., ... on behalf of the MAGNIMS study group (2018). Deep gray matter volume loss drives disability worsening in multiple sclerosis. Annals of Neurology, 83(2), 210-222. https://doi.org/10.1002/ana.25145
Eshaghi, Arman ; Prados, Ferran ; Brownlee, Wallace J. ; Altmann, Daniel R. ; Tur, Carmen ; Cardoso, M. Jorge ; De Angelis, Floriana ; van de Pavert, Steven H. ; Cawley, Niamh ; De Stefano, Nicola ; Stromillo, M. Laura ; Battaglini, Marco ; Ruggieri, Serena ; Gasperini, Claudio ; Filippi, Massimo ; Rocca, Maria A. ; Rovira, Alex ; Sastre-Garriga, Jaume ; Vrenken, Hugo ; Leurs, Cyra E. ; Killestein, Joep ; Pirpamer, Lukas ; Enzinger, Christian ; Ourselin, Sebastien ; Wheeler-Kingshott, Claudia A.M.Gandini ; Chard, Declan ; Thompson, Alan J. ; Alexander, Daniel C. ; Barkhof, Frederik ; Ciccarelli, Olga ; on behalf of the MAGNIMS study group. / Deep gray matter volume loss drives disability worsening in multiple sclerosis. In: Annals of Neurology. 2018 ; Vol. 83, No. 2. pp. 210-222.
@article{1cbfd7769cd1407e84143d015c668396,
title = "Deep gray matter volume loss drives disability worsening in multiple sclerosis",
abstract = "Objective: 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. Methods: 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. Results: 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). Interpretation: 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.",
author = "Arman Eshaghi and Ferran Prados and Brownlee, {Wallace J.} and Altmann, {Daniel R.} and Carmen Tur and Cardoso, {M. Jorge} and {De Angelis}, Floriana and {van de Pavert}, {Steven H.} and Niamh Cawley and {De Stefano}, Nicola and Stromillo, {M. Laura} and Marco Battaglini and Serena Ruggieri and Claudio Gasperini and Massimo Filippi and Rocca, {Maria A.} and Alex Rovira and Jaume Sastre-Garriga and Hugo Vrenken and Leurs, {Cyra E.} and Joep Killestein and Lukas Pirpamer and Christian Enzinger and Sebastien Ourselin and Wheeler-Kingshott, {Claudia A.M.Gandini} and Declan Chard and Thompson, {Alan J.} and Alexander, {Daniel C.} and Frederik Barkhof and Olga Ciccarelli and {on behalf of the MAGNIMS study group}",
year = "2018",
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doi = "10.1002/ana.25145",
language = "English",
volume = "83",
pages = "210--222",
journal = "Annals of Neurology",
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Eshaghi, A, Prados, F, Brownlee, WJ, Altmann, DR, Tur, C, Cardoso, MJ, De Angelis, F, van de Pavert, SH, Cawley, N, De Stefano, N, Stromillo, ML, Battaglini, M, Ruggieri, S, Gasperini, C, Filippi, M, Rocca, MA, Rovira, A, Sastre-Garriga, J, Vrenken, H, Leurs, CE, Killestein, J, Pirpamer, L, Enzinger, C, Ourselin, S, Wheeler-Kingshott, CAMG, Chard, D, Thompson, AJ, Alexander, DC, Barkhof, F, Ciccarelli, O & on behalf of the MAGNIMS study group 2018, 'Deep gray matter volume loss drives disability worsening in multiple sclerosis' Annals of Neurology, vol. 83, no. 2, pp. 210-222. https://doi.org/10.1002/ana.25145

Deep gray matter volume loss drives disability worsening in multiple sclerosis. / Eshaghi, Arman; Prados, Ferran; Brownlee, Wallace J.; Altmann, Daniel R.; Tur, Carmen; Cardoso, M. Jorge; De Angelis, Floriana; van de Pavert, Steven H.; Cawley, Niamh; De Stefano, Nicola; Stromillo, M. Laura; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A.; Rovira, Alex; Sastre-Garriga, Jaume; Vrenken, Hugo; Leurs, Cyra E.; Killestein, Joep; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Wheeler-Kingshott, Claudia A.M.Gandini; Chard, Declan; Thompson, Alan J.; Alexander, Daniel C.; Barkhof, Frederik; Ciccarelli, Olga; on behalf of the MAGNIMS study group.

In: Annals of Neurology, Vol. 83, No. 2, 01.02.2018, p. 210-222.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Deep gray matter volume loss drives disability worsening in multiple sclerosis

AU - Eshaghi, Arman

AU - Prados, Ferran

AU - Brownlee, Wallace J.

AU - Altmann, Daniel R.

AU - Tur, Carmen

AU - Cardoso, M. Jorge

AU - De Angelis, Floriana

AU - van de Pavert, Steven H.

AU - Cawley, Niamh

AU - De Stefano, Nicola

AU - Stromillo, M. Laura

AU - Battaglini, Marco

AU - Ruggieri, Serena

AU - Gasperini, Claudio

AU - Filippi, Massimo

AU - Rocca, Maria A.

AU - Rovira, Alex

AU - Sastre-Garriga, Jaume

AU - Vrenken, Hugo

AU - Leurs, Cyra E.

AU - Killestein, Joep

AU - Pirpamer, Lukas

AU - Enzinger, Christian

AU - Ourselin, Sebastien

AU - Wheeler-Kingshott, Claudia A.M.Gandini

AU - Chard, Declan

AU - Thompson, Alan J.

AU - Alexander, Daniel C.

AU - Barkhof, Frederik

AU - Ciccarelli, Olga

AU - on behalf of the MAGNIMS study group

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Objective: 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. Methods: 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. Results: 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). Interpretation: 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.

AB - Objective: 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. Methods: 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. Results: 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). Interpretation: 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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U2 - 10.1002/ana.25145

DO - 10.1002/ana.25145

M3 - Article

VL - 83

SP - 210

EP - 222

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 2

ER -

Eshaghi A, Prados F, Brownlee WJ, Altmann DR, Tur C, Cardoso MJ et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Annals of Neurology. 2018 Feb 1;83(2):210-222. https://doi.org/10.1002/ana.25145