Deep gray matter volume loss drives disability worsening in multiple sclerosis

A Eshaghi, F Prados, WJ Brownlee, DR Altmann, C Tur, MJ Cardoso, F De Angelis, SH van de Pavert, N Cawley, N De Stefano, ML Stromillo, M Battaglini, S Ruggieri, C Gasperini, M Filippi, MA Rocca, A Rovira, J Sastre-Garriga, H Vrenken, CE LeursJ Killestein, L Pirpamer, C Enzinger, S Ourselin, CAMG Wheeler-Kingshott, D Chard, AJ Thompson, DC Alexander, F Barkhof, O Ciccarelli, on behalf of the MAGNIMS study group

Research output: Contribution to journalArticle

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 identif ied 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. © 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association
Original languageEnglish
Pages (from-to)210-222
Number of pages13
JournalAnnals of Neurology
Volume83
Issue number2
DOIs
Publication statusPublished - 2018

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Multiple Sclerosis
Atrophy
Phenotype
Gray Matter
Therapeutic Uses
Neurology
Brain Stem
Multicenter Studies
Longitudinal Studies
Magnetic Resonance Imaging
Confidence Intervals
Brain

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Eshaghi, A., Prados, F., Brownlee, WJ., Altmann, DR., Tur, C., Cardoso, MJ., ... group, O. B. O. T. MAGNIMS. S. (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

Deep gray matter volume loss drives disability worsening in multiple sclerosis. / 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; group, on behalf of the MAGNIMS study.

In: Annals of Neurology, Vol. 83, No. 2, 2018, p. 210-222.

Research output: Contribution to journalArticle

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 & group, OBOTMAGNIMSS 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
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;83(2):210-222. https://doi.org/10.1002/ana.25145
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 ; group, on behalf of the MAGNIMS study. / Deep gray matter volume loss drives disability worsening in multiple sclerosis. In: Annals of Neurology. 2018 ; Vol. 83, No. 2. pp. 210-222.
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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 identif ied 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. {\circledC} 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association",
author = "A Eshaghi and F Prados and WJ Brownlee and DR Altmann and C Tur and MJ Cardoso and {De Angelis}, F and {van de Pavert}, SH and N Cawley and {De Stefano}, N and ML Stromillo and M Battaglini and S Ruggieri and C Gasperini and M Filippi and MA Rocca and A Rovira and J Sastre-Garriga and H Vrenken and CE Leurs and J Killestein and L Pirpamer and C Enzinger and S Ourselin and CAMG Wheeler-Kingshott and D Chard and AJ Thompson and DC Alexander and F Barkhof and O Ciccarelli and group, {on behalf of the MAGNIMS study}",
year = "2018",
doi = "10.1002/ana.25145",
language = "English",
volume = "83",
pages = "210--222",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
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TY - JOUR

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

AU - Eshaghi, A

AU - Prados, F

AU - Brownlee, WJ

AU - Altmann, DR

AU - Tur, C

AU - Cardoso, MJ

AU - De Angelis, F

AU - van de Pavert, SH

AU - Cawley, N

AU - De Stefano, N

AU - Stromillo, ML

AU - Battaglini, M

AU - Ruggieri, S

AU - Gasperini, C

AU - Filippi, M

AU - Rocca, MA

AU - Rovira, A

AU - Sastre-Garriga, J

AU - Vrenken, H

AU - Leurs, CE

AU - Killestein, J

AU - Pirpamer, L

AU - Enzinger, C

AU - Ourselin, S

AU - Wheeler-Kingshott, CAMG

AU - Chard, D

AU - Thompson, AJ

AU - Alexander, DC

AU - Barkhof, F

AU - Ciccarelli, O

AU - group, on behalf of the MAGNIMS study

PY - 2018

Y1 - 2018

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 identif ied 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. © 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association

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 identif ied 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. © 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association

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 -