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; 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; Jette Lautrup Battistini Frederiksen; MAGNIMS Study Group

doi:10.1002/ana.25145

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 LeursJoep 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, Jette Lautrup Battistini Frederiksen (Medlem af forfattergruppering), MAGNIMS Study Group

Afdeling for Hjerne- og Nervesygdomme

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.

Originalsprog	Engelsk
Tidsskrift	Annals of Neurology
Vol/bind	83
Udgave nummer	2
Sider (fra-til)	210-222
Antal sider	13
ISSN	0364-5134
DOI	https://doi.org/10.1002/ana.25145
Status	Udgivet - 2018

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10.1002/ana.25145

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Eshaghi, A., Prados, F., Brownlee, W. J., Altmann, D. R., Tur, C., Cardoso, M. J., De Angelis, F., van de Pavert, S. H., Cawley, N., De Stefano, N., Stromillo, M. L., Battaglini, M., Ruggieri, S., Gasperini, C., Filippi, M., Rocca, M. A., Rovira, A., Sastre-Garriga, J., Vrenken, H., ... 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, 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, Frederiksen, JLB & MAGNIMS Study Group 2018, 'Deep gray matter volume loss drives disability worsening in multiple sclerosis', Annals of Neurology, bind 83, nr. 2, s. 210-222. https://doi.org/10.1002/ana.25145

@article{0ecf810183d646bcb7f6463f8a5791d2,

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.",

keywords = "Adult, Atrophy/pathology, Brain/diagnostic imaging, Disability Evaluation, Disease Progression, Female, Gray Matter/diagnostic imaging, Humans, Image Interpretation, Computer-Assisted, Longitudinal Studies, Magnetic Resonance Imaging/methods, Male, Middle Aged, Multiple Sclerosis/diagnostic imaging, Neuroimaging/methods, Retrospective Studies",

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 Frederiksen, {Jette Lautrup Battistini} and {MAGNIMS Study Group}",

note = "{\textcopyright} 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.",

year = "2018",

doi = "10.1002/ana.25145",

language = "English",

volume = "83",

pages = "210--222",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John/Wiley & Sons, Inc. John/Wiley & Sons Ltd",

number = "2",

}

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 - MAGNIMS Study Group

A2 - Frederiksen, Jette Lautrup Battistini

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 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.

KW - Adult

KW - Atrophy/pathology

KW - Brain/diagnostic imaging

KW - Disability Evaluation

KW - Disease Progression

KW - Female

KW - Gray Matter/diagnostic imaging

KW - Humans

KW - Image Interpretation, Computer-Assisted

KW - Longitudinal Studies

KW - Magnetic Resonance Imaging/methods

KW - Male

KW - Middle Aged

KW - Multiple Sclerosis/diagnostic imaging

KW - Neuroimaging/methods

KW - Retrospective Studies

U2 - 10.1002/ana.25145

DO - 10.1002/ana.25145

M3 - Journal article

C2 - 29331092

SN - 0364-5134

VL - 83

SP - 210

EP - 222

JO - Annals of Neurology

JF - Annals of Neurology

IS - 2

ER -

Deep gray matter volume loss drives disability worsening in multiple sclerosis

Abstract

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