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

Arman Eshaghi,Serena Ruggieri,Cyra E Leurs,Daniel C Alexander,Carmen Tur,Daniel R Altmann,Massimo Filippi,Maria A Rocca,Hugo Vrenken,Lukas Pirpamer,Floriana De Angelis,Frederik Barkhof,Declan Chard,Marco Battaglini,M Jorge Cardoso,Christian Enzinger,Nicola De Stefano,Olga Ciccarelli,Niamh Cawley,Alan J Thompson,Jaume Sastre‐Garriga,Claudio Gasperini,Joep Killestein,Ml Stromillo ,C Wheeler-Kingshott ,Álex Rovira ,Ferrán Prados ,Sébastien Ourselin ,Wallace Brownlee ,Steven H Van De Pavert

doi:10.1002/ana.25145

Abstract

ObjectiveGray 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.MethodsWe 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.ResultsSPMS 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).InterpretationThis 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

Highlights

Spatiotemporal Pattern of Gray matter (GM) Volume Loss in Clinical Phenotypes SPMS showed the lowest baseline volumes of cortical GM and deep GM (DGM), and the rate of the DGM volume loss was faster in SPMS, PPMS, and RRMS than clinically isolated syndrome (CIS) and healthy controls (HCs), there was no significant association between rate of loss in specific regions and clinical phenotypes, which suggests that all clinical phenotypes share a similar spatiotemporal pattern of GM loss
Multicenter study, we have shown that volume loss in DGM over time was faster than that observed in other brain regions across all clinical phenotypes, and DGM volume loss was the only GM region associated with disability accumulation
We found that the smaller DGM volume at baseline was associated with increased risk of shorter time to Expanded Disability Status Scale (EDSS) progression, in agreement with previous studies that showed smaller DGM volume associated with higher disability.[14,15]

Summary

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. 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). 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. Multicenter cohort, which included all MS phenotypes and HCs, we tested the following hypotheses: (1) Some GM regions show faster atrophy rate than others and their rate may differ between MS phenotypes; (2) smaller baseline volumes of brain structures, reflecting a more extensive neurodegeneration, predict disability accrual; and (3) the rate of regional volume loss is associated with the rate of disability accumulation

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