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.
Ann Neurol. 2018 Feb;83(2):210-222. doi: 10.1002/ana.25145. Epub 2018 Feb 6.
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.
灰质（GM）萎缩发生在所有多发性硬化症（MS）表型中。我们研究了 GM 萎缩是否存在与 MS 中更快残疾累积相关的时空模式。
我们分析了来自 1417 名参与者的 3604 例脑部高分辨率 T1 加权磁共振成像扫描：1214 例 MS 患者（253 例临床孤立综合征 [CIS]、708 例复发缓解 [RRMS]、128 例继发进展 [SPMS]和 125 例原发进展 [PPMS]），平均随访 2.41 年（标准差 [SD] = 1.97），203 名健康对照者（HC；平均随访= 1.83 年；SD = 1.77），参加了七个欧洲中心的研究。残疾采用扩展残疾状态量表（EDSS）进行评估。我们获得了深部 GM（DGM）、颞叶、额叶、顶叶、枕叶和小脑 GM、脑干和大脑白质的体积。分层混合模型评估了区域组织丢失的年百分比率，并确定了与 EDSS 进展时间相关的区域体积。
SPMS 在皮质 GM 和 DGM 的基线体积中显示出最低的水平。在所有基线区域体积中，只有 DGM 基线体积预测 EDSS 进展时间（危险比= 0.73；95%置信区间，0.65，0.82；p < 0.001）：DGM 基线体积每降低一个标准差，在随访期间出现 EDSS 恶化的风险增加 27%。在所有纵向测量中，DGM 显示出最快的年度萎缩率，SPMS（-1.45%）、PPMS（-1.66%）和 RRMS（-1.34%）比 CIS（-0.88%）和 HCs（-0.94%；p < 0.01）更快。SPMS 中颞叶 GM 的萎缩率（-1.21%）明显快于 RRMS（-0.76%）、CIS（-0.75%）和 HCs（-0.51%）。同样，SPMS 中顶叶 GM 的萎缩率（-1.24-%）也快于 CIS（-0.63%）和 HCs（-0.23%；所有 p 值均<0.05）。只有患者的 DGM 萎缩率与残疾累积显著相关（β= 0.04；p < 0.001）。
这项大型、多中心和纵向研究表明，DGM 体积损失导致 MS 中残疾的累积，SPMS 中颞叶皮质 GM 的萎缩速度快于 RRMS。在评估治疗干预的治疗效果时，需要考虑表型之间 GM 萎缩发展的差异。Ann Neurol 2018；83：210-222。
