Progression of regional grey matter atrophy in multiple sclerosis.
Progression of regional grey matter atrophy in multiple sclerosis.
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多发性硬化症中区域灰质萎缩的进展。
DOI：
10.1093/brain/awy088
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发表时间：
2018-06-01
期刊：
影响因子：
--
通讯作者：
Ciccarelli O
中科院分区：
文献类型：
--
作者：
Eshaghi A;Marinescu RV;Young AL;Firth NC;Prados F;Jorge Cardoso M;Tur C;De Angelis F;Cawley N;Brownlee WJ;De Stefano N;Laura Stromillo M;Battaglini M;Ruggieri S;Gasperini C;Filippi M;Rocca MA;Rovira A;Sastre-Garriga J;Geurts JJG;Vrenken H;Wottschel V;Leurs CE;Uitdehaag B;Pirpamer L;Enzinger C;Ourselin S;Gandini Wheeler-Kingshott CA;Chard D;Thompson AJ;Barkhof F;Alexander DC;Ciccarelli O
有关本文的科学评论，请参见Stankoff and Louapre(DOI：)。多发性硬化症的灰质萎缩优先影响某些区域。Eshaghi等人。使用数据驱动的计算模型来预测区域萎缩的顺序，并使用该序列来对患者进行分期。萎缩始于深部灰质核和后皮质区域，然后扩散到其他皮质区域。有关本文的科学评论，请参见Stankoff and Louapre(DOI：)。灰质萎缩始于多发性硬化症的早期阶段，但对其时间顺序知之甚少。我们的目标是确定多发性硬化症患者灰质区域萎缩的顺序及其与残疾累积的关系。在这项纵向研究中，我们纳入了1417名受试者：253名临床孤立综合征患者，708名复发-缓解型多发性硬化症患者，128名继发性进展型多发性硬化症患者，125名原发进展型多发性硬化症患者，以及来自7个欧洲中心的203名健康对照组受试者。受试者接受了重复的MRI检查(总扫描次数为3604次)；患者的平均随访时间为2.41年(标准差=1.97)。使用扩展的残疾状况量表对残疾进行评分。我们使用无偏的受试者内模板计算大脑灰质区域和脑干的体积，并使用建立的数据驱动的基于事件的模型来确定萎缩的发生顺序及其不确定性。我们根据受试者萎缩区域的数量，将每个受试者分配到一个特定的基于事件的模型阶段。线性混合效应模型被用来探索基于事件的模型阶段的增长率与T2病变负荷、疾病修改治疗、共病、疾病持续时间和残疾累积之间的关系。在临床孤立综合征和复发性多发性硬化症患者中，最先萎缩的区域是后扣带回皮质和楔前叶，其次是中扣带回皮质、脑干和丘脑。在原发进行性多发性硬化症中也发现了类似的萎缩序列，受累于丘脑、楔叶、前楔叶和苍白球，其次是脑干和后扣带皮质。小脑、尾状核和壳核在复发性多发性硬化症中表现为早期萎缩，在原发进展型多发性硬化症中表现为晚期萎缩。继发性进展性多发性硬化症患者在研究开始时表现出最高的基于事件的模型阶段(萎缩区的最高数量，P<；0.001)。所有多发性硬化症的表型，除了临床孤立综合征，在基于事件的模型阶段显示出比健康对照组更快的增长速度。所有患者的T2病变负荷和病程与基于事件的模型阶段的增加有关，但没有观察到疾病修改治疗和共病对基于事件的模型阶段的影响。基于事件的模型阶段的年化率与复发-缓解型多发性硬化症的残疾累积相关，与病程无关(P<；0.0001)。在一个大型多发性硬化症样本中，以数据为导向的萎缩进展分期表明，随着时间的推移，灰质萎缩扩散到更多的区域。区域萎缩的顺序在多发性硬化症表型中是相当一致的。在复发-缓解型多发性硬化症中，萎缩的扩散与病程和随时间积累的残疾有关。
See Stankoff and Louapre (doi:) for a scientific commentary on this article. Grey matter atrophy in multiple sclerosis affects certain areas preferentially. Eshaghi et al. use a data-driven computational model to predict the order in which regions atrophy, and use this sequence to stage patients. Atrophy begins in deep grey matter nuclei and posterior cortical regions, before spreading to other cortical areas. See Stankoff and Louapre (doi:) for a scientific commentary on this article. Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple sclerosis and late atrophy in primary-progressive multiple sclerosis. Patients with secondary-progressive multiple sclerosis showed the highest event-based model stage (the highest number of atrophic regions, P < 0.001) at the study entry. All multiple sclerosis phenotypes, but clinically isolated syndrome, showed a faster rate of increase in the event-based model stage than healthy controls. T2 lesion load and disease duration in all patients were associated with increased event-based model stage, but no effects of disease-modifying treatments and comorbidity on event-based model stage were observed. The annualized rate of event-based model stage was associated with the disability accumulation in relapsing-remitting multiple sclerosis, independent of disease duration (P < 0.0001). The data-driven staging of atrophy progression in a large multiple sclerosis sample demonstrates that grey matter atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across multiple sclerosis phenotypes. The spread of atrophy was associated with disease duration and with disability accumulation over time in relapsing-remitting multiple sclerosis.
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