Abstract：
OBJECTIVE: The first randomized placebo-controlled therapeutic trial in radiologically isolated syndrome (RIS), ARISE, demonstrated that treatment with dimethyl fumarate (DMF) delayed the onset of a first clinical event related to CNS demyelination and was associated with a significant reduction in new and/or newly enlarging T2-weighted hyperintense lesions. The purpose of this study was to explore the effect of DMF on volumetric measures, including whole brain, thalamic, and subcortical gray matter volumes, brainstem and upper cervical spine three-dimensional (3D) volumes, and brainstem and upper cervical spine surface characteristics.
METHODS: Standardized 3T MRIs including 3D isotropic T1-weighted gradient echo images were acquired at baseline and end-of-study according to the ARISE study protocol. The acquired data were analyzed using Structural Image Evaluation Using Normalization of Atrophy (SIENA), FreeSurfer v7.3, and an in-house pipeline for 3D conformational metrics. Multivariate mixed models for repeated measures were used to analyze rates of change in whole brain, thalamic, subcortical gray matter, as well as change in the 3D surface curvature of the dorsal pons and dorsal medulla and 3D volume change at the medulla-upper cervical spinal cord.
RESULTS: The study population consisted of 64 RIS subjects (DMF:30, placebo:34). No significant difference was seen in whole brain, thalamic, or subcortical gray matter volumes in treated vs. untreated RIS patients. A significant difference was observed in dorsal pons curvature with the DMF group having a lower least squares mean change of - 4.46 (standard estimate (SE): 3.77) when compared to placebo [6.94 (3.71)] (p = 0.036). In individuals that experienced a first clinical event, a greater reduction in medulla-upper cervical spinal cord volume (p = 0.044) and a decrease in surface curvature was observed at the dorsal medulla (p = 0.009) but not at the dorsal pons (p = 0.443).
CONCLUSIONS: The benefit of disease-modifying therapy in RIS may extend to CNS structures impacted by neurodegeneration that is below the resolution of conventional volumetric measures.
METHODS: Standardized 3T MRIs including 3D isotropic T1-weighted gradient echo images were acquired at baseline and end-of-study according to the ARISE study protocol. The acquired data were analyzed using Structural Image Evaluation Using Normalization of Atrophy (SIENA), FreeSurfer v7.3, and an in-house pipeline for 3D conformational metrics. Multivariate mixed models for repeated measures were used to analyze rates of change in whole brain, thalamic, subcortical gray matter, as well as change in the 3D surface curvature of the dorsal pons and dorsal medulla and 3D volume change at the medulla-upper cervical spinal cord.
RESULTS: The study population consisted of 64 RIS subjects (DMF:30, placebo:34). No significant difference was seen in whole brain, thalamic, or subcortical gray matter volumes in treated vs. untreated RIS patients. A significant difference was observed in dorsal pons curvature with the DMF group having a lower least squares mean change of - 4.46 (standard estimate (SE): 3.77) when compared to placebo [6.94 (3.71)] (p = 0.036). In individuals that experienced a first clinical event, a greater reduction in medulla-upper cervical spinal cord volume (p = 0.044) and a decrease in surface curvature was observed at the dorsal medulla (p = 0.009) but not at the dorsal pons (p = 0.443).
CONCLUSIONS: The benefit of disease-modifying therapy in RIS may extend to CNS structures impacted by neurodegeneration that is below the resolution of conventional volumetric measures.
摘要：
目的：第一个放射学孤立综合征（RIS）的随机安慰剂对照治疗试验，ARISE,证明富马酸二甲酯(DMF)治疗可延迟与中枢神经系统脱髓鞘相关的首次临床事件的发生,并与新的和/或新的T2加权高强度病变的显著减少相关.这项研究的目的是探讨DMF对容量测量的影响，包括整个大脑,丘脑,皮质下灰质体积,脑干和上颈椎三维（3D）体积，和脑干和上颈椎表面特征。
方法：根据ARISE研究方案，在基线和研究结束时采集包括3D各向同性T1加权梯度回波图像的标准化3TMRI。使用使用萎缩归一化的结构图像评估（SIENA）分析获得的数据，FreeSurferv7.3，以及用于3D构象度量的内部管道。重复测量的多变量混合模型用于分析全脑的变化率，丘脑,皮质下灰质,以及背桥和延髓的3D表面曲率变化以及延髓-上颈脊髓的3D体积变化。
结果:研究群体由64名RIS受试者(DMF:30,安慰剂:34)组成。在整个大脑中没有发现显着差异，丘脑,或皮质下灰质体积在治疗与未经治疗的RIS患者。当与安慰剂[6.94(3.71)](p=0.036)相比时,DMF组具有较低的最小二乘均值变化-4.46(标准估计(SE):3.77),在背桥曲率中观察到显著差异。在经历了第一次临床事件的个体中，在延髓背侧(p=0.009)但在背桥(p=0.443)观察到延髓-上颈脊髓体积的减小(p=0.044)和表面曲率的减小。
结论：在RIS中疾病改善治疗的益处可能扩展到受神经变性影响的CNS结构，其低于常规体积测量的分辨率。
方法：根据ARISE研究方案，在基线和研究结束时采集包括3D各向同性T1加权梯度回波图像的标准化3TMRI。使用使用萎缩归一化的结构图像评估（SIENA）分析获得的数据，FreeSurferv7.3，以及用于3D构象度量的内部管道。重复测量的多变量混合模型用于分析全脑的变化率，丘脑,皮质下灰质,以及背桥和延髓的3D表面曲率变化以及延髓-上颈脊髓的3D体积变化。
结果:研究群体由64名RIS受试者(DMF:30,安慰剂:34)组成。在整个大脑中没有发现显着差异，丘脑,或皮质下灰质体积在治疗与未经治疗的RIS患者。当与安慰剂[6.94(3.71)](p=0.036)相比时,DMF组具有较低的最小二乘均值变化-4.46(标准估计(SE):3.77),在背桥曲率中观察到显著差异。在经历了第一次临床事件的个体中，在延髓背侧(p=0.009)但在背桥(p=0.443)观察到延髓-上颈脊髓体积的减小(p=0.044)和表面曲率的减小。
结论：在RIS中疾病改善治疗的益处可能扩展到受神经变性影响的CNS结构，其低于常规体积测量的分辨率。
