Savini Giovanni, Asteggiano Carlo, Paoletti Matteo, Parravicini Stefano, Pezzotti Elena, Solazzo Francesca, Muzic Shaun I, Santini Francesco, Deligianni Xeni, Gardani Alice, Germani Giancarlo, Farina Lisa M, Bergsland Niels, Gandini Wheeler-Kingshott Claudia A M, Berardinelli Angela, Bastianello Stefano, Pichiecchio Anna
Advanced Imaging and Radiomics Center, Neuroradiology Department, IRCCS Mondino Foundation, Pavia, Italy.
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
Front Neurol. 2021 Mar 29;12:613834. doi: 10.3389/fneur.2021.613834. eCollection 2021.
Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA. Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally. Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content. In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.
诺西那生是一种最近获批用于治疗脊髓性肌萎缩症（SMA）的有前景的疗法，SMA是一种罕见疾病，其特征是脊髓（SC）中的α运动神经元（αMN）退化，导致进行性肌肉萎缩和功能障碍。肌肉和颈段脊髓定量磁共振成像（qMRI）从未用于监测SMA的药物治疗。这项初步研究的目的是调查qMRI是否能为监测SMA的治疗效果提供有用的生物标志物。3例接受诺西那生治疗的成年SMA 3a患者从基线开始每4个月接受一次纵向临床和qMRI检查，直至21个月随访。qMRI方案旨在量化大腿肌肉脂肪分数（FF）和水-T2（w-T2），并对脊髓体积和微观结构进行表征。11名健康对照者接受相同的脊髓检查方案（单时间点）。我们纵向评估了SMA患者的临床和影像学结果，并横向比较了各组之间的脊髓数据。患者的运动功能稳定，只有患者2有中度改善。平均肌肉FF在基线时已经很高（50%），并随时间进展（57%）。w-T2在基线时也略高于先前发表的数据，并随时间略有下降。与对照组相比，患者1和患者3的整个脊髓、灰质（GM）和腹角（VH）的横截面积减小，并随时间保持稳定，而患者2的GM和VH面积略有增加。与对照组相比，我们发现SMA患者脊髓结构中的扩散和磁化传递参数发生了改变，因此提示组织微观结构和髓鞘含量发生了变化。在这项初步研究中，我们发现SMA 3a患者在接受诺西那生治疗期间大腿肌肉FF有所进展，同时w-T2随时间略有降低。脊髓qMRI分析证实了先前的影像学和组织病理学研究，提示VH的αMN退化，导致GM萎缩和脱髓鞘。我们的纵向数据表明，qMRI可能是一种捕捉SMA引起的微观结构变化的可行技术，并且一旦在更大的队列中得到重复验证，可能成为监测治疗效果的候选方法。
