Kim Su-Hyun, Gomes Ana Beatriz Ayroza Galvão Ribeiro, Schindler Patrick, Hyun Jae-Won, Kim Ki Hoon, Lee Dong-Eun, Schoeps Vinicius Andreoli, Matos Aline de Moura Brasil, Mendes Natalia Trombini, Apóstolos-Pereira Samira Luisa Dos, Callegaro Dagoberto, Lerner Jasmine, Benkert Pascal, Kuhle Jens, Ruprecht Klemens, Paul Friedemann, Pröbstel Anne-Katrin, Kim Ho Jin
Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea.
Department of Neurology, University Hospital Basel and University of Basel, Basel, Switzerland.
JAMA Neurol. 2025 Feb 1;82(2):168-175. doi: 10.1001/jamaneurol.2024.4400.
The temporal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) as biomarkers of disease activity for neuromyelitis optica spectrum disorder (NMOSD) remain underexplored.
To determine optimal timing for assessing sGFAP and sNfL, establish cutoff values differentiating between attacks and remissions in NMOSD, and evaluate these findings across independent cohorts.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective, longitudinal, multicenter cohort study was conducted among patients with aquaporin-4 antibody (AQP4-IgG)-positive NMOSD. Patients with available stored serum samples were included, totaling 181 patients with 625 samples. Discovery cohort samples were collected from February 2008 to October 2023 and validation cohort samples were collected from January 2013 to October 2023. A combined analysis of both cohorts was conducted from November 2023 to March 2024.
sNfL and sGFAP concentrations, measured by a single-molecule array assay.
The primary outcomes were the optimal timing of assessing sGFAP and sNfL and the adjusted cutoff values for evaluating disease activity in NMOSD.
The discovery cohort consisted of 366 samples from 78 Korean patients (median [IQR] age, 35 [30-42] years; 73 female patients [95%]), while the validation cohort included 190 samples from 34 German patients (median [IQR] age, 54 [39-61] years; 32 female patients [94%]) and 69 samples from 69 Brazilian patients (median [IQR] age, 46 [35-55] years; 62 female patients [90%]). Six-month postattack temporal biomarker dynamics were analyzed in 202 samples from 74 patients in the discovery cohort: sGFAP levels peaked within the first week and sNfL levels peaked at 5 weeks postattack. The optimal time frames for evaluating attacks were within 1 week for sGFAP and from 1 to 8 weeks for sNfL, with remission defined as at least 6 months postattack. z Score cutoffs of 3.0 for sGFAP and 2.1 for sNfL effectively distinguished between attack and remission phases, indicated by area under the curve values of 0.95 (95% CI, 0.88-1.02) and 0.87 (95% CI, 0.82-0.91), respectively. The discovery cohort time frames and cutoff values were applied to the validation cohort, achieving 71% sensitivity and 94% specificity for sNfL and 100% sensitivity and specificity for sGFAP in the German and Brazilian cohorts.
This longitudinal cohort study established optimal timing and thresholds for sGFAP and sNfL, which were consistent in independent cohorts, supporting these biomarkers' effectiveness in distinguishing NMOSD attacks from remission.
血清胶质纤维酸性蛋白（sGFAP）和血清神经丝轻链（sNfL）作为视神经脊髓炎谱系障碍（NMOSD）疾病活动生物标志物的时间动态变化仍未得到充分研究。
确定评估sGFAP和sNfL的最佳时间，建立区分NMOSD发作和缓解的临界值，并在独立队列中评估这些结果。
设计、设置和参与者：这项回顾性、纵向、多中心队列研究在水通道蛋白4抗体（AQP4-IgG）阳性的NMOSD患者中进行。纳入有可用储存血清样本的患者，共181例患者625份样本。发现队列样本收集于2008年2月至2023年10月，验证队列样本收集于2013年1月至2023年10月。2023年11月至2024年3月对两个队列进行了联合分析。
通过单分子阵列分析测量sNfL和sGFAP浓度。
主要结局是评估sGFAP和sNfL的最佳时间以及评估NMOSD疾病活动的调整后临界值。
发现队列包括来自78名韩国患者的366份样本（中位[四分位间距]年龄，35[30-42]岁；73名女性患者[95%]），而验证队列包括来自34名德国患者的190份样本（中位[四分位间距]年龄，54[39-61]岁；32名女性患者[94%]）和来自69名巴西患者的69份样本（中位[四分位间距]年龄，46[35-55]岁；62名女性患者[90%]）。对发现队列中74例患者的202份样本分析了发作后6个月的时间生物标志物动态变化：sGFAP水平在第一周内达到峰值，sNfL水平在发作后5周达到峰值。评估发作的最佳时间范围是sGFAP在1周内，sNfL在1至8周内，缓解定义为发作后至少6个月。sGFAP的z评分临界值为3.0，sNfL为2.1，有效区分了发作期和缓解期，曲线下面积值分别为0.95（95%CI，0.88-1.02）和0.87（95%CI，0.82-0.91）。发现队列的时间范围和临界值应用于验证队列，在德国和巴西队列中，sNfL的敏感性为71%，特异性为94%，sGFAP的敏感性和特异性均为100%。
这项纵向队列研究确定了sGFAP和sNfL的最佳时间和阈值，在独立队列中是一致的，支持这些生物标志物在区分NMOSD发作和缓解方面的有效性。
