ImportanceBiomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology.ObjectiveTo identify CSF biological measures associated with progressive MS pathobiology.Design, Setting, and ParticipantsThis cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023).ExposuresTest-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies.Main Outcomes and MeasuresTwenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]).ResultsThe test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = –0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = –0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002).Conclusions and RelevanceIn this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

中文翻译：

---

多发性硬化症疾病活动和进展的新兴脑脊液生物标志物

重要性 目前缺乏区分多发性硬化症 (MS) 中非复发进行性疾病生物学与复发生物学的生物标志物。脑脊液 (CSF) 是一种最能反映中枢神经系统生物学的易接近液体。目的确定与进行性 MS 病理学相关的 CSF 生物学指标。设计、设置和参与者本队列研究评估了 2 个前瞻性 MS 队列的数据：一个测试队列提供了序列对开始抗 CD20 治疗的复发性多发性硬化症 (RMS) 或原发性进展性多发性硬化症 (PPMS) 患者进行的多中心研究中的脑脊液、临床和影像学评估（招募：2016-2018 年；分析：2020-2023 年）。使用单中心确认队列来评估基线和长期（> 10 年）临床随访（分析：2022-2023）的 CSF。暴露测试队列参与者开始标准护理 ocrelizumab 治疗。确认队列参与者未经治疗或接受了标准护理疾病缓解多发性硬化症治疗。主要结果和测量二十五个脑脊液标记物，包括神经丝轻链、神经丝重链和神经胶质纤维酸性蛋白 (GFAP)；24 周确认残疾进展 (CDP24)；反映局灶性损伤、组织损失和进展性生物学（缓慢扩大的病变 [SEL]）的脑磁共振成像测量结果。结果测试队列 (n = 131) 包括 100 名 RMS 患者（平均 [SD] 年龄，36.6 [10.4] 岁） ; 68 [68%] 女性和 32 [32%] 男性；扩展残疾状态量表 [EDSS] 评分，0-5.5），31 名 PPMS 患者（平均 [SD] 年龄，44.9 [7.4] 岁；15 [48 %] 女性和 16 [52%] 男性；EDSS 评分，3.0-6.5）。确认队列 (n = 68) 包括诊断时入组的 41 名 RMS 患者和 27 名 PPMS 患者（年龄，40 岁 [范围，20-61 岁]；47 名女性 [69%] 和 21 名男性 [31%]）。在测试队列中，GFAP 与 SEL 计数相关（r= 0.33），来自 SEL 的 T2 病变体积比例更大（r= 0.24），并且 SEL 内的 T1 加权强度较低（r= –0.33）但不适用于急性炎症措施。神经丝重链与 SEL 计数相关（r= 0.25）和 SEL 内较低的 T1 加权强度（r= –0.28)。免疫标志物与急性炎症的测量相关，并且与 GFAP 不同，它受到抗 CD20 的影响。在确认队列中，较高的基线 CSF GFAP 水平与长期 CDP24 相关（风险比，2.1；95% CI，1.3-3.4；磷= .002）。结论和相关性在这项研究中，活化的神经胶质标记物（特别是 GFAP）和神经丝重链与非复发性进展性疾病结果特异性相关（独立于急性炎症活动）。CSF GFAP 升高与 MS 疾病的长期进展相关。