Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease of the human motor neuron system, where variability in progression rate limits clinical trial efficacy. Therefore, better prognostication will facilitate therapeutic progress. In this study, we investigated the potential of plasma cell-free microRNAs (miRNAs) as ALS prognostication biomarkers in 252 patients with detailed clinical phenotyping. First, we identified, in a longitudinal cohort, miRNAs whose plasma levels remain stable over the course of disease. Next, we showed that high levels of miR-181, a miRNA enriched in neurons, predicts a greater than two-fold risk of death in independent discovery and replication cohorts (126 and 122 patients, respectively). miR-181 performance is similar to neurofilament light chain (NfL), and when combined together, miR-181 + NfL establish a novel RNA–protein biomarker pair with superior prognostication capacity. Therefore, plasma miR-181 alone and a novel miRNA–protein biomarker approach, based on miR-181 + NfL, boost precision of patient stratification. miR-181-based ALS biomarkers encourage additional validation and might enhance the power of clinical trials.

肌萎缩性侧索硬化症 (ALS) 是人类运动神经元系统的一种无情的神经退行性疾病，其进展速度的变异性限制了临床试验的疗效。因此，更好的预后将促进治疗进展。在这项研究中，我们调查了 252 名具有详细临床表型的患者的无浆细胞 microRNA (miRNA) 作为 ALS 预后生物标志物的潜力。首先，我们在纵向队列中确定了血浆水平在疾病过程中保持稳定的 miRNA。接下来，我们发现高水平的 miR-181（一种富含神经元的 miRNA）预测独立发现和复制队列（分别为 126 名和 122 名患者）的死亡风险增加两倍以上。miR-181 的性能类似于神经丝轻链 (NfL)，当组合在一起时，miR-181 + NfL 建立了一种新型 RNA-蛋白质生物标志物对，具有出色的预测能力。因此，单独使用血浆 miR-181 和基于 miR-181 + NfL 的新型 miRNA-蛋白质生物标志物方法可以提高患者分层的精确度。基于 miR-181 的 ALS 生物标志物鼓励进行额外的验证，并可能增强临床试验的效力。