Abstract
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.
Highlights
2 Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder of the motor 3 neuron system, for which no effective disease-modifying treatment exists
We demonstrated that high levels of miR-181, a miRNA enriched in neurons of the brain and spinal cord, predicts a >2 fold risk of death in discovery cohort (126 patients) and an independent replication cohort. miR-181 performance is comparable with the established neurofilament light chain (NfL) biomarker and when combined together, miR181+Neurofilament light chain (NfL) establish a novel RNA-protein biomarker pair with superior prediction capacity of ALS prognosis
We identified 125 miRNA candidate biomarkers, whose plasma levels 44 were relatively stable during disease progression in the same sub-cohort of 22 longitudinal samples 45 (Figure 1A, Table S1) that could be tested as candidate prognostic biomarkers
Summary
Neurofilament light chain (NfL) was the first blood biomarker to aid in predicting ALS progression rate, but further markers are needed to improve stratification and allow for more effective trials. We take a hypothesis-free approach by applying generation sequencing (RNA-seq) to comprehensively study plasma miRNAs in a large cohort of 252 ALS cases. These studies focused our attention on the miR-181 family, which are expressed from two homologs, polycistronic genes, mir-181a-1/b-1 (human chromosome 9) and mir-181a-2/b-2 (human chromosome 1). We reveal that miR-181 levels predict disease progression in large discovery and a replication cohort, and demonstrate the effectiveness of combining miR-181 with established neurofilament light chain as a prognostic biomarker pair for ALS
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