miRNA-214 Shows Potential as Biomarker to Predict ALS Disease Progression

Seung Hyun Kim, PhD

A research study published in Neurology, Neurosurgery, & Psychiatry found that microRNA (miRNA)-214, which targets the NCKAP1 gene, is linked to disease progression, severity, and survival in amyotrophic lateral sclerosis (ALS). Overall, investigators concluded that miRNA-214 may serve as a potentially important biomarker and regulator of disease processes in patients with ALS.¹

The trial featured 2 cohorts: a discovery cohort (n = 29) used to identify miRNA-214 targeting NCKAP1 genes, and a validation cohort (n = 132) used to determine the clinical usability of miRNA-214 for predicting disease progression speed and survival time. Within the discovery cohort, 15 participants were classified as having rapidly progressing ALS, while the other 14 were categorized as having slowly progressive ALS. For the validation cohort, participants with familial histories or ALS-related gene variants were excluded to minimize genetic influence on disease progression.

Led by senior author Seung Hyun Kim, PhD, Department of Public Health Science, Hanyang University, South Korea, plasma miRNA-214 was shown to be more elevated among rapidly progressing patients vs those with more slowly progressive disease. Additional data from the discovery cohort revealed that plasma miRNA-214 levels at enrollment were associated with faster ALS progression (r = 0.372; P = .047) and shorter survival, as shown by Kaplan-Meier analysis (log-rank X² = 4.0; P = .046).

The utility of miRNA-214 as a plasma biomarker was further proven in the validation cohort, where levels were shown to be significantly higher among patients with ALS than in controls (area under the curve, 0.86; P <.0001). More importantly, changes in these levels negatively correlated with ALS Functional Rating Scale-Revised (ALSFRS-R) scores and disease duration. These correlations were also significantly associated with disease progression speeds (T₀–T₁: r = 0.410, P <0.0001; T₁–T₂: r = 0.232, P = 0.0076; T₀–T₂: r = 0.291, P = 0.0007).

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"Considering that miR-214, identified in this study, is a reliable biomarker associated with microglial phagocytic dysfunction and proinflammatory milieu in the ALS progression, the level of plasma miR-214 is thought to reflect the underlying pathological mechanisms," Kim et al wrote. "High miR-214 levels predicted shorter survival and distinguished between rapidly and slowly progressive ALS. While miR-214 alone was not superior to NfL in predicting outcomes, combining both markers improved survival predictions. These findings suggest that miR-214 could serve as a valuable biomarker in ALS."

When stratifying patients based on their miRNA-214 levels, rapid progressors of the disease demonstrated the highest concentration of levels. An additional analysis of 11 cerebrospinal fluid cytokines and plasma neurofilament light (NfL) revealed that plasma miRNA-214 levels and NfL levels were significantly positively correlated (P = .004). This finding is notable considering that NfL has become an established surrogate biomarker for ALS, playing a major role in the 2023 FDA decision of tofersen (Qalsody; Biogen), the first approved therapy for SOD1-ALS.

In quartile-based analyses, higher plasma miRNA-214 levels were associated with elevated NfL and pro-inflammatory cytokines (MCP-1, TNF-α, IL-15), and longitudinal tracking showed persistently high miR-214 in rapid progressors—suggesting its potential as a dynamic marker of disease progression. Investigators also showed that miRNA-214 and NfL could stratify patients with ALS by survival length using quartile stratification. Here, a Kaplan-Meier curve estimate showed significant survival differences for both markers (miR-214: log-rank χ²=5.34, P = 0.0208; NfL: log-rank χ²=15.31, P <0.0001), with a median survival of 47 months for low levels and 20 months for high levels.

High plasma NfL levels are considered strong predictors of ALS progression, and combining miR-214 with either NfL or CSF MCP-1 significantly improved survival prediction over miR-214 alone (log-rank P < .01). Cox regression confirmed higher hazard ratios for the combined markers, indicating enhanced prognostic value. While miR-214 alone was less predictive than NfL, its combination with NfL or MCP-1 offers a more robust assessment of disease progression, highlighting its role as an inflammation-linked prognostic biomarker.

REFERENCE
1. Noh MY, Kwon MS, Oh K, et al. miRNA-214 to predict progression and survival in ALS. Neurology, Neurosurg, & Psych. Published online February 5, 2025. doi:10.1136/jnnp-2024-335177