Plasma miR-34a-5p outperforms miR-126-3p in predicting cognitive decline in cerebral small vessel disease patients with impaired glucose regulation.

Introduction: MicroRNAs (miRNAs) are promising biomarkers for the diagnosis and prognosis of neurodegenerative diseases. Over the past few years, miR-34a-5p and miR-126-3p have become some of the most characterized miRNA, the former being associated with cellular senescence and apoptosis and the latter with the maintenance of vascular endothelial function. The present study aimed to evaluate diagnostic performance of miR-34a-5p and miR-126-3p for cognitive dysfunction in CSVD patients. In addition, we investigated whether these miR-34a-5p and miR-126-3p have mediating effect of impaired glucose regulation (IGR) status on cognitive dysfunction. The final objective was to the identification of better diagnostic biomarkers and further investigation on their value of practical application in Chinese population. Methods: The study included 300 patients with cerebral small vessel disease (CSVD), who were further stratified by oral glucose tolerance test into those with impaired glucose regulation (IGR, Results: The results show that, in the analysis based on cognitive stratification, plasma miR-126-3p expression levels were negatively correlated with the severity of cognitive impairment in CSVD patients, whereas miR-34a-5p levels showed a positive correlation. miR-126-3p exhibited a stepwise decrease with increasing cognitive severity, while miR-34a-5p significantly distinguished between normal and impaired cognitive status. Mediation analysis revealed that only miR-34a-5p demonstrated a significant mediating effect in the pathway from IGR to cognitive dysfunction (indirect effect = 0.4519, 95% BootCI: 0.0277-0.8879), and it exhibited superior diagnostic performance for cognitive impairment within the CSVD cohort. Following evaluation using the Youden index, miR-34a-5p at the 2-year follow-up demonstrated a balanced diagnostic performance with an area under the curve (AUC) of 0.803, a sensitivity of 65.3%, and a specificity of 84.0% at the optimal cut-off of 2.49, indicating its potential utility for risk stratification. Compared with its performance at baseline (AUC: 0.679, sensitivity: 58.3%, specificity: 75.0%), the diagnostic performance of miR-34a-5p at the 2-year follow-up showed improvements across all metrics, particularly in specificity. In contrast, miR-126-3p (an inverse indicator) showed a moderate sensitivity (64.6-70.5%) and specificity (60.7-63.2%), which may limit its standalone diagnostic application. Enrichment analysis indicated that miR-34a-5p could be involved in the pathological aspects of cognitive impairment by regulating pathways related to apoptosis, oxidative stress, and synaptic function. Discussion: The IGR stage may represent a potential early pathological window of cognitive impairment in CSVD patients. Plasma miR-34a-5p is more valuable as diagnostic and long-term prognostic marker in IGR patients than miR-126-3p and may mediate association between IGR and cognitive decline via apoptosis, oxidative stress and synaptic pathway.