Plasma miR-21-5p, miR-195-5p, and clusterin profiles in relapsing-remitting multiple sclerosis and their relationship with cognitive function.

Cognitive impairment is a debilitating aspect of multiple sclerosis (MS), and reliable blood biomarkers to assess it are still scarce. MicroRNAs such as miR-21-5p and miR-195-5p, together with clusterin, are involved in neuroinflammation and synaptic plasticity, which suggests a potential role in MS. The aim of the study was to investigate the relationship between plasma clusterin, miR-21-5p, and miR-195-5p expression and cognitive performance in patients with relapsing-remitting multiple sclerosis (pwRRMS). The study included 30 treatment-naïve pwRRMS, 30 pwRRMS on disease-modifying therapy (DMT), and 30 healthy controls. Plasma clusterin was determined by enzyme-linked immunosorbent assay, relative expression levels of the miRNAs were determined using real-time quantitative PCR, and cognitive performance was assessed using the Brief International Cognitive Assessment for MS. In silico network analysis was performed to explore the regulatory architecture of the miRNA-CLU axis. miR-21-5p expression was significantly elevated in treatment-naïve pwRRMS, while miR-195-5p was downregulated across all pwRRMS compared with controls and these differences persisted after adjustment for age and sex. Plasma clusterin levels were similar across groups. Neither the miRNAs nor clusterin significantly correlated with cognitive impairment status or adjusted BICAMS scores. Cognitive impairment in the pwRRMS on DMT group was associated with higher lesion burdens. In silico analysis positioned miR-21-5p, miR-195-5p, and clusterin among genes involved in neuroinflammatory pathways, generating cellular-level hypotheses; their circulating levels primarily reflected systemic inflammatory activity. In this cohort, magnetic resonance imaging lesion burden showed a stronger association with cognitive impairment than circulating biomarkers, and these findings warrant validation in larger multi-center studies.