The behavioural variant of frontotemporal dementia (bvFTD) often overlaps clinically with primary psychiatric disorders (PPD), leading to frequent misdiagnosis and delayed intervention. The “Diagnostic and Prognostic Precision Algorithm for behavioural variant Frontotemporal Dementia” (DIPPA-FTD) study aims to enhance bvFTD diagnosis by integrating clinical and molecular biomarkers. Among these, neuron-derived extracellular vesicles (NDEVs) isolated from plasma offer a minimally invasive means to investigate central nervous system alterations through microRNA (miRNA) profiling.

This study analyzed miRNAs expression in NDEVs from patients with bvFTD, PPD, and healthy controls. In a retrospective cohort of 80 participants, six miRNAs differentiated bvFTD from PPD; however, these findings were not replicated in a prospective cohort comprised of 86 participants, suggesting heterogeneity within PPD. Further analysis identified three miRNAs (hsa-miR-106b-5p, hsa-miR-126-3p, and hsa-miR-342-3p) that significantly distinguished bvFTD from a sub-group of PPD, namely bipolar disorder (BD). The downregulation of hsa-miR-106b-5p and hsa-miR-126-3p, implicated in neuroprotection and vascular integrity, contrasted with the upregulation of hsa-miR-342-3p, which is associated with neuroinflammation.

Bioinformatics analysis revealed E2F1, a transcription factor linked to autophagy and neuronal apoptosis, as a common target of significantly de-regulated miRNAs, further highlighting their potential pathophysiological role. These findings suggest that miRNAs signatures in NDEVs may serve as valuable biomarkers to differentiate bvFTD from BD, although further validation is required.