Abstract Body: Introduction: Familial cerebral cavernous malformations (FCCM), Sturge-Weber Syndrome (SWS), and hereditary hemorrhagic telangiectasia with brain arteriovenous malformations (HHT) are neurovascular disorders driven by genetic mutations while cerebral microbleeds (CMBs) are primarily associated with the aging process. All are associated with different vascular dysmorphisms and/or propensity to bleed.

Hypothesis: We hypothesized that common and distinct circulating microribonucleic acids (miRNAs), reflecting shared and different pathobiology, can serve as potential biomarkers and therapeutic targets.

Methods: Plasma miRNAs from patients with FCCM (n=10), SWS (n=10), and HHT (n=10) compared to age and sex-propensity-matched healthy young (HY) subjects (n=10) were extracted and sequenced. Similarly, CMB patients (n=10) were age and sex propensity-matched with healthy old (HO) subjects (n=10). Differentially expressed (DE) miRNAs of each disorder were identified (p<0.05, FDR corrected, absolute fold change [|FC|]>1.5]). Ingenuity Pathway Analysis (IPA) was conducted to determine gene targets and pathways of DE miRNAs. DE genes based on the transcriptome of each disorder were identified and utilized to filter gene targets of circulating miRNAs.

Results: Eleven DE miRNAs were identified in FCCM, 40 in SWS, 41 in HHT, and 26 in CMB (p<0.05, FDR-corrected, [|FC|]>1.5]). Further analyses showed that 18 miRNAs were commonly dysregulated in two of the studied neurovascular disorders. IPA identified 17 genes targeted by at least two DE miRNAs in each of the four cerebrovascular disorders. Functional enrichment of those shared gene targets showed that PTEN, CDKN1A, NCL2L1, and CCND2 were involved in the PI3K-Akt Signaling Pathway. Moreover, the ROBO SLIT Signaling Pathway was identified as an involved pathway across all four disorders.

Conclusion: The common dysregulated miRNAs across the disorders underscore their potential as biomarkers and therapeutic targets, reflecting their mechanistic involvement in shared pathophysiological pathways. Furthermore, the commonly targeted genes and implicated pathways suggest shared functionality of the miRNAs. These findings pave the way for further exploration of these miRNAs, aiming at the clinical application for disease monitoring and therapeutic intervention.