Integrated Serum Multiomics Reveal Subtype-Specific Immune Dysregulation and Sex-Dimorphic Pathophysiology in Moyamoya Disease.

BACKGROUND

Moyamoya disease (MMD) is a rare cerebrovascular disorder with unknown pathogenesis, partly due to limited access to human cerebral vascular tissue and suitable animal models. Using a large biobank of frozen serum samples, this study aimed to explore molecular signatures of ischemic and hemorrhagic MMD.

METHODS

Serum from 30 patients with MMD (18 ischemic, 12 hemorrhagic) and 30 matched healthy controls underwent proteomic and metabolomic profiling. Data were analyzed for differential expression, pathway enrichment, and protein-metabolite networks, with adjustment for age, sex, and body mass index.

RESULTS

In a separate large Chinese cohort (n=6167), female patients had a higher proportion of hemorrhagic MMD (19.9% versus 16.9%) and a higher prevalence of anterior choroidal artery dilation (15.1% versus 13.2%) than male patients (both P<0.05). At the molecular level, ischemic MMD showed complement C4-B deficiency and disrupted natural killer cell cytotoxicity; both subtypes shared immunoglobulin perturbations (eg, decreased heavy-chain variable regions). Sex-specific alterations included anti-folate-binding protein, serum amyloid A2, glycolithocholic acid, and estradiol. All omics data are publicly accessible.

CONCLUSIONS

Integrated serum multiomics defines distinct immune-related signatures for ischemic and hemorrhagic MMD and reveals sex-dimorphic molecular pathways. These findings, together with clinical sex differences in disease subtype and vascular anatomy, provide a framework for personalized, sex-aware management of MMD.