Association of leucine pathway metabolites with moyamoya disease and its clinical phenotypes

Background Leucine and its metabolic derivatives have emerged as promising candidates for biomarker discovery in cardio-cerebrovascular diseases. Despite this, their involvement in the pathophysiology and phenotypic expression of moyamoya disease (MMD) remains largely unexplored. This investigation therefore sought to delineate the potential links between perturbations in the leucine metabolic pathway and susceptibility to MMD. Methods This was a cross-sectional case–control study with prospective participant enrollment (337 MMD patients; 84 age- and sex-comparable healthy controls). Serum leucine, glycine, and N-isovalerylglycine (N-IVA) were quantified via LC–MS/MS. Multivariable logistic regression and ROC analysis (including NRI and IDI) were used to assess independent associations and incremental predictive value. Results Relative to healthy controls, patients with MMD exhibited higher serum leucine concentrations [median (IQR): 217.91 (186.70–245.32) vs. 188.05 (166.09–217.76) μmol/L, p < 0.001], accompanied by lower N-isovalerylglycine (N-IVA) levels ( p = 0.004). After adjustment for clinical and laboratory variables, higher leucine levels remained independently linked to an increased probability of MMD (OR = 1.01, 95% CI: 1.00–1.02, p = 0.010), whereas higher N-isovalerylglycine (N-IVA) levels were associated with lower odds of MMD (per 1-SD increase, OR = 0.74, 95% CI: 0.55–1.00, p = 0.049). Incorporation of leucine into the baseline clinical model resulted in improved risk stratification (categorical NRI = 0.140, p = 0.007). In addition, the basic clinical model achieved an AUC of 0.880, which increased to 0.892 after incorporating leucine, glycine, and N-IVA, reflecting a modest but consistent increase in discrimination, and further enhanced reclassification performance (NRI: 0.193, p < 0.001; IDI: 0.032, p = 0.011). Serum leucine concentrations also showed positive correlations with inflammatory and lipid-related indicators. Conclusion Alterations in leucine metabolism, reflected by elevated leucine and reduced N-isovalerylglycine levels, are associated with MMD and contribute additional predictive value beyond conventional clinical factors. These results indicate that alterations in leucine pathway metabolism are associated with MMD and may reflect broader systemic metabolic disturbances relevant to its pathophysiology, warranting further mechanistic investigation.