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Peer-reviewedCC BY 4.0Frontiers in Neurology

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

  • Miaoran Fu1,2,3,4
  • Jixuan Xu5
  • Tianjiao Zhang1
  • Yueming Luo6
  • Lijun Wang1
  • Lulu Qi1
  • Min Zhang1
  • Chuming Tao2,3,4
6 affiliations
  1. 1Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University
  2. 2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University
  3. 3Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University
  4. 4Department of Neurology, The Second Affiliated Hospital of Nanchang University
  5. 5Department of Gastrointestinal & Thyroid Surgery, The Fifth Affiliated Hospital of Zhengzhou University
  6. 6Medicine School, Hubei Minzu University
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{fu2026association,
  title = {{Association of leucine pathway metabolites with moyamoya disease and its clinical phenotypes}},
  author = {Miaoran Fu and Jixuan Xu and Tianjiao Zhang and Yueming Luo and Lijun Wang and Lulu Qi and Min Zhang and Chuming Tao},
  journal = {Frontiers in Neurology},
  year = {2026},
  month = oct,
  doi = {10.3389/fneur.2026.1875390},
  url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1875390/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Association of leucine pathway metabolites with moyamoya disease and its clinical phenotypes
AU  - Miaoran Fu
AU  - Jixuan Xu
AU  - Tianjiao Zhang
AU  - Yueming Luo
AU  - Lijun Wang
AU  - Lulu Qi
AU  - Min Zhang
AU  - Chuming Tao
PY  - 2026
DA  - 2026/10/08
JO  - Frontiers in Neurology
DO  - 10.3389/fneur.2026.1875390
UR  - https://www.frontiersin.org/articles/10.3389/fneur.2026.1875390/full
AB  - 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.
SN  - 1664-2295
ER  -