Abstract
Background
To investigate mechanisms of injury and recovery in neonatal encephalopathy (NE), we performed targeted metabolomic analysis of plasma using liquid chromatography with tandem mass spectrometry (LC/MS/MS) from healthy term neonates or neonates with NE.
Methods
Plasma samples from the NE (n = 45, day of life 0–1) or healthy neonatal (n = 30, ≥36 weeks gestation) cohorts had LC/MS/MS metabolomic profiling with a 193-plex targeted metabolite assay covering >366 metabolic pathways. Metabolite levels were compared to 2-year neurodevelopmental outcomes measured by the Bayley Scales of Infant and Toddler Development III (Bayley-III).
Results
Out of 193 metabolites, 57 met the pre-defined quality control criteria for analysis. Significant (after false discovery rate correction) KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways included aminoacyl-tRNA biosynthesis, arginine biosynthesis, and metabolism of multiple amino acids. Significant disease pathways included seizures. In regression models, histidine and C6 sugar amine were significantly associated with cognitive, motor, and language and betaine with cognitive and motor Bayley-III composite scores. The addition of histidine, C6 sugar amine, and betaine to a Sarnat score-based clinical regression model significantly improved model performance (Akaike information criterion and adjusted r2) for Bayley-III cognitive, motor, and language scores.
Conclusions
Plasma metabolites may help to predict neurological outcomes in neonatal brain injury and enhance current clinical predictors.
Impact
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Plasma metabolites may help to predict neurological outcomes in NE and supplement current clinical predictors.
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Current metabolomics research is limited in terms of clinical application and association with long-term outcomes.
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Our study presents novel associations of plasma metabolites from the first 24 h of life and 2-year neurodevelopmental outcomes for infants with NE.
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Our metabolomics discovery provides insight into possible disease mechanisms and methods to rescue and/or supplement metabolic pathways involved in NE.
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Our metabolomics discovery of metabolic pathway supplementations and/or rescue mechanisms may serve as adjunctive therapies for NE.
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Acknowledgements
We thank the patients and their families for their participation and contributions to this study. We also thank the Everett research group at Johns Hopkins University School of Medicine for their support and contributions. We thank the Johns Hopkins University School of Medicine Scholarly Concentration mentor Dr. Meredith Atkinson and the Johns Hopkins University School of Medicine Dean’s Funding for their support and contributions.
Funding
This work was supported by NIH NICHD R01HD086058 (to A.D.E. and F.N.); Health Research Board, Ireland; Trinity College Dublin; National Children’s Research Centre.
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Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: B.D.F., E.M., T.S., J.Z., M.S., V.D., D.S., L.K., M.O’D., A.R., R.H., G.E., C.M., D.G., F.N. and A.D.E. Drafting the article or revising it critically for important intellectual content: B.D.F., E.M., A.R., R.H., C.M., D.G., F.N. and A.D.E. Final approval of the version to be published: B.D.F., E.M., T.S., J.Z., M.S., V.D., D.S., L.K., M.O’D., A.R., R.H., G.E., C.M., D.G., F.N. and A.D.E.
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Friedes, B.D., Molloy, E., Strickland, T. et al. Neonatal encephalopathy plasma metabolites are associated with neurodevelopmental outcomes. Pediatr Res 92, 466–473 (2022). https://doi.org/10.1038/s41390-021-01741-x
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DOI: https://doi.org/10.1038/s41390-021-01741-x
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