Metabolic Phenotypes of Hypoxic-Ischemic Encephalopathy with Normal vs. Pathologic Magnetic Resonance Imaging Outcomes

Abstract

Hypoxic-Ischemic Encephalopathy (HIE) is one of the most relevant contributors to neurological disability in term infants. We hypothesized that clinical outcomes of newborns with (HIE) can be associated with changes at plasma metabolic level enabling the detection of brain injury. Plasma samples of a cohort of 55 asphyxiated infants who evolved to moderate/severe HIE were collected between birth and completion of therapeutic hypothermia (TH). Samples were analyzed employing a quantitative gas chromatography–mass spectrometry method for the determination of lactate and pyruvate and an untargeted liquid chromatography–time-of-flight mass spectrometry method for metabolic fingerprinting. Brain injury was assessed employing magnetic resonance imaging (MRI). A critical assessment of the usefulness of lactate, pyruvate, and pyruvate/lactate for outcome prediction was carried out. Besides, metabolic fingerprinting identified a dynamic perturbation of eleven metabolic pathways, including amino acid and purine metabolism, and the steroid hormone biosynthesis, in newborns with pathologic MRI outcomes. Although data suggest the usefulness of lactate and pyruvate monitoring during 72 h for discerning outcomes, only the steroid hormone biosynthesis pathway was significantly altered in early plasma samples (i.e., before the initiation of TH). This study highlights pathways that might potentially be targeted for biomarker discovery or adjuvant therapies to be combined with TH.

A Metabolomic Approach in Search of Neurobiomarkers of Perinatal Asphyxia: A Review of the Current Literature

“…Pyruvate levels did not however predict the severity of the grade of asphyxia, as the authors could not find a significant difference between neonates presenting with mild, moderate and severe HIE (Sarnat 3) compared to the control group. Even in the HYPOTOP trial, the analysis of pyruvate cord blood levels among neonates presenting with HIE and treated with TH, did not identify and differentiate those with pathological brain MRI findings (46). There were higher pyruvate levels 48 h after the administration of topiramate in neonates presenting with HIE and treated with TH, in comparison to the control group.…”

“…In terms of prognosis, Frey et al showed that asphyxiated neonates who died during the first week of life had significantly higher lactate levels than those presenting with more mild neurological deficits (45). Pineiro-Ramos et al however, could not demonstrate a relation between the cord blood lactate levels of neonates presenting with HIE and the severity of pathological cerebral magnetic resonance imaging (MRI) performed between day 4 and 8 of life (46). Ahearne et al also showed that cord blood lactate levels in asphyxiated neonates did not predict outcome at 3 years of age (47).…”

Precision Medicine in Neonates: A Tailored Approach to Neonatal Brain Injury

“…Metabolomics can also provide valuable information for outcome prediction. Metabolites offer a unique signature potentially usable to predict neonatal diseases and evaluate disease progression and treatments' effect (156)(157)(158).…”

Metabolomics Applications in Children: A Right Way to Go

“…A new study [ 3 ] evaluating early evolving blood metabolome provides, for the first time, useful data to identify newborns who will show pathologic Magnetic Resonance Imaging (MRI) patterns after TH. The authors demonstrated changes of purines (i.e., xanthine and xanthosine), as well as of the steroid hormone biosynthesis pathway, in newborns with pathologic MRI outcomes in blood samples drawn before the initiation of TH during the whole study period.…”