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Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy.

ABSTRACT: A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth, predicts adverse neurodevelopmental outcome eighteen months after neonatal encephalopathy. We performed next generation sequencing on whole blood ribonucleic acid obtained within six hours of birth from the first 47 encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX) trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855 genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1 and SMC4 were the most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatonin and polo-like kinase in babies with adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanisms and identify novel therapeutic targets for neuroprotection.

SUBMITTER: Montaldo P

PROVIDER: S-EPMC7403382 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy.

Montaldo Paolo P Cunnington Aubrey A Oliveira Vania V Swamy Ravi R Bandya Prathik P Pant Stuti S Lally Peter J PJ Ivain Phoebe P Mendoza Josephine J Atreja Gaurav G Padmesh Vadakepat V Baburaj Mythili M Sebastian Monica M Yasashwi Indiramma I Kamalarathnam Chinnathambi C Chandramohan Rema R Mangalabharathi Sundaram S Kumaraswami Kumutha K Kumar Shobha S Benakappa Naveen N Manerkar Swati S Mondhkar Jayashree J Prakash Vinayagam V Sajjid Mohammed M Seeralar Arasar A Jahan Ismat I Moni Sadeka Choudhury SC Shahidullah Mohammod M Sujatha Radhika R Chandrasekaran Manigandan M Ramji Siddarth S Shankaran Seetha S Kaforou Myrsini M Herberg Jethro J Thayyil Sudhin S

Scientific reports 20200804 1

A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth, predicts adverse neurodevelopmental outcome eighteen months after neonatal encephalopathy. We performed next generation sequencing on whole blood ribonucleic acid obtained within six hours of birth from the first 47 encephalopathic babies recruited to the Hypothermia ...[more]

PMID: 32753750

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Project description:BackgroundTo 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.MethodsPlasma 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).ResultsOut 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.ConclusionsPlasma metabolites may help to predict neurological outcomes in neonatal brain injury and enhance current clinical predictors.ImpactPlasma metabolites may help to predict neurological outcomes in NE and supplement current clinical predictors. Current metabolomics research is limited in terms of clinical application and association with long-term outcomes. Our study presents novel associations of plasma metabolites from the first 24 h of life and 2-year neurodevelopmental outcomes for infants with NE. Our metabolomics discovery provides insight into possible disease mechanisms and methods to rescue and/or supplement metabolic pathways involved in NE. Our metabolomics discovery of metabolic pathway supplementations and/or rescue mechanisms may serve as adjunctive therapies for NE.

Project description:Reliably assessing the early neurodevelopmental outcomes in infants with neonatal encephalopathy (NE) is of utmost importance to advise parents and implement early and personalized interventions. We aimed to evaluate the accuracy of neuroimaging modalities, including functional magnetic resonance imaging (fMRI) in predicting neurodevelopmental outcomes in NE. Eighteen newborns with NE due to presumed perinatal asphyxia (PA) were included in the study, 16 of whom underwent therapeutic hypothermia. Structural magnetic resonance imaging (MRI), and fMRI during passive visual, auditory, and sensorimotor stimulation were acquired between the 10th and 14th day of age. Clinical follow-up protocol included visual and auditory evoked potentials and a detailed neurodevelopmental evaluation at 12 and 18 months of age. Infants were divided according to sensory and neurodevelopmental outcome: severe, moderate disability, or normal. Structural MRI findings were the best predictor of severe disability with an AUC close to 1.0. There were no good predictors to discriminate between moderate disability versus normal outcome. Nevertheless, structural MRI measures showed a significant correlation with the scores of neurodevelopmental assessments. During sensorimotor stimulation, the fMRI signal in the right hemisphere had an AUC of 0.9 to predict absence of cerebral palsy (CP). fMRI measures during auditory and visual stimulation did not predict sensorineural hearing loss or cerebral visual impairment.ConclusionIn addition to structural MRI, fMRI with sensorimotor stimulation may open the gate to improve the knowledge of neurodevelopmental/motor prognosis if proven in a larger cohort of newborns with NE.What is known• Establishing an early, accurate neurodevelopmental prognosis in neonatal encephalopathy remains challenging. • Although structural MRI has a central role in neonatal encephalopathy, advanced MRI modalities are gradually being explored to optimize neurodevelopmental outcome knowledge.What is new• Newborns who later developed cerebral palsy had a trend towards lower fMRI measures in the right sensorimotor area during sensorimotor stimulation. • These preliminary fMRI results may improve future early delineation of motor prognosis in neonatal encephalopathy.

Project description:BackgroundIn newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear.MethodsInfants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years.ResultsOf 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury.ConclusionIn the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes.ImpactHalf of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

Dataset Information

Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy.

Publications

Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy.

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