Plasma and Cerebrospinal Fluid Candidate Biomarkers of Neonatal Encephalopathy Severity and Neurodevelopmental Outcomes

Dietrick, Barbara; Molloy, Eleanor J.; Massaro, An N.; Strickland, Tammy; Zhu, Jie; Slevin, Marie; Donoghue, Veronica; Sweetman, Deirdre; Kelly, Lynne; O’Dea, Mary; McGowan, Meaghan; Vézina, Gilbert; Glass, Penny; Vaidya, Dhananjay; Brooks, Sandra; Northington, Frances J.

doi:10.1016/j.jpeds.2020.06.078

Cited by 29 publications

(48 citation statements)

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“…Our transcriptomic analysis showed that a significant number of genes crucial for neuronal development and functional differentiation were differentially expressed during HX in piglet cortex, but were normalized following EGFR blockade. Importantly, a number of these genes are also known to be involved in human brain injury, further supporting the notion that phosphorylated EGFR plays a crucial role in HX-induced apoptotic cell death in the piglet and human perinatal brain ( Dietrick et al., 2020 ; Korhonen et al., 1998 ; Maussion et al., 2019 ; Yu et al., 2016 ; Pardini et al., 2014 ; Yue et al., 2017 ).…”

Section: Introductionsupporting

confidence: 54%

“…Interestingly, specific genes that are known to be involved in human brain injury, such as BDNF, CAMKK2A, CAMK2A, DRD1, DRD2, FEZF2, and CREB5 ( Dietrick et al., 2020 ; Korhonen et al., 1998 ; Maussion et al., 2019 ; Yu et al., 2016 ; Pardini et al., 2014 ; Yue et al., 2017 ), were also altered in the piglet cortex, further emphasizing the significance and clinical relevance of the piglet model of neonatal HX brain injury. The above transcripts identified through RNA-seq as altered by HX and EGFRi HX were confirmed by RT-PCR ( Figures S3 A–S3G).…”

Section: Resultsmentioning

confidence: 95%

“…Finally, we present for the first time a high-throughput analysis of the newborn piglet brain, which provides novel and crucial insights into HX-induced molecular alterations in neurotransmitters and neurotrophins, as well as abnormalities in neuronal development and synaptogenesis. Importantly, we identified genes that are directly associated with HX-induced EGFR signaling that are also altered in human brain injury ( Dietrick et al., 2020 ; Korhonen et al., 1998 ; Maussion et al., 2019 ; Yu et al., 2016 ; Pardini et al., 2014 ; Yue et al., 2017 ). Moreover, we identify transcripts regulated by HX that could not be mapped to the annotated pig genome, but were mapped to the more complete human genome (human homologs) ( Data S4 ).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, BDNF was significantly altered by HX and fully reversed by EGFRi treatment. BDNF has been shown to be a main biomarker in human neonatal HX encephalopathy, with most studies suggesting lower levels of BDNF during HX ( Dietrick et al., 2020 ; Korhonen et al., 1998 ; Liu et al., 2013 ). BDNF promotes the survival and differentiation of neurons, mediates axonal growth and pathfinding, and promotes dendritic growth and morphological maturation.…”

Section: Discussionmentioning

confidence: 99%

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Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain

et al. 2020

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Summary Acute hypoxia (HX) causes extensive cellular damage in the developing human cerebral cortex. We found increased expression of activated-EGFR in affected cortical areas of neonates with HX and investigated its functional role in the piglet, which displays a highly evolved, gyrencephalic brain, with a human-like maturation pattern. In the piglet, HX-induced activation of EGFR and Ca 2+ /calmodulin kinase IV (CaMKIV) caused cell death and pathological alterations in neurons and glia. EGFR blockade inhibited CaMKIV activation, attenuated neuronal loss, increased oligodendrocyte proliferation, and reversed HX-induced astrogliosis. We performed for the first time high-throughput transcriptomic analysis of the piglet cortex to define molecular responses to HX and to uncover genes specifically involved in EGFR signaling in piglet and human brain injury. Our results indicate that specific molecular responses modulated by EGFR may be targeted as a therapeutic strategy for HX injury in the neonatal brain.

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Section: Introductionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain

et al. 2020

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“…New-born babies with congenital anomalies or evidence of maternal substance abuse were excluded. Blood samples were also obtained from 10 school-age children post NE, 10 children with CP and 23 healthy school-age control children (Zareen et al, 2020a(Zareen et al, , 2020bDietrick et al, 2020).…”

Section: Study Participantsmentioning

confidence: 99%

Altered distributions and functions of natural killer T cells and γδ T cells in neonates with neonatal encephalopathy, in school-age children at follow-up, and in children with cerebral palsy

Taher

Kelly

Al-Harbi

et al. 2021

Journal of Neuroimmunology

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We enumerated conventional and innate lymphocyte populations in neonates with neonatal encephalopathy (NE), school-age children post-NE, children with cerebral palsy and age-matched controls. Using flow cytometry, we demonstrate alterations in circulating T, B and natural killer cell numbers. Invariant natural killer T cell and Vδ2 + γδ T cell numbers and frequencies were strikingly higher in neonates with NE, children post-NE and children with cerebral palsy compared to age-matched controls, whereas mucosal-associated invariant T cells and Vδ1 T cells were depleted from children with cerebral palsy. Upon stimulation ex vivo, T cells, natural killer cells and Vδ2 T cells from neonates with NE more readily produced inflammatory cytokines than their counterparts from healthy neonates, suggesting that they were previously primed or activated. Thus, innate and conventional lymphocytes are numerically and functionally altered in neonates with NE and these changes may persist into school-age.

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Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy

et al. 2023

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ImportanceThe ability to predict neurodevelopmental impairment (NDI) for infants diagnosed with hypoxic ischemic encephalopathy (HIE) is important for parental guidance and clinical treatment as well as for stratification of patients for future neurotherapeutic studies.ObjectivesTo examine the effect of erythropoietin on plasma inflammatory mediators in infants with moderate or severe HIE and to develop a panel of circulating biomarkers that improves the projection of 2-year NDI over and above the clinical data available at the time of birth.Design, Setting, and ParticipantsThis study is a preplanned secondary analysis of prospectively collected data from infants enrolled in the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which tested the efficacy of erythropoietin as an adjunctive neuroprotective therapy to therapeutic hypothermia. The study was conducted at 17 academic sites comprising 23 neonatal intensive care units in the United States between January 25, 2017, and October 9, 2019, with follow-up through October 2022. Overall, 500 infants born at 36 weeks’ gestation or later with moderate or severe HIE were included.InterventionErythropoietin treatment 1000 U/kg/dose on days 1, 2, 3, 4 and 7.Main Outcomes and MeasuresPlasma erythropoietin was measured in 444 infants (89%) within 24 hours after birth. A subset of 180 infants who had plasma samples available at baseline (day 0/1), day 2, and day 4 after birth and either died or had 2-year Bayley Scales of Infant Development III assessments completed were included in the biomarker analysis.ResultsThe 180 infants included in this substudy had a mean (SD) gestational age of 39.1 (1.5) weeks, and 83 (46%) were female. Infants who received erythropoietin had increased concentrations of erythropoietin at day 2 and day 4 compared with baseline. Erythropoietin treatment did not alter concentrations of other measured biomarkers (eg, difference in interleukin [IL] 6 between groups on day 4: −1.3 pg/mL; 95% CI, −4.8 to 2.0 pg/mL). After adjusting for multiple comparisons, we identified 6 plasma biomarkers (C5a, interleukin [IL] 6, and neuron-specific enolase at baseline; IL-8, tau, and ubiquitin carboxy-terminal hydrolase-L1 at day 4) that significantly improved estimations of death or NDI at 2 years compared with clinical data alone. However, the improvement was only modest, increasing the AUC from 0.73 (95% CI, 0.70-0.75) to 0.79 (95% CI, 0.77-0.81; P = .01), corresponding to a 16% (95% CI, 5%-44%) increase in correct classification of participant risk of death or NDI at 2 years.Conclusions and RelevanceIn this study, erythropoietin treatment did not reduce biomarkers of neuroinflammation or brain injury in infants with HIE. Circulating biomarkers modestly improved estimation of 2-year outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT02811263

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Plasma and Cerebrospinal Fluid Candidate Biomarkers of Neonatal Encephalopathy Severity and Neurodevelopmental Outcomes

Cited by 29 publications

References 61 publications

Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain

Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain

Altered distributions and functions of natural killer T cells and γδ T cells in neonates with neonatal encephalopathy, in school-age children at follow-up, and in children with cerebral palsy

Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy

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