@article{85db4f9a154747428e0b89087054ee00,
title = "Plasma Biomarkers of Evolving Encephalopathy and Brain Injury in Neonates with Hypoxic-Ischemic Encephalopathy",
abstract = "Objective: The objective of the study was to evaluate the relationship between a panel of candidate plasma biomarkers and (1) death or severe brain injury on magnetic resonance imaging (MRI) and (2) dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy. Study design: Neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) at 2 level IV neonatal intensive care units were enrolled into this observational study. Patients were treated with therapeutic hypothermia (TH) and monitored with continuous blood pressure monitoring and near-infrared spectroscopy. Cerebral pressure autoregulation was measured by the hemoglobin volume phase (HVP) index; a higher HVP index indicates poorer autoregulation. Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein, and neurogranin. MRIs were assessed using National Institutes of Child Health and Human Development scores. The relationships between the candidate biomarkers and (1) death or severe brain injury on MRI (defined as a National Institutes of Child Health and Human Development score of ≥ 2B) and (2) autoregulation were evaluated using bivariate and adjusted logistic regression models. Results: Sixty-two patients were included. Elevated Tau levels on days 2-3 of TH were associated with death or severe injury on MRI (aOR: 1.06, 95% CI: 1.03-1.09; aOR: 1.04, 95% CI: 1.01-1.06, respectively). Higher Tau was also associated with poorer autoregulation (higher HVP index) on the same day (P = .022). Conclusions: Elevated plasma levels of Tau are associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE. Larger-scale validation of Tau as a biomarker of brain injury in neonates with HIE is warranted.",
keywords = "MRI, NIRS, Tau, cerebral autoregulation, hypothermia, neonatal hypoxia-ischemia",
author = "Ruoying Li and Lee, {Jennifer K.} and Govindan, {Rathinaswamy B.} and Graham, {Ernest M.} and Everett, {Allen D.} and Jamie Perin and Gilbert Vezina and Aylin Tekes and Chen, {May W.} and Frances Northington and Charlamaine Parkinson and Alexandra O'Kane and Meaghan McGowan and Colleen Krein and Tareq Al-Shargabi and Taeun Chang and Massaro, {An N.}",
note = "Funding Information: This project was funded by the American Heart Association Grant-in-Aid. J.L. also received support from National Institutes of Health grants R01 NS107417 and R01 NS113921. A.M. is a member of The Journal of Pediatrics Editorial Board. J.L. was a paid consultant for Medtronic and is currently a paid consultant for Edwards Life Sciences. The other authors declare no conflicts of interest.Tau is a microtubule-associated protein in neurons and oligodendrocytes.5 During the initial hypoxic insult, aberrant Tau phosphorylation disrupts microtubule formation and promotes neuronal damage.34 Our data support findings from other studies that also demonstrate an association between elevated Tau during and after TH9,11 and severe brain injury on MRI. 9-11 The findings of our current study are consistent with our prior report that showed late Tau measurements after DOL 3 had a predictive value (AUC receiver operating curve = 0.883) that exceeded Tau measurements early in TH.11 However, other reports demonstrated significant associations between Tau measured in the first 48 hours of life and brain injury by MRI.9 Discrepancies in timing may be explained by differences in sampling practices or the impact of limited sample size to detect significant differences across all time points evaluated. It is possible that Tau is most reflective of ongoing secondary injury rather than purely a measure of the initial hypoxic-ischemic insult, contributing to more reliable distinction of outcome groups later in the course of TH. Similar to studies evaluating amplitude integrated electroencephalogram in HIE in which a positive predictive value improves over time,35,36 Tau may similarly reflect early uncertainty in brain injury trajectory that can help define a therapeutic window for neuroprotective interventions. Although the role of Tau in early (<48 hours) prediction of outcome is unclear, the use of Tau in the later stages of hypothermia may provide clinically meaningful information by identifying infants with a poor response to hypothermia, directing adjuvant neuroprotective intervention, and allowing for early reliable prognostication. Larger studies evaluating serial measurements of Tau are needed to validate Tau's utility as a biomarker. These studies will need to assess the potential role of Tau as a complement to other neuromonitoring tools (eg, amplitude integrated electroencephalogram, NIRS), as well as its value as a stand-alone indicator of brain injury severity in settings where these alternate tools are unavailable. Funding Information: This project was funded by the American Heart Association Grant-in-Aid. J.L. also received support from National Institutes of Health grants R01 NS107417 and R01 NS113921. A.M. is a member of The Journal of Pediatrics Editorial Board. J.L. was a paid consultant for Medtronic and is currently a paid consultant for Edwards Life Sciences. The other authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2022",
year = "2023",
month = jan,
doi = "10.1016/j.jpeds.2022.07.046",
language = "English (US)",
volume = "252",
pages = "146--153.e2",
journal = "Journal of Pediatrics",
issn = "0022-3476",
publisher = "Elsevier Inc.",
}