Approximately 10 000 children experience in-hospital or out-of-hospital cardiac arrest annually in the US.^1,2 Children with return of spontaneous circulation (ROSC) are at high risk of neurological morbidity and death due to global hypoxic-ischemic brain injury.³ Accurate early understanding of the risk of neurological injury could support clinician and family decision-making and treatment. However, a standardized validated approach is lacking.⁴

Background. Epigenetic biomarkers have the potential to explain outcome heterogeneity following traumatic brain injury (TBI) but are largely unexplored. Objective. This exploratory pilot study characterized brain-derived neurotrophic factor (BDNF) DNA methylation trajectories following severe TBI. Methods. Brain-derived neurotrophic factor DNA methylation trajectories in cerebrospinal fluid (CSF) over the first 5 days following severe TBI in 112 adults were examined in association with 3- and 12-month outcomes. Results. Group-based trajectory analysis revealed low and high DNA methylation groups at two BDNF cytosine-phosphate-guanine (CpG) targets that showed suggestive associations (P < .05) with outcomes. Membership in the high DNA methylation groups was associated with better outcomes after controlling for age, sex, and injury severity. Associations of age × trajectory group interactions with outcomes at a third CpG site revealed a pattern of the same or better outcomes with higher ages in the high DNA methylation group and worse outcomes with higher ages in the low DNA methylation group. Conclusions. Although no observed associations met the empirical significance threshold after correcting for multiple comparisons, suggestive associations of the main effect models were consistent in their direction of effect and were observed across two CpG sites and two outcome time points. Results suggest that higher acute CSF BDNF DNA methylation may promote recovery following severe TBI in adults, and this effect may be more robust with higher age. While the results require replication in larger and racially diverse independent samples, BDNF DNA methylation may serve as an early postinjury biomarker helping to explain outcome heterogeneity following TBI.

Parent behaviors moderate the adverse consequences of pediatric traumatic brain injury (TBI); however, it is unknown how these moderating effects change over time. This study examined the moderating effect of observed parent behaviors over time since injury on the relation between TBI and behavioral outcomes. Participants included children, ages 3-7 years, hospitalized for moderate (n = 52) or severe (n = 20) TBI or orthopedic injury (OI; n = 95). Parent-child dyads were videotaped during structured task and free play conditions, and parents completed child behavior ratings. Linear mixed models using a lagged, time-varying moderator analysis examined the relationship of observed parent behaviors at the baseline, 6-month, and 12-month assessments to child behavior problems at 6 months, 12 months, and 18 months postinjury, after controlling for preinjury levels of child behavior problems. The effect of TBI on behavior was exacerbated by less favorable parent behaviors, and buffered by more favorable parent behaviors, in children with severe TBI over the first 12 months postinjury. By 18 months postinjury, however, the moderating effect of parent behaviors diminished, such that children with severe TBI showed more behavior problems relative to children with moderate TBI or OI regardless of parent behaviors or in response to parent behaviors that were initially protective. The results suggest that the moderating effects of the family environment are complex and likely vary in relation to both recovery and developmental factors, with potentially important implications for targets and timing of intervention. (PsycINFO Database Record

We review emerging preclinical and clinical evidence regarding brain-derived neurotrophic factor (BDNF) protein, genotype, and DNA methylation (DNAm) as biomarkers of outcomes in three important etiologies of pediatric acquired brain injury (ABI), traumatic brain injury, global cerebral ischemia, and stroke. We also summarize evidence suggesting that BDNF is (1) involved in the biological embedding of the psychosocial environment, (2) responsive to rehabilitative therapies, and (3) potentially modifiable. BDNF’s unique potential as a biomarker of neuroplasticity and neural repair that is reflective of and responsive to both pre- and post-injury environmental influences separates it from traditional protein biomarkers of structural brain injury with exciting potential to advance pediatric ABI management by increasing the accuracy of prognostic tools and informing clinical decision making through the monitoring of therapeutic effects.

Introduction: Unexplained heterogeneity in outcomes following pediatric traumatic brain injury (TBI) is one of the most critical barriers to the development of effective prognostic tools and therapeutics. The addition of personal biological factors to our prediction models may account for a significant portion of unexplained variance and advance the field toward precision rehabilitation medicine. The overarching goal of the Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR) study is to investigate an epigenetic biomarker involved in both childhood adversity and postinjury neuroplasticity to better understand heterogeneity in neurobehavioral outcomes following pediatric TBI. Our primary hypothesis is that childhood adversity will be associated with worse neurobehavioral recovery in part through an epigenetically mediated reduction in brain-derived neurotrophic factor (BDNF) expression in response to TBI. Methods and analysis: EETR is an observational, prospective, longitudinal concurrent cohort study of children aged 3–18 years with either TBI (n = 200) or orthopedic injury (n = 100), recruited from the UPMC Children's Hospital of Pittsburgh. Participants complete study visits acutely and at 6 and 12 months postinjury. Blood and saliva biosamples are collected at all time points—and cerebrospinal fluid (CSF) when available acutely—for epigenetic and proteomic analysis of BDNF. Additional measures assess injury characteristics, pre- and postinjury child neurobehavioral functioning, childhood adversity, and potential covariates/confounders. Recruitment began in July 2017 and will occur for ~6 years, with data collection complete by mid-2023. Analyses will characterize BDNF DNA methylation and protein levels over the recovery period and investigate this novel biomarker as a potential biological mechanism underlying the known association between childhood adversity and worse neurobehavioral outcomes following pediatric TBI. Ethics and dissemination: The study received ethics approval from the University of Pittsburgh Institutional Review Board. Participants and their parents provide informed consent/assent. Research findings will be disseminated via local and international conference presentations and manuscripts submitted to peer-reviewed journals. Trial Registration: The study is registered with clinicaltrials.org (ClinicalTrials.gov Identifier: NCT04186429).