Clinical trial NCT04186429: Epigenetic Effects on Traumatic Brain Injury Recovery
Official title: Epigegenetic Influences on Neurobehavioral Recovery Following Pediatric Traumatic Brain Injury
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Traumatic Brain Injury
Orthopedic Injury
Keywords: traumatic brain injury
rehabilitation
neuropsychology
precision medicine
epigenetic
proteomic
brain-derived neurotrophic factor
recovery
neurobehavioral outcomes
children
childhood adversity
biomarkers
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2019-12-04
Enrollment: 401
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Children hospitalized overnight at UPMC Children's Hospital of Pittsburgh for complicated mild to severe traumatic brain injury or orthopedic injury.

Brief summary: Methylation of the brain-derived neurotrophic factor (BDNF) gene is involved in both the biological encoding of childhood adversity and neuroplasticity following traumatic brain injury (TBI). This research will characterize BDNF methylation during recovery from TBI in children and investigate this novel biomarker as a potential biological mechanism underlying the known association between childhood adversity and poorer neurobehavioral outcomes following TBI in childhood. Findings from this research will contribute to an improved understanding of why some children display good recovery following TBI, whereas many others suffer from chronic neurobehavioral impairments.

Detailed description: 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 towards 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 post-injury neuroplasticity to better understand heterogeneity in neurobehavioral outcomes following pediatric TBI. The primary hypothesis is that childhood adversity will be associated with poorer neurobehavioral recovery in part through an epigenetically mediated reduction in brain-derived neurotrophic factor (BDNF) expression in response to TBI.

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 post-injury. Blood and saliva biosamples are collected at all time points-and CSF when available acutely-for epigenetic and proteomic analysis of BDNF. Additional measures assess injury characteristics, pre- and post-injury child neurobehavioral functioning, childhood adversity, and potential covariates/confounders. 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 poorer neurobehavioral outcomes following pediatric TBI.

Eligibility criteria: Inclusion criteria:

-hospitalized overnight for a non-penetrating complicated mild to severe TBI as defined by the lowest post-resuscitation Glasgow Coma Scale (GCS) score or orthopedic injury.

Complicated mild TBI is defined as a GCS of 13-15 with neuroimaging indicating intracranial or parenchymal injury or depressed/displaced skull fracture. Moderate TBI is defined as GCS 9-12. Severe TBI is defined as GCS 3-8. Children are included in the OI group if they sustain a bone fracture, excluding to the skull or face, without any signs of head trauma or brain injury (e.g. nausea/vomiting, headache, loss of consciousness, GCS below 15 at any point).

Exclusion criteria:

* non-English-speaking child or non-English-speaking parents/guardians
* documented or parent-reported history of previous TBI/concussion requiring overnight hospitalization
* pre-injury neurological disorder or intellectual disability
* pre-injury psychiatric disorder requiring hospitalization
* sensory or motor impairment precluding study measure completion
* pregnancy at the time of study participation
* participants are also excluded if at least one biosample is not able to be collected within 7 days of the injury

Primary outcomes:
measure: NIH Toolbox Cognition Battery (NIHTB-CB)
timeFrame: 6 months post-injury
measure: NIH Toolbox Cognition Battery (NIHTB-CB)
timeFrame: 12 months post-injury
measure: Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) or Preschool Version (BRIEF-P)
timeFrame: 6 months post-injury
measure: Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) or Preschool Version (BRIEF-P)
timeFrame: 12 months post-injury
measure: Strengths and Difficulties Questionnaire
timeFrame: 6 months post-injury
measure: Strengths and Difficulties Questionnaire
timeFrame: 12 months post-injury
measure: Vineland Adaptive Behavior Scales, Third Edition (Vineland-3)
timeFrame: 6 months post-injury
measure: Vineland Adaptive Behavior Scales, Third Edition (Vineland-3)
timeFrame: 12 months post-injury
Secondary outcomes:
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Amery Treble, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Treble-Barna A, Patronick J, Uchani S, Marousis NC, Zigler CK, Fink EL, Kochanek PM, Conley YP, Yeates KO. Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR): An Observational, Prospective, Longitudinal Concurrent Cohort Study Protocol. Front Neurol. 2020 Jun 12;11:460. doi: 10.3389/fneur.2020.00460. eCollection 2020.