Neonatal hypoxic-ischemic encephalopathy (HIE) occurs in 2.5/1000 term live births with a death or neurologic disability rate of 48-57% with moderate HIE and 85-91% for severe HIE. Neonates with moderate to severe HIE who receive mild cooling within 6 hours of birth have a 12%-21% decline in death and disability. Although therapies are being developed to treat the neonate with HIE, we have no clinically available biomarkers to acutely identify brain-specific injury, to follow HIE therapy efficacy or to evaluate new therapies in the child at risk. The current proposal extends an ongoing parent trial, a randomized controlled NICHD Neonatal Research Network (NRN) Trial NCT00614744/NICHD-NRN-0036, """"""""Optimizing Cooling for Hypoxic-Ischemic Encephalopathy"""""""". The NRN trial will test whether longer (120 vs 72 hours) and/or deeper (320C vs 33.50C) cooling further decreases death and neurologic disability at 18-22 months and will begin to enroll patients in late 2010 (n=726). The current proposal represents a unique, time-sensitive opportunity to extend the parent trial by adding serial blood sample data collection and thus enable the identification and evaluation of brain- specific circulating biomarkers of brain injury among infants at high risk. The central hypothesis of this proposal is that circulating astrocyte-specific protein levels, as a biomarker of white matter injury, measured serially over 0-6 days of life in neonates with HIE will predict infants at risk for death or moderate-severe neurologic disability, will predict therapeutic efficacy for whole body cooling, and in future studies serve as a basis for triaging neonates to appropriate therapies to decrease morbidity and improve outcomes. Using preliminary data based on a non-biased plasma proteomic discovery project of subacute brain injury biomarkers, we have identified that the astrocyte-specific protein glial fibrillary acidic protein (GFAP) is a circulating biomarker of brain injury in neonates with HIE and neonates on ECMO support and significantly associated with MRI measures of hypoxic brain injury with HIE. To examine our hypothesis we will utilize a novel, rapid (4 hour) test of GFAP to (1 determine whether peri-cooling levels of circulating GFAP predict adverse outcomes including A) death or neurologic disability at 18-22 months and B) MRI abnormalities at 7-14 days within and between the NRN trial whole body cooling treatment groups and 2) determine if peri-cooling levels of circulating GFAP can serve as a benchmark of longer cooling (120 vs 72 hours) and deeper cooling (32.00C vs 33.50C) therapeutic efficacy. The significance is that a rapid perinatal test of neonatal brain injury would be of immediate clinical benefit to acutely and accurately identify brain injury, to follow the efficacy of HIE therapy or to benchmark new therapies in neonates at risk. The innovation is that by focusing on an exquisitely brain-specific protein, GFAP, we minimize problems of sensitivity and disease specificity that diminish the utility of relatively non-specific biomarkers, such as inflammatory mediators and metabolic by- products.

Public Health Relevance

We will take advantage of imaging and clinical data in an ongoing NIH multi-center randomized clinical trial to test longer and deeper whole body cooling to better protect the brain in babies with birth related brain injury. Using this data and blood samples that we will collect, our team of pediatric cardiologists, neonatologists, hematologists and epidemiologists will determine if a circulating brain protein, glial fibrillary acidic protein (GFAP), can serve as a rapid measure of brain injury and how well the cooling therapy is protecting the brain. Development of this novel approach would: 1) fill an immediate clinical void;2) take advantage of the large investment already made in the NIH clinical trial;3) provide early information on outcomes for families using a simple blood test and 4) guide clinicians to the best therapy to protect the brain in these ill infants.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Higgins, Rosemary
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Johns Hopkins University
Schools of Medicine
United States
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Stewart, Amanda; Tekes, Aylin; Huisman, Thierry A G M et al. (2013) Glial fibrillary acidic protein as a biomarker for periventricular white matter injury. Am J Obstet Gynecol 209:27.e1-7