Plasma glial fibrillary acidic protein as a biomarker of prevalent and incident cerebrovascular injury in children

The overall goal of this thesis is to address the hypothesis that plasma glial fibrillary acidic protein (GFAP) concentration is a biomarker of cerebrovascular injury in children. Chapter 1 outlines biomarker fundamentals, with considerations for applying biomarker research to children. Chapter 2 describes the GFAP electrochemiluminescent immunoassay development and technical assay validations. Clinical validations are discussed in Chapters 3 and 4 in children at high risk for cerebrovascular injury. Chapter 3 describes the associations of plasma GFAP with prevalent brain injury in the form of silent cerebral infarct in children with sickle cell disease (SCD) participating in the Silent Infarct Transfusion (SIT) trial. Silent cerebral infarct is an MRI diagnosed, clinically silent form of cerebrovascular disease that affects approximately 30% of children with SCD. Seven patients with acute (incident) injury are also evaluated. Sixteen percent (16/100) of children with SCD and cerebral infarct in the SIT trial had GFAP elevations above the 95th percentile of 60 healthy pediatric controls (P=0.04). A slightly higher proportion of children with SCD and cerebral infarct had elevated GFAP levels than children with SCD and no infarct (16/100, 16.0% vs. 14/168, 8.3%; P=0.07). Children with SCD and acute brain ischemia in the SIT trial had a higher proportion of elevated GFAP than SCD children with normal MRI (3/6, 50% vs. 8.3%; P=0.01). Chapter 4 describes the associations of GFAP with incident cerebrovascular disease in a cohort of 22 children receiving extracorporeal membrane oxygen (ECMO), a therapy that carries a 20% risk of acute cerebrovascular injury. Seven of 22 (32%) patients developed acute neurologic injury (intracranial hemorrhage, brain death, or cerebral edema diagnosed by imaging). Peak GFAP levels were higher in children with brain injury than those without (median, 5.9 vs. 0.09 ng/mL, p=0.04). The odds ratio (OR) for brain injury for GFAP >95th percentile of age-matched controls vs. normal was 11.5 (95%CI: 1.3-98.3). Chapter 5 describes how experience garnered from assay development can be applied to the next steps in developing the GFAP assay into a clinical test. Plasma GFAP shows more promise as a biomarker of incident, rather than prevalent, cerebrovascular disease.