Early predictors of perinatal brain damage: the role of neurobiomarkers

Abstract

The early detection of perinatal brain damage in preterm and term newborns (i.e. intraventricular hemorrhage, periventricular leukomalacia and perinatal asphyxia) still constitute an unsolved issue. To date, despite technological improvement in standard perinatal monitoring procedures, decreasing the incidence of perinatal mortality, the perinatal morbidity pattern has a flat trend. Against this background, the measurement of brain constituents could be particularly useful in the early detection of cases at risk for short-/long-term brain injury. On this scenario, the main European and US international health-care institutions promoted perinatal clinical and experimental neuroprotection research projects aimed at validating and including a panel of biomarkers in the clinical guidelines. Although this is a promising attempt, there are several limitations that do not allow biomarkers to be included in standard monitoring procedures. The main limitations are: (i) the heterogeneity of neurological complications in the perinatal period, (ii) the small cohort sizes, (iii) the lack of multicenter investigations, (iv) the different techniques for neurobiomarkers assessment, (iv) the lack of consensus for the validation of assays in biological fluids such as urine and saliva, and (v), the lack of reference curves according to measurement technique and biological fluid. In the present review we offer an up-to-date overview of the most promising developments in the use of biomarkers in the perinatal period such as calcium binding proteins (S100B protein), vasoactive agents (adrenomedullin), brain biomarkers (activin A, neuron specific enolase, glial fibrillary acidic protein, ubiquitin carboxyl-terminal hydrolase-L1) and oxidative stress markers.

Intraventricular Hemorrhage in Very Preterm Infants: A Comprehensive Review

“…The circulating AM level was elevated in preterm patients presenting GMH-IVH-IPH, suggesting that it may be secreted in response to altered cerebral blood circulation [ 76 ]. Various potential biomarkers are being investigated, such as neuron-specific enolase, activin A or glial fibrillary acidic protein [ 74 , 77 , 78 ].…”

“…The protein S100B, expressed in glial cells, is proposed as an early neurobiomarker of intracerebral bleeding and GMH-IVH-IPH in neonates. The S100B level is increased in several biological fluids, such as CSF, saliva and, with high specificity, in cord blood [74,75]. Other possible biomarkers are vasoactive agents such as adrenomedullin (AM), a vasodilatator peptide.…”

Oxidative Stress Markers and the Retinopathy of Prematurity

“…In this setting, before any conclusion can be drawn on a panel of BM pros and cons, it is necessary to focus on the predetermined criteria requested for a BM before inclusion in clinical guidelines. In detail, the "optimal" BM needs to fulfill the following criteria: (i) alternative and direct indicator of damage, (ii) early predictor of the degree and location of the injury, (iii) indicator of the extent of the lesion, monitoring the progression of the disease, (iv) well studied in the pediatric population, (v) measurable by available commercially kits worldwide, with good reproducibility, (vi) presence of reference range for the pediatric population, and (vii) assessment in different biological fluids [37].…”

“…In the last decades, there has been a growing interest in investigating the potential usefulness of BMs in the early detection of oxidative stress damage in newborns [19,36]. Recently, the Food and Drugs Administration (FDA), the European Medicine Agency (EMA), and, more recently, the National Institute of Health (NIH) established several statements for BM inclusion in perinatal clinical guidelines [37]. One of the main limitations refers to the possibility of BM assessment in different biological fluids, such as amniotic, urine, plasma, and cerebrospinal (CSF) fluids.…”

“…One of the main limitations refers to the possibility of BM assessment in different biological fluids, such as amniotic, urine, plasma, and cerebrospinal (CSF) fluids. In this respect, free radical measurement might be limited due to the different reactive and short-lived species, as well as to the possibility of their measurement in the so-called noninvasive biological fluids (urine, saliva) [19,37].…”