Neuroinflammatory markers at school age in preterm born children with neurodevelopmental impairments

Background: Immune system activation in the neonatal period is associated with white matter injury in preterm infants. In animal studies, neonatal priming of the immune system leads to chronic activation of i.e. microglia cells and altered neuroinflammatory responses potentially years after preterm birth. This may contribute further to brain injury and neurodevelopmental impairment. It is unknown to what extend this also occurs in human. Aim: To identify neuro-inflammatory markers at school age that relate to motor, cognitive and behavioral impairments in preterm born children in a pilot case-control study. Methods: We included n = 20 preterm born children (GA < 28 weeks) in this study, of which n = 10 with motor, cognitive and behavorial impairments and n =10 preterm born controls next to n = 30 healthy adult controls. In the preterm children, at 8-9 years, 39 inflammatory markers were assessed by Luminex assay in blood serum samples. Firstly, the preterm concentrations of these markers were compared to n = 30 adult controls. Then a univariate analysis was performed to determine differences in values between preterm children with and without impairment at school age. Finally, a principal component analysis and hierarchical clustering was performed to identify protein profiles in preterm born children that relate to impairment at school age. Results: Inflammatory proteins in preterm children at school age differed from values of adult controls. Within the group of preterm children, we found significantly higher levels of GM-CSF in preterms with impairment (p < 0.01) and a trend towards significance for Gal1 and TRAIL (p = 0.06 and p = 0.06 respectively) when compared to preterms without impairment. In addition, differences in clustering of proteins between preterm children was observed, however this variance was not explained by presence of neurodevelopmental impairments. Conclusion: The inflammatory profile at school age in preterm children is different from that of adult controls. The immune modulating cytokines GM-CSF, Gal1 and TRAIL were higher in preterm children with impairment than control preterm children, suggesting that immune responses are altered in these children. No specific cluster of inflammatory markers could be identified. Results indicate that even at school age, neuroinflammatory pathways are activated in preterm born children with neurodevelopmental impairments.