Line Christiansen: Neurodevelopment Following Preterm Birth - Effect of Insulin-like Growth Factor 1 and Necrotizing

PhD student: Line Iadsatian Christiansen
Email: Line.christiansen@sund.ku.dk

THE PROJECT
Preterm infants are predisposed to complications like infections, hypoxia-ischemia, and necrotizing enterocolitis (NEC), which can result in brain damage, altered neural connectivity, and impaired myelination. Advances in neonatal care have improved survival rates, but effective treatments to prevent brain injury are still needed. Preterm infants have lower systemic levels of insulin-like growth factor 1 (IGF-1) compared to full-term infants, a deficiency linked to impaired brain growth and neurodevelopmental issues. Clinical trials have shown that postnatal IGF-1 supplementation to restore normal levels may protect the brain from injury. Additionally, studies in preterm pigs have demonstrated that IGF-1 supplementation reduces the severity and mortality of NEC, a gastrointestinal disorder that increases the risk of neurodevelopmental impairments in preterm infants.

THE PURPOSE
The aim of this PhD project is to explore methods to support and enhance brain development in preterm infants under healthy and pathological conditions. Using the premature pig as a preclinical model, this research will investigate molecular, structural, and neurofunctional outcomes. The primary aim of this project is to investigate the effects of insulin-like growth factor 1 supplementation on preterm brain development. The secondary aim is to investigate the effects of necrotizing enterocolitis on brain development.

THE RESULTS
This thesis presents preclinical evidence that supplementing insulin-like growth factor 1 (IGF-1) within the first two weeks after birth promotes the maturation of both white and gray matter and enhances motor coordination with extended treatment. However, while early treatment showed positive effects on neuron maturation and myelination, these benefits did not persist with extended treatment. In fact, prolonged IGF-1 supplementation led to adverse effects on myelination. Despite this, overall white matter volume and cognitive and motor function were not negatively impacted.

Additionally, IGF-1 has previously been shown to reduce the severity of necrotizing enterocolitis (NEC) in preterm pigs. This thesis further reveals that early brain damage caused by NEC is associated with hippocampal neuroinflammation, abnormal neuron maturation, and microglial activation toward a pro-inflammatory, phagocytic state. While a direct causal link was not established, the results suggest that the protein S100A8/A9 may play a role in this pathological process.