Markers and mechanisms of abnormal neurovascular development in the preterm infant

Link directly to the doctoral thesis GUPEA.

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Overall, the results in the thesis contribute to future knowledge base in the attempt to map early factors important for brain development and later outcomes in children who are born prematurely.

Background: The extremely preterm infant is at risk of lifelong neurodevelopmental impairments due to brain injuries or abnormal neurovascular development. Mechanisms are largely unknown and biomarkers for adverse outcomes are sparse. The growth factor insulin-like growth factor (IGF)-1 is a key regulator of neurovascular developmental processes and endogenous levels are low following preterm birth.

Aim of the thesis:
To investigate the impact of growth factors on neurovascular development, e.g. retinopathy of prematurity (ROP), brain injury, brain volumes measured by magnetic resonance imaging, and neurodevelopmental outcome in preterm infants and in an animal model. In addition to identify possible biomarkers for abnormal neurovascular development in preterm infants. Materials and

Methods:
Paper I: Associations between serum glucose levels, serum IGF-1, and ROP were explored in preterm infants (n=117) and in an oxygen-induced retinopathy/hyperglycemia mice model including IGF-1 substitution treatment.
Paper II: Longitudinal serum Neurofilament Light (NfL, biomarker for axonal injury) levels were evaluated in preterm infants (n=221) as a biomarker for ROP, brain injury, and neurodevelopmental outcome at 2 years of age.
Paper III: Longitudinal serum growth factor levels were correlated with total and regional brain volumes at term in extremely preterm infants (n=49).

Paper IV: Longitudinal serum levels of NfL and IGF-1 and the association to neurodevelopmental outcomes at early school age were investigated (n=72).

Results:
Paper I: Hyperglycemia was associated with lower IGF-1 levels, increased number of any ROP and with ROP severity. Hyperglycemia decreased endogenous IGF-1 expression, and IGF-1 treatment decreased ROP-associated vascular changes in the mice model.

Paper II: NfL levels increased after birth and remained high, with increased levels independently associated with ROP development. High NfL levels were associated with unfavorable neurodevelopmental outcomes at 2 years.
Paper III: Low serum IGF-1 levels were independently associated with reduced total brain, white matter, cortical grey matter, deep grey matter, and cerebellar volumes.
Paper IV: Unpublished results, see Paper IV.

Conclusion: IGF-1 may have a beneficial role in brain development and may have a protective role in ROP development. NfL may serve as a biomarker for ROP and adverse neurodevelopmental out come.