2018

Background: Preterm birth is the leading risk factor for perinatal white matter injury, which can lead to motor and neuropsychiatric impairment across the life course. There is an unmet clinical need for therapeutics. White matter injury is associated with an altered inflammatory response in the brain, primarily led by microglia, and subsequent hypomyelination. However, microglia can release both damaging and trophic factors in response to injury, and a comprehensive assessment of these factors in the preterm central nervous system (CNS) has not been carried out. Method: A custom antibody array was used to assess relative levels of 50 inflammation- and myelination-associated proteins in the cerebrospinal fluid (CSF) of preterm infants in comparison to term controls. Results: Fifteen proteins differed between the groups: BDNF, BTC, C5a, FasL, Follistatin, IL-1β, IL-2, IL-4, IL-9, IL-17A, MIP-1α, MMP8, SPP1, TGFβ, and TNFβ (p < 0.05). To investigate the temporal regulation of these proteins after injury, we mined a gene expression dataset of microglia isolated from a mouse model of developmental white matter injury. Microglia in the experimental model showed dynamic temporal expression of genes encoding these proteins, with an initial and sustained pro-inflammatory response followed by a delayed anti-inflammatory response, and a continuous expression of genes predicted to inhibit healthy myelination. Conclusion: Preterm CSF shows a distinct neuroinflammatory profile compared to term controls, suggestive of a complex neural environment with concurrent damaging and reparative signals. We propose that limitation of pro-inflammatory responses, which occur early after perinatal insult, may prevent expression of myelination-suppressive genes and support healthy white matter development.

Measures of white matter (WM) microstructure inferred from diffusion magnetic resonance imaging (dMRI) are useful for studying brain development. There is uncertainty about agreement between FA and MD values obtained from region-of-interest (ROI) versus whole tract approaches. We investigated agreement between dMRI measures using ROI and Probabilistic Neighbourhood Tractography (PNT) in genu of corpus callosum (gCC) and corticospinal tracts (CST).

Materials and methods: 81 neonates underwent 64 direction DTI at term equivalent age. FA and MD values were extracted from a 8 mm3 ROI placed within the gCC, right and left posterior limbs of internal capsule. PNT was used to segment gCC and CSTs to calculate whole tract-averaged FA and MD. Agreement between values obtained by each method was compared using Bland-Altman statistics and Pearson’s correlation.

Results: Across the 3 tracts the mean difference in FA measured by PNT and ROI ranged between 0.13 and 0.17, and the 95% limits of agreement did not include the possibility of no difference. For MD, the mean difference in values obtained from PNT and ROI ranged between 0.101 and 0.184 mm2/s × 10-3 mm2/s: the mean difference in gCC was 0.101 × 10-3 mm2/s with 95% limits of agreement that included the possibility of no difference, but there was significant disagreement in MD values measured in the CSTs.

Conclusion: Agreement between dMRI measures of neonatal WM microstructure calculated from ROI and whole tract averaged methods is weak. ROI approaches may not provide sufficient representation of tract microstructure at the level of neural systems in newborns.

Preterm Birth (PTB) accounts for approximately 11% of all births worldwide each year and is a profound physiological stressor in early life. The burden of neuropsychiatric and developmental impairment is high, with severity and prevalence correlated with gestational age at delivery. PTB is a major risk factor for the development of cerebral palsy, lower educational attainment and deficits in cognitive functioning, and individuals born preterm have higher rates of schizophrenia, autistic spectrum disorder and attention deficit/hyperactivity disorder. Factors such as gestational age at birth, systemic inflammation, respiratory morbidity, sub-optimal nutrition, and genetic vulnerability are associated with poor outcome after preterm birth, but the mechanisms linking these factors to adverse long term outcome are poorly understood. One potential mechanism linking PTB with neurodevelopmental effects is changes in the epigenome. Epigenetic processes can be defined as those leading to altered gene expression in the absence of a change in the underlying DNA sequence and include DNA methylation/hydroxymethylation and histone modifications. Such epigenetic modifications may be susceptible to environmental stimuli, and changes may persist long after the stimulus has ceased, providing a mechanism to explain the long-term consequences of acute exposures in early life. Many factors such as inflammation, fluctuating oxygenation and excitotoxicity which are known factors in PTB related brain injury, have also been implicated in epigenetic dysfunction. In this review, we will discuss the potential role of epigenetic dysregulation in mediating the effects of PTB on neurodevelopmental outcome, with specific emphasis on DNA methylation and the α-ketoglutarate dependent dioxygenase family of enzymes.