Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.

Altered Expression of Umbilical Cord Blood Levels of miR-181b and Its Downstream Target mUCH-L1 in Infants with Moderate and Severe Neonatal Hypoxic-Ischaemic Encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) remains one of the leading causes of neurological disability worldwide. No blood biomarker capable of early detection and classification of injury severity in HIE has been identified. This study aimed to investigate the potential of miRNA-181b (miR-181b) and its downstream target, ubiquitin C-terminal hydrolase-L1 (UCH-L1), to predict the severity of HIE. Full-term infants with perinatal asphyxia were recruited at birth and observed for the development of HIE, along with healthy controls. Levels of miR-181b and messenger UCH-L1 (mUCH-L1) in umbilical cord blood were determined using qRT-PCR. In total, 131 infants; 40 control, 50 perinatal asphyxia without HIE (PA) and 41 HIE, recruited across two separate cohorts (discovery and validation) were included in this study. Significant and consistent downregulation of miR-181b was observed in infants with moderate/severe HIE compared to all other groups in both cohorts: discovery 0.25 (0.16-0.32) vs 0.61 (0.26-1.39), p = 0.027 and validation 0.33 (0.15-1.78) vs 1.2 (0.071-2.09), p = 0.035. mUCH-L1 showed increased expression in infants with HIE in both cohorts. The expression ratio of miR-181b to mUCH-L1 was reduced in those infants with moderate/severe HIE in both cohorts: discovery cohort 0.23 (0.06-0.44) vs 1.59 (0.46-2.54), p = 0.01 and validation cohort 0.41 (0.10-0.81) vs 1.38 (0.59-2.56) in all other infants, p = 0.009. We have validated consistent patterns of altered expression in miR-181b/mUCH-L1 in moderate/severe neonatal HIE which may have the potential to guide therapeutic intervention in HIE.

Downstream mRNA Target Analysis in Neonatal Hypoxic-Ischaemic Encephalopathy Identifies Novel Marker of Severe Injury: a Proof of Concept Paper.

Human microRNA miR-374a is downregulated in the umbilical cord blood (UCB) of infants with hypoxic-ischaemic encephalopathy (HIE). The downstream targets of this microRNA (miRNA) are unclear, but one putative target is the activin-A receptor type IIb (ACVR2B). ACVR2B is required for activin-A function and previous reports have shown alterations of activin-A levels in neonatal HIE. Our aim was to investigate the expression of the potential downstream targets of miR-374a, activin-A and ACVR2B, at birth in a cohort of full-term infants with perinatal asphyxia (PA) only, and those with PA who developed clinical and electrographic HIE. UCB was drawn and processed immediately after delivery. Levels of serum activin-A were measured using ELISA. mRNA levels of ACVR2B in whole blood were quantified using qRT-PCR. Outcome was assessed at 3 years of age using standardised developmental assessment. In total, 171 infants were enrolled: 88 healthy controls, 56 PA and 27 HIE. A statistically significant elevation of median (IQR) ACVR2B was detected in infants with severe HIE compared to moderate/mild HIE, PA and control groups (3.3 (2.94-3.67) vs. 0.91 (0.55-1.21) vs. 0.88 (0.57-1.38) vs. 0.84 (0.74-1.24), p values = 0.04, 0.027 and 0.025, respectively). Although serum activin-A levels were elevated in infants with severe HIE, this elevation did not reach significance. ACVR2B may be a potential novel marker of HIE severity. This is the first study to examine the relationship between activin-A, its receptor AVCR2B and potentially upstream miRNA miR-374a in a cohort of carefully categorised and phenotyped infants. We have shown that miRNA analysis, combined with downstream target exploration, may yield novel biomarkers for the prediction of HIE severity.