Neuronal let-7b-5p acts through the Hippo-YAP pathway in neonatal encephalopathy.

Despite increasing knowledge on microRNAs, their role in the pathogenesis of neonatal encephalopathy remains to be elucidated. Herein, we identify let-7b-5p as a significant microRNA in neonates with moderate to severe encephalopathy from dried blood spots using next generation sequencing. Validation studies using Reverse Transcription and quantitative Polymerase Chain Reaction on 45 neonates showed that let-7b-5p expression was increased on day 1 in neonates with moderate to severe encephalopathy with unfavourable outcome when compared to those with mild encephalopathy. Mechanistic studies performed on glucose deprived cell cultures and the cerebral cortex of two animal models of perinatal brain injury, namely hypoxic-ischaemic and intrauterine inflammation models confirm that let-7b-5p is associated with the apoptotic Hippo pathway. Significant reduction in neuronal let-7b-5p expression corresponded with activated Hippo pathway, with increased neuronal/nuclear ratio of Yes Associated Protein (YAP) and increased neuronal cleaved caspase-3 expression in both animal models. Similar results were noted for let-7b-5p and YAP expression in glucose-deprived cell cultures. Reduced nuclear YAP with decreased intracellular let-7b-5p correlated with neuronal apoptosis in conditions of metabolic stress. This finding of the Hippo-YAP association with let-7b needs validation in larger cohorts to further our knowledge on let-7b-5p as a biomarker for neonatal encephalopathy.

Raised Plasma Neurofilament Light Protein Levels After Rewarming Are Associated With Adverse Neurodevelopmental Outcomes in Newborns After Therapeutic Hypothermia.

Aim: To determine the predictive value of plasma neurofilament light protein (NfL) as a prognostic marker for outcomes in babies who have undergone therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE). Method: NfL levels from three groups of term newborns were compared: (1) those with mild HIE who did not receive TH, (2) newborns treated with TH who had minimal or no brain injury on MRI, and (3) newborns treated with TH who had substantial brain injury on MRI. Follow-up outcomes were collected from 18 months onward. Results: Follow-up was available for 33/37 (89%) of children. A cutoff NfL level >436 pg/ml after rewarming (median age 98 h) was associated with adverse outcome with a diagnostic sensitivity 75%, specificity 77%, PPV 75%, and NPV 77%. NfL levels at earlier time points were not predictive of outcome. Interpretation: This pilot study shows that persistently raised plasma NfL levels after rewarming are associated with adverse outcomes in babies with HIE who have undergone TH.

In clinical practice, cerebral MRI in newborns is highly predictive of neurodevelopmental outcome after therapeutic hypothermia.

OBJECTIVE: In the trials, a substantial proportion of newborns who underwent therapeutic hypothermia (TH) had an adverse outcome after hypoxic-ischaemic encephalopathy (HIE). Cooled babies were noted to have fewer cerebral lesions on MRI but when present lesions were predictive of adverse outcome. We investigate the predictive value of cerebral MRI in babies who undergo cooling in the clinical setting outside of the clinical trials in a prospective UK cohort. RESULTS: Of 75 babies recruited from four centres, neurodevelopment was available for 69 (92%) with 29% (20/69) being abnormal. The unfavourable MRI group (n = 22) had significantly lower motor (p < 0.001), language (p < 0.001) and cognition (p < 0.001) scores on Bayley-III assessment, compared to the favourable MRI group (n = 47). On multiple regression there was a significant relationship between basal ganglia and thalami abnormality and motor (p = 0.002), cognition (p = 0.011) and language (p = 0.013) outcomes. Half of the babies who had an MRI predictive of adverse outcome (11/22) had highest grade cerebral palsy. Cerebral MRI had 95% sensitivity, 94% specificity, 91% PPV and 98% NPV in predicting neurodevelopment. CONCLUSIONS: In this clinical cohort, fewer children had adverse neurodevelopment after TH compared to the TH trials. However, half the children who had an MRI predictive of adverse ND outcome had the most severe form of cerebral palsy. In this cohort, cerebral MRI was found to be highly predictive of neurodevelopmental outcome.

WITHDRAWN: In clinical practice, cerebral MRI in newborns is highly predictive of neurodevelopmental outcome after therapeutic hypothermia.

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