Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer's disease-related genes in mice.

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aß plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aß deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

Newborn Weight Loss Tool and Readmission for Hyperbilirubinemia.

OBJECTIVE: The aim of this study was to determine if the Newborn Weight Loss Tool (NEWT) can predict hospital readmission due to hyperbilirubinemia. STUDY DESIGN: This is a case-control study of 93 newborns and 186 controls ≥35 weeks' gestation. All were discharged from the Mother-Baby unit of an urban academic center and subsequently readmitted for hyperbilirubinemia. Controls were matched for date of birth, gestational age, and Bhutani risk zone. All infants were screened for hyperbilirubinemia prior to discharge and managed according to American Academy of Pediatrics guidelines in place at the time. Chi-square, Fisher's exact test, and multivariate analysis were utilized as appropriate. RESULTS: There was no significant difference between the groups for a NEWT < 50% at discharge. More cases than controls breastfed. A significantly greater percentage of cases had NEWT > 50% at readmission than discharge. NEWT > 90% was moderately associated with readmission for hyperbilirubinemia (p = 0.081). CONCLUSION: NEWT provides a more nuanced assessment of weight loss following birth and can aid in highlighting newborns at risk for readmission due to hyperbilirubinemia. KEY POINTS: · Weight loss is a risk factor for readmission after birth.. · NEWT is a more nuanced assessment of weight loss.. · NEWT > 90% is associated with readmission for jaundice..

The Neuroprotective Effects of Hypothermia on Bilirubin-Induced Neurotoxicity in vitro.

BACKGROUND: In high-risk newborns indirect hyperbilirubinemia can lead to acute bilirubin encephalopathy and kernicterus. Despite the current therapeutic modalities, preventing or reversing the neurotoxicity cannot be achieved in all infants. OBJECTIVE: To investigate the neuroprotective effects of hypothermia on bilirubin-induced toxicity in primary mouse neuronal cell cultures. METHODS: Hippocampal cell cultures, isolated from newborn mouse brains, were incubated with unconjugated bilirubin (UCB) at 3 days in vitro (DIV) and immediately exposed to varying degrees of hypothermia. Neuronal viability and mitochondrial health were compared between the normothermia (37°C), mild (34°C), moderate (32°C) and severe (29°C) hypothermia groups. Confocal microscopy and fluorescent dyes (propidium iodide and JC-1) were used for cell evaluation. To determine the late effects of hypothermia, the cultures were also examined at 7 DIV after returning to normothermic conditions. RESULTS: Induction of any degree of hypothermia increased the neuronal survival after 24 h of UCB treatment. Neuronal death rate and mitochondrial membrane potential loss were lowest in the neurons exposed to moderate hypothermia. We also observed that mild to moderate hypothermia had late protective effects on neuronal cell viability, whereas deep hypothermia did not improve neuronal survival. CONCLUSIONS: We conclude that hypothermia reduces the cell death induced by bilirubin toxicity in neuronal cells. Although moderate hypothermia has a better outcome than mild hypothermia, deep hypothermia as low as 29°C has adverse effects on neuronal cell viability.