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Background and PurposeSerum neurofilament light chain (sNfL) has recently emerged as a promising biomarker reflecting structural neuro-axonal damage in different neurological diseases. Our study aimed at assessing whether sNfL can predict the functional outcome in preterm infants who suffered from neonatal haemorrhagic brain injury.MethodsIn this prospective observational study, we used an ultrasensitive single-molecule array assay to measure serum and cerebrospinal fluid (CSF) concentrations of NfL in preterm infants diagnosed with intraventricular haemorrhage (IVH) in the first few days of life. We determined the temporal profile of serum and CSF NfL levels from first diagnosis of IVH until term equivalent age, their association with cerebral imaging markers, and with clinical and functional outcome until 2 years of age assessed by Bayley Scales of Infant Development. We fitted univariable and multivariable logistic regression models to determine risk factors for low motor and cognitive development. Longitudinal mixed effects models modelled NfL levels using cubic spline smoothers to track the trajectory over time.ResultsThe study included 48 infants born with less than 32 weeks of gestation. At the time point of IVH diagnosis, NfL median levels were 271.9 pg/mL (IQR 151.2–389.7), and strongly decreased until term equivalent age to 15.7 pg/mL (IQR 11.1–32.2). CSF values were 113-fold higher (IQR 40–211) than corresponding serum values. Additional cerebral infarction (n=23) but not post-haemorrhagic hydrocephalus with permanent external ventricular drainage (n=29) or other diseases independently determined sNfL levels. In multivariate logistic regression models, the only significant predictor of poor motor outcome at 2 years or death was sNfL level (p=0.02).There was a clear difference between the NfL trajectory for those with poor motor outcome at 1 year.ConclusionsThis study shows that early sNfL is an independent prognostic biomarker for motor functional outcome in preterm infants after IVH.Disclosure(s)Nothing to disclose

Background: The pituitary-secreted nonapeptide Arginine-Vasopressin (AVP) is unstable and therefore unsuited for diagnostic use but its secretion can be gauged by measuring copeptin, the C-terminal portion of the AVP precursor (CT-proAVP). We determined copeptin in umbilical cord blood and at 3 days of age in order to establish normal values and perinatal factors affecting copeptin concentrations.Methods: Paired arterial/venous umbilical cord samples were obtained from 117 infants and umbilical venous-only samples from additional 46 infants. In 102 infants, blood was also obtained at 3 days of life. Copeptin levels were determined using the CT-proAVP-Luminescence-immunoassay.Results: Arterial umbilical cord copeptin concentrations were consistently higher that matched venous ones (p< 0.001) but copeptin concentrations were closely related (Rs= 0.825, p < 0.001). Exceedingly high copeptin concentrations were observed after vaginal birth in umbilical cord venous (median [5-95% range]: 793 [6-4836] pmol/L) and arterial plasma [1610 [85-5000] pmol/L). In addition, copeptin concentrations in umbilical venous and arterial blood were negatively related with birth acidosis (pH, Rs = -0.578 and -0.639, both p < 0.001). Postnatal body weight was associated with increased copeptin concentrations at day 3 (Rs = 0.438, p < 0.001) and was inversely related with copeptin concentrations at birth in umbilical venous and artery plasma (Rs = -0.289 and -0.309, both p = 0.001).Conclusion: Vaginal birth is associated with a huge release of AVP/copeptin. Umbilical cord copeptin concentrations exceed values published so far, including those in critically ill adult patients with myocardial infarction, shock, or brain injury.

Background: Copeptin is a stable by-product of arginine-vasopressin (AVP) synthesis and reflects its secretion by the pituitary. We investigated perinatal factors affecting copeptin concentrations in preterm infants at birth and at 3 days of life.Methods: A prospective cross-sectional study at two Swiss university hospitals was performed. 167 preterm infants were enrolled, 59 infants born between 24 and 31 weeks gestational age, 50 infants between 32 and 34 weeks, and 58 between 35 and 36 weeks. Plasma copeptin concentrations were determined by a CT-proAVP-Luminescence-immunoassay in umbilical cord blood at birth and in blood samples obtained at 2-3 days of life.Results: Copeptin at birth was significantly higher in preterm infants born vaginally (median [range] 366 [1-2900] pmol/L, n=43) than those born by caesarean section (6.9 [2-1580], n=124). In infants born after caesarean without prior labour (n=66), small for gestational age (< 5th percentile), suspect fetal heart rate, compromised placental perfusion, and chorioamnionitis were each associated with significantly elevated cord copeptin. Copeptin at 3 days of life was not associated with cord blood copeptin but inversely related to gestational age (Rs -0.6, p< 0.001) and birth weight (Rs -0.612, p< 0.001). Day 3 copeptin increased alongside the level of mechanical respiratory support.Conclusion: Copeptin is a highly sensitive marker of fetal and neonatal stress.

Background: Induced hypothermia is the only therapy with proven efficacy to reduce brain damage after perinatal asphyxia. While hypothermia downregulates global protein synthesis and cell metabolism, low temperature induces a small subset of proteins that includes the RNA-binding protein RBM3, which is transcriptionally induced also in response to hypoxia and has recently been implicated in cell survival.Methods/results: We studied RBM3 expression in the developing murine brain by immunohistochemistry and found RBM3 widely expressed in neurons of the hippocampus, the subventricular zone, and the cerebellum during the first postnatal days. In adult brains, RBM3 was present only in neuronal precursor and stem cells, characterized by the presence of doublecortin. Hypothermia profoundly promoted RBM3 expression in juvenile as well as in mature neurons, and hypothermia-induced RBM3 expression was associated with protection of primary neurons and neuronal cell lines from forced apoptosis. Blocking RBM3 expression by siRNAs in neuronal cells significantly diminished the neuroprotective effect of hypothermia while vector-driven RBM3 overexpression prevented activation of caspase-3.Conclusion: Together, the RNA-binding protein RBM3 protects neuronal cells from apoptosis. RBM3 upregulation apparently accounts for a substantial proportion of hypothermia-induced neuroprotection.

Objective: Pontosubicular neuron necrosis (PSN) represents an age-specific response to severe hypoxic-ischemic injury (HII) occurring in human neonates but not in older children or adults. Histologically, PSN is characterised by acute neuronal death in the pontine nuclei and the hippocampal subiculum bearing the hallmarks of apoptosis. The expression of Rbm3, a glycine-rich RNA-binding protein, is enhanced under hypoxic conditions and independent of HIF (hypoxia inducible factor). It is well known, that proteins which are dependant on HIF, e.g. Erythropoetin play an important role in HII. This study aims to determine whether the HIF-independent activation of Rbm3 is also a significant factor in the pathogenesis of PSN. Methods: We have investigated the expression of Rbm3 in human autopsy material consisting of 12 PSN cases and 10 age-matched controls without PSN. Immunohistochemistry and double labeling for Rbm3 and the astrocyte marker glial fibrillary acid protein (GFAP), the microglia/macrophage specific marker KiM1P and the neuronal marker NeuN was performed on formalin-fixed, paraffin-embedded brain specimens.Results: In PSN cases and controls, mainly neuronal cells expressed Rbm3. The number of immunopositive cells was significantly increased (p=0.001) in PSN cases. Predominantly degenerating cells with signs of later apoptotic stages showed Rbm3 expression. In earlier stages of apoptosis immunopositivity for Rbm3 was increased compared to contols, but less prominent.Conclusion: In addition to HIF-dependant proteins, the induction of the HIF-independent protein RMB3 is observed in response to human hypoxic-ischemic injury.