Magnetic resonance spectroscopy biomarkers in term perinatal asphyxial encephalopathy: from neuropathological correlates to future clinical applications.

Neonatal brain injury remains a devastating condition, with poor outcomes despite the institution of an effective neuroprotective strategy of therapeutic hypothermia. There is an urgent need to develop additional neuroprotective strategies and to tailor our clinical predictive ability for families and their infants. Such goals could be more readily achieved if reliable early clinical indicators or biomarkers existed.

Neonatal encephalopathic cerebral injury in South India assessed by perinatal magnetic resonance biomarkers and early childhood neurodevelopmental outcome.

Unlabelled: Although brain injury after neonatal encephalopathy has been characterised well in high-income countries, little is known about such injury in low- and middle-income countries. Such injury accounts for an estimated 1 million neonatal deaths per year. We used magnetic resonance (MR) biomarkers to characterise perinatal brain injury, and examined early childhood outcomes in South India.

White matter NAA/Cho and Cho/Cr ratios at MR spectroscopy are predictive of motor outcome in preterm infants.

Purpose: To determine (a) whether diffuse white matter injury of prematurity is associated with an increased choline (Cho)-to-creatine (Cr) ratio and a reduced N-acetylaspartate (NAA)-to-Cho ratio and whether these measures can be used as biomarkers of outcome and (b) if changes in peak area metabolite ratios at magnetic resonance (MR) spectroscopy are associated with changes in T2 and fractional anisotropy (FA) at MR imaging.

Materials And Methods: The local ethics committee approved this study, and informed parental consent was obtained for each infant. At term-equivalent age, 43 infants born at less than 32 weeks gestation underwent conventional and quantitative diffusion-tensor and T2-weighted MR imaging.

Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation study.

Background: Post-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children.

Methods: In this prospective validation study, we did pre-autopsy, post-mortem, whole-body MRI at 1·5 T in an unselected population of fetuses (≤24 weeks' or >24 weeks' gestation) and children (aged <16 years) at two UK centres in London between March 1, 2007 and Sept 30, 2011.

Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis.

Unlabelled: Although selective or whole body cooling combined with optimal intensive care improves outcomes following neonatal encephalopathy in high-income countries, the safety and efficacy of cooling in low-and middle-income countries is not known.

Objective: We performed a systematic review and meta-analysis of all published randomised or quasi-randomised controlled trials of cooling therapy for neonatal encephalopathy in low-and middle-income countries.

Results: Seven trials, comprising a total of 567 infants were included in the meta-analysis.

Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model.

Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models.

Regional neonatal brain absolute thermometry by 1H MRS.

Therapeutic hypothermia is standard care for infants with moderate to severe encephalopathy. (1) H MRS thermometry (MRSt) measures regional brain absolute temperature using the temperature-dependent water chemical shift. This study evaluates the clinical feasibility of MRSt in human neonates, and correlates white matter (WM) and thalamus (Thal) MRSt with conventional rectal temperature (Trectal ) measurement.

Systemic effects of whole-body cooling to 35 °C, 33.5 °C, and 30 °C in a piglet model of perinatal asphyxia: implications for therapeutic hypothermia.

Introduction: The precise temperature for optimal neuroprotection in infants with neonatal encephalopathy is unclear. Our aim was to assess systemic effects of whole-body cooling to 35 °C, 33.5 °C, and 30 °C in a piglet model of perinatal asphyxia.

Improved reproducibility of MRS regional brain thermometry by 'amplitude-weighted combination'.

Brain temperature is important in stroke and trauma. In birth asphyxia, hypothermia improves outcome, but local brain temperature information is needed to optimise therapy. The proton MRS water chemical shift (δ(water) ) is temperature dependent, and the in vivo brain temperature has often been estimated by measuring δ(water) relative to the N-acetylaspartate (NAA) singlet methyl resonance.

Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia.

Objective: Additional treatments for therapeutic hypothermia are required to maximize neuroprotection for perinatal asphyxial encephalopathy. We assessed neuroprotective effects of combining inhaled xenon with therapeutic hypothermia after transient cerebral hypoxia-ischemia in a piglet model of perinatal asphyxia using magnetic resonance spectroscopy (MRS) biomarkers supported by immunohistochemistry.

Methods: Thirty-six newborn piglets were randomized (all groups n = 9), with intervention from 2 to 26 hours, to: (1) normothermia; (2) normothermia + 24 hours 50% inhaled xenon; (3) 24 hours hypothermia (33.

Post-mortem cerebral magnetic resonance imaging T1 and T2 in fetuses, newborns and infants.

Unlabelled: Post-mortem magnetic resonance imaging (PM MRI) of brain is increasingly used in clinical practice; understanding of normal PM contrast to noise ratio (CNR), T1 and T2 values relaxation times is important for optimisation and accurate interpretation of PM MRI.

Methods: We obtained T1- and T2-weighted images at 1.5 T.

Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis.

Objective: Accurate prediction of neurodevelopmental outcome in neonatal encephalopathy (NE) is important for clinical management and to evaluate neuroprotective therapies. We undertook a meta-analysis of the prognostic accuracy of cerebral magnetic resonance (MR) biomarkers in infants with neonatal encephalopathy.

Methods: We reviewed all studies that compared an MR biomarker performed during the neonatal period with neurodevelopmental outcome at > or =1 year.

T2 at MR imaging is an objective quantitative measure of cerebral white matter signal intensity abnormality in preterm infants at term-equivalent age.

Purpose: To compare quantitative T2 relaxometry of cerebral white matter (WM) with qualitative assessment of conventional T2-weighted magnetic resonance (MR) images, to assess the relationship between cerebral WM T2 and region-specific apparent diffusion coefficient (ADC), and to examine WM T2 regional variation in preterm infants at term.

Materials And Methods: The local ethical committee granted ethical permission for this study; informed parental consent was obtained for each infant. Sixty-two preterm infants born at less than 32 weeks gestation and nine control infants were examined at 1.

Phosphorus magnetic resonance spectroscopy 2 h after perinatal cerebral hypoxia-ischemia prognosticates outcome in the newborn piglet.

Phosphorus magnetic resonance spectroscopy ((31)P MRS) often reveals apparently normal brain metabolism in the first hours after intrapartum hypoxia-ischemia (HI) at a time when conventional clinical assessment of injury severity is problematic. We aimed to elucidate very-early, injury-severity biomarkers. Twenty-seven newborn piglets underwent cerebral HI: (31)P-MRS measures approximately 2 h after HI were compared between injury groups defined by secondary-energy-failure severity as quantified by the minimum nucleotide triphosphate (NTP) observed after 6 h.

Supra- and sub-baseline phosphocreatine recovery in developing brain after transient hypoxia-ischaemia: relation to baseline energetics, insult severity and outcome.

Following hypoxia-ischaemia (HI), an early biomarker of insult severity is desirable to target neuroprotective therapies to patients most likely to benefit; currently there are no biomarkers within the 'latent phase' period before the establishment of secondary energy failure. Brief transient phosphocreatine (PCr) recovery overshoot (measured absolutely or relative to nucleotide triphosphate, NTP) following HI has been observed in cardiac and skeletal muscle; its significance however is unclear. To investigate cerebral PCr recovery levels after HI in relation to (i) baseline metabolism, (ii) insult severity, (iii) energy metabolism at recovery and (iv) subsequent metabolic derangement, cerebral NTP, PCr and inorganic phosphate (relative to the exchangeable high-energy phosphate pool) were measured serially in an in vivo model of perinatal asphyxial encephalopathy using phosphorus-31 magnetic resonance spectroscopy.

Greater hypoxia-induced cell death in prenatal brain after bacterial-endotoxin pretreatment is not because of enhanced cerebral energy depletion: a chicken embryo model of the intrapartum response to hypoxia and infection.

Infection is a risk factor for adult stroke and neonatal encephalopathy. We investigated whether exposure to bacterial endotoxin increases hypoxia-induced brain cell death and impairs cerebral metabolic compensatory responses to hypoxia. Prehatching chicken embryos (incubation day 19) were exposed to bacterial lipopolysaccharide (LPS) (3 mg Salmonella typhimurium LPS per egg) or hypoxia (4% ambient O(2) for 1 h), alone or in combination with LPS, followed 4 h later by hypoxia.

"Therapeutic time window" duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets.

Objective: For optimal neuroprotection following transient perinatal hypoxia-ischaemia (HI), therapy should start before overt secondary energy failure and its irreversible neurotoxic cascade. Hypothermia is a promising neuroprotective intervention that also prolongs the therapeutic time window ("latent-phase"; the period between re-establishment of apparently normal cerebral metabolism after HI, and the start of secondary energy failure). The influences of HI severity on latent-phase duration and regional neuroprotection are unclear.

Magnetic resonance imaging of neonatal encephalopathy at 4.7 tesla: initial experiences.

Objectives: The goals were to develop safe 4.7-T MRI examination protocols for newborn infants and to explore the advantages of this field strength in neonatal encephalopathy.

Methods: Nine ventilated newborn infants with moderate or severe encephalopathy were studied at 4.

Superficial brain is cooler in small piglets: neonatal hypothermia implications.

Objective: Hypothermia was not neuroprotective in low body weight (BW) infants on subgroup analysis in a recent clinical trial of selective head cooling (SHC) in neonatal encephalopathy (CoolCap Trial).

Methods: The BW dependence of regional cerebral temperature was investigated in 14 newborn piglets under normothermia (38.5 degrees C), whole-body cooling (WBC; 36.

Comparative prognostic utilities of early quantitative magnetic resonance imaging spin-spin relaxometry and proton magnetic resonance spectroscopy in neonatal encephalopathy.

Objective: We sought to compare the prognostic utilities of early MRI spin-spin relaxometry and proton magnetic resonance spectroscopy in neonatal encephalopathy.

Methods: Twenty-one term infants with neonatal encephalopathy were studied at a mean age of 3.1 days (range: 1-5).

Delayed whole-body cooling to 33 or 35 degrees C and the development of impaired energy generation consequential to transient cerebral hypoxia-ischemia in the newborn piglet.

Objectives: Fundamental questions remain about the precise temperature providing optimal neuroprotection after perinatal hypoxia-ischemia (HI). Furthermore, if hypothermia delays the onset of the neurotoxic cascade and the secondary impairment in cerebral energy generation, the "latent phase" may be prolonged, thus extending the period when additional treatments may be effective. The aims of this study were to investigate the effects of delayed systemic cooling at either 33 degrees C or 35 degrees C on the following: (1) latent-phase duration, and (2) cerebral metabolism during secondary energy failure itself, in the 48-hour period after transient HI.

Growth restriction and the cerebral metabolic response to acute hypoxia of chick embryos in-ovo: a proton magnetic resonance spectroscopy study.

Introduction: Perinatal brain injury is more common in growth-restricted (GR) than normally grown (NG) fetuses. This study addresses the hypothesis that chronic oxygen and substrate deprivation during pregnancy will engender an abnormal fetal cerebral metabolic response to acute hypoxia.

Method: Cerebral metabolite resonance amplitudes relative to that of creatine were measured by proton magnetic resonance spectroscopy in chick embryos on day 19 of incubation.

Depth of delayed cooling alters neuroprotection pattern after hypoxia-ischemia.

Hypothermia after perinatal hypoxia-ischemia (HI) is neuroprotective; the precise brain temperature that provides optimal protection is unknown. To assess the pattern of brain injury with 3 different rectal temperatures, we randomized 42 newborn piglets: (Group i) sham-normothermia (38.5-39 degrees C); (Group ii) sham-33 degrees C; (Group iii) HI-normothermia; (Group iv) HI-35 degrees C; and (Group v) HI-33 degrees C.

The oxygen dependency of cerebral oxidative metabolism in the newborn piglet studied with 31P NMRS and NIRS.

Mean cerebral saturation and changes in the oxidation state of the CuA centre of cytochrome oxidase were measured by near infra-red spectroscopy simultaneously with phosphorous metabolites and intracellular pH measured using 31P NMR spectroscopy during transient anoxia (inspired oxygen fraction = 0.0 for 105 seconds) in the newborn piglet brain. By collecting high quality 31P spectra every 10 seconds, it was possible to resolve the delay between the onset of anoxia and the fall in PCr and to show that the CuA centre of cytochrome oxidase reduced simultaneously with the fall in PCr.