Abstract
Despite therapeutic hypothermia, survivors of neonatal encephalopathy have high rates of adverse outcome. Early surrogate outcome measures are needed to speed up the translation of neuroprotection trials. Thalamic lactate (Lac)/N-acetylaspartate (NAA) peak area ratio acquired with proton (1H) magnetic resonance spectroscopy (MRS) accurately predicts 2-year neurodevelopmental outcome. We assessed the relationship between MR biomarkers acquired at 24–48 h following injury with cell death and neuroinflammation in a piglet model following various neuroprotective interventions. Sixty-seven piglets with hypoxia–ischemia, hypoxia alone, or lipopolysaccharide (LPS) sensitization were included, and neuroprotective interventions were therapeutic hypothermia, melatonin, and magnesium. MRS and diffusion-weighted imaging (DWI) were acquired at 24 and 48 h. At 48 h, experiments were terminated, and immunohistochemistry was assessed. There was a correlation between Lac/NAA and overall cell death [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)] [mean Lac/NAA basal ganglia and thalamus (BGT) voxel r = 0.722, white matter (WM) voxel r = 0.784, p < 0.01] and microglial activation [ionized calcium-binding adapter molecule 1 (Iba1)] (BGT r = −0.786, WM r = −0.632, p < 0.01). Correlation with marker of caspase-dependent apoptosis [cleaved caspase 3 (CC3)] was lower (BGT r = −0.636, WM r = −0.495, p < 0.01). Relation between DWI and TUNEL was less robust (mean diffusivity BGT r = −0.615, fractional anisotropy BGT r = 0.523). Overall, Lac/NAA correlated best with cell death and microglial activation. These data align with clinical studies demonstrating Lac/NAA superiority as an outcome predictor in neonatal encephalopathy (NE) and support its use in preclinical and clinical neuroprotection studies.
Highlights
Neonatal encephalopathy (NE) secondary to intrapartum hypoxia–ischemia is a significant cause of brain injury in term infants affecting 2–3 per 1,000 live births in the UK [1]
There was a strong correlation between Lac/Cr and NAA/Cr at 24 h, and both these metabolite ratios correlated with transferase dUTP nick end labeling (TUNEL) in the basal ganglia
Lac/Cr did not correlate with brain infarct volume at 4 weeks, which they argued was due to using a single voxel that may not reflect whole-brain injury
Summary
Neonatal encephalopathy (NE) secondary to intrapartum hypoxia–ischemia is a significant cause of brain injury in term infants affecting 2–3 per 1,000 live births in the UK [1]. NE has a complex and multifactorial etiology; over the last decade, preclinical [5] and clinical [6] studies suggest that coexisting infection and inflammation with hypoxia–ischemia (HI) exacerbate brain injury. In single [8] and multicenter [9] studies of NE babies who have been cooled, the 1H magnetic resonance spectroscopy (MRS) thalamic lactate (Lac)/N-acetylaspartate (NAA) peak area ratio acquired within 15 days of birth accurately predicts neurodevelopmental outcomes. In the TOBY Xenon early-phase clinical neuroprotection trial, adverse outcomes were correctly identified in 95.65% of cases by basal ganglia and thalamus (BGT) Lac/NAA, whereas prediction of adverse outcome using fractional anisotropy (FA) was 78.79% [10]. Using Lac/NAA peak area ratio as a qualified biomarker in the clinical context in a small proof-of-concept neuroprotection trial avoids substantial financial and opportunity costs associated with large randomized controlled trials (RCTs)
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