AUTHOR=Pang Raymand , Martinello Kathryn A. , Meehan Christopher , Avdic-Belltheus Adnan , Lingam Ingran , Sokolska Magda , Mutshiya Tatenda , Bainbridge Alan , Golay Xavier , Robertson Nicola J. 

TITLE=Proton Magnetic Resonance Spectroscopy Lactate/N-Acetylaspartate Within 48 h Predicts Cell Death Following Varied Neuroprotective Interventions in a Piglet Model of Hypoxia–Ischemia With and Without Inflammation-Sensitization

JOURNAL=Frontiers in Neurology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2020.00883

DOI=10.3389/fneur.2020.00883

ISSN=1664-2295

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/N-acetyl aspartate (Lac/NAA) peak area ratio acquired with proton (1H) magnetic resonance spectroscopy accurately predicts 2-year neurodevelopmental outcome. We assessed the relationship between MR biomarkers acquired at 24-48h following injury with cell death and neuroinflammation in a piglet model following various neuroprotective interventions. 67 piglets with either hypoxia-ischemia, hypoxia alone or LPS sensitization were included and neuroprotective interventions included therapeutic hypothermia, melatonin and magnesium. MRS and diffusion-weighted imaging were acquired at 24h and 48h. At 48h, experiments were terminated and immunohistochemistry assessed. There was a correlation between Lac/NAA and overall cell death (TUNEL)(mean Lac/NAA BGT voxel r=0.722, WM voxel r=0.784, p<0.01) and microglial activation (Iba1)(BGT r=-0.786, WM r=-0.632, p<0.01). Correlation with marker of caspase dependent apoptosis (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 NE and supports its use in pre-clinical and clinical neuroprotection studies.