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Thalamic N-Acetyl Aspartate Level Predicts Adverse Neurodevelopmental Outcomes In Babies With Isolated White Matter/Cortical Injury After Neonatal

P Ivain1 P Montaldo1, PJ Lally1, V Oliveira1, J Mendoza1, M Morales1, S Shankaran2, and S Thayyil1 
Institutions
Centre for Perinatal Neuroscience, Imperial College London1 
Neonatal-Perinatal Medicine, Wayne State University, USA2 
Imperial College London1, UK; Wayne State University, USA2 
Introduction (include hypothesis) 
Although histological injury to basal ganglia/thalamus (BGT) invariably occurs after an acute hypoxic ischemic insult in preclinical models1, only a small proportion of babies with neonatal encephalopathy (NE) show BGT injury on magnetic resonance imaging (MRI). In this secondary analysis of the MARBLE study2, we examined if thalamic spectroscopy metabolic changes occur in babies with isolated white matter (WM) or cortical MRI injury after NE. 
Methods (include source of funding and ethical approval if required) 
We recruited 223 babies who had therapeutic hypothermia for NE from 8 centres in the UK and USA. All babies had MRI and thalamic proton magnetic resonance spectroscopy (MRS) between 4-14 days after birth and neurodevelopmental outcomes (Bayley III) between 18 and 22 months. We excluded 58 (26%) patients with normal MRI and 52 (23%) babies with BGT/posterior limb of internal capsule (PLIC) injury, with or without WM or cortical injury. We used general linear models to assess the relationship between MRS metabolites and WM/cortical MRI scores (WM score >0 or cortex score >0) and calculated the prognostic accuracy of the MRS metabolites in predicting adverse neurodevelopmental outcomes. 
Results 
The data from 113 babies were analysed, of which 85 (75%) had isolated WM injury, 6 (5%) had isolated cortical injury, and 22 (20%) had combined WM/cortical injury. Thalamic N-acetyl aspartate and N-acetylaspartylglutamate concentration [tNAA] was normally distributed. However, Lactate and Threonine (tLac/tNAA) peak area metabolite ratios were highly skewed and hence were log transformed for analysis. Both [tNAA] and Log10tLac/tNAA were significantly associated with WM injury scores (p=0.03 and p=0.01 respectively), but not with cortical injury scores (p>0.05) on MRI (left figure). There was a significant correlation between [tNAA] and mean fractional anisotropy (FA) in the PLIC (r=0.68; p<0.001) (right figure) and between Log10tLac/tNAA and PLIC FA (-0.48; p=0.008).  Thalamic [tNAA] (< 5.6 mmol/kg/ww) was more accurate in predicting later adverse outcome (sensitivity of 1.00 (95% CI 0.44 to 1.0) and specificity of 0.96 (95% CI 0.85 to 0.99), than tLac/tNAA (>0.22) (sensitivity 0.83 (95% CI 0.44 to 0.97); specificity 0.84 (95% CI 0.74 to 0.91), in babies with isolated WM and/or cortical injury. 
Conclusions 
Isolated WM and mixed WM/cortical injury are associated with decreased thalamic [tNAA]. Thalamic t[NAA] is a superior surrogate biomarker for early phase neuroprotection trials in NE than tLac/tNAA peak area metabolite ratio. 
References (include acknowledgement here if appropriate) 

1. Williams et al., Ann Neurol 1992; 31(1): 14-212  2. Lally et al., The Lancet Neurology 2019, 18(1), pp.35-45. 
Thalamic N-Acetyl Aspartate Level Predicts Adverse Neurodevelopmental Outcomes In Babies With Isolated White Matter/Cortical Injury After Neonatal
Thalamic N-Acetyl Aspartate Level Predicts Adverse Neurodevelopmental Outcomes In Babies With Isolated White Matter/Cortical Injury After Neonatal

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