Background Although diffusion tensor imaging (DTI) fractional anisotropy (FA) is commonly used to quantify neural injury, it is non-specific and affected by a number of microstructural changes. Objective To examine alterations in white matter (WM) associated with neonatal encephalopathy (NE), and relate these to tangible biophysical changes using the neurite orientation dispersion and density imaging (NODDI) model. Design/Methods We recruited with parental consent consecutive encephalopathic neonates (Thompson score ≥6) admitted to Calicut Medical College, India over a 6 month period. At age <3 wk diffusion tensor magnetic resonance imaging (DTI, TR/TE = 2800 ms/94 ms, 20 directions, b = 0&1000 s/mm2, 1.8 × 1.8 × 5 mm3) was performed at 1.5T (Siemens Avanto). Sarnat encephalopathy stage (none, mild, moderate or severe) was allocated at day 3. DTI data were fitted to the NODDI model, generating maps of orientation dispersion index (ODI) and neurite density index (NDI). These were compared between infants grouped by encephalopathy severity using tract-based spatial statistics (TBSS). Results Fifty-four infants were recruited; 31 had usable data. The mean FA skeleton is shown in green (Figure 1a). Compared to normal/mild (n = 22) the moderate/severe encephalopathy group (n = 9) had significantly reduced WM FA (Figure 1b: red p < 0.05; yellow p < 0.01) and increased radial diffusivity (RD, Figure 1c). This corresponded to a decrease in NDI (Figure 1d), but not ODI (Figure 1e). Conclusions In this cohort, NODDI fitting indicates that microstructural changes in NE may be due to a reduced neurite density. Further work will establish whether these findings are consistent with those obtained from gold-standard multi-shell diffusion data. Abstract 8.9 Figure 1

Background Therapeutic hypothermia improves outcomes after neonatal encephalopathy in high-income countries, however the safety and efficacy of cooling in low- and middle-income countries (LMIC) is not known. Objective To examine the feasibility of whole body cooling using an inexpensive servo-controlled cooling device developed for use in LMIC. Design We recruited 28 newborns (>36 wk and >1.8 kg) aged <6 h, admitted to the neonatal unit at Madras Medical College, India, with moderate or severe neonatal encephalopathy. After informed parental consent, infants were kept naked on a cooling mattress attached to the device (Tecotherm-HELIX), circulating water mixed with alcohol. Following 72 h of cooling, infants were passively rewarmed by switching off the machine and covering the infant with warm clothes. Results 4/16(25%) infants with moderate encephalopathy, and 8/12(67%) with severe encephalopathy died. Thrombocytopenia was seen in 19(68%) infants, gastric bleeds in 10(36%), persistent acidosis in 1(4%) and sclerema in 1(4%). Mean (SD) age and temperature at start of cooling was 4.1(1.1) h, and 35.7(1.5)°C respectively. Mean (SD) induction time was 79(47) minutes, core temperature during cooling was 33.5(0.1) °C, and passive re-warming rate was 0.3(0.1) °C/h (Figure). The ambient temperature of the intensive care unit was 26–33°C. No additional nursing input was required to maintain cooling except refilling the machine with water every 6–8h. The cooling mattress had to be replaced once during the six month study period. Abstract PC.110 Figure Conclusions Effective therapeutic hypothermia can be provided using Tecotherm-HELIX with minimal additional nursing input in LMIC. Future clinical trials should examine the safety and efficacy of cooling in these settings.

Background Early cerebral proton magnetic resonance spectroscopy (MRS) predicts medium-term outcomes in neonatal encephalopathy (NE). Metabolite peak-area ratios are most commonly used for prognosis, but conflate pathological information from different metabolites. N-acetylaspartate (NAA) is predominantly neuronal and neuronal loss should result in reduced NAA absolute-concentration ([NAA]). Thus, thalamic [NAA] should offer significant prognostic value but is difficult to measure in a clinical setting. We have established a protocol for multi-centre [NAA] measurement with the aim to use it as a surrogate biomarker in phase II clinical trials. Objective To investigate the feasibility and utility of [NAA] quantitation across multiple centres. Design/Methods We recruited cooled, term neonates with NE (by Sarnat grade) with parental consent across participating sites. Using various 3T scanners, thalamic MRS was performed aged 7 ± 4d (PRESS; water-suppressed TR = 2s/TE = 288/60 ms;TR/TE = 5s/60 ms; non-water-suppressed TR = 10s, TE = 60/124/205/316/495/1000 ms, ~30min acquisition). Spectra were post-processed in jMRUI and metabolite contributions determined with LCModel. [NAA] was calculated, correcting for T2 effects and cerebrospinal fluid partial volume. Results Ten cases had sufficient data for [NAA] quantification. Sarnat grading <6h identified infants with highest [NAA] (median (IQR) 10.0(9.7–10.3) mmol/kg wet weight) as mild NE, with a lower [NAA] range for moderate NE (7.0(5.0–7.8) mmol/kg wet weight). Conclusions [NAA] quantification is achievable in a multi-centre setting, and agrees with clinical NE grading during the therapeutic window. Follow-up examinations will allow comparison of neonatal [NAA] with later neurodevelopmental outcomes. Abstract PC.45 Figure

Background Proton magnetic resonance spectroscopy (MRS) has high prognostic value in hypoxic ischaemic encephalopathy (HIE), however its multi-centre application is limited by inconsistencies between scanners and protocols. N-acetylaspartate (NAA) is predominantly neuronal: cerebral NAA concentration may be a more reliable HIE-severity biomarker than lactate/NAA. Objective To quantify the inter-site and inter-subject variability of NAA concentration measurements. Design/Methods We recruited 5 healthy adult volunteers (aged 24–38, 2 male, 3 female) whom we scanned at 3 UK sites participating in a multi-centre neonatal-brain study (University Hospital, Coventry (UHC); Alder Hey Children’s Hospital, Liverpool (AH); University College Hospital, London (UCLH)). Thalamic NAA concentration was measured using the neonatal brain-water concentration reference protocol (15 × 15 × 15mm3 voxel; PRESS; water-suppressed TR/TE = 2s/288&60ms; TR/TE = 5s/60ms; non-water-suppressed TR = 10s, TE = 60/124/205/316/495/1000 ms). Spectra were post-processed in jMRUI and metabolites fitted with LCModel. Results One volunteer was unavailable for scanning at AH. The mean (SD) NAA concentrations across the remaining four subjects were 15.5(3.4)mmol/kg wet weight, 14.4(0.1) mmol/kg wet weight, and 15.2(0.1) mmol/kg wet weight at UHC, AH and UCLH respectively. This corresponds to a maximum inter-site group mean variation (range/mean) of 8%. The inter-subject variability of mean NAA concentration (SD/mean) was 10%. Conclusions The variation of thalamic NAA concentration between sites was 8% and the standard deviation across subjects was 10%, hence [NAA] may be suitable for multi-centre studies. Abstract PC.26 Figure

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