Title: Magnetic Resonance in Infection-Primed Neonatal Encephalopathy (MARINE)
Funder: Health Education England

Abstract: Background Where the neonatal brain experiences a transient period of substantial hypoxia and ischaemia, the resultant injury often causes long term disability or in the most severe cases, death within days. Therapeutic hypothermia has recently become the standard of care for babies in many high income countries, where it has been shown to improve the likelihood of disability-free survival. Despite this, up to 50% of these treated infants still have adverse long term neurodevelopmental outcomes, and there is pre-clinical evidence which suggests that this may be partly due to the pre-existence of infection at the time of the insult. Quantitative MR spectroscopy has been shown to predict long term outcomes after neonatal encephalopathy (NE). In particular, the concentration of N-acetylaspartate ([NAA]), a surrogate marker of neuronal integrity, discriminates between varying grades of long-term disability. Despite its promise, the gold standard approach to acquire [NAA] takes unfeasibly long to perform outside of a research environment. Though the method can be shortened, it is important to do so while maintaining precision so that it retains its value as a surrogate outcome in clinical trials. Aims In this project I aim to investigate the characteristics of brain injury in encephalopathic neonates throughout the first weeks of life, determining differences between infants with and without exposure to perinatal infection. To best achieve this, I aim to optimise the acquisition of [NAA] for widespread use on clinical scanners, alongside a state-of-the-art diffusion model of neuronal integrity (Neurite Orientation Dispersion and Density Imaging, NODDI) which will explain inter-subject variations. Methods The feasibility and accuracy of the shortened [NAA] acquisition scheme will be compared with the existing gold standard in a series of phantom studies, adult volunteers (n=10) and encephalopathic neonates (n=12). The optimised NAA and NODDI protocols will be implemented in 60 infants with NE at days 7 after birth, recruited from four centres in the UK and 1 centre in the US. In addition serial MR scanning (Day 1, 7, 30) will be performed on a subgroup of ~40 infants with neonatal encephalopathy. Benefit to patients and the NHS The close network of NHS Trusts in the MARBLE consortium will facilitate rapid translation of [NAA] as a feasible biomarker in leading neonatal units throughout the country. Once implemented, this can serve as an early surrogate endpoint in clinical trials which involve many centres. This has the potential to become a powerful platform for translational research throughout the NHS.

Lay abstract: Infants who suffer lack of blood and oxygen at birth are at high risk of long-term brain injury, and strong evidence suggests that therapies are less effective in babies who have been exposed to infection in the womb. Novel magnetic resonance techniques can predict the long-term outcomes of these babies, and I aim to investigate differences in brain injury throughout the first weeks after birth. In addition, I aim to deploy methods that can be used in neonatal units throughout the NHS, as a surrogate endpoint in neuroprotection clinical trials, thus enabling participation of hospitals without specialist MR physics expertise.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH