1st Supervisor: Po-Wah So, King’s College London
2nd Supervisor: Enrico De Vita, King’s College London
Clinical Champions: Catherine Williamson and Mary Rutherford, King’s College London
Additional Supervisors: Jo Hajnal and Jana Hutter, King’s College London
Aim of the PhD Project:
- Development of a novel non-invasive robust and reliable methodology, incorporating effective motion correction, using both MRI and MR Spectroscopy to quantify:
- fetal liver/placental fat content
- fetal adipose tissue
- Implementation of the optimised technique on a clinical population (intrahepatic cholestasis of pregnancy, ICP; gestational diabetes mellitus, GDM).
Project Description / Background:
A healthy placenta and uterine environment during the whole duration of pregnancy is essential for the healthy development of fetuses and the best neonatal outcomes. Ultrasound is the first and most accessible modality when potential pregnancy complications are suspected, followed by MRI where appropriate.
With the technical advances of the last 15 years, fetal MRI has grown into a robust modality able to provide unprecedented images of the fetal brain [Story 2018, Ferrazzi 2018], heart [Roy 2013, Lloyd 2018] and placenta [Hutter 2019] allowing the detection of structural and vascular abnormalities. However, in a number of situations, more invasive and potentially risky procedures such as amniocentesis or umbilical cord blood sampling are required.
Magnetic Resonance spectroscopy (MRS) allows regional non-invasive quantification of metabolites and neurotransmitter levels providing direct information on organ energetics and viability/development [Oz 2014]; it also allows accurate lipid quantification [Liimatainen 2006]. It is a widely used clinical and research tool in adults but rarely used prenatally as fetal MRS is challenging.
This is because, with the relatively small dimensions of fetal organs, acquisition times of 5-10 minutes are often necessary and motion sensitivity ensues; due to the commonly sustained fetal together with maternal respiration/bowel movements, using conventional MRS methodology the current success rate of fetal MRS is only 50-65% and few fetal MRS studies have been published.
Intrahepatic cholestasis of pregnancy (ICP) and gestational diabetes mellitus (GDM) are complications of pregnancy with a relatively high incidence of 0.5-2% and 3.5%, respectively. ICP is a metabolic disease of pregnancy that impairs bile acid homeostasis and is associated with impaired metabolic health (increased BMI and waist/hip girth) in the offspring. In mouse models, a severely obese, diabetic phenotype is observed in the offspring [Papacleovoulou 2013].
In both conditions maternal and fetal circulating glucose and lipid concentrations are elevated and increase the risk of pre-eclampsia. Pre-eclampsia results in newborns that are abnormally large for their gestational age; increased risk of preterm birth and the need for caesarean section. Further, offspring of women with GDM have higher than normal levels of subcutaneous fat at 2 years and increased risk of metabolic diseases [Rowan 2011].
Lipid levels in serum from umbilical blood collected after birth was demonstrated to be elevated in the offspring of mothers with ICP. Preclinical studies have also confirmed increased lipids in the placenta and fetal organs prenatally. As there are risks associated with cordocentesis, in vivo fetal/placental lipid measurements have not yet been demonstrated.
Having access to accurate fetal/placental lipid levels prenatally would allow determination of the role of maternal ICP/GDM on modulating fetal lipid metabolism, and also monitoring of interventions to attenuate ICP/GDM in the mother (e.g. with insulin, metaformin or recently proposed ursodeoxylic acid for GDM). This information will likely influence and improve pregnancy management.
Developing an effective methodology to measure fetal/placental lipid levels accurately will be the focus of this project.
We will develop a motion-robust MRS method, resilient to motion of the target anatomical volume of interest (VOI). This will be done by interleaving snapshot (400ms acquisition) low-resolution 3D dual-echo volume navigator images with MRS data collection occurring approximately every 2 seconds [Henningson 2014]. Using deep-learning algorithms for registration, the imaging data will provide information to track the organ of interest and with real-time feedback update the position of the VOI before each MRS dataset acquisition (and maintain it in the same anatomical position irrespective of motion). The dual-echo data will also produce field-map enabling ‘re-shimming’, i.e. to maintain the magnetic field within the VOI as homogenous as possible, hence minimising spectral linewidths and enhancing SNR and spectral resolvability/quantification accuracy [Bogner 2014].
With such methodology we aim to be able to produce a motion-robust fetal MRS acquisition allowing accurate lipid quantification in both fetal liver and placenta. MRI methods such as Dixon and IDEAL CPMG [Sinclair 2016] will also be used for whole-body fetal adipose tissue quantification.
Required candidate background: The candidate will have an academic background in Physics, Engineering, Maths or a similarly relevant subject with a strong interest in human development and aspiration to contribute to novel advances in diagnostic techniques.
- Bogner W, Gagoski B, Hess AT, Bhat H, Tisdall MD, van der Kouwe AJW, Strasser B, Marjańska M, Trattnig S, Grant E, Rosen B, Andronesi OC, 3D GABA imaging with real-time motion correction, shim update and reacquisition of adiabatic spiral MRSI, Neuroimage. 2014;103:290-302.
- Ferrazzi G, Price AN, Teixeira RPAG, Cordero-Grande L, Hutter J, Gomes A, Padormo F, Hughes E, Schneider T, Rutherford M, Kuklisova Murgasova M, Hajnal JV, An efficient sequence for fetal brain imaging at 3T with enhanced T1 contrast and motion robustness. Magn Reson Med. 2018 Jul;80(1):137-146.
- Henningsson M, Prieto C, Chiribiri A, Vaillant G, Razavi R, Botnar RM, Whole‐heart coronary MRA with 3D affine motion correction using 3D image‐based navigation, Magnetic resonance in medicine 2014, 71 (1), 173-181.
- Hutter J et al., Multi-modal functional MRI to explore placental function over gestation.Magn Reson Med. 2019;81(2):1191-1204.
- Liimatainen T et al., Identification of mobile cholesterol compounds in experimental gliomas by (1)H MRS in vivo: effects of ganciclovir-induced apoptosis on lipids. FEBS Lett. 2006;580(19):4746-50.
- Lloyd et al., Three-dimensional visualisation of the fetal heart using prenatal MRI with motion-corrected slice-volume registration, Lancet 2018, accepted, THELANCET=D-18-04346R1
- Morrow JM, Sinclair CD, Fischmann A, Machado PM, Reilly MM, Yousry TA, Thornton JS, Hanna MG, MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study. Lancet Neurol. 2016;15(1):65-77.
- Oz G et al., Clinical proton MR spectroscopy in central nervous system disorders. Radiology 2014 270(3):658-79.