The application of in utero magnetic resonance imaging in the study of the metabolic and cardiovascular consequences of the developmental origins of health and disease

Observing fetal development in utero is vital to further the understanding of later-life diseases. Magnetic resonance imaging (MRI) offers a tool for obtaining a wealth of information about fetal growth, development, and programming not previously available using other methods. This review provides an overview of MRI techniques used to investigate the metabolic and cardiovascular consequences of the developmental origins of health and disease (DOHaD) hypothesis. These methods add to the understanding of the developing fetus by examining fetal growth and organ development, adipose tissue and body composition, fetal oximetry, placental microstructure, diffusion, perfusion, flow, and metabolism. MRI assessment of fetal growth, organ development, metabolism, and the amount of fetal adipose tissue could give early indicators of abnormal fetal development. Noninvasive fetal oximetry can accurately measure placental and fetal oxygenation, which improves current knowledge on placental function. Additionally, measuring deficiencies in the placenta\u27s transport of nutrients and oxygen is critical for optimizing treatment. Overall, the detailed structural and functional information provided by MRI is valuable in guiding future investigations of DOHaD

Combined Diffusion-Relaxometry MRI to Identify Dysfunction in the Human Placenta

Purpose: A combined diffusion-relaxometry MR acquisition and analysis pipeline for in-vivo human placenta, which allows for exploration of coupling between T2* and apparent diffusion coefficient (ADC) measurements in a sub 10 minute scan time. Methods: We present a novel acquisition combining a diffusion prepared spin-echo with subsequent gradient echoes. The placentas of 17 pregnant women were scanned in-vivo, including both healthy controls and participants with various pregnancy complications. We estimate the joint T2*-ADC spectra using an inverse Laplace transform. Results: T2*-ADC spectra demonstrate clear quantitative separation between normal and dysfunctional placentas. Conclusions: Combined T2*-diffusivity MRI is promising for assessing fetal and maternal health during pregnancy. The T2*-ADC spectrum potentially provides additional information on tissue microstructure, compared to measuring these two contrasts separately. The presented method is immediately applicable to the study of other organs

Placental abnormalities and hypertension in pregnancy

Preeclampsia is a significant and common complication of pregnancy, with characteristic signs of hypertension and proteinuria. Current theories postulate a role for altered placental perfusion as a consequence of abnormal placental development in the aetiology of preeclampsia. Animal models of human preeclampsia have shown that an imbalance of the inflammatory cytokine TNF-α leads to a similar maternal phenotype as seen with a surgical reduction of placental perfusion pressure. This suggests a role for the inflammatory response in generating the maternal signs of hypertension and proteinuria. Currently, there is no direct link showing that a cytokine imbalance (specifically increased TNF-) affects placental development in such a way as to result in altered blood flow. The ability to detect morphological changes and alterations in blood flow in experimental models of preeclampsia would provide a significant boost in our understanding of the syndrome. The aim of this study was to develop an “imbalance in pro-inflammatory cytokine (TNF-α)” experimental mouse model of preeclampsia and to utilize magnetic resonance imaging (MRI) for visualization of placental anatomy and for the analysis of changes in tissue morphology and function including blood flow and perfusion. Secondly, this study aimed to examine the relationship between; an imbalance in inflammatory cytokines; changes in placental markers involved in inflammation, hypoxia and pH homeostasis; and changes in blood flow in the aetiology of the maternal hypertensive response. Pregnant C57BL/6JArc mice were subject to either reduced utero-placental perfusion (RUPP), subcutaneous infusion of the inflammatory cytokine TNF-α, or control procedures. Blood pressure was measured by either tail cuff sphygmomanometry or by telemetry. Urine was collected to measure proteinuria and blood was collected to measure levels of the anti-angiogenic molecule soluble fms-like tyrosine kinase 1 (sFlt-1), a biomarker of the human disease. MRI images were acquired on anaesthetised mice on day 17 of gestation using a Bruker Avance 11.7 Tesla wide-bore spectrometer. Quantitative analysis of changes in T2 relaxation measurements were carried out by using Matlab™ to generate R2 (i.e., 1/T2) maps from the acquired T2 measurement data, with the T2 values being calculated from selected regions of interest. Additional high resolution MRI images were acquired on formalin fixed, Magnevist™ contrast agent infused placenta. Placentas were harvested on day 17 of pregnancy, either formalin fixed and paraffin embedded for histology or snap frozen for proteomics and genomics. Histology was performed on sections using either Haematoxylin and Eosin (H&E) or Periodic acid-Schiff (PAS) stains. Immunohistochemistry using secondary anti rabbit horse radish peroxidise linked polymer and visualising with DAB, or quantitative immunofluorescent histochemistry using Alexa 488 goat anti-rabbit IgG was performed using primary antibodies to Cytokeratin (trophoblast marker), HIF-1a (Hypoxia inducible transcription factor 1), CLIC-3 (chloride intracellular channel 3; Cl-/H+ co-transporter) and TLR-3 and TLR-4 (Toll-like receptor 3 and 4). Quantitative PCR (qPCR) was used to measure mRNA expression of mFlt-1, sFlt-1, hif-1, tlr-3, tlr-4, clic-3 and clic-4 in placental tissue. This thesis demonstrates that infusion of the inflammatory cytokine (TNF-α) is an experimental model for hypertension and proteinuria in murine pregnancy. Hypertension in the RUPP model was not definitively confirmed despite the proteinuria. No increase in sFlt-1 above the constitutively high levels of normal pregnancy was detected in the maternal serum of either model, suggesting sFlt-1 is not a reliable marker for disease in the mouse model. This thesis demonstrates that that morphologically distinct regions of the mouse placenta can be detected and quantified by MRI. Mapping of T2 relaxation times ,which are attenuated by both hypoxia (increased levels of deoxyhaemoglobin) and acidosis (increase in free protons), indicate contrast between regions which is is lost when blood flow ceases. Similar decrease in contrast is detected upon T2 mapping in the placentas of both the artificially reduced perfusion (RUPP) and imbalance of inflammatory cytokines (TNF-α) experimental models. Immunohistochemistry and qPCR detected increases in the presence of molecules involved in response to both inflammation (TLR-3 and TLR-4) and changes in oxygen (HIF-1α) and pH (CLIC-3) levels in placentas from animals subject to either TNF-α infusion or RUPP. These results demonstrate for the first time that morphological differences or abnormalities related to blood flow can be detected by T2 mapping in the placenta of mice subject to experimental models of preeclampsia and may be used to analyse changes quantitatively. This technology has the potential to be used when studying the dynamic changes in the placenta of pregnancies complicated by preeclampsia. Analysis of the MRI images suggests changes involve both increases in deoxyhaemoglobin (hypoxia) and decreases in intracellular pH (acidosis) and suggests that pH dependent mechanisms may be as equally important as hypoxia in the perturbed placenta. The results also indicate that the metabolic changes in the placenta in response to both decreased blood flow and TNF-α infusion involve upregulation of both TLR-3 and TLR-4 protein expression and upregulation of HIF-1α mRNA and protein. Alterations in expression and localisation of the H+/Cl- co transporter CLIC-3 was demonstrated in the placenta after TNF-α infusion, consistent with the metabolic change observed by MRI. Inflammation-driven changes in both oxygen and pH-dependent signalling pathways are thus implicated in alterations of the complex metabolic pathways of homeostasis and angiogenesis in the placenta that lead to the subsequent maternal hypertensive response

The effects of maternal position, in late gestation pregnancy, on placental blood flow and oxygenation: An MRI study

KEY POINTS: Maternal supine sleep position in late pregnancy is associated with an increased risk of stillbirth. Maternal supine position in late pregnancy reduces maternal cardiac output and uterine blood flow. Using MRI, this study shows that compared to the left lateral position, maternal supine position in late pregnancy is associated with reduced uteroplacental blood flow, oxygen transfer across the placenta with an average 6.2% reduction in oxygen delivery to the fetus and an average 11% reduction in fetal umbilical venous blood flow. ABSTRACT: Maternal sleep position in late gestation is associated with an increased risk of stillbirth though the pathophysiological reasons for this are unclear. Studies using MRI have shown that compared with lateral positions, lying supine causes a reduction in cardiac output, reduced abdominal aortic blood flow and reduced vena caval flow which is only partially compensated for by increased flow in the azygos venous system. Using functional MRI techniques, including an acquistion termed Diffusion-Relaxation Combined Imaging of the Placenta (DECIDE), which combines diffusion weighted imaging and T2 relaxometry, blood flow and oxygen transfer were estimated in the maternal, fetal and placental compartments when subjects were scanned both supine and in left lateral positions. In late gestation pregnancy, lying supine caused a 23.7% (p <0.0001) reduction in total internal iliac arterial blood flow to the uterus. In addition, lying in the supine position caused a 6.2% (p = 0.038) reduction in oxygen movement across the placenta. The reductions in oxygen transfer to the fetus, termed delivery flux, of 11.2% (p = 0.0597) and in fetal oxygen saturation of 4.4% (p = 0.0793) did not reach statistical significance. It is concluded that even in healthy late gestation pregnancy, maternal position significantly affects oxygen transfer across the placenta and may in part provide an explanation for late stillbirth in vulnerable fetuses. This article is protected by copyright. All rights reserved

Spatiotemporal alignment of in utero BOLD-MRI series

Purpose: To present a method for spatiotemporal alignment of in-utero magnetic resonance imaging (MRI) time series acquired during maternal hyperoxia for enabling improved quantitative tracking of blood oxygen level-dependent (BOLD) signal changes that characterize oxygen transport through the placenta to fetal organs. Materials and Methods: The proposed pipeline for spatiotemporal alignment of images acquired with a single-shot gradient echo echo-planar imaging includes 1) signal nonuniformity correction, 2) intravolume motion correction based on nonrigid registration, 3) correction of motion and nonrigid deformations across volumes, and 4) detection of the outlier volumes to be discarded from subsequent analysis. BOLD MRI time series collected from 10 pregnant women during 3T scans were analyzed using this pipeline. To assess pipeline performance, signal fluctuations between consecutive timepoints were examined. In addition, volume overlap and distance between manual region of interest (ROI) delineations in a subset of frames and the delineations obtained through propagation of the ROIs from the reference frame were used to quantify alignment accuracy. A previously demonstrated rigid registration approach was used for comparison. Results: The proposed pipeline improved anatomical alignment of placenta and fetal organs over the state-of-the-art rigid motion correction methods. In particular, unexpected temporal signal fluctuations during the first normoxia period were significantly decreased (P < 0.01) and volume overlap and distance between region boundaries measures were significantly improved (P < 0.01). Conclusion: The proposed approach to align MRI time series enables more accurate quantitative studies of placental function by improving spatiotemporal alignment across placenta and fetal organs.National Institutes of Health (NIH) . Grant Numbers: U01 HD087211 , R01 EB017337 Consejeria de Educacion, Juventud y Deporte de la Comunidad de Madrid (Spain) through the Madrid-MIT M+Vision Consortium

Mri Methods For Imaging The Feto-Placental Vasculature And Blood

Fetal magnetic resonance imaging (MRI) in recent times has become a well-established adjunct to ultrasound (US) in routine clinical prenatal care and diagnostics. The majority of fetal MRI is restricted to T2-weighted scans, where the diagnosis is based on the appearance of normal and abnormal tissue. Although there have been many advancements in MRI and a plethora of sequences, that probe different anatomical and different physiological process, the adaptation of these in fetal imaging has been rather slow. Many of these can extract quantitative parameters that can throw light on the underlying tissue’s normal/patho-physiology. But the use of such quantitative MRI methods has been extremely limited in fetal imaging due to its unique and dynamic physiological milieu that pose several technical challenges including low signal to noise and/or resolution, artifacts associated with abdominal imaging and most importantly fetal motion. These limitations are expected to be overcome by (a) optimizing and (b) developing novel MR imaging sequences, both of which constitute the primary aim of my work. This work develops a framework that allows for vascular imaging in the fetus and placenta. This includes both qualitative vascular imaging and blood flow quantification. Towards this, three broad directions were explored (a) Moving to higher field imaging, while optimizing parameters for low energy deposition and (b) application of non-gated phase contrast MRI and (c) optimization of conventional time-of-flight angiography for fetal applications

Strategic research agenda for biomedical imaging

This Strategic Research Agenda identifies current challenges and needs in healthcare, illustrates how biomedical imaging and derived data can help to address these, and aims to stimulate dedicated research funding efforts. Medicine is currently moving towards a more tailored, patient-centric approach by providing personalised solutions for the individual patient. Innovation in biomedical imaging plays a key role in this process as it addresses the current needs for individualised prevention, treatment, therapy response monitoring, and image-guided surgery. The use of non-invasive biomarkers facilitates better therapy prediction and monitoring, leading to improved patient outcomes. Innovative diagnostic imaging technologies provide information about disease characteristics which, coupled with biological, genetic and -omics data, will contribute to an individualised diagnosis and therapy approach. In the emerging field of theranostics, imaging tools together with therapeutic agents enable the selection of best treatments and allow tailored therapeutic interventions. For prenatal monitoring, the use of innovative imaging technologies can ensure an early detection of malfunctions or disease. The application of biomedical imaging for diagnosis and management of lifestyle-induced diseases will help to avoid disease development through lifestyle changes. Artificial intelligence and machine learning in imaging will facilitate the improvement of image interpretation and lead to better disease prediction and therapy planning. As biomedical imaging technologies and analysis of existing imaging data provide solutions to current challenges and needs in healthcare, appropriate funding for dedicated research is needed to implement the innovative approaches for the wellbeing of citizens and patients.</p