Magnetic resonance imaging of placental intralobule structure and function in a preclinical nonhuman primate model†.

Although the central role of adequate blood flow and oxygen delivery is known, the lack of optimized imaging modalities to study placental structure has impeded our understanding of its vascular function. Magnetic resonance imaging is increasingly being applied in this field, but gaps in knowledge remain, and further methodological developments are needed. In particular, the ability to distinguish maternal from fetal placental perfusion and the understanding of how individual placental lobules are functioning are lacking. The potential clinical benefits of developing noninvasive tools for the in vivo assessment of blood flow and oxygenation, two key determinants of placental function, are tremendous. Here, we summarize a number of structural and functional magnetic resonance imaging techniques that have been developed and applied in animal models and studies of human pregnancy over the past decade. We discuss the potential applications and limitations of these approaches. Their combination provides a novel source of contrast to allow analysis of placental structure and function at the level of the lobule. We outline the physiological mechanisms of placental T2 and T2* decay and devise a model of how tissue composition affects the observed relaxation properties. We apply this modeling to longitudinal magnetic resonance imaging data obtained from a preclinical pregnant nonhuman primate model to provide initial proof-of-concept data for this methodology, which quantifies oxygen transfer and placental structure across and between lobules. This method has the potential to improve our understanding and clinical management of placental insufficiency once validation in a larger nonhuman primate cohort is complete.

Effects of early daily alcohol exposure on placental function and fetal growth in a rhesus macaque model.

BACKGROUND: Prenatal alcohol exposure is the most common cause of birth defects and intellectual disabilities and can increase the risk of stillbirth and negatively impact fetal growth. OBJECTIVE: To determine the effect of early prenatal alcohol exposure on nonhuman primate placental function and fetal growth. We hypothesized that early chronic prenatal alcohol would alter placental perfusion and oxygen availability that adversely affects fetal growth. STUDY DESIGN: Rhesus macaques self-administered 1.5 g/kg/d of ethanol (n=12) or isocaloric maltose-dextrin (n=12) daily before conception through the first 60 days of gestation (term is approximately 168 days). All animals were serially imaged with Doppler ultrasound to measure fetal biometry, uterine artery volume blood flow, and placental volume blood flow. Following Doppler ultrasound, all animals underwent both blood oxygenation level-dependent magnetic resonance imaging to characterize placental blood oxygenation and dynamic contrast-enhanced magnetic resonance imaging to quantify maternal placental perfusion. Animals were delivered by cesarean delivery for placental collection and fetal necropsy at gestational days 85 (n=8), 110 (n=8), or 135 (n=8). Histologic and RNA-sequencing analyses were performed on collected placental tissue. RESULTS: Placental volume blood flow was decreased at all gestational time points in ethanol-exposed vs control animals, but most significantly at gestational day 110 by Doppler ultrasound (P<.05). A significant decrease in total volumetric blood flow occurred in ethanol-exposed vs control animals on dynamic contrast-enhanced magnetic resonance imaging at both gestation days 110 and 135 (P<.05); moreover, a global reduction in T2∗, high blood deoxyhemoglobin concentration, occurred throughout gestation (P<.05). Similarly, evidence of placental ischemic injury was notable by histologic analysis, which revealed a significant increase in microscopic infarctions in ethanol-exposed, not control, animals, largely present at middle to late gestation. Fetal biometry and weight were decreased in ethanol-exposed vs control animals, but the decrease was not significant. Analysis with RNA sequencing suggested the involvement of the inflammatory and extracellular matrix response pathways. CONCLUSION: Early chronic prenatal alcohol exposure significantly diminished placental perfusion at mid to late gestation and also significantly decreased the oxygen supply to the fetal vasculature throughout pregnancy, these findings were associated with the presence of microscopic placental infarctions in the nonhuman primate. Although placental adaptations may compensate for early environmental perturbations to fetal growth, placental blood flow and oxygenation were reduced, consistent with the evidence of placental ischemic injury.

Maternal high-fat diet reversal improves placental hemodynamics in a nonhuman primate model of diet-induced obesity.

BACKGROUND: In a Japanese macaque model of diet-induced obesity, we have previously demonstrated that consumption of a high-fat, "Western-style" diet (WSD) is associated with placental dysfunction and adverse pregnancy outcomes, independent of an obese maternal phenotype. Specifically, we have reported decreased uterine placental blood flow and increased inflammation with maternal WSD consumption. We also previously investigated the use of a promising therapeutic intervention that mitigated the adverse placental effects of a WSD but had unexpected detrimental effects on fetal pancreatic development. Thus, the objective of the current study was to determine whether simple preconception diet reversal (REV) would improve placental function. METHODS: Female Japanese macaques were divided into three groups: REV animals (n = 5) were switched from a chronic WSD (36% fat) to a low fat, CON diet (14% fat) prior to conception and throughout pregnancy. The CON (n = 6) and WSD (n = 6) cohorts were maintained on their respective diets throughout pregnancy. Maternal body weight and composition were regularly assessed and advanced noninvasive imaging was performed at midgestation (gestational day 90, G90, or 0.5 of gestation, where full term is G175), and G129, 1 day prior to C-section delivery at G130 (0.75 of gestation). Imaging studies comprised Doppler ultrasound (US), contrast-enhanced US, and dynamic contrast-enhanced magnetic resonance imaging to assess uteroplacental hemodynamics and maternal-side placental perfusion. RESULTS: Dietary intervention resulted in significant maternal weight loss prior to pregnancy, and improved lean to fat mass ratio. By advanced imaging we demonstrated that a chronic WSD led to decreased blood flow velocity in the intervillous space, delayed blood flow transfer through the maternal spiral arteries, and reduced total placental blood flow compared to CON fed animals. Dietary reversal ameliorated these concerning derangements, restoring these hemodynamic parameters to CON levels. CONCLUSIONS: Preconception dietary modification has beneficial effects on the maternal metabolic phenotype, and results in improved placental hemodynamics.

First trimester alcohol exposure alters placental perfusion and fetal oxygen availability affecting fetal growth and development in a non-human primate model.

BACKGROUND: Prenatal alcohol exposure leads to impaired fetal growth, brain development, and stillbirth. Placental impairment likely contributes to these adverse outcomes, but the mechanisms and specific vasoactive effects of alcohol that links altered placental function to impaired fetal development remain areas of active research. OBJECTIVE: Recently, we developed magnetic resonance imaging techniques in nonhuman primates to characterize placental blood oxygenation through measurements of T2* and perfusion using dynamic contrast-enhanced magnetic resonance imaging. The objective of this study was to evaluate the effects of first-trimester alcohol exposure on macaque placental function and to characterize fetal brain development in vivo. STUDY DESIGN: Timed-pregnant Rhesus macaques (n=12) were divided into 2 groups: control (n=6) and ethanol exposed (n=6). Animals were trained to self-administer orally either 1.5 g/kg/d of a 4% ethanol solution (equivalent to 6 drinks/d) or an isocaloric control fluid from preconception until gestational day 60 (term is G168). All animals underwent Doppler ultrasound scanning followed by magnetic resonance imaging that consisted of T2* and dynamic contrast-enhanced measurements. Doppler ultrasound scanning was used to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. After noninvasive imaging, animals underwent cesarean delivery for placenta collection and fetal necropsy at gestational day 110 (n=6) or 135 (n=6). RESULTS: Fetal weight and biparietal diameter were significantly smaller in ethanol-exposed animals compared with control animals at gestational day 110. By Doppler ultrasound scanning, placental volume blood flow was significantly lower (P=.04) at gestational day 110 in ethanol-exposed vs control animals. A significant reduction in placental blood flow was evident by dynamic contrast-enhanced magnetic resonance imaging. As we demonstrated recently, T2* values vary throughout the placenta and reveal gradients in blood deoxyhemoglobin concentration that range from highly oxygenated blood (long T2*) proximal to spiral arteries to highly deoxygenated blood (short T2*). Distributions of T2*throughout the placenta show significant global reduction in T2* (and hence high blood deoxyhemoglobin concentration) in ethanol-exposed vs control animals at gestational day 110 (P=.02). Fetal brain measurements indicated impaired growth and development at gestational day 110, but less so at gestational day 135 in ethanol-exposed vs control animals. CONCLUSION: Chronic first-trimester ethanol exposure significantly reduces placental perfusion and oxygen supply to the fetal vasculature later in pregnancy. These perturbations of placental function are associated with fetal growth impairments. However, differences between ethanol-exposed and control animals in placental function and fetal developmental outcomes were smaller at gestational day 135 than at gestational day 110. These findings are consistent with placental adaptation to early perturbations that allow for compensated placental function and maintenance of fetal growth.

A novel approach to tracer-kinetic modeling for (macromolecular) dynamic contrast-enhanced MRI.

PURPOSE: To develop a novel tracer-kinetic modeling approach for multi-agent dynamic contrast-enhanced MRI (DCE-MRI) that facilitates separate estimation of parameters characterizing blood flow and microvascular permeability within one individual. METHODS: Monte Carlo simulations were performed to investigate the performance of the constrained multi-agent model. Subsequently, multi-agent DCE-MRI was performed on tumor-bearing mice (n = 5) on a 7T Bruker scanner on three measurement days, in which two dendrimer-based contrast agents having high and intermediate molecular weight, respectively, along with gadoterate meglumine, were sequentially injected within one imaging session. Multi-agent data were simultaneously fit with the gamma capillary transit time model. Blood flow, mean capillary transit time, and bolus arrival time were constrained to be identical between the boluses, while extraction fractions and washout rate constants were separately determined for each agent. RESULTS: Simulations showed that constrained multi-agent model regressions led to less uncertainty and bias in estimated tracer-kinetic parameters compared with single-bolus modeling. The approach was successfully applied in vivo, and significant differences in the extraction fraction and washout rate constant between the agents, dependent on their molecular weight, were consistently observed. CONCLUSION: A novel multi-agent tracer-kinetic modeling approach that enforces self-consistency of model parameters and can robustly characterize tumor vascular status was demonstrated.

Gadolinium Chelate Contrast Material in Pregnancy: Fetal Biodistribution in the Nonhuman Primate.

PURPOSE: To determine the extent to which gadolinium chelate is found in nonhuman primate fetal tissues and amniotic fluid at 19-45 hours after intravenous injection of a weight-appropriate maternal dose of the contrast agent gadoteridol. MATERIALS AND METHODS: Gravid Japanese macaques (n = 14) were maintained as approved by the institutional animal care and utilization committee. In the 3rd trimester of pregnancy, the macaques were injected with gadoteridol (0.1 mmol per kilogram of maternal weight). Fetuses were delivered by means of cesarean section within 24 hours of maternal injection (range, 19-21 hours; n = 11) or 45 hours after injection (n = 3). Gadolinium chelate levels in the placenta, fetal tissues, and amniotic fluid were obtained by using inductively coupled plasma mass spectrometry. The Wilcoxon rank sum test was used for quantitative comparisons. RESULTS: Gadoteridol was present in the fetoplacental circulation at much lower quantities than in the mother. At both time points, the distribution of gadolinium chelate in the fetus was comparable to that expected in an adult. The highest concentration of the injected dose (ID) was found in the fetal kidney (0.0161% ID per gram in the 19-21-hour group). The majority of the in utero gadolinium chelate was found in the amniotic fluid and the placenta (mean, 0.1361% ID per organ ± 0.076 [standard deviation] and 0.0939% ID per organ ± 0.0494, respectively). Data acquired 45 hours after injection showed a significant decrease in the gadolinium chelate concentration in amniotic fluid compared with that in the 19-21-hour group (from 0.0017% to 0.0007% ID per gram; P = .01). CONCLUSION: Amounts of gadolinium chelate in the fetal tissues and amniotic fluid were minimal compared with the maternal ID. This may impact future clinical studies on the safety of gadolinium contrast agent use in pregnancy.

Using dynamic contrast-enhanced MRI to quantitatively characterize maternal vascular organization in the primate placenta.

PURPOSE: The maternal microvasculature of the primate placenta is organized into 10-20 perfusion domains that are functionally optimized to facilitate nutrient exchange to support fetal growth. This study describes a dynamic contrast-enhanced magnetic resonance imaging method for identifying vascular domains and quantifying maternal blood flow in them. METHODS: A rhesus macaque on the 133rd day of pregnancy (G133, term = 165 days) underwent Doppler ultrasound procedures, dynamic contrast-enhanced magnetic resonance imaging and Cesarean-section delivery. Serial T1 -weighted images acquired throughout intravenous injection of a contrast reagent bolus were analyzed to obtain contrast reagent arrival time maps of the placenta. RESULTS: Watershed segmentation of the arrival time map identified 16 perfusion domains. The number and location of these domains corresponded to anatomical cotyledonary units observed following delivery. Analysis of the contrast reagent wave front through each perfusion domain enabled determination of volumetric flow, which ranged from 9.03 to 44.9 mL/s (25.2 ± 10.3 mL/s). These estimates are supported by Doppler ultrasound results. CONCLUSIONS: The dynamic contrast-enhanced magnetic resonance imaging analysis described here provides quantitative estimates of the number of maternal perfusion domains in a primate placenta and estimates flow within each domain. Anticipated extensions of this technique are to the study placental function in non-human primate models of obstetric complications.

Cluster analysis of DCE-MRI data identifies regional tracer-kinetic changes after tumor treatment with high intensity focused ultrasound.

Evaluation of high intensity focused ultrasound (HIFU) treatment with MRI is generally based on assessment of the non-perfused volume from contrast-enhanced T1-weighted images. However, the vascular status of tissue surrounding the non-perfused volume has not been extensively investigated with MRI. In this study, cluster analysis of the transfer constant K(trans) and extravascular extracellular volume fraction ve , derived from dynamic contrast-enhanced MRI (DCE-MRI) data, was performed in tumor tissue surrounding the non-perfused volume to identify tumor subregions with distinct contrast agent uptake kinetics. DCE-MRI was performed in CT26.WT colon carcinoma-bearing BALB/c mice before (n = 12), directly after (n = 12) and 3 days after (n = 6) partial tumor treatment with HIFU. In addition, a non-treated control group (n = 6) was included. The non-perfused volume was identified based on the level of contrast enhancement. Quantitative comparison between non-perfused tumor fractions and non-viable tumor fractions derived from NADH-diaphorase histology showed a stronger agreement between these fractions 3 days after treatment (R(2) to line of identity = 0.91) compared with directly after treatment (R(2) = 0.74). Next, k-means clustering with four clusters was applied to K(trans) and ve parameter values of all significantly enhanced pixels. The fraction of pixels within two clusters, characterized by a low K(trans) and either a low or high ve , significantly increased after HIFU. Changes in composition of these clusters were considered to be HIFU induced. Qualitative H&E histology showed that HIFU-induced alterations in these clusters may be associated with hemorrhage and structural tissue disruption. Combined microvasculature and hypoxia staining suggested that these tissue changes may affect blood vessel functionality and thereby tumor oxygenation. In conclusion, it was demonstrated that, in addition to assessment of the non-perfused tumor volume, the presented methodology gives further insight into HIFU-induced effects on tumor vascular status. This method may aid in assessment of the consequences of vascular alterations for the fate of the tissue.

Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates.

OBJECTIVE: We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in nonhuman primates, and maternal vitamin C supplementation attenuates these deleterious effects. However, the effect of nicotine on placental perfusion and development is not fully understood. This study utilizes noninvasive imaging techniques and histological analysis in a nonhuman primate model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development but is ameliorated by vitamin C. STUDY DESIGN: Time-mated macaques (n = 27) were divided into 4 treatment groups: control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), and nicotine plus vitamin C (n = 9). Nicotine animals received 2 mg/kg per day of nicotine bitartrate (approximately 0.7 mg/kg per day free nicotine levels in pregnant human smokers) from days 26 to 160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100, or 250 mg/kg per day with or without nicotine. All underwent placental dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at 135-140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. Animals were delivered by cesarean delivery at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology. RESULTS: Placental volume blood flow was significantly reduced in nicotine-only animals compared with controls and nicotine plus vitamin C groups (P = .03). Maternal placental blood flow was not different between experimental groups by DCE-MRI, ranging from 0.75 to 1.94 mL/mL per minute (P = .93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (P < .05) and increased syncytiotrophoblast sprouting (P < .001) in nicotine-only animals, which was mitigated by vitamin C. CONCLUSION: Prenatal nicotine exposure significantly decreased fetal blood supply via reduced placental volume blood flow, which corresponded with placental histological findings previously associated with cigarette smoking. Vitamin C supplementation mitigated the harmful effects of prenatal nicotine exposure on placental hemodynamics and development, suggesting that its use may limit some of the adverse effects associated with smoking during pregnancy.

Impaired placental hemodynamics and function in a non-human primate model of gestational protein restriction.

Maternal malnutrition increases fetal and neonatal morbidity, partly by affecting placental function and morphology, but its impact on placental hemodynamics are unknown. Our objective was to define the impact of maternal malnutrition on placental oxygen reserve and perfusion in vivo in a rhesus macaque model of protein restriction (PR) using advanced imaging. Animals were fed control (CON, 26% protein), 33% PR diet (17% protein), or a 50% PR diet (13% protein, n = 8/group) preconception and throughout pregnancy. Animals underwent Doppler ultrasound and fetal biometry followed by MRI at gestational days 85 (G85) and 135 (G135; term is G168). Pregnancy loss rates were 0/8 in CON, 1/8 in 33% PR, and 3/8 in 50% PR animals. Fetuses of animals fed a 50% PR diet had a smaller abdominal circumference (G135, p < 0.01). On MRI, placental blood flow was decreased at G135 (p < 0.05) and placental oxygen reserve was reduced (G85, p = 0.05; G135, p = 0.01) in animals fed a 50% PR diet vs. CON. These data demonstrate that a 50% PR diet reduces maternal placental perfusion, decreases fetal oxygen availability, and increases fetal mortality. These alterations in placental hemodynamics may partly explain human growth restriction and stillbirth seen with severe PR diets in the developing world.

A unified impulse response model for DCE-MRI.

We describe the gamma capillary transit time model, a generalized impulse response model for DCE-MRI that mathematically unifies the Tofts-Kety, extended Tofts-Kety, adiabatic tissue homogeneity, and two-compartment exchange models. By including a parameter (α⁻¹) representing the width of the distribution of capillary transit times within a tissue voxel, the GCTT model discriminates tissues having relatively monodisperse transit time distributions from those having a large degree of heterogeneity. All five models were compared using in vivo data acquired in three brain tumors (one glioblastoma multiforme, one pleomorphic xanthoastrocytoma, and one anaplastic meningioma) and Monte Carlo simulations. Our principal findings are : (1) The four most commonly used models for dynamic contrast-enhanced magnetic resonance imaging can be unified within a single formalism. (2) Application of the GCTT model to in vivo data incurs only modest penalties in parameter uncertainty and computational cost. (3) Measured nonparametric impulse response functions in human brain tumors are well described by the GCTT model. (4) Estimation of α⁻¹ is feasible but achieving statistical significance requires higher SNR than is typically obtained in single voxel dynamic contrast-enhanced magnetic resonance imaging data. These results suggest that the GCTT model may be useful for extraction of information about tumor physiology beyond what is obtained using current modeling methodologies.

Myocardial perfusion acquisition without magnetization preparation or gating.

Current myocardial perfusion MRI acquisitions are performed with a saturation recovery sequence, in large part to minimize sensitivity to arrhythmia. A new approach is proposed here where the images are acquired ungated at steady state without use of a saturation pulse. The data are acquired continuously and reach steady state after the first few images. A confluence of advances has made this new paradigm of an ungated steady-state acquisition possible-very rapid undersampled readouts with new reconstruction technologies permit enough measurements that continuous acquisition becomes a feasible approach. Gating can be applied retrospectively from a logged electrocardiogram (ECG) or with self-gating methods. In this work, simulations and measurements in a concentration phantom are used to demonstrate that similar contrast and signal can be obtained with the standard saturation recovery and the proposed spoiled gradient echo (SPGR) acquisition. Specifically, for a flip angle of 14° and a saturation recovery time of 80 ms, similar signals are acquired over a range of T(1) s that reflect realistic myocardial tissue concentrations. Preliminary results in one subject are presented to show the potential of this new approach. The method may allow for cine cardiac perfusion and more signal-to-noise ratio-efficient acquisitions.

Myocardial perfusion MRI with an undersampled 3D stack-of-stars sequence.

PURPOSE: To determine the feasibility of three-dimensional (3D) hybrid radial (stack-of-stars) MRI with spatiotemporal total variation (TV) constrained reconstruction for dynamic contrast enhanced myocardial perfusion imaging. METHODS: An ECG-triggered saturation recovery turboFLASH sequence with undersampled stack-of-stars sampling with spatiotemporal TV constrained reconstruction was developed for dynamic contrast enhanced myocardial perfusion imaging. Simulations were performed to study the dependence of the approach to steady state on flip angle and saturation recovery time for this stack-of-stars acquisition. Phantom studies were used to show the effect of the flip angle selection and imperfect spoiling on image qualities. Studies were done in three humans to test the feasibility of the approach for myocardial perfusion imaging. RESULTS: The simulation and phantom studies showed that imperfect spoiling and magnetization changes during the readout were a function of flip angle and nonoptimized selection of flip angle could degrade the images. Low flip angle acquisitions in the human subjects result in images with good quality similar to multislice radial 2D images. CONCLUSIONS: 3D stack-of-stars sampling with spatiotemporal TV constrained reconstruction provides a promising alternative for myocardial perfusion imaging.

Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model.

Cannabis use in pregnancy is associated with adverse perinatal outcomes, which are likely mediated by the placenta. However, the underlying mechanisms and specific vasoactive effects of cannabis on the placenta are unknown. Our objective was to determine the impact of chronic prenatal delta-tetrahydrocannabinol (THC, main psychoactive component of cannabis) exposure on placental function and development in a rhesus macaque model using advanced imaging. Animals were divided into two groups, control (CON, n = 5) and THC-exposed (THC, n = 5). THC-exposed animals received a THC edible daily pre-conception and throughout pregnancy. Animals underwent serial ultrasound and MRI at gestational days 85 (G85), G110, G135 and G155 (full term is ~ G168). Animals underwent cesarean delivery and placental collection at G155 for histologic and RNA-Seq analysis. THC-exposed pregnancies had significantly decreased amniotic fluid volume (p < 0.001), placental perfusion (p < 0.05), and fetal oxygen availability (p < 0.05), all indicators of placental insufficiency. Placental histological analysis demonstrated evidence of ischemic injury with microinfarctions present in THC-exposed animals only. Bulk RNA-seq demonstrated that THC alters the placental transcriptome and pathway analysis suggests dysregulated vasculature development and angiogenesis pathways. The longer-term consequences of these adverse placental findings are unknown, but they suggest that use of THC during pregnancy may deleteriously impact offspring development.

Quantitative longitudinal T2* mapping for assessing placental function and association with adverse pregnancy outcomes across gestation.

Existing methods for evaluating in vivo placental function fail to reliably detect pregnancies at-risk for adverse outcomes prior to maternal and/or fetal morbidity. Here we report the results of a prospective dual-site longitudinal clinical study of quantitative placental T2* as measured by blood oxygen-level dependent magnetic resonance imaging (BOLD-MRI). The objectives of this study were: 1) to quantify placental T2* at multiple time points across gestation, and its consistency across sites, and 2) to investigate the association between placental T2* and adverse outcomes. 797 successful imaging studies, at up to three time points between 11 and 38 weeks of gestation, were completed in 316 pregnancies. Outcomes were stratified into three groups: (UN) uncomplicated/normal pregnancy, (PA) primary adverse pregnancy, which included hypertensive disorders of pregnancy, birthweight <5th percentile, and/or stillbirth or fetal death, and (SA) secondary abnormal pregnancy, which included abnormal prenatal conditions not included in the PA group such as spontaneous preterm birth or fetal anomalies. Of the 316 pregnancies, 198 (62.6%) were UN, 70 (22.2%) PA, and 48 (15.2%) SA outcomes. We found that the evolution of placental T2* across gestation was well described by a sigmoid model, with T2* decreasing continuously from a high plateau level early in gestation, through an inflection point around 30 weeks, and finally approaching a second, lower plateau in late gestation. Model regression revealed significantly lower T2* in the PA group than in UN pregnancies starting at 15 weeks and continuing through 33 weeks. T2* percentiles were computed for individual scans relative to UN group regression, and z-scores and receiver operating characteristic (ROC) curves calculated for association of T2* with pregnancy outcome. Overall, differences between UN and PA groups were statistically significant across gestation, with large effect sizes in mid- and late- pregnancy. The area under the curve (AUC) for placental T2* percentile and PA pregnancy outcome was 0.71, with the strongest predictive power (AUC of 0.76) at the mid-gestation time period (20-30 weeks). Our data demonstrate that placental T2* measurements are strongly associated with pregnancy outcomes often attributed to placental insufficiency. Trial registration: ClinicalTrials.gov: NCT02749851.

Constrained estimation of the arterial input function for myocardial perfusion cardiovascular magnetic resonance.

Accurate quantification of myocardial perfusion remains challenging due to saturation of the arterial input function at high contrast concentrations. A method for estimating the arterial input function directly from tissue curves in the myocardium that avoids these difficulties is presented. In this constrained alternating minimization with model (CAMM) algorithm, a portion of the left ventricular blood pool signal is also used to constrain the estimation process. Extensive computer simulations assessing the accuracy of kinetic parameter estimation were performed. In 5000 noise realizations, the use of the AIF given by the estimation method returned kinetic parameters with mean Ktrans error of -2% and mean kep error of 0.4%. Twenty in vivo resting perfusion datasets were also processed with this method, and pharmacokinetic parameter values derived from the blind AIF were compared with those derived from a dual-bolus measured AIF. For 17 of the 20 datasets, there were no statistically significant differences in Ktrans estimates, and in aggregate the kinetic parameters were not significantly different from the dual-bolus method. The cardiac constrained alternating minimization with model method presented here provides a promising approach to quantifying perfusion of myocardial tissue with a single injection of contrast agent and without a special pulse sequence though further work is needed to validate the approach in a clinical setting.

Towards the rational design of MRI contrast agents: δ-substitution of lanthanide(III) NB-DOTA-tetraamide chelates influences but does not control coordination geometry.

LnDOTA-tetraamide chelates (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) have received considerable recent attention as a result of their potential to act as PARACEST contrast agents for magnetic resonance imaging (MRI). Although PARACEST agents afford several advantages over conventional contrast agents they suffer from substantially higher detection limits; thus, improving the effectiveness of LnDOTA-tetraamide chelates is an important goal. In this study we investigate the potential to extend conformational control of LnDOTA-type ligands to those applicable to PARACEST. Furthermore, the question of whether δ- rather than α-substitution of the pendant arms could be used to control the chelate coordination geometry is addressed. Although δ-substitution does influence coordination geometry it does not afford control. However, it can play an important role in governing the conformation of the amide substituent relative to the chelate in such as way that suggests a PARACEST agent could be designed that has detection limits at least as low as a conventional MRI contrast agent.

Imaging Epigenetics of Prenatal THC.

Prenatal exposure to marijuana may lead to epigenetic alterations in the placenta and fetal brain, affecting short- and long-term offspring health. This Viewpoint addresses the critical need to study and characterize the impact of maternal marijuana use and consequences of in utero exposure on later development and health. We highlight the development of new PET imaging tools and the opportunity for longitudinal in vivo non-human primate studies to help elucidate epigenetic changes resulting from prenatal marijuana exposure throughout gestation.

Toward local arterial input functions in dynamic contrast-enhanced MRI.

PURPOSE: To present a method for estimating the local arterial input function (AIF) within a dynamic contrast-enhanced MRI scan, based on the alternating minimization with model (AMM) method. MATERIALS AND METHODS: This method clusters a subset of data into representative curves, which are then input to the AMM algorithm to return a parameterized AIF and pharmacokinetic parameters. Computer simulations are used to investigate the accuracy with which the AMM is able to estimate the true AIF as a function of the input tissue curves. RESULTS: Simulations show that a power law relates uncertainty in kinetic parameters and SNR and heterogeneity of the input. Kinetic parameters calculated with the measured AIF are significantly different from those calculated with either a global (P < 0.005) or a local input function (P = 0.0). The use of local AIFs instead of measured AIFs yield mean lesion-averaged parameter changes: K(trans): +24% [+15%, +70%], k(ep): +13% [-36%, +300%]. Globally estimated input functions yield mean lesion-averaged changes: K(trans): +9% [-38%, +65%], k(ep): +13% [-100%, +400%]. The observed improvement in fit quality with local AIFs was found to be significant when additional free parameters were accounted for using the Akaike information criterion. CONCLUSION: Local AIFs result in significantly different kinetic parameter values. The statistically significant improvement in fit quality suggests that changes in parameter estimates using local AIFs reflect differences in underlying tissue physiology.

Reconstruction of 3D dynamic contrast-enhanced magnetic resonance imaging using nonlocal means.

PURPOSE: To develop and test a nonlocal means-based reconstruction algorithm for undersampled 3D dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of tumors. MATERIALS AND METHODS: We propose a reconstruction technique that is based on the recently proposed nonlocal means (NLM) filter which can relax trade-offs in spatial and temporal resolutions in dynamic imaging. Unlike the original application of NLM for image denoising, the MR reconstruction framework here can offer high-quality images from undersampled k-space data. The method is based on enforcing similarity constraints in terms of neighborhoods of pixels rather than individual pixels. The method was applied on undersampled 3D DCE imaging of breast and brain tumor datasets and the results were compared to sliding window reconstructions and to a compressed sensing method using total variation constraints on the images. RESULTS: Undersampling factors of up to five were obtained with the proposed approach while preserving the spatial and temporal characteristics. The NLM reconstruction method offered improved performance over the sliding window and the total variation constrained reconstruction techniques. CONCLUSION: The reconstruction framework here can give high-quality images from undersampled DCE MRI data and has the potential to improve the quality of DCE tumor imaging.