Quantifying Brain Myelin Water Fraction in a Guinea Pig Model of Spontaneous Intrauterine Growth Restriction.

BACKGROUND: Intrauterine growth restriction (IUGR) is an obstetrical condition where a fetus has not achieved its genetic potential. A consequence of IUGR is a decrease in brain myelin content. Myelin water imaging (MWI) has been used to assess fetal myelin water fraction (MWF) and might potentially assess myelination changes associated with IUGR. PURPOSE: To quantify and compare the MWF of non-IUGR and IUGR fetal guinea pigs (GPs) in late gestation. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Dunkin-Hartley GP model of spontaneous IUGR (mean ± SD: 60 ± 1.2 days gestation; 19 IUGR, 52 control). FIELD STRENGTH/SEQUENCE: Eight spoiled gradient-recalled (SPGR) gradient echo volumes (flip angles [α]: 2°-16°), and two sets of eight balanced steady-state free precession (bSSFP) gradient echo volumes (α: 8° - 64°), at 0° and 180° phase increments, at 3.0 T. ASSESSMENT: MWF maps were generated for each fetal GP brain using multicomponent driven equilibrium single pulse observation of T1 /T2 (mcDESPOT). MWF was quantified in the fetal corpus callosum (CC), fornix (FOR), parasagittal white matter (PSW), and whole fetal brain. STATISTICAL TESTS: Linear regression was performed between five fetal IUGR markers (body volume, body-to-pregnancy volume ratio, brain-to-liver volume ratio, brain-to-placenta volume ratio, and brain-to-body volume ratio) and MWF (coefficient of determination, R2 ). A t-test with a linear mixed model compared the MWF of non-IUGR and IUGR fetal GPs (significance was determined at α < 0.05). RESULTS: The MWF of the control fetuses are (mean ± SD): 0.23 ± 0.02 (CC), 0.31 ± 0.02 (FOR), 0.28 ± 0.02 (PSW), and 0.20 ± 0.01 (whole brain). The MWF of the IUGR fetuses are (mean ± SD): 0.19 ± 0.02 (CC), 0.27 ± 0.01 (FOR), 0.24 ± 0.03 (PSW), and 0.16 ± 0.01 (whole brain). Significant differences in MWF were found between the non-IUGR and IUGR fetuses in every comparison. DATA CONCLUSION: The mean MWF of IUGR fetal GPs is significantly lower than non-IUGR fetal GPs. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Feasibility of MRI Quantification of Myelin Water Fraction in the Fetal Guinea Pig Brain.

BACKGROUND: Fetal myelination assessment is important for understanding neurodevelopment and neurodegeneration. Myelin water imaging (MWI) quantifies myelin water fraction (MWF), a validated marker for myelin content, and has been used to assess brain myelin in children and neonates. PURPOSE: To demonstrate that MWI can quantify MWF in fetal guinea pigs (GPs). STUDY TYPE: Animal model. ANIMAL MODEL: Nine pregnant, Dunkin-Hartley GPs with 31 fetuses (mean ± standard deviation = 60 ± 1.5 days gestation). FIELD STRENGTH/SEQUENCE: 3D spoiled gradient echo and balanced steady-state free precession sequences at 3.0 T. ASSESSMENT: MWF maps were reconstructed for maternal and fetal GP brains using the multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) approach. Myelin basic protein (MBP) stain provided histological validation of the MWF. Regions of interest were placed in the maternal corpus callosum (CC), maternal fornix (FOR), fetal CC, and fetal FOR in MWF maps and MBP stains. STATISTICAL TESTS: Linear regression between MWF and MBP stain intensity (SI) of all four regions (coefficient of determination, R2 ). A paired t-test compared the MWF of maternal and mean fetal CC, MBP SI of maternal and mean fetal CC, MWF of maternal and mean fetal FOR, MBP SI of maternal and mean fetal FOR. A paired t-test with a linear mixed model compared the MWF of fetal CC and fetal FOR, and MBP SI of fetal CC and fetal FOR. A  P value < 0.0083 was considered statistically significant. RESULTS: The mean MWF of the analyzed regions are as follows (mean ± standard deviation): 0.338 + 0.016 (maternal CC), 0.340 ± 0.017 (maternal FOR), 0.214 ± 0.016 (fetal CC), and 0.305 ± 0.025 (fetal FOR). MWF correlated with MBP SI in all regions (R2  = 0.81). Significant differences were found between MWF and MBP SI of maternal and fetal CC, and MWF and MBP SI of fetal CC and fetal FOR. DATA CONCLUSION: This study demonstrated the feasibility of MWI in assessing fetal brain myelin content. EVIDENCE LEVEL: 2 Technical Efficacy: Stage 1.

In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1-13 C]Pyruvate and Proton Density Fat Fraction in a Guinea Pig Model of Non-Alcoholic Fatty Liver Disease Development After Life-Long Western Diet Consumption.

BACKGROUND: Alterations in glycolysis are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non-invasive technologies to understand the development of hepatic metabolic aberrations. PURPOSE: To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) magnetic resonance imaging (MRI) techniques to investigate the effects of a chronic, life-long exposure to the Western diet (WD) in an animal model resulting in NAFLD; to investigate the hypothesis that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. STUDY TYPE: Prospective. ANIMAL MODEL: Twenty-eight male guinea pigs weaned onto a control diet (N = 14) or WD (N = 14). FIELD STRENGTH/SEQUENCE: 3 T; T1-weighted gradient echo, T2-weighted spin-echo, three-dimensional gradient multi-echo fat-water separation (IDEAL-IQ), and broadband point-resolved spectroscopy (PRESS) chemical-shift sequences. ASSESSMENT: Median PDFF was calculated in the liver and hind limbs. [1-13 C]pyruvate dynamic MRS in the liver was quantified by the time-to-peak (TTP) for each metabolite. Animals were euthanized and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity. STATISTICAL TESTS: Unpaired Student's t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. RESULTS: Life-long WD consumption resulted in significantly higher liver PDFF and elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. DATA CONCLUSION: PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD characteristic of lean, or lacking excessive subcutaneous fat, NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD-exposed livers. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Optimizing SNR for multi-metabolite hyperpolarized carbon-13 MRI using a hybrid flip-angle scheme.

PURPOSE: To improve the SNR of hyperpolarized carbon-13 MRI of [1-13 C]pyruvate using a multispectral variable flip angle (msVFA) scheme in which the spectral profile and flip angle vary dynamically with time. METHODS: Each image acquisition in a time-resolved imaging experiment used a unique spectrally varying RF pulse shape for msVFA. Therefore, the flip angle for every acquisition was optimized for pyruvate and each of its metabolites to yield the highest SNR across the acquisition. Multispectral VFA was compared with a spectrally varying constant flip-angle excitation model through simulations and in vivo. A modified broadband chemical shift-encoded gradient-echo sequence was used for in vivo experiments on six pregnant guinea pigs. Regions of interest placed in the placentae, maternal liver, and maternal kidneys were used as areas for SNR measurement. RESULTS: In vivo experiments showed significant increases in SNR for msVFA relative to constant flip angle of up to 250% for multiple metabolites. CONCLUSION: Hyperpolarized carbon-13 imaging with msVFA excitation produces improved SNR for all metabolites in organs of interest.

Quantification of fetal organ volume and fat deposition following in utero exposure to maternal Western Diet using MRI.

PURPOSE: To examine the feasibility of using MRI to identify differences in liver size and fat deposition in fetal guinea pigs exposed to an in utero environment influenced by maternal consumption of a Western diet. MATERIALS AND METHODS: Female guinea pigs fed either an energy-dense Western Diet (WD), comprised of increased saturated fats and simple sugars, or a Control Diet (CD) from weaning through pregnancy, underwent MR scanning near term (~ 60 days; term ~ 69 days). Maternal weights were collected at mating and at MR scanning. T1-weighted, T2-weighted, and IDEAL water-fat images were acquired at 3 Tesla. The images were used to segment maternal adipose tissue, fetal liver, fetal brain, fetal adipose tissue, and total fetal volumes and to measure maternal and fetal hepatic fat fractions. RESULTS: Weights of WD sows were lower prior to pregnancy (P = .04), however their weight gain over pregnancy did not differ from the CD group (P = .98). The WD sows had less total adipose tissue (TAT) at MR scanning (P = .04), while hepatic fat content was significantly elevated (P = .04). When controlling for litter size, WD fetuses had larger livers (P = .02), smaller brains (P = .01), and increased total adipose tissue volume (P = .01) when normalized by fetal volume. The WD fetuses also had increased hepatic fat fractions compared to CD fetal livers (P < .001). CONCLUSION: Maternal Western Diet consumption prior to and during pregnancy induces differences in maternal liver fat content, fetal liver volume and liver fat storage, as well as changes in fetal adipose tissue deposition that can be measured in utero using MRI.

Hyperpolarized [1-(13) C]pyruvate MRI for noninvasive examination of placental metabolism and nutrient transport: A feasibility study in pregnant guinea pigs.

PURPOSE: To test the feasibility of hyperpolarized [1-(13) C]pyruvate magnetic resonance imaging (MRI) for noninvasive examination of guinea pig fetoplacental metabolism and nutrient transport. MATERIALS AND METHODS: Seven pregnant guinea pigs with a total of 30 placentae and fetuses were anesthetized and scanned at 3T. T1 -weighted (1) H images were obtained from the maternal abdomen. An 80 mM solution of hyperpolarized [1-(13) C]pyruvate (hereafter referred to as pyruvate) was injected into a vein in the maternal foot. Time-resolved 3D (13) C images were acquired starting 10 seconds after the beginning of bolus injection and every 10 seconds after to 50 seconds. The pregnant guinea pigs were recovered after imaging. Regions of interest (ROIs) were drawn around the maternal heart and each placenta and fetal liver in all slices in the (1) H images. These ROIs were copied to the (13) C images and were used to calculate the sum of the pyruvate and lactate signal intensities for each organ. The signal intensities were normalized by the volume of the organ and the maximum signal in the maternal heart. RESULTS: No adverse events were observed in the pregnant guinea pigs and natural pupping occurred at term (∼68 days). Pyruvate signal was observed in all 30 placentae, and lactate, a by-product of pyruvate metabolism, was also observed in all placentae. The maximum pyruvate and lactate signals in placentae occurred at 20 seconds. In addition to the observation of pyruvate and lactate signals in the placentae, both pyruvate and lactate signals were observed in all fetal livers. The maximum pyruvate and lactate signals in the fetal livers occurred at 10 seconds and 20 seconds, respectively. CONCLUSION: This work demonstrates the feasibility of using hyperpolarized [1-(13) C]pyruvate MRI to noninvasively examine fetoplacental metabolism and transport of pyruvate in guinea pigs. Hyperpolarized (13) C MRI may provide a novel method for longitudinal studies of fetoplacental abnormalities.

Hyperpolarized choline as an MR imaging molecular probe: feasibility of in vivo imaging in a rat model.

PURPOSE: To assess the feasibility of choline MRI using a new choline molecular probe for dynamic nuclear polarization (DNP) hyperpolarized MRI. MATERIALS AND METHODS: Male Sprague-Dawley rats with an average weight of 400 ± 20 g (n = 5), were anesthetized and injection tubing was placed in the tail vein. [1,1,2,2-D4 , 1-(13) C]choline chloride (CMP1) was hyperpolarized by DNP and injected into rats at doses ranging from 12.6 to 50.0 mg/kg. Coronal projection (13) C imaging was performed on a 3 Tesla clinical MRI scanner (bore size 60 cm) using a variable flip angle gradient echo sequence. Images were acquired 15 to 45 s after the start of bolus injection. Signal intensities in regions of interest were determined at each time point and compared. RESULTS: (13) C MRI images of hyperpolarized CMP1 at a 50 mg/kg dose showed time-dependent organ distribution patterns. At 15 s, high intensities were observed in the inferior vena cava, heart, aorta, and kidneys. At 30 s, most of the signal intensity was localized to the kidneys. These distribution patterns were reproduced using 12.6 and 25 mg/kg doses. At 45 s, only signal in the kidneys was detected. CONCLUSION: Hyperpolarized choline imaging with MRI is feasible using a stable-isotope labeled choline analog (CMP1). Nonradioactive imaging of choline accumulation may provide a new investigatory dimension for kidney physiology. J. Magn. Reson. Imaging 2015;41:917-923. © 2014 Wiley Periodicals, Inc.

Chemical shift encoded imaging of hyperpolarized (13) C pyruvate.

PURPOSE: To demonstrate a reconstruction technique for separating signal from different hyperpolarized carbon-13 metabolites. METHODS: A reconstruction method is described for chemical shift encoded separation of the signal from pyruvate and its downstream metabolites. This method uses consistency of the data with the signal model rather than an additional free-induction decay (FID) acquisition to estimate the B0 offset. Compressed sensing was also integrated into the reconstruction allowing reconstruction of metabolite images from undersampled datasets. The performance of the reconstruction was assessed using thermal phantoms, digital phantoms, and in vivo hyperpolarized [1-(13) C] pyruvate experiments. RESULTS: Thermal and digital phantoms indicate that metabolite separation is feasible given Signal-to-noise ratio > 5 and an initial B0 offset estimate within -105 Hz to 90 Hz of the actual B0 offset. In vivo comparisons to an existing FID calibrated reconstruction show improved fidelity in regions with significant field map inhomogeneity provided that these field map variations are accounted for using an additional proton acquisition. Prospectively and retrospectively undersampled studies show acceleration factors of 2 are feasible using compressed sensing. CONCLUSION: A reconstruction framework for the separation of signal from pyruvate and its downstream metabolites is shown. This reconstruction eliminates the need to acquire additional calibration FID acquisition and allows acceleration through compressed sensing.

Fat fraction bias correction using T1 estimates and flip angle mapping.

PURPOSE: To develop a new method of reducing T1 bias in proton density fat fraction (PDFF) measured with iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL). MATERIALS AND METHODS: PDFF maps reconstructed from high flip angle IDEAL measurements were simulated and acquired from phantoms and volunteer L4 vertebrae. T1 bias was corrected using a priori T1 values for water and fat, both with and without flip angle correction. Signal-to-noise ratio (SNR) maps were used to measure precision of the reconstructed PDFF maps. PDFF measurements acquired using small flip angles were then compared to both sets of corrected large flip angle measurements for accuracy and precision. RESULTS: Simulations show similar results in PDFF error between small flip angle measurements and corrected large flip angle measurements as long as T1 estimates were within one standard deviation from the true value. Compared to low flip angle measurements, phantom and in vivo measurements demonstrate better precision and accuracy in PDFF measurements if images were acquired at a high flip angle, with T1 bias corrected using T1 estimates and flip angle mapping. CONCLUSION: T1 bias correction of large flip angle acquisitions using estimated T1 values with flip angle mapping yields fat fraction measurements of similar accuracy and superior precision compared to low flip angle acquisitions.