gadoxetic-acid-disodium and Disease-Models--Animal

To facilitate translational drug development for liver fibrosis, preclinical trials need to be run in parallel with clinical research. Liver function estimation by gadoxetate-enhanced dynamic contrast-enhanced MRI (DCE-MRI) is being established in clinical research, but still rarely used in preclinical trials. We aimed to evaluate feasibility of DCE-MRI indices as translatable biomarkers in a liver fibrosis animal model.. Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (200 mg, 150 mg, and saline for the high-dose, low-dose, and control groups, respectively). Subsequently, DCE-MRI was performed to measure: relative liver enhancement at 3-min (RLE-3), RLE-15, initial area-under-the-curve until 3-min (iAUC-3), iAUC-15, and maximum-enhancement (Emax). The correlation coefficients between these MRI indices and the histologic collagen area, indocyanine green retention at 15-min (ICG-R15), and shear wave elastography (SWE) were calculated. Diagnostic performance to diagnose liver fibrosis was also evaluated by receiver-operating-characteristic (ROC) analysis.. Animal model was successful in that the collagen area of the liver was the largest in the high-dose group, followed by the low-dose group and control group. The correlation between the DCE-MRI indices and collagen area was high for iAUC-15, Emax, iAUC-3, and RLE-3 but moderate for RLE-15 (r, - 0.81, - 0.81, - 0.78, - 0.80, and - 0.51, respectively). The DCE-MRI indices showed moderate correlation with ICG-R15: the highest for iAUC-15, followed by iAUC-3, RLE-3, Emax, and RLE-15 (r, - 0.65, - 0.63, - 0.62, - 0.58, and - 0.56, respectively). The correlation coefficients between DCE-MRI indices and SWE ranged from - 0.59 to - 0.28. The diagnostic accuracy of RLE-3, iAUC-3, iAUC-15, and Emax was 100% (AUROC 1.000), whereas those of RLE-15 and SWE were relatively low (AUROC 0.777, 0.848, respectively).. Among the gadoxetate-enhanced DCE-MRI indices, iAUC-15 and iAUC-3 might be bidirectional translatable biomarkers between preclinical and clinical research for evaluating histopathologic liver fibrosis and physiologic liver functions in a non-invasive manner.

Topics: Animals; Area Under Curve; Contrast Media; Disease Models, Animal; Drug Evaluation, Preclinical; Feasibility Studies; Gadolinium DTPA; Humans; Liver; Liver Cirrhosis; Liver Function Tests; Magnetic Resonance Imaging; Male; Rats; Rats, Sprague-Dawley; Thioacetamide

Melanocortin 4 receptor-deficient (MC4R-KO) mice fed a high-fat diet (HFD) develop liver pathology similar to human nonalcoholic steatohepatitis (NASH). However, although liver histology and blood biochemistry have been reported, hepatic function has not been evaluated. In the present study, we evaluated hepatic function in MC4R-KO mice fed an HFD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium‑ethoxybenzyl‑diethylenetriamine pentaacetic acid (Gd-EOB-DTPA).. Wild type (WT) mice and MC4R-KO mice were fed a standard diet (SD) or an HFD for 20 weeks. The hepatic signal intensity was obtained from DCE-MRI images, and relative enhancement (RE), the time to maximum RE (T. Histological analysis with nonalcoholic fatty liver disease activity score (NAS) revealed that MC4R-KO mice fed an HFD achieved the NAS of 5. There was moderate fibrosis in MC4R-KO mice fed an HFD. DCE-MRI with Gd-EOB-DTPA showed that T. MC4R-KO mice fed an HFD developed obesity and NASH. The liver kinetics of Gd-EOB-DTPA were significantly different in MC4R-KO mice fed an HFD from WT mice, and correlated with the histopathologic score. These results suggest that MC4R-KO mice fed an HFD mimic the hepatic pathology and liver function of human NASH, and therefore might be useful for the study of hepatic dysfunction during the fibrotic stage of NASH.

Topics: Animals; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Image Enhancement; Liver; Magnetic Resonance Imaging; Mice; Non-alcoholic Fatty Liver Disease; Receptor, Melanocortin, Type 4

Multimodality reporter gene imaging provides valuable, noninvasive information on the fate of engineered cell populations. To complement magnetic resonance imaging (MRI) measures of tumor volume and 2-dimensional reporter-based optical measures of cell viability, reporter-based MRI may offer 3-dimensional information on the distribution of viable cancer cells in deep tissues.. Here, we engineered human and murine triple-negative breast cancer cells with lentivirus encoding tdTomato and firefly luciferase for fluorescence imaging and bioluminescence imaging (BLI). A subset of these cells was additionally engineered with lentivirus encoding organic anion transporting polypeptide 1a1 (Oatp1a1) for MRI. Oatp1a1 operates by transporting gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) into cells, and it concomitantly improves BLI substrate uptake. After orthotopic implantation of engineered cells expressing or not expressing Oatp1a1, longitudinal fluorescence imaging, BLI, and 3-Tesla MRI were performed.. Oatp1a1-expressing tumors displayed significantly increased BLI signals relative to control tumors at all time points (P < 0.05). On MRI, post-Gd-EOB-DTPA T1-weighted images of Oatp1a1-expressing tumors exhibited significantly increased contrast-to-noise ratios compared with control tumors and precontrast images (P < 0.05). At endpoint, tumors expressing Oatp1a1 displayed intratumoral MR signal heterogeneity not present at earlier time points. Pixel-based analysis of matched in vivo MR and ex vivo fluorescence microscopy images revealed a strong, positive correlation between MR intensity and tdTomato intensity for Oatp1a1-expressing tumors (P < 0.05), but not control tumors.. These results characterize Oatp1a1 as a sensitive, quantitative, positive contrast MRI reporter gene for 3-dimensional assessment of viable cancer cell intratumoral distribution and concomitant BLI enhancement. This multimodality reporter gene system can provide new insights into the influence of viable cancer cell intratumoral distribution on tumor progression and metastasis, as well as improved assessments of anticancer therapies.

Topics: Animals; Breast Neoplasms; Cells, Cultured; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Humans; Image Enhancement; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Mice; Microscopy, Fluorescence; Organic Anion Transporters

Clinical studies have reported different results regarding the signal intensity (SI) increase in the dentate nucleus on unenhanced T1-weighted magnetic resonance imaging (MRI) after repeated administrations of gadolinium-based contrast agents (GBCAs). The aim of this study was to evaluate MRI SI changes and gadolinium (Gd) brain concentrations in an animal model after repeated administration of liver-specific linear gadoxetate in comparison to multipurpose linear and macrocyclic GBCAs. Recently, it was demonstrated that small amounts of GBCAs are able to cross the blood-cerebrospinal fluid (CSF) barrier. Therefore, a secondary aim was to test if the administration of these GBCAs directly into the CSF results in a similar MRI pattern and brain Gd concentration than after systemic intravenous injection.. Forty-eight Han-Wistar rats were equally divided into the following 4 groups: gadoxetate (liver-specific linear), gadodiamide (multipurpose linear), gadobutrol (multipurpose macrocyclic), and control (saline, artificial CSF). For systemic application, 6 animals per group received 8 intravenous injections on 4 consecutive days per week over 2 weeks using a dose of 0.15 mmol/kg for gadoxetate and 0.6 mmol/kg for multipurpose GBCAs per injection, which corresponds to the recommended clinical dose in humans. For CSF application, 6 animals per group received one intracisternal administration of 0.31 μmol Gd (gadoxetate) and 1.25 μmol Gd (multipurpose GBCAs) or an equal volume of artificial CSF. Brain MRI was performed after a period of 5 weeks to evaluate the SI in deep cerebellar nuclei (DCN) and brain stem. Subsequently, animals were euthanized and their brains were dissected for Gd quantification by inductively coupled plasma-mass spectrometry.. Visually evident increased SIs in the DCN were observed in blinded image review only after administration of gadodiamide. The respective SI ratios between DCN and brain stem were significantly higher compared with the control groups (P = 0.009 and P = 0.002 for intravenous and intracisternal application, respectively), whereas no difference was found for gadoxetate and gadobutrol (P ≥ 0.9). Inductively coupled plasma-mass spectrometry revealed the lowest Gd content in the brain tissue after administration for gadoxetate. The mean Gd concentrations in the cerebellum were 0.08 nmol/g (gadoxetate), 2.66 nmol/g (gadodiamide), and 0.26 nmol/g (gadobutrol) after intravenous administration, and 0.28 nmol/g (gadoxetate), 3.23 nmol/g (gadodiamide), and 0.69 nmol/g (gadobutrol) after intracisternal application.. This rat study demonstrates distinct differences in the presence of gadolinium in the brain between the liver-specific linear gadoxetate and the multipurpose linear GBCA gadodiamide. No MRI signal alterations were observed after 8 dose-adapted intravenous or a single intracisternal administrations of gadoxetate and multipurpose macrocyclic gadobutrol. The Gd concentrations in the brain 5 weeks after intravenous administration of gadoxetate were an order of magnitude lower compared with gadodiamide and slightly lower than for gadobutrol. Likely reasons for these differences are the 4-fold lower dose, the dual excretion pathway, and the higher complex stability of gadoxetate compared with multipurpose linear GBCAs. The similar findings for both routes of GBCA administration underlines the assumption that the very small amount of GBCAs that cross the blood-CSF barrier is further transported into the brain tissue.

Topics: Animals; Brain; Contrast Media; Disease Models, Animal; Gadolinium; Gadolinium DTPA; Humans; Injections, Intravenous; Liver; Magnetic Resonance Imaging; Organometallic Compounds; Rats; Rats, Wistar

Objective To explore the ability of texture analysis of gadoxetic acid-enhanced magnetic resonance imaging (MRI) T1 mapping images, as well as T1-weighted (T1W), T2-weighted (T2W) and apparent diffusion coefficient (ADC) maps for distinguishing between varying degrees of hepatic fibrosis in an experimental rat model.Methods Liver fibrosis in rats was induced by carbon tetrachloride intraperitoneal injection for 4-12 weeks (n=30). In the control group (n=10) normal saline was applied. The MRI protocol contained T2W, diffusion weighted imaging, pre-and post-contrast image series of T1W and T1 mapping images. METAVIR score was used to grade liver fibrosis as normal (F0), mild fibrosis (F1-2), and advanced fibrosis (F3-4). Texture parameters including mean gray-level intensity (Mean), standard deviation (SD), Entropy, mean of positive pixels (MPP), Skewness, and Kurtosis were obtained. Nonparametric Mann-Whitney U test was used to compare the average value of each texture parameter in each sequence for assessing the difference between F0 and F≥1 as well as F0-2 and F3-4. Receiver operating characteristic (ROC) curves were obtained to assess the diagnosing accuracy of the parameters for differentiating no liver fibrosis from liver fibrosis and rats with liver fibrosis grading F0-2 from those with grading F3-4. The area under ROC curve (AUC) was calculated to evaluate the diagnostic efficiency of texture parameters.Results Finally, 20 rats completed MR T1 mapping image scan. The pathologic staging of these 20 rats was no fibrosis (F0, n=6), mild fibrosis (F1-2, n=5) and advanced fibrosis (F3-4, n=9). On pre-contrast T1 mapping image, Entropy was seen to be statistically significant higher in the F≥1 group than that in the F0 group at each spatial scaling factor (SSF) setting (P=0.015, 0.015, 0.015, 0.013, 0.015 and 0.018 respectively to SSF=0, 2, 3, 4, 5, 6), and Mean of the F≥1 rats was statistically significant higher than that of the F0 rats at SSF 4, 5, 6 (P=0.004, 0.006, and 0.013, respectively). Entropy and Mean showed a moderate diagnostic performance in most SSF settings of T1 mapping pre-contrast images for differentiation of normal liver from liver fibrosis.Conclusions Certain texture features of gadoxetic acid-enhanced MR images, especially the Entropy of non-contrast T1 mapping image, was found to be a useful biomarker for the diagnosis of liver fibrosis.

Topics: Animals; Contrast Media; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Gadolinium DTPA; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley

The goals of this study were to compare the efficacy of the new manganese-based magnetic resonance imaging (MRI) contrast agent Mn-PyC3A to the commercial gadolinium-based agents Gd-DOTA and to Gd-EOB-DTPA to detect tumors in murine models of breast cancer and metastatic liver disease, respectively, and to quantify the fractional excretion and elimination of Mn-PyC3A in rats.. T1-weighted contrast-enhanced MRI with 0.1 mmol/kg Mn-PyC3A was compared with 0.1 mmol/kg Gd-DOTA in a breast cancer mouse model (n = 8) and to 0.025 mmol/kg Gd-EOB-DTPA in a liver metastasis mouse model (n = 6). The fractional excretion, 1-day biodistribution, and 7-day biodistribution in rats after injection of 2.0 mmol/kg [Mn]Mn-PyC3A or Gd-DOTA were quantified by Mn gamma counting or Gd elemental analysis. Imaging data were compared with a paired t test; biodistribution data were compared with an unpaired t test.. The postinjection-preinjection increases in tumor-to-muscle contrast-to-noise ratio (ΔCNR) 3 minutes after injection of Mn-PyC3A and Gd-DOTA (mean ± standard deviation) were 17 ± 3.8 and 20 ± 4.4, respectively (P = 0.34). Liver-to-tumor ΔCNR values at 8 minutes postinjection of Mn-PyC3A and Gd-EOB-DTPA were 28 ± 9.0 and 48 ± 23, respectively (P = 0.11). Mn-PyC3A is eliminated with 85% into the urine and 15% into the feces after administration to rats. The percentage of the injected doses (%ID) of Mn and Gd recovered in tissues after 1 day were 0.32 ± 0.12 and 0.57 ± 0.12, respectively (P = 0.0030), and after 7 days were 0.058 ± 0.051 and 0.19 ± 0.052, respectively (P < 0.0001).. Mn-PyC3A provides comparable tumor contrast enhancement to Gd-DOTA in a mouse breast cancer model and is more completely eliminated than Gd-DOTA; partial hepatobiliary elimination of Mn-PyC3A enables conspicuous delayed phase visualization of liver metastases.

Topics: Animals; Breast Neoplasms; Contrast Media; Diamines; Disease Models, Animal; Female; Gadolinium; Gadolinium DTPA; Heterocyclic Compounds; Image Enhancement; Liver Neoplasms; Magnetic Resonance Imaging; Manganese; Manganese Compounds; Mice; Mice, Inbred BALB C; Organometallic Compounds; Picolinic Acids; Tissue Distribution

To assess the value of T1ρ,T1ρ on hepatobiliary phase (HBP) and diffusion metrics in staging of Non-alcoholic fatty liver disease (NAFLD) activity scores, inflammation, fibrosis in NASH rabbits model. Non-alcoholic steatohepatitis (NASH) rabbits model was induced by feeding a varied duration of high-fat, high-cholesterol diet. T1ρ,T1ρ (HBP) 20min after administration of Gd-EOB-DTPA, and Intravoxel incoherent motion imaging (IVIM) diffusion-weighted imaging were performed on a 3.0T magnetic resonance (MR) imaging unit. The diagnostic value of each parameter for NAS, inflammation and fibrosis severity were determined. T1ρ (r=0.658) and T1ρ (HBP) (r=0.750) have strong association with NASH overall activity, T1ρ (HBP) is strongly relevant to inflammation stage (r=0.812). There was negative association between f and inflammation (r=-0.480), whilst no significant relation between other three parameters (apparent diffusion coefficient (ADC), pseudo-diffusion coefficient (D*) and true diffusion coefficient (D)) and inflammation or overall activity. The areas under the receiver operating characteristic curves (AUCs) of f, ADC, T1ρ and T1ρ-HBP were 0.871, 0.728, 0.849 and 0.949 for differentiating NASH; 0.731, 0.552, 0.925 and 0.922 for G2-3 inflammation; and 0.767, 0.625, 0.816, and 0.882 for S1-2 fibrosis. Comparison of ROC curve showed T1ρ (HBP) had an optimal diagnostic performance for NASH [T1ρ (HBP) vs ADC, AUC:0.949 vs 0.728, P=0.043], inflammation [T1ρ (HBP) vs ADC, AUC:0.922 vs 0.552, P=0.003], fibrosis [T1ρ (HBP) vs ADC, AUC:0.882 vs 0.625, P=0.046]. The combination of T1ρ (HBP)+perfusion fraction (f) showed highest diagnostic value for NASH (AUC:0.971), inflammation (AUC:0.935). Among T1ρ imaging and IVIM diffusion metrics, combination of T1rho (HBP)+f was found to be superior noninvasive imaging biomarker for NASH activity assessment.

Topics: Animals; Area Under Curve; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Gadolinium DTPA; Humans; Image Enhancement; Inflammation; Liver; Magnetic Resonance Imaging; Male; Non-alcoholic Fatty Liver Disease; Rabbits; ROC Curve

Changes in the expression of hepatocyte membrane transporters in advanced fibrosis decrease the hepatic transport function of organic anions. The aim of our study was to assess if these changes can be evaluated with pharmacokinetic analysis of the hepatobiliary transport of the MR contrast agent gadoxetate.. Dynamic gadoxetate-enhanced MRI was performed in 17 rats with advanced fibrosis and 8 normal rats. After deconvolution, hepatocyte three-compartmental analysis was performed to calculate the hepatocyte influx, biliary efflux and sinusoidal backflux rates. The expression of Oatp1a1, Mrp2 and Mrp3 organic anion membrane transporters was assessed with reverse transcription polymerase chain reaction.. In the rats with advanced fibrosis, the influx and efflux rates of gadoxetate decreased and the backflux rate increased significantly (p = 0.003, 0.041 and 0.010, respectively). Significant correlations were found between influx and Oatp1a1 expression (r = 0.78, p < 0.001), biliary efflux and Mrp2 (r = 0.50, p = 0.016) and sinusoidal backflux and Mrp3 (r = 0.61, p = 0.002).. These results show that changes in the bidirectional organic anion hepatocyte transport function in rats with advanced liver fibrosis can be assessed with compartmental analysis of gadoxetate-enhanced MRI.. • Expression of hepatocyte transporters is modified in rats with advanced liver fibrosis. • Kinetic parameters at gadoxetate-enhanced MRI are correlated with hepatocyte transporter expression. • Hepatocyte transport function can be assessed with compartmental analysis of gadoxetate-enhanced MRI. • Compartmental analysis of gadoxetate-enhanced MRI might provide biomarkers in advanced liver fibrosis.

Topics: Animals; Bile Ducts, Intrahepatic; Biomarkers; Carbon Tetrachloride; Case-Control Studies; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Hepatocytes; Image Processing, Computer-Assisted; Liver; Liver Cirrhosis; Magnetic Resonance Imaging; Male; Membrane Transport Proteins; Rats; Rats, Wistar

To clarify the development of HCC, temporal change of steatosis and Gd-EOB-DTPA enhancement of non-alcoholic steatohepatitis (NASH) model mice by magnetic resonance imaging (MRI).. All animal experiments were approved by the institution's Animal Research Committee. MRI was performed on six NASH and six simple steatosis (SS) model mice every 2weeks from the ages of 8weeks to 16weeks. The sequential changes in the number and size of the focal liver lesions detected on Gd-EOB-DTPA-enhanced MRI were evaluated. Additionally, the hepatic fat fraction (HFF), contrast-to-noise ratio (CNR) and relative enhancement (RE) were calculated at each time point. The temporal changes and correlations in these parameters were evaluated.. All alive NASH model mice demonstrated focal liver lesions from week 10, at the latest. Number of the lesions increased with time, and all the lesion enlarged with time. All the lesions larger than 1mm were confirmed as hepatocellular carcinoma (HCC) pathologically. While the HFF remained constant in NASH model mice, HFF in SS model mice dramatically increased with time. CNR of the NASH model mice remained constant through the study period, while CNR in SS model mice decreased with time. Although no correlation was seen in NASH model mice, the HFF showed a negative correlation against CNR and RE in SS model mice.. Development of HCC was observed using Gd-EOB-DTPA-enhanced MRI only in NASH model mice. Degree of steatosis and hepatic enhancement by Gd-EOB-DTPA was both constant in NASH model mice, while steatosis increased and hepatic enhancement decreased with time in SS model mice.

Topics: Animals; Animals, Newborn; Carcinoma, Hepatocellular; Contrast Media; Disease Models, Animal; Female; Gadolinium DTPA; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Streptozocin

To compare hepatobiliary phase (HBP) images obtained at 10 and 20 min after Gd-EOB-DTPA-enhanced MRI for assessment of liver function in rabbit fibrosis model on 3.0 T MR imaging.. 34 animals were separated into three groups: 5 for a control group, 14 for a mild fibrosis group, and 15 for a severe fibrosis group based on pathological proof. T1 relaxation times (T1rt) were measured on T1 mapping and reduction rates of T1rt (rrT1rt) were calculated. HBP images were obtained at 10 and 20 min after Gd-EOB-DTPA enhancement. Indocyanine green retention rates at 15 min (ICG R15) were performed for all animals.. T1rt on pre-enhancement imaging showed no significant difference (p > 0.05) among all groups. T1rt on 10 min HBP and 20 min HBP showed significant difference (p < 0.05) among all groups. T1rt and rrT1rt in three groups showed no-significant difference (p > 0.05) between 10 min HBP and 20 min HBP. T1rt on both 10 and 20 min HBP showed significant correlation with ICG R15 (p < 0.05); rrT1rt on both 10 min HBP and 20 min HBP showed significant inverse correlation with ICG R15 (p < 0.05).. Comparing 10 min HBP and 20 min HBP T1 mapping after Gd-EOB-DTPA enhancement, our results suggest that 10 min HBP T1 mapping is feasible for quantitatively assessing liver function.

Topics: Animals; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Image Enhancement; Image Processing, Computer-Assisted; Liver Cirrhosis; Liver Function Tests; Magnetic Resonance Imaging; Prospective Studies; Rabbits; Random Allocation; Time Factors

The purpose of this study is to investigate the correlation between the liver kinetics of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) and liver histopathology in a mouse model of NASH by using dynamic contrast-enhanced MRI.. Twenty male C57/BL6 mice aged 8weeks were fed a methionine-choline-deficient (MCD) diet for 2, 4 and 6weeks (MCD groups: MCD 2w, 4w, or 6w). Gd-EOB-DTPA-enhanced MR imaging of the liver was performed at 2, 4 and 6weeks after the MCD feeding. The signal intensity of the liver was obtained from dynamic MR images and relative enhancement (RE), and the time to maximum RE (Tmax) and half-life of elimination RE (T1/2) were calculated. After MRI scan, histopathological scores of hepatic steatosis and inflammation and blood biochemistry data, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were obtained.. Plasma AST and ALT levels were significantly increased in mice fed MCD. Histopathological scores indicated that steatohepatitis progressed with the MCD feeding period from 2 to 6weeks, but significant fibrosis was observed only in mice fed MCD for 6weeks. Gd-EOB-DTPA-enhanced MRI showed that Tmax was significantly prolonged in the livers of the 6-week group compared to the control group (control, 4.0±0.7min; MCD 6w, 12.1±1.6min), although there was no alteration in the 2- and 4-week groups. T1/2 was significantly prolonged in mice fed MCD for 4 and 6weeks compared to the control group (control, 19.9±2.0min; MCD 4w, 46.7±8.7min; MCD 6w, 65.4±8.8min). The parameters of Gd-EOB-DTPA kinetics (Tmax and T1/2) in the liver were positively correlated with the liver histopathological score (steatosis vs Tmax, rho=0.69, P=0.0007; inflammation vs Tmax, rho=0.66, P=0.00155; steatosis vs T1/2, rho=0.77, P<0.0001; inflammation vs T1/2, rho=0.73, P=0.0003).. The liver kinetics of Gd-EOB-DTPA correlated well with the inflammation score in the mouse model of NASH, suggesting the possibility of detecting the steatohepatitis stage without fibrosis by Gd-EOB-DTPA-enhanced MR imaging.

Topics: Animals; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Image Enhancement; Inflammation; Liver; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease

The aim of this study was to assess the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)-derived pharmacokinetic parameters between two contrast agents in a murine orthotopic pancreatic cancer model and to evaluate the tumor heterogeneity and the potential association between kinetic parameters and angiogenic markers such as the microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression by immunohistochemistry.. Human pancreatic adenocarcinoma cell line MIAPaCa-2 was injected into the pancreas of BALB/C nu/nu mice. DCE-MRI was performed using Gd-DTPA and Gd-EOB-DTPA. Quantitative and semi-quantitative vascular parameters (K(trans), Kep, Ve and AUC) were calculated by using a dedicated postprocessing software program. Values were compared with tumor rim, tumor core and the entire tumor. The MVD and VEGF expressions between tumor rim and tumor core were also compared.. There were no significant differences in K(trans), Kep, Ve, and AUC values of the three groups when using Gd-DTPA. However there were significant differences in K(trans), Kep, and AUC values of the three groups when using Gd-EOB-DTPA (P=0.014, 0.022, 0.007, respectively), in addition, the K(trans) and Kep values of tumor core were significantly lower than those of the entire tumor (adjusted P=0.014 and 0.027, respectively), the AUC values of core were significantly lower than those of the entire tumor and rim (adjusted P=0.039 and 0.009, respectively). Immunohistology results revealed that MVD and VEGF expression in the tumor rim was significantly higher than that in the core. There was positive correlation between AUC and MVD, VEGF.. The murine orthotopic pancreatic cancer model provides an ideal animal model to study human pancreatic cancer. It can more sensitively semi-quantitatively and quantitatively analyze tumor angiogenesis through selecting the albumin-binding contrast agent.

Topics: Animals; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Image Enhancement; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microvessels; Neovascularization, Pathologic; Pancreas; Pancreatic Neoplasms; Vascular Endothelial Growth Factor A

To evaluate the hepatocyte phase of Gd-EOB-DTPA-enhanced MRI in the early diagnosis of hepatic fibrosis and cirrhosis and assessment of liver function in a rat model.. In 2 groups of SD rats, liver fibrosis was induced in experimental animals by repetitive carbon tetrachloride injections, while the control group received saline injections. Five experimental rats and 2 control rats were randomly selected at weeks 4, 8, 12. One week after carbon tetrachloride administration, MRI (FIRM T1WI) scan was performed. Gd-EOB-DTPA (0.08mL) was injected into the rat's tail vein and hepatocyte phase images were obtained after 20min. The pre-enhanced phase and hepatocyte phase signal intensities (SI) were measured, and the relative contrast enhancement index (RCEI) was calculated. ANOVA analysis (LSD) of RCEI values in controls (n=6), hepatic fibrosis (n=7), and histopathologically-determined early cirrhosis group (n=6) was performed.. RECI values showed a decreasing trend in the control group, hepatic fibrosis and early cirrhosis groups (1.11±0.43, 0.96±0.22, and 0.57±0.33, respectively). While the difference between the control and early cirrhosis groups was statistically significant (p=0.013), there was no significant difference in the hepatic fibrosis group vs the control (p=0.416) and the hepatic fibrosis group vs the early cirrhosis group (p=0.054).. Hepatocyte phase RCEI values obtained with Gd-EOB-DTPA-enhanced MRI scan indicate liver injury in hepatic fibrosis and early cirrhosis. RCEI values are helpful for early diagnosis of liver cirrhosis.

Topics: Analysis of Variance; Animals; Carbon Tetrachloride; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Hepatocytes; Liver Cirrhosis; Liver Function Tests; Magnetic Resonance Imaging; Male; Rats; Rats, Sprague-Dawley; Time Factors

This study aimed to compare the performance of gadoxetic acid -enhanced magnetic resonance imaging (MRI) and sonoelastography in evaluating chemopreventive effects of Sho-Saiko-To (SST) in thioacetamide (TAA)-induced early liver fibrosis in rats.. Ten of Sprague-Dawley rats receiving TAA (200 mg/kg of body weight) intraperitoneal injection were divided into three groups: Group 1 (TAA only, n = 3), Group 2 (TAA +0.25 g/kg SST, n = 4) and Group 3 (TAA+1 g/kg SST, n = 3). Core needle liver biopsy at week 2 and liver specimens after sacrifice at week 6 confirmed liver fibrosis using histological examinations, including Sirius red staining, Ishak and Metavir scoring systems. Gadoxetic acid-enhanced MRI and shear-wave sonoelastography were employed to evaluate liver fibrosis. The expression of hepatic transporter organic anion transporter 1 (Oatp1), multidrug-resistant protein 2 (Mrp2) and alpha-smooth muscle actin (α-Sma) were also analyzed in each group by immunohistochemistry (IHC) and Western blot.. According to histological grading by Sirius red staining, Ishak scores of liver fibrosis in Groups 1, 2 and 3 were 3, 2 and 1, respectively. As shown in gadoxetic acid-enhanced MRI, the ratio of relative enhancement was significantly lower in Group 1 (1.87 ± 0.21) than in Group 2 of low-dose (2.82 ± 0.25) and Group 3 of high-dose (2.72 ± 0.12) SST treatment at 10 minutes after gadoxetic acid intravenous injection (p < 0.05). Sonoelastography showed that the mean difference before and after experiments in Groups 1, 2 and 3 were 4.66 ± 0.1, 4.4 ± 0.57 and 3 ± 0.4 KPa (p < 0.1), respectively. Chemopreventive effects of SST reduced the Mrp2 protein level (p < 0.01) but not Oatp1 and α-Sma levels.. Sonoelastography and gadoxetic acid-enhanced MRI could monitor the treatment effect of SST in an animal model of early hepatic fibrosis.

Topics: Animals; Biomarkers; Contrast Media; Disease Models, Animal; Drugs, Chinese Herbal; Elasticity Imaging Techniques; Gadolinium DTPA; Immunoenzyme Techniques; Liver Cirrhosis; Liver Function Tests; Magnetic Resonance Imaging; Male; Plant Extracts; Rats; Rats, Sprague-Dawley; Thioacetamide; Tissue Distribution

The cholangiopathies are a diverse group of biliary tract disorders, many of which lack effective treatment. Murine models are an important tool for studying their pathogenesis, but existing noninvasive methods for assessing biliary disease in vivo are not optimal. Here we report our experience with using micro-computed tomography (microCT) and nuclear magnetic resonance (MR) imaging to develop a technique for live-mouse cholangiography. Using mdr2 knockout (mdr2KO, a model for primary sclerosing cholangitis (PSC)), bile duct-ligated (BDL), and normal mice, we performed in vivo: (1) microCT on a Siemens Inveon PET/CT scanner and (2) MR on a Bruker Avance 16.4 T spectrometer, using Turbo Rapid Acquisition with Relaxation Enhancement, IntraGate Fast Low Angle Shot, and Half-Fourier Acquisition Single-shot Turbo Spin Echo methods. Anesthesia was with 1.5-2.5% isoflurane. Scans were performed with and without contrast agents (iodipamide meglumine (microCT), gadoxetate disodium (MR)). Dissection and liver histology were performed for validation. With microCT, only the gallbladder and extrahepatic bile ducts were visualized despite attempts to optimize timing, route, and dose of contrast. With MR, the gallbladder, extra-, and intrahepatic bile ducts were well-visualized in mdr2KO mice; the cholangiographic appearance was similar to that of PSC (eg, multifocal strictures) and could be improved with contrast administration. In BDL mice, MR revealed cholangiographically distinct progressive dilation of the biliary tree without ductal irregularity. In normal mice, MR allowed visualization of the gallbladder and extrahepatic ducts, but only marginal visualization of the diminutive intrahepatic ducts. One mouse died during microCT and MR imaging, respectively. Both microCT and MR scans could be obtained in ≤20 min. We, therefore, demonstrate that MR cholangiography can be a useful tool for longitudinal studies of the biliary tree in live mice, whereas microCT yields suboptimal duct visualization despite requiring contrast administration. These findings support further development and application of MR cholangiography to the study of mouse models of PSC and other cholangiopathies.

Topics: Animals; Bile Duct Diseases; Cholangiography; Contrast Media; Disease Models, Animal; Female; Gadolinium DTPA; Magnetic Resonance Imaging; Male; Mice; X-Ray Microtomography

To evaluate hyperintense Gd-DTPA- compared with hyper- and hypointense Gd-EOB-DTPA-enhanced magnet resonance imaging (MRI) in c-myc/TGFα transgenic mice for detecting hepatocellular carcinoma (HCC).. Twenty HCC-bearing transgenic mice with overexpression of the protooncogene c-myc and transforming growth factor-alpha (TGF-α) were analyzed. MRI was performed using a 3-T MRI scanner and an MRI coil. The imaging protocol included Gd-DTPA- and Gd-EOB-DTPA-enhanced T1-weighted images. The statistically evaluated parameters are signal intensity (SI), signal intensity ratio (SIR), contrast-to-noise ratio (CNR), percentage enhancement (PE), and signal-to-noise ratio (SNR).. On Gd-DTPA-enhanced MRI compared with Gd-EOB-DTPA-enhanced MRI, the SI of liver was 265.02 to 573.02 and of HCC 350.84 to either hyperintense with 757.1 or hypointense with 372.55 enhancement. Evaluated parameters were SNR of HCC 50.1 to 56.5/111.5 and SNR of liver parenchyma 37.8 to 85.8, SIR 1.32 to 1.31/0.64, CNR 12.2 to 26.1/-30.08 and PE 42.08% to 80.5/-98.2%, (P < 0.05).. Gd-EOB-DTPA is superior to Gd-DTPA for detecting HCC in contrast agent-enhanced MRI in the c-myc/TGFα transgenic mouse model and there was no difference between the hyperintense or hypointense appearance of HCC. Either way, HCCs can easily be distinguished from liver parenchyma in mice.

Topics: Animals; Carcinoma, Hepatocellular; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Humans; Image Enhancement; Liver Neoplasms; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Reproducibility of Results; Sensitivity and Specificity

We evaluated concanavalin A (Con A)-induced acute hepatic injury in rats using an empirical mathematical model (EMM) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA).. We allocated 18 rats into 3 groups of six each and intravenously injected them with either 10 mg/kg body weight (BW) of Con A (Con A [10] group), 20 mg/kg BW of Con A (Con A [20] group), or a single dose of of saline (4 mL/kg BW, normal control group). We performed the DCE-MRI studies using Gd-EOB-DTPA (0.025 mmol Gd/kg; 0.1 mL/kg BW) as the contrast agent 24 hours after injection of Con A or saline. We then sampled blood, measured serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and calculated the rate of contrast uptake (α), rate of contrast washout (β), area under the curve (AUC), time to maximum relative enhancement (RE) (T(max)), and elimination half-life of RE (T(1/2)) from the time-signal intensity curves using the EMM.. β values were significantly smaller in the Con A (10) and Con A (20) groups than the control group, but α did not differ significantly among the 3 groups. The AUC value was significantly greater in the Con A (10) group than controls, and the T(max) and T(1/2) values were significantly greater in the Con A (20) group than controls. The β, T(max), and T(1/2) values correlated significantly with AST and ALT.. In conclusion, the EMM is useful for evaluating Con A-induced acute hepatic injury using DCE-MRI with Gd-EOB-DTPA.

Topics: Acute Lung Injury; Animals; Computer Simulation; Concanavalin A; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Humans; Image Enhancement; Magnetic Resonance Imaging; Male; Models, Biological; Rats; Rats, Wistar; Reproducibility of Results; Sensitivity and Specificity

To evaluate the effect of gadoxetate disodium on fibrosis in a rat model of active hepatic fibrosis.. The local committee for animal research approved this study. Hepatic fibrosis was induced during 12 weeks of intraperitoneal injection of carbon tetrachloride (CCl(4)). Gadoxetate disodium was administered at 10 mmol/kg for 5 consecutive days starting after the final dose of CCl(4) (clinical dose of gadoxetate disodium is 0.25 mmol/kg). Three groups of Sprague-Dawley rats were studied. Group 1 consisted of six rats treated only with gadoxetate disodium, group 2 consisted of nine rats treated only with CCl(4), and group 3 consisted of nine rats treated with both gadoxetate disodium and CCl(4). Seven days after the final injection of gadoxetate disodium, the rats were sacrificed, and histologic findings and gadolinium deposition in the liver were examined. Fibrosis stage and gadolinium deposition were compared by using the Mann-Whitney test and Student t test.. Fibrosis grading in groups 2 and 3 did not differ significantly (mean Batts-Ludwig fibrosis stage in group 2 was 2.67 and in group 3 was 2.78, P = .70; mean Ishak fibrosis stage in group 2 was 3.89 and in group 3 was 4.11, P = .71). Gadolinium deposition in the liver was slightly increased in group 3 in comparison to group 1 (3.2 ppm versus 4.0 ppm, P = .01), although this reversed when corrected as a percentage of total injected dose (0.022% versus 0.017%, P = .003).. The high-dose administration of gadoxetate disodium in the setting of active hepatic fibrosis was not associated with increased fibrosis, suggesting that gadoxetate disodium does not incite a nephrogenic systemic fibrosis-like fibrotic change in the setting of active hepatic inflammation.

Topics: Analysis of Variance; Animals; Carbon Tetrachloride; Disease Models, Animal; Gadolinium DTPA; Liver Cirrhosis; Liver Function Tests; Male; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric

The aims of this study were to evaluate the morphologic characteristics and growth pattern of hepatic tumors in H-ras 12V transgenic (TG) mice using a micro-magnetic resonance (MR) system and to assess the usefulness of gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) enhancement for the detection of hepatic tumors in these mice.. Hepatocellular carcinoma lines were established to allow insertion of the H-ras 12V transgene under the control of the albumin enhancer/promoter. Seven H-ras 12V TG mice and four wild-type mice were included in this study. The mice underwent various MR imaging examinations, including T1-weighted imaging (repetition time, 300 ms; echo time, 11 ms), Gd-EOB-DTPA-enhanced T1-weighted imaging (dose, 0.025 mmol/kg), and T2-weighted imaging (repetition time, 3500 ms; echo time, 36 ms), with a 4.7-T MR scanner, at 4, 6, 8, and 9 months of age. All mice were euthanized after the final MR imaging procedure, except for one TG mouse and two wild-type mice that were euthanized after MR imaging procedures at 4 months of age. For imaging analysis, the tumor characteristics in each MR sequence, including tumor size, number, and signal intensity (SI), were recorded, and the contrast-to-noise ratio and contrast enhancement ratio were calculated to quantify the SI of the tumor. The MR images were correlated with the findings of histopathologic examinations.. No tumors were detected in the four wild-type mice. In the six TG mice, a total of 67 tumors were found in histopathologic specimens obtained at 9 months of age. Of the 67 tumors, 62 were detected on Gd-EOB-DTPA-enhanced T1-weighted images with fat saturation. The majority of hepatic tumors showed high SI on T1-weighted images without fat saturation. The SI diminished on T1-weighted images with fat saturation. The tumor contrast-to-noise ratio for Gd-EOB-DTPA-enhanced T1-weighted imaging was significantly better than that for the other sequences. The tumors were histopathologically confirmed as hepatocellular adenomas (n = 32) and well-differentiated hepatocellular carcinomas (n = 35).. Micro-MR imaging can reveal the characteristics of hepatic tumors in a live murine model. Gd-EOB-DTPA-enhanced T1-weighted imaging is helpful in the detection of hepatic tumors in H-ras 12V TG mice.

Topics: Animals; Carcinoma, Hepatocellular; Contrast Media; Diagnosis, Differential; Disease Models, Animal; Gadolinium DTPA; Genes, ras; Image Enhancement; Liver; Liver Neoplasms, Experimental; Magnetic Resonance Imaging; Mice; Mice, Transgenic; Observer Variation

Non-invasive MR imaging is expected to be used for accurate diagnosis and quantification of non-alcoholic steatohepatitis (NASH), because NASH is a progressive fatty liver disease. New MR techniques, such as fat fraction ratio (FFR) and T2* value measurement, have attracted an increasing attention, because those techniques can measure quantitative parameters of fibrosis, fat and iron deposition in the liver.. To investigate the potential of FFR and T2* value in NASH with pre-enhancement, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) or super-paramagnetic iron oxide (SPIO)-enhanced MRI.. Twenty-eight rats were divided equally into four groups (one control group and three NASH groups). All rats underwent unenhanced, Gd-EOB-DTPA, and SPIO-enhanced MRI. The T2* value of the liver was measured for each image sequence, and then changes in T2* values before and after each injection were analyzed using Dunnett's test. The reduction rate of T2* value before and 13 min after injection of Gd-EOB-DTPA or SPIO was analyzed using Mann-Whitney's U test. Moreover, FFR of the liver was measured before enhancement, and the relationship between fat fraction and the calculated fat area percentage on a pathological specimen was examined using Spearman's correlation test.. On pre-enhancement, FFR and T2* value were 26.0% ± 12.0% and 21.5 ± 4.2 ms for all NASH groups, and 0.9% ± 0.5% and 30.8 ±-5.5 ms for control, respectively. Both FFR and T2* values were significantly different between the NASH and control groups. The reduction rate of T2* value was significantly lower in the NASH groups than in the control group on SPIO-enhanced MRI, though there was no significant difference on Gd-EOB-DTPA-enhanced MRI. FFR was correlated with the calculated fat area percentage for the pathological specimen.. Pre-enhancement FFR, T2* value measurement and reduction rate of T2* value on SPIO-enhanced MRI may help estimate the progress of liver fat deposition and fibrosis in NASH.

Topics: Animals; Contrast Media; Dextrans; Disease Models, Animal; Fatty Liver; Gadolinium DTPA; Image Enhancement; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetite Nanoparticles; Male; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric

To investigate whether dynamic and delayed magnetic resonance imaging (MRI) with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), a hepatobiliary MRI contrast agent, has potential for the differential diagnosis of experimental hepatic tumors.. Twelve male rats received N-nitrosomorpholine solution as drinking water to induce hepatic tumors. After injection of Gd-EOB-DTPA, rats were subjected to dynamic and delayed MRI. The relative enhancement (RE) was calculated, and the time of the maximum RE (Tmax) was evaluated. After MRI, liver was histologically analyzed.. One hundred sixty-three hepatic tumors 3-12 mm in diameter were induced after 18 weeks of treatment with 0.01 wt/vol% of N-nitrosomorpholine, and 81 of them were evaluated. The RE in hyperplastic nodules (HPNs) was significantly higher than that in moderately or poorly differentiated hepatocellular carcinomas (HCCs) in the late phase, whereas there was no significant difference in RE between well-differentiated HCCs and HPNs. The average Tmax in HPNs was about 13 minutes, whereas that of each differentiated HCCs was about 1 minute.. It was possible to differentiate benign HPNs and malignant HCCs (especially well-differentiated HCCs) by evaluating the change of RE or comparison of Tmax with Gd-EOB-DTPA-enhanced MRI.

Topics: Animals; Contrast Media; Diagnosis, Differential; Disease Models, Animal; Gadolinium DTPA; Image Enhancement; Liver Neoplasms; Liver Neoplasms, Experimental; Magnetic Resonance Imaging; Male; Rats; Time Factors

Topics: Animals; Contrast Media; Dextrans; Disease Models, Animal; Female; Ferrosoferric Oxide; Gadolinium DTPA; Hepatitis; Iron; Liver Cirrhosis, Experimental; Magnetic Resonance Imaging; Magnetite Nanoparticles; Organometallic Compounds; Oxides; Rats; Rats, Sprague-Dawley