Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T.

Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild-type rats who had received an intravenous bolus of either 10, 25 or 40 µmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small-animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol-1 s-1 ) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well-known bias in gadoxetate rate constants. This will promote the clinical translation of MR-based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies.

Robust arterial spin labeling MRI measurement of pharmacologically induced perfusion change in rat kidneys.

Kidney diseases such as acute kidney injury, diabetic nephropathy and chronic kidney disease (CKD) are related to dysfunctions of the microvasculature in the kidney causing a decrease in renal blood perfusion (RBP). Pharmacological intervention to improve the function of the microvasculature is a viable strategy for the potential treatment of these diseases. The measurement of RBP is a reliable biomarker to evaluate the efficacy of pharmacological agents' actions on the microvasculature, and measurement of RBP responses to different pharmacological agents can also help elucidate the mechanism of hemodynamic regulation in the kidney. Magnetic resonance imaging (MRI) with flow-sensitive alternating inversion recovery (FAIR) arterial spin labeling (ASL) has been used to measure RBP in humans and animals. However, artifacts caused by respiratory and peristaltic motions limit the potential of FAIR ASL in drug discovery and kidney research. In this study, the combined anesthesia protocol of inactin with a low dose of isoflurane was used to fully suppress peristalsis in rats, which were ventilated with an MRI-synchronized ventilator. FAIR ASL data were acquired in eight axial slices using a single-shot, gradient-echo, echo-planar imaging (EPI) sequence. The artifacts in the FAIR ASL RBP measurement due to respiratory and peristaltic motions were substantially eliminated. The RBP responses to fenoldopam and L-NAME were measured, and the increase and decrease in RBP caused by fenoldopam and L-NAME, respectively, were robustly observed. To further validate FAIR ASL, the renal blood flow (RBF) responses to the same agents were measured by an invasive perivascular flow probe method. The pharmacological agent-induced responses in RBP and RBF are similar. This indicates that FAIR ASL has the sensitivity to measure pharmacologically induced changes in RBP. FAIR ASL with multislice EPI can be a valuable tool for supporting drug discovery, and for elucidating the mechanism of hemodynamic regulation in kidneys.

fMRI study of olfactory processing in mice under three anesthesia protocols: Insight into the effect of ketamine on olfactory processing.

Functional magnetic resonance imaging (fMRI) is a valuable tool for studying neural activations in the central nervous system of animals due to its wide spatial coverage and non-invasive nature. However, the advantages of fMRI have not been fully realized in functional studies in mice, especially in the olfactory system, possibly due to the lack of suitable anesthesia protocols with spontaneous breathing. Since mice are widely used in biomedical research, it is desirable to evaluate different anesthesia protocols for olfactory fMRI studies in mice. Dexmedetomidine (DEX) as a sedative/anesthetic has been introduced to fMRI studies in mice, but it has a limited anesthesia duration. To extend the anesthesia duration, DEX has been combined with a low dose of isoflurane (ISO) or ketamine (KET) in previous functional studies in mice. In this report, olfactory fMRI studies were performed under three anesthesia protocols (DEX alone, DEX/ISO, and DEX/KET) in three different groups of mice. Isoamyl-acetate was used as an odorant, and the odorant-induced neural activations were measured by blood oxygenation-level dependent (BOLD) fMRI. BOLD fMRI responses were observed in the olfactory bulb (OB), anterior olfactory nuclei (AON), and piriform cortex (Pir). Interestingly, BOLD fMRI activations were also observed in the prefrontal cortical region (PFC), which are most likely caused by the draining vein effect. The response in the OB showed no adaptation to either repeated odor stimulations or continuous odor exposure, but the response in the Pir showed adaptation during the continuous odor exposure. The data also shows that ISO suppresses the olfactory response in the OB and AON, while KET enhances the olfactory response in the Pir. Thus, DEX/KET should be an attractive anesthesia for olfactory fMRI in mice.

Brain findings associated with risperidone in rhesus monkeys: magnetic resonance imaging and pathology perspectives.

Brain changes associated with risperidone, a dopamine-2/serotonin-2 receptor antagonist, have been documented in rats and humans, but not in nonhuman primates. This study characterized brain changes associated with risperidone in nonhuman primates. Rhesus monkeys were orally administered risperidone in a dose-escalation paradigm up to a maximum tolerated dose of 0.5 mg/kg/day for 3 weeks, or 3 months followed by a 3-month recovery period. Transient and fully reversible neurological signs consistent with risperidone pharmacology were observed. The results of a magnetic resonance imaging evaluation after 3 months of treatment and at the end of the 3-month recovery period showed no meaningful changes in the brain. There were no risperidone-related brain weight changes or gross findings. Histomorphological evaluation of brain sections stained with hematoxylin and eosin, ionized calcium binding adaptor molecule 1 (Iba1), and luxol fast blue/cresyl violet double staining showed no notable differences between control and risperidone groups. However, evaluation of the brain after glial fibrillary acidic protein (GFAP) immunohistochemical staining revealed increased staining in the cell bodies and processes of astrocytes in the putamen without apparent alterations in numbers or distribution. The increase in GFAP staining was present after 3 weeks and 3 months of treatment, but no increase in staining was observed after the 3-month recovery period, demonstrating the reversibility of this finding. The reversible increase in GFAP expression was likely an adaptive, non-adverse response of astrocytes, associated with the pharmacology of risperidone. These observations are valuable considerations in the nonclinical risk assessment of new drug candidates for psychiatric disorders.

fMRI study of the role of glutamate NMDA receptor in the olfactory adaptation in rats: Insights into cellular and molecular mechanisms of olfactory adaptation.

Olfactory adaptation, characterized by attenuation of response to repeated odor stimulations or continuous odor exposure, is an intrinsic feature of olfactory processing. Adaptation can be induced by either "synaptic depression" due to depletion of neurotransmitters, or "enhanced inhibition" onto principle neurons by local inhibitory interneurons in olfactory structures. It is not clear which mechanism plays a major role in olfactory adaptation. More importantly, molecular sources of enhanced inhibition have not been identified. In this study, olfactory responses to either repeated 40-s stimulations with interstimulus intervals (ISI) of 140-s or 30-min, or a single prolonged 200-s stimulus were measured by fMRI in different naïve rats. Olfactory adaptations in the olfactory bulb (OB), anterior olfactory nucleus (AON), and piriform cortex (PC) were observed only with repeated 40-s odor stimulations, and no olfactory adaptations were detected during the prolonged 200-s stimulation. Interestingly, in responses to repeated 40-s odor stimulations in the PC, the first odor stimulation induced positive activations, and odor stimulations under adapted condition induced negative activations. The negative activations suggest that "sparse coding" and "global inhibition" are the characteristics of olfactory processing in PC, and the global inhibition manifests only under an adapted condition, not a naïve condition. Further, we found that these adaptations were NMDA receptor dependent; an NMDA receptor antagonist (MK801) blocked the adaptations. Based on the mechanism that glutamate NMDA receptor plays a role in the inhibition onto principle neurons by interneurons, our data suggest that the olfactory adaptations are caused by enhanced inhibition from interneurons. Combined with the necessity of the interruption of odor stimulation to observe the adaptations, the molecular source for the enhanced inhibition is most likely an increased glutamate release from presynaptic terminals due to glutamate over-replenishment during the interruption of odor stimulation. Furthermore, with blockage of the adaptations, the data reveal that orbital, medial & prefrontal, and cingulate cortices (OmPFC) are involved in the olfactory processing.

Comparison of R2* correction methods for accurate fat quantification in fatty liver.

PURPOSE: To compare the performance of fat fraction quantification using single-R(2)* and dual-R(2)* correction methods in patients with fatty liver, using MR spectroscopy (MRS) as the reference standard. MATERIALS AND METHODS: From a group of 97 patients, 32 patients with hepatic fat fraction greater than 5%, as measured by MRS, were identified. In these patients, chemical shift encoded fat-water imaging was performed, covering the entire liver in a single breathhold. Fat fraction was measured from the imaging data by postprocessing using 6 different models: single- and dual-R(2)* correction, each performed with complex fitting, magnitude fitting, and mixed magnitude/complex fitting to compare the effects of phase error correction. Fat fraction measurements were compared with co-registered spectroscopy measurements using linear regression. RESULTS: Linear regression demonstrated higher agreement with MRS using single-R(2)* correction compared with dual-R(2)* correction. Among single-R(2)* models, all 3 fittings methods performed similarly well (slope = 1.0 ± 0.06, r(2) = 0.89-0.91). CONCLUSION: Single-R(2)* modeling is more accurate than dual-R(2)* modeling for hepatic fat quantification in patients, even in those with high hepatic fat concentrations.

Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug-Drug Interactions in Rats.

Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (khe), and biliary excretion (kbh). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate khe and kbh by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in khe (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97-98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans.

Validation of MRI biomarkers of hepatic steatosis in the presence of iron overload in the ob/ob mouse.

PURPOSE: To validate the utility and performance of a T 2 correction method for hepatic fat quantification in an animal model of both steatosis and iron overload. MATERIALS AND METHODS: Mice with low (n = 6), medium (n = 6), and high (n = 8) levels of steatosis were sedated and imaged using a chemical shift-based fat-water separation method to obtain magnetic resonance imaging (MRI) fat-fraction measurements. Imaging was performed before and after each of two superparamagnetic iron oxide (SPIO) injections to create hepatic iron overload. Fat-fraction maps were reconstructed with and without T 2 correction. Fat-fraction with and without T 2 correction and T 2 measurements were compared after each injection. Liver tissue was harvested and imaging results were compared to triglyceride extraction and histology grading. RESULTS: Excellent correlation was seen between MRI fat-fraction and tissue-based fat quantification. Injections of SPIOs led to increases in R 2 (=1/T 2). Measured fat-fraction was unaffected by the presence of iron when T 2 correction was used, whereas measured fat-fraction dramatically increased without T 2 correction. CONCLUSION: Hepatic fat-fraction measured using a T 2-corrected chemical shift-based fat-water separation method was validated in an animal model of steatosis and iron overload. T 2 correction enables robust fat-fraction estimation in both the presence and absence of iron, and is necessary for accurate hepatic fat quantification.

Quantification of hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy.

PURPOSE: To prospectively compare an investigational version of a complex-based chemical shift-based fat fraction magnetic resonance (MR) imaging method with MR spectroscopy for the quantification of hepatic steatosis. MATERIALS AND METHODS: This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained before all studies. Fifty-five patients (31 women, 24 men; age range, 24-71 years) were prospectively imaged at 1.5 T with quantitative MR imaging and single-voxel MR spectroscopy, each within a single breath hold. The effects of T2 correction, spectral modeling of fat, and magnitude fitting for eddy current correction on fat quantification with MR imaging were investigated by reconstructing fat fraction images from the same source data with different combinations of error correction. Single-voxel T2-corrected MR spectroscopy was used to measure fat fraction and served as the reference standard. All MR spectroscopy data were postprocessed at a separate institution by an MR physicist who was blinded to MR imaging results. Fat fractions measured with MR imaging and MR spectroscopy were compared statistically to determine the correlation (r(2)), and the slope and intercept as measures of agreement between MR imaging and MR spectroscopy fat fraction measurements, to determine whether MR imaging can help quantify fat, and examine the importance of T2 correction, spectral modeling of fat, and eddy current correction. Two-sided t tests (significance level, P = .05) were used to determine whether estimated slopes and intercepts were significantly different from 1.0 and 0.0, respectively. Sensitivity and specificity for the classification of clinically significant steatosis were evaluated. RESULTS: Overall, there was excellent correlation between MR imaging and MR spectroscopy for all reconstruction combinations. However, agreement was only achieved when T2 correction, spectral modeling of fat, and magnitude fitting for eddy current correction were used (r(2) = 0.99; slope ± standard deviation = 1.00 ± 0.01, P = .77; intercept ± standard deviation = 0.2% ± 0.1, P = .19). CONCLUSION: T1-independent chemical shift-based water-fat separation MR imaging methods can accurately quantify fat over the entire liver, by using MR spectroscopy as the reference standard, when T2 correction, spectral modeling of fat, and eddy current correction methods are used.

Combination of complex-based and magnitude-based multiecho water-fat separation for accurate quantification of fat-fraction.

Multipoint water-fat separation techniques rely on different water-fat phase shifts generated at multiple echo times to decompose water and fat. Therefore, these methods require complex source images and allow unambiguous separation of water and fat signals. However, complex-based water-fat separation methods are sensitive to phase errors in the source images, which may lead to clinically important errors. An alternative approach to quantify fat is through "magnitude-based" methods that acquire multiecho magnitude images. Magnitude-based methods are insensitive to phase errors, but cannot estimate fat-fraction greater than 50%. In this work, we introduce a water-fat separation approach that combines the strengths of both complex and magnitude reconstruction algorithms. A magnitude-based reconstruction is applied after complex-based water-fat separation to removes the effect of phase errors. The results from the two reconstructions are then combined. We demonstrate that using this hybrid method, 0-100% fat-fraction can be estimated with improved accuracy at low fat-fractions.

Effects of postprandial state and mesenteric blood flow on the repeatability of MR elastography in asymptomatic subjects.

PURPOSE: To determine the repeatability of stiffness measurements in the liver using MR elastography (MRE) during the fasted and fed states. MRE has gained increased recognition as a noninvasive method to quantify fibrotic changes in the liver. It is well known that eating increases splanchnic blood flow, and fasting status of patients has been recognized as a factor that may affect hepatic stiffness measured with MRE. MATERIALS AND METHODS: Hepatic MRE stiffness and flow through the superior mesenteric vein (SMV) were measured in 12 healthy subjects in fasted and fed states, and measurements were repeated 5 weeks later. A linear mixed effects model was used to estimate the sources of variability in the data, which included day (exams on different days) and subject. Sources were combined to calculate the overall standard deviation of a single MRE measurement. RESULTS: The total within-subject standard deviation of an MRE exam is 8.5% (standard error [SE] = 1.7%) or 9.0% (SE = 1.8%) for fasted and fed states, respectively. No significant differences between fasted/fed state stiffness and no correlation between hepatic stiffness and SMV flow were observed. CONCLUSION: As seen in this smaller population, healthy subjects scanned in a known fasted or fed state provide repeatable stiffness estimates with no relationship to SMV flow.

T(1) independent, T(2) (*) corrected chemical shift based fat-water separation with multi-peak fat spectral modeling is an accurate and precise measure of hepatic steatosis.

PURPOSE: To determine the precision and accuracy of hepatic fat-fraction measured with a chemical shift-based MRI fat-water separation method, using single-voxel MR spectroscopy (MRS) as a reference standard. MATERIALS AND METHODS: In 42 patients, two repeated measurements were made using a T(1) -independent, T 2*-corrected chemical shift-based fat-water separation method with multi-peak spectral modeling of fat, and T(2) -corrected single voxel MR spectroscopy. Precision was assessed through calculation of Bland-Altman plots and concordance correlation intervals. Accuracy was assessed through linear regression between MRI and MRS. Sensitivity and specificity of MRI fat-fractions for diagnosis of steatosis using MRS as a reference standard were also calculated. RESULTS: Statistical analysis demonstrated excellent precision of MRI and MRS fat-fractions, indicated by 95% confidence intervals (units of absolute percent) of [-2.66%,2.64%] for single MRI ROI measurements, [-0.81%,0.80%] for averaged MRI ROI, and [-2.70%,2.87%] for single-voxel MRS. Linear regression between MRI and MRS indicated that the MRI method is highly accurate. Sensitivity and specificity for detection of steatosis using averaged MRI ROI were 100% and 94%, respectively. The relationship between hepatic fat-fraction and body mass index was examined. CONCLUSION: Fat-fraction measured with T(1) -independent T 2*-corrected MRI and multi-peak spectral modeling of fat is a highly precise and accurate method of quantifying hepatic steatosis.

Simultaneous multielement imaging of liver tissue using laser ablation inductively coupled plasma mass spectrometry.

Analysis of the spatial distribution of metals, metalloids, and non-metals in biological tissues is of significant interest in the life sciences, helping to illuminate the function and roles these elements play within various biological pathways. Chemical imaging methods are commonly employed to address biological questions and reveal individual spatial distributions of analytes of interest. Elucidation of these spatial distributions can help determine key elemental and molecular information within the respective biological specimens. However, traditionally utilized imaging methods prove challenging for certain biological tissue analysis, especially with respect to applications that require high spatial resolution or depth profiling. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been shown to be effective for direct elemental analysis of solid materials with high levels of precision. In this work, chemical imaging using LA-ICP-MS has been applied as a powerful analytical methodology for the analysis of liver tissue samples. The proposed analytical methodology successfully produced both qualitative and quantitative information regarding specific elemental distributions within images of thin tissue sections with high levels of sensitivity and spatial resolution. The spatial resolution of the analytical methodology was innovatively enhanced, helping to broaden applicability of this technique to applications requiring significantly high spatial resolutions. This information can be used to further understand the role these elements play within biological systems and impacts dysregulation may have.

Imaging Beta-Cell Function in the Pancreas of Non-Human Primates Using a Zinc-Sensitive MRI Contrast Agent.

Non-invasive beta cell function measurements may provide valuable information for improving diabetes diagnostics and disease management as the integrity and function of pancreatic beta cells have been found to be compromised in Type-1 and Type-2 diabetes. Currently, available diabetes assays either lack functional information or spatial identification of beta cells. In this work, we introduce a method to assess the function of beta cells in the non-human primate pancreas non-invasively with MRI using a Gd-based zinc(II) sensor as a contrast agent, Gd-CP027. Additionally, we highlight the role of zinc(II) ions in the paracrine signaling of the endocrine pancreas via serological measurements of insulin and c-peptide. Non-human primates underwent MRI exams with simultaneous blood sampling during a Graded Glucose Infusion (GGI) with Gd-CP027 or with a non-zinc(II) sensitive contrast agent, gadofosveset. Contrast enhancement of the pancreas resulting from co-release of zinc(II) ion with insulin was observed focally when using the zinc(II)-specific agent, Gd-CP027, whereas little enhancement was detected when using gadofosveset. The contrast enhancement detected by Gd-CP027 increased in parallel with an increased dose of infused glucose. Serological measurements of C-peptide and insulin indicate that Gd-CP027, a high affinity zinc(II) contrast agent, potentiates their secretion only as a function of glucose stimulation. Taken in concert, this assay offers the possibility of detecting beta cell function in vivo non-invasively with MRI and underscores the role of zinc(II) in endocrine glucose metabolism.

Soluble Guanylate Cyclase Stimulator Vericiguat Enhances Long-Term Memory in Rats without Altering Cerebral Blood Volume.

Vascular cognitive impairment (VCI) is characterized by impairments in cerebral blood flow (CBF), endothelial function and blood-brain barrier (BBB) integrity. These processes are all physiologically regulated by the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling pathway. Additionally, cGMP signaling plays an important role in long-term potentiation (LTP) underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating VCI. Hence, in this study we investigated whether sGC stimulator vericiguat has potential as a cognitive enhancer. The effects of vericiguat on long-term memory were measured in rats using an object location task. Due to the low brain-penetrance of vericiguat found in this study, it was investigated whether in the absence of BBB limitations, vericiguat enhanced hippocampal plasticity using an ex vivo memory acquisition-like chemical LTP model. Finally, peripheral effects were measured by means of blood pressure and cerebral blood volume. Vericiguat successfully enhanced long-term memory and increased hippocampal plasticity via enhanced translocation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to the cell membrane, while blood pressure and cerebral blood volume were unaltered. Although the memory enhancing effects in this study are likely due to peripheral effects on the cerebral microvasculature, sGC stimulation may provide a new therapeutic strategy for treating VCI, especially when BBB integrity is reduced.

Quantification of hepatic steatosis with 3-T MR imaging: validation in ob/ob mice.

PURPOSE: To validate quantitative imaging techniques used to detect and measure steatosis with magnetic resonance (MR) imaging in an ob/ob mouse model of hepatic steatosis. MATERIALS AND METHODS: The internal research animal and resource center approved this study. Twenty-eight male ob/ob mice in progressively increasing age groups underwent imaging and were subsequently sacrificed. Six ob/+ mice served as control animals. Fat fraction imaging was performed with a chemical shift-based water-fat separation method. The following three methods of conventional fat quantification were compared with imaging: lipid extraction and qualitative and quantitative histologic analysis. Fat fraction images were reconstructed with single- and multiple-peak spectral models of fat and with and without correction for T2* effects. Fat fraction measurements obtained with the different reconstruction methods were compared with the three methods of fat quantification, and linear regression analysis and two-sided and two-sample t tests were performed. RESULTS: Lipid extraction and qualitative and quantitative histologic analysis were highly correlated with the results of fat fraction imaging (r(2) = 0.92, 0.87, 0.82, respectively). No significant differences were found between imaging measurements and lipid extraction (P = .06) or quantitative histologic (P = .07) measurements when multiple peaks of fat and T2* correction were included in image reconstruction. Reconstructions in which T2* correction, accurate spectral modeling, or both were excluded yielded lower agreement when compared with the results yielded by other techniques. Imaging measurements correlated particularly well with histologic grades in mice with low fat fractions (intercept, -1.0% +/-1.2 [standard deviation]). CONCLUSION: MR imaging can be used to accurately quantify fat in vivo in an animal model of hepatic steatosis and may serve as a quantitative biomarker of hepatic steatosis.

Independent estimation of T*2 for water and fat for improved accuracy of fat quantification.

Noninvasive biomarkers of intracellular accumulation of fat within the liver (hepatic steatosis) are urgently needed for detection and quantitative grading of nonalcoholic fatty liver disease, the most common cause of chronic liver disease in the United States. Accurate quantification of fat with MRI is challenging due the presence of several confounding factors, including T*(2) decay. The specific purpose of this work is to quantify the impact of T*(2) decay and develop a multiexponential T*(2) correction method for improved accuracy of fat quantification, relaxing assumptions made by previous T*(2) correction methods. A modified Gauss-Newton algorithm is used to estimate the T*(2) for water and fat independently. Improved quantification of fat is demonstrated, with independent estimation of T*(2) for water and fat using phantom experiments. The tradeoffs in algorithm stability and accuracy between multiexponential and single exponential techniques are discussed.

Repeatability of magnetic resonance elastography for quantification of hepatic stiffness.

PURPOSE: To determine the sources of variability of MRE hepatic stiffness measurements using healthy volunteers and patients and to calculate the minimum change required for statistical significance. Hepatic stiffness measured with magnetic resonance elastography (MRE) has demonstrated tremendous potential as a noninvasive surrogate of hepatic fibrosis, although the underlying repeatability of MRE for longitudinal tracking of liver disease has not been documented. MATERIALS AND METHODS: MRE stiffness measurements from 20 healthy volunteers and 10 patients were obtained twice on the same day, and repeated 2-4 weeks later for volunteers in this institutional review board-approved study. A linear mixed effects model was used to estimate the component sources of variability in the data. RESULTS: The standard deviation of MRE measurements of the same individual on different days is 11.9% (percent of the measured stiffness) using the same reader and 12.0% using different readers. The standard deviation of the difference between two measurements (i.e., longitudinal change in an individual) is 17.4%; the corresponding 95% confidence interval for zero change is (-27.0%, 37.0%). CONCLUSION: MRE is a repeatable method for quantifying liver stiffness. Using the described MRE technique, changes greater than 37.0% of the smaller measured stiffness value represent meaningful changes in longitudinal liver stiffness measurements.

T1 independent, T2* corrected MRI with accurate spectral modeling for quantification of fat: validation in a fat-water-SPIO phantom.

PURPOSE: To validate a T(1)-independent, T(2)*-corrected fat quantification technique that uses accurate spectral modeling of fat using a homogeneous fat-water-SPIO phantom over physiologically expected ranges of fat percentage and T(2)* decay in the presence of iron overload. MATERIALS AND METHODS: A homogeneous gel phantom consisting of vials with known fat-fractions and iron concentrations is described. Fat-fraction imaging was performed using a multiecho chemical shift-based fat-water separation method (IDEAL), and various reconstructions were performed to determine the impact of T(2)* correction and accurate spectral modeling. Conventional two-point Dixon (in-phase/out-of-phase) imaging and MR spectroscopy were performed for comparison with known fat-fractions. RESULTS: The best agreement with known fat-fractions over the full range of iron concentrations was found when T(2)* correction and accurate spectral modeling were used. Conventional two-point Dixon imaging grossly underestimated fat-fraction for all T(2)* values, but particularly at higher iron concentrations. CONCLUSION: This work demonstrates the necessity of T(2)* correction and accurate spectral modeling of fat to accurately quantify fat using MRI.

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems.

BACKGROUND: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking. OBJECTIVE: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. METHODS: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured. RESULTS: CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R1-based MR biomarkers were found to be quite sensitive even to such small errors in R1, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1 mM-1 at 3 T and 0.94 s-1 mM-1 at 11.7T. INTERPRETATION: While several factors affect the reproducibility of R1-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R1-reproducibility.