Glaser, Kevin J.

AbstractPurposeTo demonstrate a novel MR elastography (MRE) technique, termed here wavelet MRE. With this technique, broadband motion sensitivity is achievable. Moreover, the true tissue displacement can be reconstructed with a simple inverse transform.MethodsA wavelet MRE sequence was developed with motion‐encoding gradients based on Haar wavelets. From the phase images' displacement was estimated using an inverse transform. Simulations were performed using a frequency sweep and a transient as ground‐truth motions. A PVC phantom was scanned using wavelet MRE and standard MRE with both transient (one and 10 cycles of 90‐Hz motion) and steady‐state dual‐frequency motion (30 and 60 Hz) for comparison. The technique was tested in a human brain, and motion trajectories were estimated for each voxel.ResultsIn simulation, the displacement information estimated from wavelet MRE closely matched the true motion. In the phantom test, the MRE phase data generated from the displacement information derived from wavelet MRE agreed well with standard MRE data. Testing of wavelet MRE to assess transient motion waveforms in the brain was successful, and the tissue motion observed was consistent with a previous study.ConclusionThe uniform and broadband frequency response of wavelet MRE makes it a promising method for imaging transient, multifrequency motion, or motion with unknown frequency content. One potential application is measuring the response of brain tissue undergoing low‐amplitude, transient vibrations as a model for the study of traumatic brain injury.

Background and Aims: The presence of at-risk NASH is associated with an increased risk of cirrhosis and complications. Therefore, noninvasive identification of at-risk NASH with an accurate biomarker is a critical need for pharmacologic therapy. We aim to explore the performance of several magnetic resonance (MR)-based imaging parameters in diagnosing at-risk NASH. Approach and Results: This prospective clinical trial (NCT02565446) includes 104 paired MR examinations and liver biopsies performed in patients with suspected or diagnosed NAFLD. Magnetic resonance elastography-assessed liver stiffness (LS), 6-point Dixon-derived proton density fat fraction (PDFF), and single-point saturation-recovery acquisition-calculated T1 relaxation time were explored. Among all predictors, LS showed the significantly highest accuracy in diagnosing at-risk NASH [AUCLS: 0.89 (0.82, 0.95), AUCPDFF: 0.70 (0.58, 0.81), AUCT1: 0.72 (0.61, 0.82), z-score test z >1.96 for LS vs any of others]. The optimal cutoff value of LS to identify at-risk NASH patients was 3.3 kPa (sensitivity: 79%, specificity: 82%, negative predictive value: 91%), whereas the optimal cutoff value of T1 was 850 ms (sensitivity: 75%, specificity: 63%, and negative predictive value: 87%). PDFF had the highest performance in diagnosing NASH with any fibrosis stage [AUCPDFF: 0.82 (0.72, 0.91), AUCLS: 0.73 (0.63, 0.84), AUCT1: 0.72 (0.61, 0.83), |z| <1.96 for all]. Conclusion: Magnetic resonance elastography-assessed LS alone outperformed PDFF, and T1 in identifying patients with at-risk NASH for therapeutic trials.

BackgroundTreatments for nonalcoholic steatohepatitis (NASH) are urgently needed. Hepatic fat fraction and shear stiffness quantified by magnetic resonance imaging (MRI‐HFF) and magnetic resonance elastography (MRE‐SS), respectively, are biomarkers for hepatic steatosis and fibrosis.PurposeThis study assessed the longitudinal effects of fibroblast growth factor 21 variant (polyethylene glycol [PEG]‐FGF21v) on MRI‐HFF and MRE‐SS in a NASH mouse model.Study TypePreclinical.Animal ModelThis study included a choline‐deficient, amino acid‐defined, high‐fat diet (CDAHFD) model and 6‐week‐old, male C57BL/6J mice (N = 78).Field Strength/SequenceThis study was performed using: 3T: gradient‐echo two‐point Dixon and spin‐echo (SE) echo‐planar imaging elastography (200 Hz) and 7T: SE two‐point Dixon and SE elastography (200 Hz).AssessmentMRI and MRE were performed before control diet (CD) or CDAHFD (BD), before PEG‐FGF21v dosing (baseline), and after PEG‐FGF21v treatment (WK4/8). Regions of interest for MRI‐HFF and MRE‐SS were delineated by J.L. and H.T. (>5 years of experience each). Fibrosis and steatosis were measured histologically after picrosirius red and H&E staining. Alkaline phosphatase, alanine transaminase, bile acids, and triglycerides (TGs) were measured.Statistical TestsTwo‐tailed Dunnett's tests were used for statistical analysis; untreated CDAHFD or baseline was used for comparisons. Imaging and histology/biochemistry data were determined using Spearman correlations. Bayesian posterior distributions for MRE‐SS at WK8, posterior means, and 95% credible intervals were presented.ResultsCDAHFD significantly increased baseline MRI‐HFF (3T: 21.97% ± 0.29%; 7T: 40.12% ± 0.35%) and MRE‐SS (3T: 1.25 ± 0.02; 7T: 1.78 ± 0.06 kPa) vs. CD (3T: 3.45% ± 0.7%; 7T: 12.06% ± 1.4% and 3T: 1.01 ± 0.02; 7T: 0.89 ± 0.06 kPa). At 7T, PEG‐FGF21v significantly decreased MRI‐HFF (WK4: 28.97% ± 1.22%; WK8: 20.93% ± 1.15%) and MRE‐SS (WK4: 1.57 ± 0.04; WK8: 1.36 ± 0.05 kPa) vs. untreated (WK4: 36.36% ± 0.62%; WK8: 30.58% ± 0.81% and WK4: 2.03 ± 0.06; WK8: 2.01 ± 0.04 kPa); 3T trends were similar. WK8 SS posterior mean percent attenuation ratios (RDI) were −68% (−90%, −44%; 3T) and −64% (−78%, −52%; 7T). MRI‐HFF was significantly correlated with H&E (3T, r = 0.93; 7T, r = 0.94) and TGs (both, r = 0.92).Data ConclusionsMRI‐HFF and MRE‐SS showed PEG‐FGF21v effects on hepatic steatosis and fibrosis across 3 and 7T, consistent with histological and biochemical data.Level of Evidence1Technical Efficacy Stage2

Abstract Background Magnetic resonance imaging (MRI) and MRI‐based elastography (MRE) are the most promising noninvasive techniques in assessing liver diseases. The purpose of this study was to evaluate an advanced multiparametric imaging method for staging disease and assessing treatment response in realistic preclinical alcohol‐associated liver disease (ALD). Methods We utilized four different preclinical mouse models in our study: Model 1—mice were fed a fast‐food diet and fructose water for 48 weeks to induce nonalcoholic fatty liver disease; Model 2—mice were fed chronic‐binge ethanol (EtOH) for 10 days or 8 weeks to induce liver steatosis/inflammation. Two groups of mice were treated with interleukin‐22 at different time points to induce disease regression; Model 3—mice were administered CCl 4 for 2 to 4 weeks to establish liver fibrosis followed by 2 or 4 weeks of recovery; and Model 4—mice were administered EtOH plus CCl 4 for 12 weeks. Mouse liver imaging biomarkers including proton density fat fraction (PDFF), liver stiffness (LS), loss modulus (LM), and damping ratio (DR) were assessed. Liver and serum samples were obtained for histologic and biochemical analyses. Ordinal logistic regression and generalized linear regression analyses were used to model the severity of steatosis, inflammation, and fibrosis, and to assess the regression of these conditions. Results Multiparametric models with combinations of biomarkers (LS, LM, DR, and PDFF) used noninvasively to predict the histologic severity and regression of steatosis, inflammation, and fibrosis were highly accurate (area under the curve > 0.84 for all). A three‐parameter model that incorporates LS, DR, and ALT predicted histologic fibrosis progression ( r = 0.84, p < 0.0001) and regression ( r = 0.79, p < 0.0001) as measured by collagen content in livers. Conclusion This preclinical study provides evidence that multiparametric MRI/MRE can be used noninvasively to assess disease severity and monitor treatment response in ALD.

PurposeTo address the need for a method to acquire 3D data for MR elastography (MRE) of the whole brain with substantially improved spatial resolution, high SNR, and reduced acquisition time compared with conventional methods.MethodsWe combined a novel 3D spiral staircase data‐acquisition method with a spoiled gradient‐echo pulse sequence and MRE motion‐encoding gradients (MEGs). The spiral‐out acquisition permitted use of longer‐duration motion‐encoding gradients (ie, over two full oscillatory cycles) to enhance displacement SNR, while still maintaining a reasonably short TE for good phase‐SNR. Through‐plane parallel imaging with low noise penalties was implemented to accelerate acquisition along the slice direction. Shared anatomical information was exploited in the deblurring procedure to further boost SNR for stiffness inversion.ResultsIn vivo and phantom experiments demonstrated the feasibility of the proposed method in producing brain MRE results comparable to the spin‐echo–based approaches, both qualitatively and quantitatively. High‐resolution (2‐mm isotropic) brain MRE data were acquired in 5 minutes using our method with good SNR. Joint deblurring with shared anatomical information produced SNR‐enhanced images, leading to upward stiffness estimation.ConclusionA novel 3D gradient‐echo–based approach has been designed and implemented, and shown to have promising potential for fast and high‐resolution in vivo MRE of the whole brain.

PurposeTo develop a novel magnetic resonance elastography (MRE) acquisition using a hybrid radial EPI readout scheme (TURBINE), and to demonstrate its feasibility to obtain wave images and stiffness maps in a phantom and in vivo brain.MethodThe proposed 3D TURBINE‐MRE is based on a spoiled gradient‐echo MRE sequence with the EPI readout radially rotating about the phase‐encoding axis to sample a full 3D k‐space. A polyvinyl chloride phantom and 6 volunteers were scanned on a compact 3T GE scanner with a 32‐channel head coil at 80 Hz and 60 Hz external vibration, respectively. For comparison, a standard 2D, multislice, spin‐echo (SE) EPI‐MRE acquisition was also performed with the same motion encoding and resolution. The TURBINE‐MRE images were off‐line reconstructed with iterative SENSE algorithm. The regional ROI analysis was performed on the 6 volunteers, and the median stiffness values were compared between SE‐EPI‐MRE and TURBINE‐MRE.ResultsThe 3D wave‐field images and the generated stiffness maps were comparable between TURBINE‐MRE and standard SE‐EPI‐MRE for the phantom and the volunteers. The Bland–Altman plot showed no significant difference in the median regional stiffness values between the two methods. The stiffness measured with the 2 methods had a strong linear relationship with a Pearson correlation coefficient of 0.943.ConclusionWe demonstrated the feasibility of the new TURBINE‐MRE sequence for acquiring the desired 3D wave‐field data and stiffness maps in a phantom and in‐vivo brains. This pilot study encourages further exploration of TURBINE‐MRE for functional MRE, free‐breathing abdominal MRE, and cardiac MRE applications.

Disease monitoring in nonalcoholic steatohepatitis (NASH) is limited by absence of noninvasive biomarkers of disease regression or progression. We aimed to examine the role of multiparametric three‐dimensional magnetic resonance elastography (3D‐MRE) and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) in the detection of NASH regression after interventions. This is a single‐center prospective clinical trial of 40 patients who underwent bariatric surgery. Imaging and liver biopsies were obtained at baseline and 1 year after surgery. The imaging protocol consisted of multifrequency 3D‐MRE to determine the shear stiffness at 60 Hz and damping ratio at 40 Hz, and MRI‐PDFF to measure the fat fraction. A logistic regression model including these three parameters was previously found to correlate with NASH. We assessed the model performance in the detection of NASH resolution after surgery by comparing the image‐predicted change in NAFLD activity score (delta NAS) to the histologic changes. A total of 38 patients (median age 43, 87% female, 30 of 38 with NAS ≥ 1, and 13 of 38 with NASH) had complete data at 1 year. The NAS decreased in all subjects with NAS ≥ 1 at index biopsy, and NASH resolved in all 13. There was a strong correlation between the predicted delta NAS by imaging and the delta NAS by histology (r = 0.73, P < 0.001). The strength of correlation between histology and the predicted delta NAS using single conventional parameters, such as the fat fraction by MRI‐PDFF or shear stiffness at 60 Hz by MRE, was r = 0.69 (P < 0.001) and r = 0.43 (P = 0.009), respectively. Conclusion: Multiparametric 3D‐MRE and MRI‐PDFF can detect histologic changes of NASH resolution after bariatric surgery. Studies in a nonbariatric setting are needed to confirm the performance as a composite noninvasive biomarker for longitudinal NASH monitoring.

BackgroundMagnetic resonance elastography (MRE) can determine the presence and stage of liver fibrosis. Data on normative MRE values, while reported in adults, are limited in children.PurposeTo determine the distribution of MRE‐measured liver stiffness in children without liver disease.Study TypeProspective, observational.PopulationEighty‐one healthy children (mean 12.6 ± 2.6 years, range 8–17 years).Field Strength/Sequence3.0T Signa HDxt, General Electric MR Scanner; 2D GRE MRE sequence.AssessmentHistory, examination, laboratory evaluation, and (MR) exams (proton density fat fraction, PDFF, and MRE) were performed. MR elastograms were analyzed manually at two reading centers and compared with each other for agreement and with published values in healthy adults and thresholds for fibrosis in adult and pediatric patients.Statistical TestsDescriptive statistics, Bland–Altman analysis, t‐test to compare hepatic stiffness values with reference standards.ResultsStiffness values obtained at both reading centers were similar, without significant bias (P = 0.362) and with excellent correlation (intraclass correlation coefficient [ICC] = 0.782). Mean hepatic stiffness value for the study population was 2.45 ± 0.35 kPa (95th percentile 3.19 kPa), which was significantly higher than reported values for healthy adult subjects (2.10 ± 0.23 kPa, P < 0.001). In all, 74–85% of subjects had stiffness measurements suggestive of no fibrosis.Data ConclusionMean liver stiffness measured with MRE in this cohort was significantly higher than that reported in healthy adults. Despite rigorous screening, some healthy children had stiffness measurements suggestive of liver fibrosis using current published thresholds. Although MRE has the potential to provide noninvasive assessment in patients with suspected hepatic disease, further refinement of this technology will help advance its use as a diagnostic tool for evidence of fibrosis in pediatric populations.Level of Evidence: 1Technical Efficacy: 5J. Magn. Reson. Imaging 2020;51:919–927.

BackgroundAn understanding of potential age‐related changes in brain stiffness and its regional variation is important for further clinical application of MR elastography.PurposeTo investigate the effect of age on global and regional brain stiffness in young and middle‐aged adults.Study TypeProspective.SubjectsFifty subjects with normal brains and aged in their 20s, 30s, 40s, 50s, or 60s (five men, five women per decade).Field Strength/Sequence3.0T MRI and elastography with a vibration frequency of 60 Hz.AssessmentStiffness was measured in nine brain regions (cerebrum, temporal lobes, sensorimotor areas, frontotemporal composite region, deep gray matter and white matter (deep GM/WM), parietal lobes, occipital lobes, frontal lobes, and cerebellum) using an atlas‐based region‐of‐interest approach. The influence of age on regional brain stiffness was evaluated.Statistical TestsMultiple linear regression analysis, followed by Dunnett's multiple comparisons test, using subjects in their 20s as controls.ResultsFollowing adjustment for sex, multiple linear regression revealed a significant negative correlation between age and stiffness of the cerebrum (P < 0.0001), temporal lobes (P < 0.0001), sensorimotor areas (P < 0.0001), frontotemporal composite region (P < 0.0001), deep GM/WM (P = 0.0028), parietal lobes (P < 0.0001), occipital lobes (P = 0.0055), and frontal lobes (P < 0.0001). Dunnett's multiple comparison test showed that the stiffness of the sensorimotor areas, frontotemporal composite region, and frontal lobes was significantly decreased in subjects in their 40s (P < 0.0367), 50s (P < 0.0001), and 60s (P < 0.0001), while that of the cerebrum, temporal lobes, and parietal lobes was significantly decreased only in subjects in their 50s (P < 0.0012) and 60s (P < 0.0031) when compared with the controls.Data ConclusionThere is an age‐related decrease in brain stiffness that varies across the different regions.Level of Evidence: 1Technical Efficacy Stage: 2J. Magn. Reson. Imaging 2020;51:727–733.