Single Breath-Hold MR Elastography for Fast Biomechanical Probing of Pancreatic Stiffness.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) stromal disposition is thought to influence chemotherapy efficacy and increase tissue stiffness, which could be quantified noninvasively via MR elastography (MRE). Current methods cause position-based errors in pancreas location over time, hampering accuracy. It would be beneficial to have a single breath-hold acquisition. PURPOSE: To develop and test a single breath-hold three-dimensional MRE technique utilizing prospective undersampling and a compressed sensing reconstruction (CS-MRE). STUDY TYPE: Prospective. POPULATION: A total of 30 healthy volunteers (HV) (31 ± 9 years; 33% male) and five patients with PDAC (69 ± 5 years; 80% male). FIELD STRENGTH/SEQUENCE: 3-T, GRE Ristretto MRE. ASSESSMENT: First, optimization of multi breath-hold MRE was done in 10 HV using four combinations of vibration frequency, number of measured wave-phase offsets, and TE and looking at MRE quality measures in the pancreas head. Second, viscoelastic parameters delineated in the pancreas head or tumor of CS-MRE were compared against (I) 2D and (II) 3D four breath-hold acquisitions in HV (N = 20) and PDAC patients. Intrasession repeatability was assessed for CS-MRE in a subgroup of healthy volunteers (N = 15). STATISTICAL TESTS: Tests include repeated measures analysis of variance (ANOVA), Bland-Altman analysis, and coefficients of variation (CoVs). A P-value <.05 was considered statistically significant. RESULTS: Optimization of the four breath-hold acquisitions resulted in 40 Hz vibration frequency, five wave-phases, and echo time (TE) = 6.9 msec as the preferred method (4BH-MRE). CS-MRE quantitative results did not differ from 4BH-MRE. Shear wave speed (SWS) and phase angle differed significantly between HV and PDAC patients using 4BH-MRE or CS-MRE. The limits of agreement for SWS were [-0.09, 0.10] m/second and the within-subject CoV was 4.8% for CS-MRE. DATA CONCLUSION: CS-MRE might allow a single breath-hold MRE acquisition with comparable SWS and phase angle as 4BH-MRE, and it may still enable to differentiate between HV and PDAC. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2.

Magnetic resonance elastography with guided pressure waves.

Magnetic resonance elastography aims to non-invasively and remotely characterize the mechanical properties of living tissues. To quantitatively and regionally map the shear viscoelastic moduli in vivo, the technique must achieve proper mechanical excitation throughout the targeted tissues. Although it is straightforward, ante manibus, in close organs such as the liver or the breast, which practitioners clinically palpate already, it is somewhat fortunately highly challenging to trick the natural protective barriers of remote organs such as the brain. So far, mechanical waves have been induced in the latter by shaking the surrounding cranial bones. Here, the skull was circumvented by guiding pressure waves inside the subject's buccal cavity so mechanical waves could propagate from within through the brainstem up to the brain. Repeatable, reproducible and robust displacement fields were recorded in phantoms and in vivo by magnetic resonance elastography with guided pressure waves such that quantitative mechanical outcomes were extracted in the human brain.

MR elastography: Principles, guidelines, and terminology.

Magnetic resonance elastography (MRE) is a phase contrast-based MRI technique that can measure displacement due to propagating mechanical waves, from which material properties such as shear modulus can be calculated. Magnetic resonance elastography can be thought of as quantitative, noninvasive palpation. It is increasing in clinical importance, has become widespread in the diagnosis and staging of liver fibrosis, and additional clinical applications are being explored. However, publications have reported MRE results using many different parameters, acquisition techniques, processing methods, and varied nomenclature. The diversity of terminology can lead to confusion (particularly among clinicians) about the meaning of and interpretation of MRE results. This paper was written by the MRE Guidelines Committee, a group formalized at the first meeting of the ISMRM MRE Study Group, to clarify and move toward standardization of MRE nomenclature. The purpose of this paper is to (1) explain MRE terminology and concepts to those not familiar with them, (2) define "good practices" for practitioners of MRE, and (3) identify opportunities to standardize terminology, to avoid confusion.

Robustness of MR Elastography in the Healthy Brain: Repeatability, Reliability, and Effect of Different Reconstruction Methods.

BACKGROUND: Changes in brain stiffness can be an important biomarker for neurological disease. Magnetic resonance elastography (MRE) quantifies tissue stiffness, but the results vary between acquisition and reconstruction methods. PURPOSE: To measure MRE repeatability and estimate the effect of different reconstruction methods and varying data quality on estimated brain stiffness. STUDY TYPE: Prospective. SUBJECTS: Fifteen healthy subjects. FIELD STRENGTH/SEQUENCE: 3T MRI, gradient-echo elastography sequence with a 50 Hz vibration frequency. ASSESSMENT: Imaging was performed twice in each subject. Images were reconstructed using a curl-based and a finite-element-model (FEM)-based method. Stiffness was measured in the whole brain, in white matter, and in four cortical and four deep gray matter regions. Repeatability coefficients (RC), intraclass correlation coefficients (ICC), and coefficients of variation (CV) were calculated. MRE data quality was quantified by the ratio between shear waves and compressional waves. STATISTICAL TESTS: Median values with range are presented. Reconstruction methods were compared using paired Wilcoxon signed-rank tests, and Spearman's rank correlation was calculated between MRE data quality and stiffness. Holm-Bonferroni corrections were employed to adjust for multiple comparisons. RESULTS: In the whole brain, CV was 4.3% and 3.8% for the curl and the FEM reconstruction, respectively, with 4.0-12.8% for subregions. Whole-brain ICC was 0.60-0.74, ranging from 0.20 to 0.89 in different regions. RC for the whole brain was 0.14 kPa and 0.17 kPa for the curl and FEM methods, respectively. FEM reconstruction resulted in 39% higher stiffness than the curl reconstruction (P < 0.05). MRE data quality, defined as shear-compression wave ratio, was higher in peripheral regions than in central regions of the brain (P < 0.05). No significant correlations were observed between MRE data quality and stiffness estimates. DATA CONCLUSION: MRE of the human brain is a robust technique in terms of repeatability. Caution is warranted when comparing stiffness values obtained with different techniques. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Assessment of Imaging Modalities Against Liver Biopsy in Nonalcoholic Fatty Liver Disease: The Amsterdam NAFLD-NASH Cohort.

BACKGROUND: Noninvasive diagnostic methods are urgently required in disease stratification and monitoring in nonalcoholic fatty liver disease (NAFLD). Multiparametric magnetic resonance imaging (MRI) is a promising technique to assess hepatic steatosis, inflammation, and fibrosis, potentially enabling noninvasive identification of individuals with active and advanced stages of NAFLD. PURPOSE: To examine the diagnostic performance of multiparametric MRI for the assessment of disease severity along the NAFLD disease spectrum with comparison to histological scores. STUDY TYPE: Prospective, cohort. POPULATION: Thirty-seven patients with NAFLD. FIELD STRENGTH/SEQUENCE: Multiparametric MRI at 3.0 T consisted of magnetic resonance (MR) spectroscopy (MRS) with multi-echo stimulated-echo acquisition mode, magnitude-based and three-point Dixon using a two-dimensional multi-echo gradient echo, MR elastography (MRE) using a generalized multishot gradient-recalled echo sequence and intravoxel incoherent motion (IVIM) using a multislice diffusion weighted single-shot echo-planar sequence. ASSESSMENT: Histological steatosis grades were compared to proton density fat fraction measured by MRS (PDFFMRS ), magnitude-based MRI (PDFFMRI-M ), and three-point Dixon (PDFFDixon ), as well as FibroScan® controlled attenuation parameter (CAP). Fibrosis and disease activity were compared to IVIM and MRE. FibroScan® liver stiffness measurements were compared to fibrosis levels. Diagnostic performance of all imaging parameters was determined for distinction between simple steatosis and nonalcoholic steatohepatitis (NASH). STATISTICAL TESTS: Spearman's rank test, Kruskal-Wallis test, Dunn's post-hoc test with Holm-Bonferroni P-value adjustment, receiver operating characteristic curve analysis. A P-value <0.05 was considered statistically significant. RESULTS: Histological steatosis grade correlated significantly with PDFFMRS (rs  = 0.66, P < 0.001), PDFFMRI-M (rs  = 0.68, P < 0.001), and PDFFDixon (rs  = 0.67, P < 0.001), whereas no correlation was found with CAP. MRE and IVIM diffusion and perfusion significantly correlated with disease activity (rs  = 0.55, P < 0.001, rs  = -0.40, P = 0.016, rs  = -0.37, P = 0.027, respectively) and fibrosis (rs  = 0.55, P < 0.001, rs  = -0.46, P = 0.0051; rs  = -0.53, P < 0.001, respectively). MRE and IVIM diffusion had the highest area-under-the-curve for distinction between simple steatosis and NASH (0.79 and 0.73, respectively). DATA CONCLUSION: Multiparametric MRI is a promising method for noninvasive, accurate, and sensitive distinction between simple hepatic steatosis and NASH, as well as for the assessment of steatosis and fibrosis severity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: 2.

The apparent mechanical effect of isolated amyloid-ß and α-synuclein aggregates revealed by multi-frequency MRE.

Several biological processes are involved in dementia, and fibrillar aggregation of misshaped endogenous proteins appears to be an early hallmark of neurodegenerative disease. A recently developed means of studying neurodegenerative diseases is magnetic resonance elastography (MRE), an imaging technique investigating the mechanical properties of tissues. Although mechanical changes associated with these diseases have been detected, the specific signal of fibrils has not yet been isolated in clinical or preclinical studies. The current study aims to exploit the fractal-like properties of fibrils to separate them from nonaggregated proteins using a multi-frequency MRE power law exponent in a phantom study. Two types of fibril, α-synuclein (α-Syn) and amyloid-ß (Aß), and a nonaggregated protein, bovine serum albumin, used as control, were incorporated in a dedicated nondispersive agarose phantom. Elastography was performed at multiple frequencies between 400 and 1200 Hz. After 3D-direct inversion, storage modulus (G'), phase angle (ϕ), wave speed and the power law exponent (y) were computed. No significant changes in G' and ϕ were detected. Both α-Syn and Aß inclusions showed significantly higher y values than control inclusions (P = 0.005) but did not differ between each other. The current phantom study highlighted a specific biomechanical effect of α-Syn and Aß aggregates, which was better captured with the power law exponent derived from multi-frequency MRE than with single frequency-derived parameters.

Unipolar MR elastography: Theory, numerical analysis and implementation.

In MR elastography (MRE), zeroth moment balanced motion-encoding gradients (MEGs) are incorporated into MRI sequences to induce a phase shift proportional to the local displacement caused by external actuation. To maximize the signal-to-noise ratio (SNR), fractional encoding is employed, i.e., the MEG duration is reduced below the wave period. Here, gradients encode primarily the velocity of the motion-reducing encoding efficiency. Thus, in GRE-MRE, T2 * decay and motion sensitivity have to be balanced, imposing a lower limit on repetition times (TRs). We propose to use a single trapezoidal gradient, a "unipolar gradient", to directly encode spin displacement. Such gradients cannot be used in conventional sequences as they exhibit a large zeroth moment and dephase magnetization. By time-reversing a spoiled SSFP sequence, the spoiling gradient becomes an efficient unipolar MEG. The proposed "unipolar MRE" technique benefits from this approach in three ways: first, displacement encoding is split over multiple TRs increasing motion sensitivity; second, spoiler and MEG coincide, allowing a reduction in TR; third, motion sensitivity of a typical unipolar lobe is of an order of magnitude higher than a bipolar MEG of equal duration. In this work, motion encoding using unipolar MRE is analyzed using the extended phase graph (EPG) formalism with a periodic motion propagator. As an approximation, the two-transverse TR approximation for diffusion-weighted SSFP is extended to incorporate cyclic motion. A complex encoding efficiency metric is introduced to compare the displacement fields of unipolar and conventional GRE-MRE sequences in both magnitude and phase. The derived theoretical encoding equations are used to characterize the proposed sequence using an extensive parameter study. Unipolar MRE is validated against conventional GRE-MRE in a phantom study showing excellent agreement between measured displacement fields. In addition, unipolar MRE yields significantly increased octahedral shear strain-SNR relative to conventional GRE-MRE and allows for the recovery of high stiffness inclusions, where conventional GRE-MRE fails.

Biomarkers of liver fibrosis: prospective comparison of multimodal magnetic resonance, serum algorithms and transient elastography.

BACKGROUND AND AIMS: Accurate biomarkers for quantifying liver fibrosis are important for clinical practice and trial end-points. We compared the diagnostic performance of magnetic resonance imaging (MRI), including gadoxetate-enhanced MRI and 31P-MR spectroscopy, with fibrosis stage and serum fibrosis algorithms in a clinical setting. Also, in a subset of patients, MR- and transient elastography (MRE and TE) was evaluated when available. METHODS: Patients were recruited prospectively if they were scheduled to undergo liver biopsy on a clinical indication due to elevated liver enzyme levels without decompensated cirrhosis. Within a month of the clinical work-up, an MR-examination and liver needle biopsy were performed on the same day. Based on late-phase gadoxetate-enhanced MRI, a mathematical model calculated hepatobiliary function (relating to OATP1 and MRP2). The hepatocyte gadoxetate uptake rate (KHep) and the normalised liver-to-spleen contrast ratio (LSC_N10) were also calculated. Nine serum fibrosis algorithms were investigated (GUCI, King's Score, APRI, FIB-4, Lok-Index, NIKEI, NASH-CRN regression score, Forns' score, and NAFLD-fibrosis score). RESULTS: The diagnostic performance (AUROC) for identification of significant fibrosis (F2-4) was 0.78, 0.80, 0.69, and 0.78 for MRE, TE, LSC_N10, and GUCI, respectively. For the identification of advanced fibrosis (F3-4), the AUROCs were 0.93, 0.84, 0.81, and 0.82 respectively. CONCLUSION: MRE and TE were superior for non-invasive identification of significant fibrosis. Serum fibrosis algorithms developed for specific liver diseases are applicable in this cohort of diverse liver diseases aetiologies. Gadoxetate-MRI was sufficiently sensitive to detect the low function losses associated with fibrosis. None was able to efficiently distinguish between stages within the low fibrosis stages.Lay summaryExcessive accumulation of scar tissue, fibrosis, in the liver is an important aspect in chronic liver disease. To replace the invasive needle biopsy, we have explored non-invasive methods to assess liver fibrosis. In our study we found that elastographic methods, which assess the mechanical properties of the liver, are superior in assessing fibrosis in a clinical setting. Of interest from a clinical trial point-of-view, none of the tested methods was sufficiently accurate to distinguish between adjacent moderate fibrosis stages.

Ristretto MRE: A generalized multi-shot GRE-MRE sequence.

In order to acquire consistent k-space data in MR elastography, a fixed temporal relationship between the MRI sequence and the underlying period of the wave needs to be ensured. To this end, conventional GRE-MRE enforces synchronization through repeated triggering of the transducer and forcing the sequence repetition time to be equal to an integer multiple of the wave period. For wave frequencies below 100 Hz, however, this leads to prolonged acquisition times, as the repetition time scales inversely with frequency. A previously developed multi-shot approach (eXpresso MRE) to multi-slice GRE-MRE tackles this issue by acquiring an integer number of slices per wave period, which allows acquisition to be accelerated in typical scenarios by a factor of two or three. In this work, it is demonstrated that the constraints imposed by the eXpresso scheme are overly restrictive. We propose a generalization of the sequence in three steps by incorporating sequence delays into imaging shots and allowing for interleaved wave-phase acquisition. The Ristretto scheme is compared in terms of imaging shot and total scan duration relative to eXpresso and conventional GRE-MRE and is validated in three different phantom studies. First, the agreement of measured displacement fields in different stages of the sequence generalization is shown. Second, performance is compared for 25, 36, 40, and 60 Hz actuation frequencies. Third, the performance is assessed for the acquisition of different numbers of slices (13 to 17). In vivo feasibility is demonstrated in the liver and the breast. Here, Ristretto is compared with an optimized eXpresso sequence, leading to scan accelerations of 15% and 5%, respectively, without compromising displacement field and stiffness estimates in general. The Ristretto concept allows us to choose imaging shot durations on a fine grid independent of the number of slices and the wave frequency, permitting 2- to 4.5-fold acceleration of conventional GRE-MRE acquisitions.

Magnetic resonance elastography of skeletal muscle deep tissue injury.

The current state-of-the-art diagnosis method for deep tissue injury in muscle, a subcategory of pressure ulcers, is palpation. It is recognized that deep tissue injury is frequently preceded by altered biomechanical properties. A quantitative understanding of the changes in biomechanical properties preceding and during deep tissue injury development is therefore highly desired. In this paper we quantified the spatial-temporal changes in mechanical properties upon damage development and recovery in a rat model of deep tissue injury. Deep tissue injury was induced in nine rats by two hours of sustained deformation of the tibialis anterior muscle. Magnetic resonance elastography (MRE), T2 -weighted, and T2 -mapping measurements were performed before, directly after indentation, and at several timepoints during a 14-day follow-up. The results revealed a local hotspot of elevated shear modulus (from 3.30 ± 0.14 kPa before to 4.22 ± 0.90 kPa after) near the center of deformation at Day 0, whereas the T2 was elevated in a larger area. During recovery there was a clear difference in the time course of the shear modulus and T2 . Whereas T2 showed a gradual normalization towards baseline, the shear modulus dropped below baseline from Day 3 up to Day 10 (from 3.29 ± 0.07 kPa before to 2.68 ± 0.23 kPa at Day 10, P < 0.001), followed by a normalization at Day 14. In conclusion, we found an initial increase in shear modulus directly after two hours of damage-inducing deformation, which was followed by decreased shear modulus from Day 3 up to Day 10, and subsequent normalization. The lower shear modulus originates from the moderate to severe degeneration of the muscle. MRE stiffness values were affected in a smaller area as compared with T2 . Since T2 elevation is related to edema, distributing along the muscle fibers proximally and distally from the injury, we suggest that MRE is more specific than T2 for localization of the actual damaged area.

Assessing Tumor Mechanics by MR Elastography at Different Strain Levels.

BACKGROUND: Malignant tumors are associated with increased tissue rigidity, which can be an indicator of tumor progression. MR elastography (MRE) has the potential to study the variations of tumor mechanical properties. ex vivo studies have shown the ability of MRE to assess increase of mechanical properties; nevertheless, it has not yet been observed in vivo. PURPOSE: To propose a method to assess the increase in mechanical properties of tumors in vivo under static external compression using MRE. STUDY TYPE: Prospective, experimental study. ANIMAL MODEL: Forty-six SCID mice with subcutaneous tumor implantation (patient-derived hepatocellular carcinoma xenografts, Model 1, n = 13, and Model 2, n = 33). FIELD STRENGTH/SEQUENCE: 7.0T; a spin echo sequence was used for anatomical images and a modified spin echo sequence for elastography acquisitions with a vibration frequency of 600 Hz. ASSESSMENT: An inflatable balloon was placed on the abdomen to apply a load to the tumor. MRE acquisitions were performed at the basal state and at increasing compression levels. Anatomical images were used to calculate the octahedral shear strain between the tumor at the basal strain state and each strain level. For six mice (Model 2), each static preloading scan was acquired twice consecutively without moving the mouse to evaluate repeatability. Statistical Tests: The Bland-Altman method was used to assess repeatability. Correlations between tumor stiffness and deformation were evaluated with Pearson correlation coefficients. RESULTS: For stiffness (G*), a good repeatability was obtained between the acquisitions; the limits of agreement of the Bland-Altman test were [-10.17%; 11.49%] with an absolute bias of 0.66%. A significant correlation between tumor stiffness and deformation was observed for both models (Model 1: r = 0.57, P < 0.0001 and Model 2: r = 0.31, P < 0.0001). DATA CONCLUSION: We establish that tumor mechanical properties can increase under mechanical compression. This increase can effectively be monitored using a proposed MRE setup. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1982-1989.

Stiffness reconstruction methods for MR elastography.

Assessment of tissue stiffness is desirable for clinicians and researchers, as it is well established that pathophysiological mechanisms often alter the structural properties of tissue. Magnetic resonance elastography (MRE) provides an avenue for measuring tissue stiffness and has a long history of clinical application, including staging liver fibrosis and stratifying breast cancer malignancy. A vital component of MRE consists of the reconstruction algorithms used to derive stiffness from wave-motion images by solving inverse problems. A large range of reconstruction methods have been presented in the literature, with differing computational expense, required user input, underlying physical assumptions, and techniques for numerical evaluation. These differences, in turn, have led to varying accuracy, robustness, and ease of use. While most reconstruction techniques have been validated against in silico or in vitro phantoms, performance with real data is often more challenging, stressing the robustness and assumptions of these algorithms. This article reviews many current MRE reconstruction methods and discusses the aforementioned differences. The material assumptions underlying the methods are developed and various approaches for noise reduction, regularization, and numerical discretization are discussed. Reconstruction methods are categorized by inversion type, underlying assumptions, and their use in human and animal studies. Future directions, such as alternative material assumptions, are also discussed.

Analysis and improvement of motion encoding in magnetic resonance elastography.

Magnetic resonance elastography (MRE) utilizes phase contrast magnetic resonance imaging (MRI), which is phase locked to externally generated mechanical vibrations, to measure the three-dimensional wave displacement field. At least four measurements with linear-independent encoding directions are necessary to correct for spurious phase contributions if effects from imaging gradients are non-negligible. In MRE, three encoding schemes have been used: unbalanced four- and six-point and balanced four-point ('tetrahedral') encoding. The first two sensitize to motion with orthogonal gradients, with the four-point method acquiring a single reference scan without motion sensitization, whereas three additional scans with inverted gradients are used with six-point encoding, leading to two-fold higher displacement-to-noise ratio (DNR) and 50% longer scan duration. Balanced four-point (tetrahedral) encoding encodes along the four diagonals of a cube, with one direction serving as a reference for the other three encoding directions, similar to four-point encoding. The objective of this work is to introduce a theoretical framework to compare different motion sensitization strategies with respect to their motion encoding efficiency in two fundamental encoding limits, the gradient strength limit and the dynamic range limit, which are both placed in relation to conventional gradient recalled echo (GRE)- and spin echo (SE)-based MRE sequences. We apply the framework to the three aforementioned schemes and show that the motion encoding efficiency of unbalanced four- and six-point encoding schemes in the gradient-limited regime can be increased by a factor of 1.5 when using all physical gradient channels concurrently. Furthermore, it is demonstrated that reversing the direction of the reference in balanced four-point (tetrahedral) encoding results in the Hadamard encoding scheme, which leads to increased DNR by 2 compared with balanced four-point encoding and 2.8 compared with unbalanced four-point encoding. As an example, we show that optimal encoding can be utilized to reduce the acquisition time of standard liver MRE in vivo from four to two breath holds.

Value of whole breast magnetic resonance elastography added to MRI for lesion characterization.

The purpose of this work was to assess the diagnostic value of magnetic resonance elastography (MRE) in addition to MRI to differentiate malignant from benign breast tumors, and the feasibility of performing MRE on the whole breast. MRE quantified biomechanical properties within the entire breast (50 slices) using an 11 min acquisition protocol at an isotropic image acquisition resolution of 2 × 2 × 2 mm3 . Fifty patients were included. Finally, 43 patients (median age 52) with a suspect breast lesion detected by mammography and/or ultrasound were examined by MRI and MRE at 1.5 T. The viscoelastic parameters, i.e. elasticity (Gd ), viscosity (Gl ), the magnitude of the complex shear modulus Gd2+Gl2, and the phase angle y=2πatanGlGd, were measured via MRE and correlated with MRI Breast Imaging-Reporting and Data System (BI-RADS) score, histological type, and histological grade. Stroma component and angiogenesis were also correlated with viscoelastic properties. In the 43 lesions, Gd decreased and y increased with the MRI BI-RADS score (pGd  = 0.02, py  = 0.002), whereas (Gl ) and y were increased in malignant lesions (pGl  = 0.045, py  = 0.0004). The area under the curve increased from 0.84 for MRI BI-RADS alone to 0.92 with the MRI BI-RADS and y (AUC increase +0.08; 95% CI (-0.003; 0.16)). Lesion characterization using the y parameter increased the diagnostic accuracy. The phase angle y was found to have a significant role (p = 0.01) in predicting malignancy independently of the MRI BI-RADS. Interestingly, histological analysis showed no correlation between viscoelastic parameters and percentage and type of stroma, CD34 quantification of vessels, or histological grade. The combination of MRE and MRI improves the diagnostic accuracy for breast lesions in the studied cohort. In particular, the phase angle y was found to have a significant role in predicting malignancy in addition to BI-RADS.

Characterization of glioblastoma in an orthotopic mouse model with magnetic resonance elastography.

Glioblastoma (GBM) is the most common primary brain tumor. It is highly malignant and has a correspondingly poor prognosis. Diagnosis and monitoring are mainly accomplished with MRI, but remain challenging in some cases. Therefore, complementary methods for tumor detection and characterization would be beneficial. Using magnetic resonance elastography (MRE), we performed a longitudinal study of the biomechanical properties of intracranially implanted GBM in mice and compared the results to histopathology. The biomechanical parameters of viscoelastic modulus, shear wave speed and phase angle were significantly lower in tumors compared with healthy brain tissue and decreased over time with tumor progression. Moreover, some MRE parameters revealed sub-regions at later tumor stages, which were not easily detectable on anatomical MRI images. Comparison with histopathology showed that softer tumor regions contained necrosis and patches of viable tumor cells. In contrast, areas of densely packed tumor cells and blood vessels identified with histology coincided with higher values of viscoelastic modulus and shear wave speed. Interestingly, the phase angle was independent from these anatomical variations. In summary, MRE depicted longitudinal and morphological changes in GBM and may prove valuable for tumor characterization in patients.

Rheological determinants for simultaneous staging of hepatic fibrosis and inflammation in patients with chronic liver disease.

The purpose of this study is to investigate the use of fundamental rheological parameters as quantified by MR elastography (MRE) to measure liver fibrosis and inflammation simultaneously in humans. MRE was performed on 45 patients at 3 T using a vibration frequency of 56 Hz. Fibrosis and inflammation scores were obtained from liver biopsies. Biomechanical properties were quantified in terms of complex shear modulus G* as well as shear wave phase velocity c and shear wave attenuation α. A rheological fractional derivative order model was used to investigate the linear dependence of the free model parameters (dispersion slope y, intrinsic speed c0 , and intrinsic relaxation time τ) on histopathology. Leave-one-out cross-validation was then utilized to demonstrate the effectiveness of the model. The intrinsic speed c0 increases with hepatic fibrosis, while an increased relaxation time τ is reflective of more inflammation of the liver parenchyma. The dispersion slope y does not depend either on fibrosis or on inflammation. The proposed rheological model, given this specific parameterization, establishes the functional dependences of biomechanical parameters on histological fibrosis and inflammation. The leave-one-out cross-validation demonstrates that the model allows identification, from the MRE measurements, of the histology scores when grouped into low-/high-grade fibrosis and low-/high-grade inflammation with significance levels of P = 0.0004 (fibrosis) and P = 0.035 (inflammation). The functional dependences of intrinsic speed and relaxation time on fibrosis and inflammation, respectively, shed new light onto the impact hepatic pathological changes on liver tissue biomechanics in humans. The dispersion slope y appears to represent a structural parameter of liver parenchyma not impacted by the severity of fibrosis/inflammation present in this patient cohort. This specific parametrization of the well-established rheological fractional order model is valuable for the clinical assessment of both fibrosis and inflammation scores, going beyond the capability of the plain shear modulus measurement commonly used for MRE.

Liver Stiffness Values Are Lower in Pediatric Subjects than in Adults and Increase with Age: A Multifrequency MR Elastography Study.

Purpose To determine if healthy hepatic mechanical properties differ between pediatric and adult subjects at magnetic resonance (MR) elastography. Materials and Methods Liver shear moduli in 24 healthy pediatric participants (13 children aged 5-14 years [seven boys, six girls] and 11 adolescents aged 15-18 years [six boys, five girls]) and 10 healthy adults (aged 22-36 years [five men, five women]) were obtained with 3-T MR elastography at 28, 56, and 84 Hz. Relationships between shear moduli and age were assessed with Spearman correlations. Differences between age groups were determined with one-way analysis of variance and Tukey multiple comparisons tests. Results Liver stiffness values (means ± standard deviations) were significantly lower in children and adolescents than in adults at 56 Hz (children, 2.2 kPa ± 0.3; adolescents, 2.2 kPa ± 0.2; adults, 2.6 kPa ± 0.3; analysis of variance, P = .009) and 84 Hz (children, 5.6 kPa ± 0.8; adolescents, 6.5 kPa ± 1.2; adults, 7.8 kPa ± 1.2; analysis of variance, P = .0003) but not at 28 Hz (children, 1.2 kPa ± 0.2; adolescents, 1.3 kPa ± 0.3; adults, 1.2 kPa ± 0.2; analysis of variance, P = .40). At 56 and 84 Hz, liver stiffness increased with age (Spearman correlation, r = 0.38 [P = .03] and r = 0.54 [P = .001], respectively). Stiffness varied less with frequency in children and adolescents than in adults (analysis of variance, P = .0009). No significant differences were found in shear moduli at 28, 56, or 84 Hz or frequency dependence between children and adolescents (P = .38, P = .99, P = .14, and P = .30, respectively, according to Tukey tests). Conclusion Liver stiffness values are lower and vary less with frequency in children and adolescents than in adults. Stiffness increases with age during normal development and approaches adult values during adolescence. Comparing pediatric liver stiffness to adult baseline values to detect pediatric liver mechanical abnormalities may not allow detection of mild disease and may lead to underestimation of severity. © RSNA, 2016 Online supplemental material is available for this article.

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial.

BACKGROUND: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed. AIM: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease. METHODS: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis. RESULTS: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-ß3 and IL-10 pathways with treatment. CONCLUSION: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-ß3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.

A framework for optimization-based design of motion encoding in magnetic resonance elastography.

PURPOSE: In conventional three-dimensional magnetic resonance elastography, motion encoding gradients (MEGs) synchronized to a mechanical excitation are applied separately in each direction to encode tissue displacement generated by the corresponding waves. This requires long acquisition times that introduce errors due to patient motion and may hinder clinical deployment of magnetic resonance elastography. In this article, a framework for MEGs sequence design is proposed to reduce scanning time and increase signal-to-noise ratio. THEORY AND METHODS: The approach is based on applying MEGs in all three directions simultaneously with varying parameters, and formulation of the problem as a linear estimation of the wave properties. Multidirectional MEGs sequences are derived by setting the problem in an experimental design framework. Such designs are implemented and evaluated on simulation and phantom data. RESULTS: Estimation error of the displacement using the proposed MEGs designs is reduced up to a factor of two in comparison with a unidirectional design with a same number of acquisitions. Alternatively, for the same error, scanning time is reduced up to a factor of three using the multidirectional designs. CONCLUSION: The proposed framework generalizes acquisition of magnetic resonance elastography, and allows quantification of design performance, and optimization-based derivation of designs.

Microvasculature alters the dispersion properties of shear waves--a multi-frequency MR elastography study.

Magnetic Resonance Elastography (MRE) uses macroscopic shear wave propagation to quantify mechanical properties of soft tissues. Micro-obstacles are capable of affecting the macroscopic dispersion properties of shear waves. Since disease or therapy can change the mechanical integrity and organization of vascular structures, MRE should be able to sense these changes if blood vessels represent a source for wave scattering. To verify this, MRE was performed to quantify alteration of the shear wave speed cs due to the presence of vascular outgrowths using an aortic ring model. Eighteen fragments of rat aorta included in a Matrigel matrix (n=6 without outgrowths, n=6 with a radial outgrowth extent of ~600 µm and n=6 with ~850 µm) were imaged using a 7 Tesla MR scanner (Bruker, PharmaScan). High resolution anatomical images were acquired in addition to multi-frequency MRE (ν = 100, 115, 125, 135 and 150 Hz). Average cs was measured within a ring of ~900 µm thickness encompassing the aorta and were normalized to cs0 of the corresponding Matrigel. The frequency dependence was fit to the power law model cs ~ν(y). After scanning, optical microscopy was performed to visualize outgrowths. Results demonstrated that in presence of vascular outgrowths (1) normalized cs significantly increased for the three highest frequencies (Kruskal-Wallis test, P = 0.0002 at 125 Hz and P = 0.002 at 135 Hz and P = 0.003 at 150 Hz) but not for the two lowest (Kruskal-Wallis test, P = 0.63 at 100 Hz and P = 0.87 at 115 Hz), and (2) normalized cs followed a power law behavior not seen in absence of vascular outgrowths (ANOVA test, P < 0.0001). These results showed that vascular outgrowths acted as micro-obstacles altering the dispersion relationships of propagating shear waves and that MRE could provide valuable information about microvascular changes.