Cortical matrix remodeling as a hallmark of relapsing-remitting neuroinflammation in MR elastography and quantitative MRI.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that involves both white and gray matter. Although gray matter damage is a major contributor to disability in MS patients, conventional clinical magnetic resonance imaging (MRI) fails to accurately detect gray matter pathology and establish a clear correlation with clinical symptoms. Using magnetic resonance elastography (MRE), we previously reported global brain softening in MS and experimental autoimmune encephalomyelitis (EAE). However, it needs to be established if changes of the spatiotemporal patterns of brain tissue mechanics constitute a marker of neuroinflammation. Here, we use advanced multifrequency MRE with tomoelastography postprocessing to investigate longitudinal and regional inflammation-induced tissue changes in EAE and in a small group of MS patients. Surprisingly, we found reversible softening in synchrony with the EAE disease course predominantly in the cortex of the mouse brain. This cortical softening was associated neither with a shift of tissue water compartments as quantified by T2-mapping and diffusion-weighted MRI, nor with leukocyte infiltration as seen by histopathology. Instead, cortical softening correlated with transient structural remodeling of perineuronal nets (PNNs), which involved abnormal chondroitin sulfate expression and microgliosis. These mechanisms also appear to be critical in humans with MS, where tomoelastography for the first time demonstrated marked cortical softening. Taken together, our study shows that neuroinflammation (i) critically affects the integrity of PNNs in cortical brain tissue, in a reversible process that correlates with disease disability in EAE, (ii) reduces the mechanical integrity of brain tissue rather than leading to water accumulation, and (iii) shows similar spatial patterns in humans and mice. These results raise the prospect of leveraging MRE and quantitative MRI for MS staging and monitoring treatment in affected patients.

Tomoelastography and Pancreatic Extracellular Volume Fraction Derived From MRI for Predicting Clinically Relevant Postoperative Pancreatic Fistula.

BACKGROUND: Pancreatic stiffness and extracellular volume fraction (ECV) are potential imaging biomarkers for pancreatic fibrosis. Clinically relevant postoperative fistula (CR-POPF) is one of the most severe complications after pancreaticoduodenectomy. Which imaging biomarker performs better for predicting the risk of CR-POPF remains unknown. PURPOSE: To evaluate the diagnostic performance of ECV and tomoelastography-derived pancreatic stiffness for predicting the risk of CR-POPF in patients undergoing pancreaticoduodenectomy. STUDY TYPE: Prospective. POPULATION: Eighty patients who underwent multiparametric pancreatic MRI before pancreaticoduodenectomy, among whom 16 developed CR-POPF and 64 did not. FIELD STRENGTH/SEQUENCE: 3 T/tomoelastography and precontrast and postcontrast T1 mapping of the pancreas. ASSESSMENT: Pancreatic stiffness was measured on the tomographic c-map, and pancreatic ECV was calculated from precontrast and postcontrast T1 maps. Pancreatic stiffness and ECV were compared with histological fibrosis grading (F0-F3). The optimal cutoff values for predicting CR-POPF were determined, and the correlation between CR-POPF and imaging parameters was evaluated. STATISTICAL TESTS: The Spearman's rank correlation and multivariate linear regression analysis was conducted. The receiver operating characteristic curve analysis and logistic regression analysis was performed. A double-sided P < 0.05 indicated a statistically significant difference. RESULTS: Pancreatic stiffness and ECV both showed a significantly positive correlation with histological pancreatic fibrosis (r = 0.73 and 0.56, respectively). Patients with advanced pancreatic fibrosis had significantly higher pancreatic stiffness and ECV compared to those with no/mild fibrosis. Pancreatic stiffness and ECV were also correlated with each other (r = 0.58). Lower pancreatic stiffness (<1.38 m/sec), lower ECV (<0.28), nondilated main pancreatic duct (<3 mm) and pathological diagnosis other than pancreatic ductal adenocarcinoma were associated with higher risk of CR-POPF at univariate analysis, and pancreatic stiffness was independently associated with CR-POPF at multivariate analysis (odds ratio: 18.59, 95% confidence interval: 4.45, 77.69). DATA CONCLUSION: Pancreatic stiffness and ECV were associated with histological fibrosis grading, and pancreatic stiffness was an independent predictor for CR-POPF. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.

Three-Dimensional Multifrequency MR Elastography for Microvascular Invasion and Prognosis Assessment in Hepatocellular Carcinoma.

BACKGROUND: Pretreatment identification of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is important when selecting treatment strategies. PURPOSE: To improve models for predicting MVI and recurrence-free survival (RFS) by developing nomograms containing three-dimensional (3D) MR elastography (MRE). STUDY TYPE: Prospective. POPULATION: 188 patients with HCC, divided into a training cohort (n = 150) and a validation cohort (n = 38). In the training cohort, 106/150 patients completed a 2-year follow-up. FIELD STRENGTH/SEQUENCE: 1.5T 3D multifrequency MRE with a single-shot spin-echo echo planar imaging sequence, and 3.0T multiparametric MRI (mp-MRI), consisting of diffusion-weighted echo planar imaging, T2-weighted fast spin echo, in-phase out-of-phase T1-weighted fast spoiled gradient-recalled dual-echo and dynamic contrast-enhanced gradient echo sequences. ASSESSMENT: Multivariable analysis was used to identify the independent predictors for MVI and RFS. Nomograms were constructed for visualization. Models for predicting MVI and RFS were built using mp-MRI parameters and a combination of mp-MRI and 3D MRE predictors. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, chi-squared or Fisher's exact tests, multivariable analysis, area under the receiver operating characteristic curve (AUC), DeLong test, Kaplan-Meier analysis and log rank tests. P < 0.05 was considered significant. RESULTS: Tumor c and liver c were independent predictors of MVI and RFS, respectively. Adding tumor c significantly improved the diagnostic performance of mp-MRI (AUC increased from 0.70 to 0.87) for MVI detection. Of the 106 patients in the training cohort who completed the 2-year follow up, 34 experienced recurrence. RFS was shorter for patients with MVI-positive histology than MVI-negative histology (27.1 months vs. >40 months). The MVI predicted by the 3D MRE model yielded similar results (26.9 months vs. >40 months). The MVI and RFS nomograms of the histologic-MVI and model-predicted MVI-positive showed good predictive performance. DATA CONCLUSION: Biomechanical properties of 3D MRE were biomarkers for MVI and RFS. MVI and RFS nomograms were established. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Summary and overview of the first ISMRM workshop on magnetic resonance elastography, August 25-26, 2022, Berlin, Germany.

An ISMRM workshop on MR elastography was held at Charité-Universitätsmedizin Berlin on August 25-26, 2022. As an exclusively in-person event, 65 participants from 9 countries attended the workshop despite COVID-19-related restrictions. The topics of the workshop covered cellular and microtissue mechanical interactions, the development of MR elastography driver technology, approaches to inverse problems, clinical applications, and integration of MR elastography into multiparametric MRI protocols. The workshop was a great success by promoting direct knowledge exchange as well as for strategizing future directions for MR elastography. In this symposium review, we briefly summarized all oral presentations as well as the concluding panel discussion.

Characterization of renal fibrosis in rats with chronic kidney disease by in vivo tomoelastography.

Chronic kidney disease (CKD) is characterized by structural changes, such as tubular atrophy, renal fibrosis, and glomerulosclerosis, all of which affect the viscoelastic properties of biological tissues. However, detection of renal viscoelasticity changes because diagnostic markers by in vivo elastography lack histopathological validation through animal models. Therefore, we investigated in vivo multiparametric magnetic resonance imaging (mp-MRI), including multifrequency magnetic resonance elastography-based tomoelastography, in the kidneys of 10 rats with adenine-induced CKD and eight healthy controls. Kidney volume (in mm3 ), water diffusivity (apparent diffusion coefficient [ADC] in mm2 /s), shear wave speed (SWS; in m/s; related to stiffness), and wave penetration rate (PR; in m/s; related to inverse viscosity) were quantified by mp-MRI and correlated with histopathologically determined renal fibrosis (collagen area fraction [CAF]; in %). Kidney volume (40% ± 29%, p = 0.009), SWS (11% ± 12%, p = 0.016), and PR (20% ± 15%, p = 0.004) were significantly increased in CKD, which was accompanied by ADC (-24% ± 27%, p = 0.02). SWS, PR, and ADC were correlated with CAF with R = 0.63, 0.75, and -0.5 (all p < 0.05), respectively. In the CKD rats, histopathology showed tubule dilation due to adenine crystal deposition. Collectively, our results suggest that collagen accumulation during CKD progression transforms soft-compliant renal tissue into a more rigid-solid state with reduced water mobility. We hypothesized that tubule dilation-a specific feature of our model-might lead to higher intraluminal pressure, which could also contribute to elevated renal stiffness. Tomoelastography is a promising tool for noninvasively assessing disease progression, detecting biomechanical properties that are sensitive to different pathologic features of CKD.

How tissue fluidity influences brain tumor progression.

Mechanical properties of biological tissues and, above all, their solid or fluid behavior influence the spread of malignant tumors. While it is known that solid tumors tend to have higher mechanical rigidity, allowing them to aggressively invade and spread in solid surrounding healthy tissue, it is unknown how softer tumors can grow within a more rigid environment such as the brain. Here, we use in vivo magnetic resonance elastography (MRE) to elucidate the role of anomalous fluidity for the invasive growth of soft brain tumors, showing that aggressive glioblastomas (GBMs) have higher water content while behaving like solids. Conversely, our data show that benign meningiomas (MENs), which contain less water than brain tissue, are characterized by fluid-like behavior. The fact that the 2 tumor entities do not differ in their soft properties suggests that fluidity plays an important role for a tumor's aggressiveness and infiltrative potential. Using tissue-mimicking phantoms, we show that the anomalous fluidity of neurotumors physically enables GBMs to penetrate surrounding tissue, a phenomenon similar to Saffman-Taylor viscous-fingering instabilities, which occur at moving interfaces between fluids of different viscosity. Thus, targeting tissue fluidity of malignant tumors might open horizons for the diagnosis and treatment of cancer.

Comparison of inversion methods in MR elastography: An open-access pipeline for processing multifrequency shear-wave data and demonstration in a phantom, human kidneys, and brain.

PURPOSE: Magnetic resonance elastography (MRE) maps the viscoelastic properties of soft tissues for diagnostic purposes. However, different MRE inversion methods yield different results, which hinder comparison of values, standardization, and establishment of quantitative MRE markers. Here, we introduce an expandable, open-access, webserver-based platform that offers multiple inversion techniques for multifrequency, 3D MRE data. METHODS: The platform comprises a data repository and standard MRE inversion methods including local frequency estimation (LFE), direct-inversion based multifrequency dual elasto-visco (MDEV) inversion, and wavenumber-based (k-) MDEV. The use of the platform is demonstrated in phantom data and in vivo multifrequency MRE data of the kidneys and brains of healthy volunteers. RESULTS: Detailed maps of stiffness were generated by all inversion methods showing similar detail of anatomy. Specifically, the inner renal cortex had higher shear wave speed (SWS) than renal medulla and outer cortex without lateral differences. k-MDEV yielded higher SWS values than MDEV or LFE (full kidney/brain k-MDEV: 2.71 ± 0.19/1.45 ± 0.14 m/s, MDEV: 2.14 ± 0.16/0.99 ± 0.11 m/s, LFE: 2.12 ± 0.15/0.89 ± 0.06 m/s). CONCLUSION: The freely accessible platform supports the comparison of MRE results obtained with different inversion methods, filter thresholds, or excitation frequencies, promoting reproducibility in MRE across community-developed methods.

Microscopic multifrequency MR elastography for mapping viscoelasticity in zebrafish.

PURPOSE: The zebrafish (Danio rerio) has become an important animal model in a wide range of biomedical research disciplines. Growing awareness of the role of biomechanical properties in tumor progression and neuronal development has led to an increasing interest in the noninvasive mapping of the viscoelastic properties of zebrafish by elastography methods applicable to bulky and nontranslucent tissues. METHODS: Microscopic multifrequency MR elastography is introduced for mapping shear wave speed (SWS) and loss angle (φ) as markers of stiffness and viscosity of muscle, brain, and neuroblastoma tumors in postmortem zebrafish with 60 µm in-plane resolution. Experiments were performed in a 7 Tesla MR scanner at 1, 1.2, and 1.4 kHz driving frequencies. RESULTS: Detailed zebrafish viscoelasticity maps revealed that the midbrain region (SWS = 3.1 ± 0.7 m/s, φ = 1.2 ± 0.3 radian [rad]) was stiffer and less viscous than telencephalon (SWS = 2.6 ± 0. 5 m/s, φ = 1.4 ± 0.2 rad) and optic tectum (SWS = 2.6 ± 0.5 m/s, φ = 1.3 ± 0.4 rad), whereas the cerebellum (SWS = 2.9 ± 0.6 m/s, φ = 0.9 ± 0.4 rad) was stiffer but less viscous than both (all p < .05). Overall, brain tissue (SWS = 2.9 ± 0.4 m/s, φ = 1.2 ± 0.2 rad) had similar stiffness but lower viscosity values than muscle tissue (SWS = 2.9 ± 0.5 m/s, φ = 1.4 ± 0.2 rad), whereas neuroblastoma (SWS = 2.4 ± 0.3 m/s, φ = 0.7 ± 0.1 rad, all p < .05) was the softest and least viscous tissue. CONCLUSION: Microscopic multifrequency MR elastography-generated maps of zebrafish show many details of viscoelasticity and resolve tissue regions, of great interest in neuromechanical and oncological research and for which our study provides first reference values.

Feasibility of Intestinal MR Elastography in Inflammatory Bowel Disease.

BACKGROUND: While MR enterography allows detection of inflammatory bowel disease (IBD), the findings continue to be of limited use in guiding treatment-medication vs. surgery. PURPOSE: To test the feasibility of MR elastography of the gut in healthy volunteers and IBD patients. STUDY TYPE: Prospective pilot. POPULATION: Forty subjects (healthy volunteers: n = 20, 37 ± 14 years, 10 women; IBD patients: n = 20 (ulcerative colitis n = 9, Crohn's disease n = 11), 41 ± 15 years, 11 women). FIELD STRENGTH/SEQUENCE: Multifrequency MR elastography using a single-shot spin-echo echo planar imaging sequence at 1.5 T with drive frequencies of 40, 50, 60, and 70 Hz. ASSESSMENT: Maps of shear-wave speed (SWS, in m/s) and loss angle (φ, in rad), representing stiffness and solid-fluid behavior, respectively, were generated using tomoelastography data processing. Histopathological analysis of surgical specimens was used as reference standard in patients. STATISTICAL TESTS: Unpaired t-test, one-way analysis of variance followed by Tukey post hoc analysis, Pearson's correlation coefficient and area under the receiver operating characteristic curve (AUC) with 95%-confidence interval (CI). Significance level of 5%. RESULTS: MR elastography was feasible in all 40 subjects (100% technical success rate). SWS and φ were significantly increased in IBD by 21% and 20% (IBD: 1.45 ± 0.14 m/s and 0.78 ± 0.12 rad; healthy volunteers: 1.20 ± 0.14 m/s and 0.65 ± 0.06 rad), whereas no significant differences were found between ulcerative colitis and Crohn's disease (P = 0.74 and 0.90, respectively). In a preliminary assessment, a high diagnostic accuracy in detecting IBD was suggested by an AUC of 0.90 (CI: 0.81-0.96) for SWS and 0.84 (CI: 0.71-0.95) for φ. DATA CONCLUSION: In this pilot study, our results demonstrated the feasibility of MR elastography of the gut and showed an excellent diagnostic performance in predicting IBD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Alterations of Central Liver Metabolism of Pediatric Patients with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and is associated with overweight and insulin resistance (IR). Almost nothing is known about in vivo alterations of liver metabolism in NAFLD, especially in the early stages of non-alcoholic steatohepatitis (NASH). Here, we used a complex mathematical model of liver metabolism to quantify the central hepatic metabolic functions of 71 children with biopsy-proven NAFLD. For each patient, a personalized model variant was generated based on enzyme abundances determined by mass spectroscopy. Our analysis revealed statistically significant alterations in the hepatic carbohydrate, lipid, and ammonia metabolism, which increased with the degree of obesity and severity of NAFLD. Histologic features of NASH and IR displayed opposing associations with changes in carbohydrate and lipid metabolism but synergistically decreased urea synthesis in favor of the increased release of glutamine, a driver of liver fibrosis. Taken together, our study reveals already significant alterations in the NASH liver of pediatric patients, which, however, are differently modulated by the simultaneous presence of IR.

Tomoelastography Based on Multifrequency MR Elastography for Prostate Cancer Detection: Comparison with Multiparametric MRI.

Background Multiparametric MRI is used for depiction of prostate cancer (PCa) but without consideration of the mechanical alteration of prostatic tissue by cancer. Purpose To investigate the diagnostic performance of stiffness and fluidity quantified with tomoelastography, a multifrequency MR elastography technique, for depiction of PCa compared with multiparametric MRI with Prostate Imaging Reporting and Data System (PI-RADS) version 2.1. Materials and Methods Prospective participants suspected to have PCa and healthy controls (HCs) underwent multiparametric MRI and tomoelastography between March 2019 and July 2020. Tomoelastography maps of shear-wave speed (c) and loss angle (φ) quantified stiffness and fluidity, respectively, for PCa and benign prostatic disease and for the peripheral and transition zones in HCs. Differences between entities and regions were analyzed by using analysis of variance or Kruskal-Wallis test. Diagnostic performance was assessed with area under the receiver operating characteristic curve (AUC) analysis. Results There were 73 participants with PCa (mean age, 72 years ± 7 [standard deviation]), 82 with benign prostatic disease (66 years ± 7), and 53 HCs (41 years ± 14). Mean ± standard deviation of c and φ were higher in PCa (3.4 m/sec ± 0.6 and 1.3 radian ± 0.2, respectively) than in benign prostatic disease (2.6 m/sec ± 0.3 and 1.0 radian ± 0.2, respectively; P < .001) and age-matched HCs (2.2 m/sec ± 0.1 and 0.8 radian ± 0.1, respectively; P < .001). Incorporating c and φ (AUC, 0.95; 95% CI: 0.92, 0.98) improved the diagnostic performance of PI-RADS version 2.1 (AUC, 0.85; 95% CI: 0.80, 0.91; P < .001). Multiparametric MRI combined with c and φ enabled detection of PCa with 95% (78 of 82 non-PCa) specificity, which was significantly higher than with use of multiparametric MRI alone (77% [63 of 82 non-PCa]; P < .001). In regional analysis, c combined with φ enabled differentiation of transition zone PCa from benign prostatic hyperplasia (AUC, 0.91; 95% CI: 0.83, 0.98) and peripheral zone PCa from chronic prostatitis (AUC, 0.94; 95% CI: 0.88, 1.00). Conclusion Use of tomoelastography-quantified stiffness and fluidity improved the diagnostic performance of multiparametric MRI with Prostate Imaging Reporting and Data System version 2.1 in detecting cancer in both the peripheral and transition zones. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Hectors and Lewis in this issue. An earlier incorrect version of this article appeared online. This article was corrected on March 24, 2021.

Separation of fluid and solid shear wave fields and quantification of coupling density by magnetic resonance poroelastography.

PURPOSE: Biological soft tissues often have a porous architecture comprising fluid and solid compartments. Upon displacement through physiological or externally induced motion, the relative motion of these compartments depends on poroelastic parameters, such as coupling density ( ρ12 ) and tissue porosity. This study introduces inversion recovery MR elastography (IR-MRE) (1) to quantify porosity defined as fluid volume over total volume, (2) to separate externally induced shear strain fields of fluid and solid compartments, and (3) to quantify coupling density assuming a biphasic behavior of in vivo brain tissue. THEORY AND METHODS: Porosity was measured in eight tofu phantoms and gray matter (GM) and white matter (WM) of 21 healthy volunteers. Porosity of tofu was compared to values obtained by fluid draining and microscopy. Solid and fluid shear-strain amplitudes and ρ12 were estimated both in phantoms and in in vivo brain. RESULTS: T1 -based measurement of tofu porosity agreed well with reference values (R = 0.99, P < .01). Brain tissue porosity was 0.14 ± 0.02 in GM and 0.05 ± 0.01 in WM (P < .001). Fluid shear strain was found to be phase-locked with solid shear strain but had lower amplitudes in both tofu phantoms and brain tissue (P < .05). In accordance with theory, tofu and brain ρ12 were negative. CONCLUSION: IR-MRE allowed for the first time separation of shear strain fields of solid and fluid compartments for measuring coupling density according to the biphasic theory of poroelasticity. Thus, IR-MRE opens horizons for poroelastography-derived imaging markers that can be used in basic research and diagnostic applications.

Inversion-recovery MR elastography of the human brain for improved stiffness quantification near fluid-solid boundaries.

PURPOSE: In vivo MR elastography (MRE) holds promise as a neuroimaging marker. In cerebral MRE, shear waves are introduced into the brain, which also stimulate vibrations in adjacent CSF, resulting in blurring and biased stiffness values near brain surfaces. We here propose inversion-recovery MRE (IR-MRE) to suppress CSF signal and improve stiffness quantification in brain surface areas. METHODS: Inversion-recovery MRE was demonstrated in agar-based phantoms with solid-fluid interfaces and 11 healthy volunteers using 31.25-Hz harmonic vibrations. It was performed by standard single-shot, spin-echo EPI MRE following 2800-ms IR preparation. Wave fields were acquired in 10 axial slices and analyzed for shear wave speed (SWS) as a surrogate marker of tissue stiffness by wavenumber-based multicomponent inversion. RESULTS: Phantom SWS values near fluid interfaces were 7.5 ± 3.0% higher in IR-MRE than MRE (P = .01). In the brain, IR-MRE SNR was 17% lower than in MRE, without influencing parenchymal SWS (MRE: 1.38 ± 0.02 m/s; IR-MRE: 1.39 ± 0.03 m/s; P = .18). The IR-MRE tissue-CSF interfaces appeared sharper, showing 10% higher SWS near brain surfaces (MRE: 1.01 ± 0.03 m/s; IR-MRE: 1.11 ± 0.01 m/s; P < .001) and 39% smaller ventricle sizes than MRE (P < .001). CONCLUSIONS: Our results show that brain MRE is affected by fluid oscillations that can be suppressed by IR-MRE, which improves the depiction of anatomy in stiffness maps and the quantification of stiffness values in brain surface areas. Moreover, we measured similar stiffness values in brain parenchyma with and without fluid suppression, which indicates that shear wavelengths in solid and fluid compartments are identical, consistent with the theory of biphasic poroelastic media.

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.

Reduction of breathing artifacts in multifrequency magnetic resonance elastography of the abdomen.

PURPOSE: With abdominal magnetic resonance elastography (MRE) often suffering from breathing artifacts, it is recommended to perform MRE during breath-hold. However, breath-hold acquisition prohibits extended multifrequency MRE examinations and yields inconsistent results when patients cannot hold their breath. The purpose of this work was to analyze free-breathing strategies in multifrequency MRE of abdominal organs. METHODS: Abdominal MRE with 30, 40, 50, and 60 Hz vibration frequencies and single-shot, multislice, full wave-field acquisition was performed four times in 11 healthy volunteers: once with multiple breath-holds and three times during free breathing with ungated, gated, and navigated slice adjustment. Shear wave speed maps were generated by tomoelastography inversion. Image registration was applied for correction of intrascan misregistration of image slices. Sharpness of features was quantified by the variance of the Laplacian. RESULTS: Total scan times ranged from 120 seconds for ungated free-breathing MRE to 376 seconds for breath-hold examinations. As expected, free-breathing MRE resulted in larger organ displacements (liver, 4.7 ± 1.5 mm; kidneys, 2.4 ± 2.2 mm; spleen, 3.1 ± 2.4 mm; pancreas, 3.4 ± 1.4 mm) than breath-hold MRE (liver, 0.7 ± 0.2 mm; kidneys, 0.4 ± 0.2 mm; spleen, 0.5 ± 0.2 mm; pancreas, 0.7 ± 0.5 mm). Nonetheless, breathing-related displacement did not affect mean shear wave speed, which was consistent across all protocols (liver, 1.43 ± 0.07 m/s; kidneys, 2.35 ± 0.21 m/s; spleen, 2.02 ± 0.15 m/s; pancreas, 1.39 ± 0.15 m/s). Image registration before inversion improved the quality of free-breathing examinations, yielding no differences in image sharpness to uncorrected breath-hold MRE in most organs (P > .05). CONCLUSION: Overall, multifrequency MRE is robust to breathing when considering whole-organ values. Respiration-related blurring can readily be corrected using image registration. Consequently, ungated free-breathing MRE combined with image registration is recommended for multifrequency MRE of abdominal organs.

Distinguishing pancreatic cancer and autoimmune pancreatitis with in vivo tomoelastography.

OBJECTIVES: To prospectively investigate the stiffness and fluidity of pancreatic ductal adenocarcinoma (PDAC) and autoimmune pancreatitis (AIP) with tomoelastography, and to evaluate its diagnostic performance in distinguishing the two entities. METHODS: Tomoelastography provided high-resolution maps of shear wave speed (c in m/s) and phase angle (φ in rad), allowing mechanical characterization of the stiffness and fluidity properties of the pancreas. Forty patients with untreated PDAC and 33 patients with untreated AIP who underwent diagnostic pancreatic MRI at 3-T together with multifrequency MR elastography and tomoelastography data processing were prospectively enrolled. Ten healthy volunteers served as controls. Two radiologists and a technician measured pancreatic stiffness and fluidity independently. The two radiologists also independently evaluated the patients' conventional MR sequences using the following diagnostic score: 1, definitely PDAC; 2, probably PDAC; 3, indeterminate; 4, probably AIP; and 5, definitely AIP. Interobserver agreement was assessed. Stiffness and fluidity of PDAC, AIP, and healthy pancreas, as well as diagnostic performance of tomoelastography and conventional MRI, were compared. RESULTS: AIP showed significantly lower stiffness and fluidity than PDAC and significantly higher stiffness and fluidity than healthy pancreas. Pancreatic fluidity was not influenced by secondary obstructive changes. The intraclass correlation coefficient for pancreatic stiffness and fluidity by the 3 readers was near-perfect (0.951-0.979, all p < 0.001). Both stiffness and fluidity allowed distinguishing PDAC from AIP. AUCs were 0.906 for stiffness, 0.872 for fluidity, and 0.842 for conventional MRI. CONCLUSIONS: Pancreatic stiffness and fluidity both allow differentiation of PDAC and AIP with high accuracy. KEY POINTS: • AIP showed significantly lower stiffness and fluidity than PDAC and significantly higher stiffness and fluidity than healthy pancreas. • Both stiffness and fluidity allowed distinguishing PDAC from AIP. • Pancreatic fluidity could distinguish malignancy from non-malignant secondary obstructive changes.

Whole tissue and single cell mechanics are correlated in human brain tumors.

Biomechanical changes are critical for cancer progression. However, the relationship between the rheology of single cells measured ex-vivo and the living tumor is not yet understood. Here, we combined single-cell rheology of cells isolated from primary tumors with in vivo bulk tumor rheology in patients with brain tumors. Eight brain tumors (3 glioblastoma, 3 meningioma, 1 astrocytoma, 1 metastasis) were investigated in vivo by magnetic resonance elastography (MRE), and after surgery by the optical stretcher (OS). MRE was performed in a 3-Tesla clinical MRI scanner and magnitude modulus |G*|, loss angle φ, storage modulus G', and loss modulus G'' were derived. OS experiments measured cellular creep deformation in response to laser-induced step stresses. We used a Kelvin-Voigt model to deduce two parameters related to cellular stiffness (µKV) and cellular viscosity (ηKV) from OS measurements in a time regimen that overlaps with that of MRE. We found that single-cell µKV was correlated with |G*| (R = 0.962, p < 0.001) and G'' (R = 0.883, p = 0.004) but not G' of the bulk tissue. These results suggest that single-cell stiffness affects tissue viscosity in brain tumors. The observation that viscosity parameters of individual cells and bulk tissue were not correlated suggests that collective mechanical interactions (i.e. emergent effects or cellular unjamming) of many cancer cells, which depend on cellular stiffness, influence the mechanical dissipation behavior of the bulk tissue. Our results are important to understand the emergent rheology of active multiscale compound materials such as brain tumors and its role in disease progression.

An analytical solution to the dispersion-by-inversion problem in magnetic resonance elastography.

PURPOSE: Magnetic resonance elastography (MRE) measures stiffness of soft tissues by analyzing their spatial harmonic response to externally induced shear vibrations. Many MRE methods use inversion-based reconstruction approaches, which invoke first- or second-order derivatives by finite difference operators (first- and second-FDOs) and thus give rise to a biased frequency dispersion of stiffness estimates. METHODS: We here demonstrate analytically, numerically, and experimentally that FDO-based stiffness estimates are affected by (1) noise-related underestimation of values in the range of high spatial wave support, that is, at lower vibration frequencies, and (2) overestimation of values due to wave discretization at low spatial support, that is, at higher vibration frequencies. RESULTS: Our results further demonstrate that second-FDOs are more susceptible to noise than first-FDOs and that FDO dispersion depends both on signal-to-noise ratio (SNR) and on a lumped parameter A, which is defined as wavelength over pixel size and over a number of pixels per stencil of the FDO. Analytical FDO dispersion functions are derived for optimizing A parameters at a given SNR. As a simple rule of thumb, we show that FDO artifacts are minimized when A/2 is in the range of the square root of 2SNR for the first-FDO or cubic root of 5SNR for the second-FDO. CONCLUSIONS: Taken together, the results of our study provide an analytical solution to a long-standing, well-recognized, yet unsolved problem in MRE postprocessing and might thus contribute to the ongoing quest for minimizing inversion artifacts in MRE.

Real-time MR elastography for viscoelasticity quantification in skeletal muscle during dynamic exercises.

PURPOSE: To develop and test real-time MR elastography for viscoelastic parameter quantification in skeletal muscle during dynamic exercises. METHODS: In 15 healthy participants, 6 groups of lower-leg muscles (tibialis anterior, tibialis posterior, peroneus, extensor digitorum longus, soleus, gastrocnemius) were investigated by real-time MR elastography using a single-shot, steady-state spiral gradient-echo pulse sequence and stroboscopic undersampling of harmonic vibrations at 40 Hz frequency. One hundred and eighty consecutive maps of shear-wave speed and loss angle (φ) covering 30.6 s of total acquisition time at 5.9-Hz frame rate were reconstructed from 360 wave images encoding 2 in-plane wave components in an interleaved manner. The experiment was carried out twice to investigate 2 exercises-isometric plantar flexion and isometric dorsiflexion-each performed over 10 s between 2 resting periods. RESULTS: Activation of lower-extremity muscles was associated with increasing viscoelastic parameters shear-wave speed and φ, both reflecting properties related to the transverse direction relative to fiber orientation. Major viscoelastic changes were observed in soleus muscle during plantar flexion (shear-wave speed: 20.0% ± 3.6%, φ: 41.3% ± 12.0%) and in the tibialis anterior muscle during dorsiflexion (41.8% ± 10.2%, φ: 27.9% ± 2.8%; all P < .0001). Two of the muscles analyzed were significantly activated by plantar flexion and 4 by dorsiflexion based on shear-wave speed, whereas φ changed significantly in 5 muscles during both exercises. CONCLUSION: Real-time MR elastography allows mapping of dynamic, nonperiodic viscoelasticity changes in soft tissues such as voluntary muscle with high spatial and temporal resolution. Real-time MR elastography thus opens new horizons for the in vivo study of physiological processes in soft tissues toward functional elastography.

Quantitative MRI for Assessment of Treatment Outcomes in a Rabbit VX2 Hepatic Tumor Model.

Globally, primary and secondary liver cancer is one of the most common cancer types, accounting 8.2% of deaths worldwide in 2018. One of the key strategies to improve the patient's prognosis is the early diagnosis, when liver function is still preserved. In hepatocellular carcinoma (HCC), the typical wash-in/wash-out pattern in conventional magnetic resonance imaging (MRI) reaches a sensitivity of 60% and specificity of 96-100%. However, in recent years functional MRI sequences such as hepatocellular-specific gadolinium-based dynamic-contrast enhanced MRI, diffusion-weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) have been demonstrated to improve the evaluation of treatment success and thus the therapeutic decision-making and the patient's outcome. In the preclinical research setting, the VX2 liver rabbit tumor, which once originated from a virus-induced anaplastic squamous cell carcinoma, has played a longstanding role in experimental interventional oncology. Especially the high tumor vascularity allows assessing the treatment response of locoregional interventions such as radiofrequency ablation (RFA) and transcatheter arterial embolization (TACE). Functional MRI has been used to monitor the tumor growth and viability following interventional treatment. Besides promising results, a comprehensive overview of functional MRI sequences used so far in different treatment setting is lacking, thus lowering the comparability of study results. This review offers a comprehensive overview of study protocols, results, and limitations of quantitative MRI sequences applied to evaluate the treatment outcome of VX2 hepatic tumor models, thus generating a unique basis for future MRI studies and potential translation into the clinical setting. Level of Evidence: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2020;52:668-685.