Associations between vascular health, brain stiffness and global cognitive function.

Vascular brain injury results in loss of structural and functional connectivity and leads to cognitive impairment. Its various manifestations, including microinfarcts, microhaemorrhages and white matter hyperintensities, result in microstructural tissue integrity loss and secondary neurodegeneration. Among these, tissue microstructural alteration is a relatively early event compared with atrophy along the aging and neurodegeneration continuum. Understanding its association with cognition may provide the opportunity to further elucidate the relationship between vascular health and clinical outcomes. Magnetic resonance elastography offers a non-invasive approach to evaluate tissue mechanical properties, providing a window into the microstructural integrity of the brain. This retrospective study evaluated brain stiffness as a potential biomarker for vascular brain injury and its role in mediating the impact of vascular dysfunction on cognitive impairment. Seventy-five participants from the Mayo Clinic Study of Aging underwent brain imaging using a 3T MR imager with a spin-echo echo-planar imaging sequence for magnetic resonance elastography and T1- and T2-weighted pulse sequences. This study evaluated the effects of vascular biomarkers (white matter hyperintensities and cardiometabolic condition score) on brain stiffness using voxelwise analysis. Partial correlation analysis explored associations between brain stiffness, white matter hyperintensities, cardiometabolic condition and global cognition. Mediation analysis determined the role of stiffness in mediating the relationship between vascular biomarkers and cognitive performance. Statistical significance was set at P-values < 0.05. Diagnostic accuracy of magnetic resonance elastography stiffness for white matter hyperintensities and cardiometabolic condition was evaluated using receiver operator characteristic curves. Voxelwise linear regression analysis indicated white matter hyperintensities negatively correlate with brain stiffness, specifically in periventricular regions with high white matter hyperintensity levels. A negative association between cardiovascular risk factors and stiffness was also observed across the brain. No significant patterns of stiffness changes were associated with amyloid load. Global stiffness (µ) negatively correlated with both white matter hyperintensities and cardiometabolic condition when all other covariables including amyloid load were controlled. The positive correlation between white matter hyperintensities and cardiometabolic condition weakened and became statistically insignificant when controlling for other covariables. Brain stiffness and global cognition were positively correlated, maintaining statistical significance after adjusting for all covariables. These findings suggest mechanical alterations are associated with cognitive dysfunction and vascular brain injury. Brain stiffness significantly mediated the indirect effects of white matter hyperintensities and cardiometabolic condition on global cognition. Local cerebrovascular diseases (assessed by white matter hyperintensities) and systemic vascular risk factors (assessed by cardiometabolic condition) impact brain stiffness with spatially and statistically distinct effects. Global brain stiffness is a significant mediator between vascular disease measures and cognitive function, highlighting the value of magnetic resonance elastography-based mechanical assessments in understanding this relationship.

MR elastography-based slip interface imaging (SII) for functional assessment of myofascial interfaces: A feasibility study.

PURPOSE: Abnormal adherence at functional myofascial interfaces is hypothesized as an important phenomenon in myofascial pain syndrome. This study aimed to investigate the feasibility of MR elastography (MRE)-based slip interface imaging (SII) to visualize and assess myofascial mobility in healthy volunteers. METHODS: SII was used to assess local shear strain at functional myofascial interfaces in the flexor digitorum profundus (FDP) and thighs. In the FDP, MRE was performed at 90 Hz vibration to each index, middle, ring, and little finger. Two thigh MRE scans were performed at 40 Hz with knees flexed and extended. The normalized octahedral shear strain (NOSS) maps were calculated to visualize myofascial slip interfaces. The entropy of the probability distribution of the gradient NOSS was computed for the two knee positions at the intermuscular interface between vastus lateralis and vastus intermedius, around rectus femoris, and between vastus intermedius and vastus medialis. RESULTS: NOSS map depicted distinct functional slip interfaces in the FDP for each finger. Compared to knee flexion, clearer slip interfaces and larger gradient NOSS entropy at the vastus lateralis-vastus intermedius interface were observed during knee extension, where the quadriceps are not passively stretched. This suggests the optimal position for using SII to visualize myofascial slip interface in skeletal muscles is when muscles are not subjected to any additional force. CONCLUSION: The study demonstrated that MRE-based SII can visualize and assess myofascial interface mobility in extremities. The results provide a foundation for investigating the hypothesis that myofascial pain syndrome is characterized by changes in the mobility of myofascial interfaces.

Wavelet MRE: Imaging propagating broadband acoustic waves with wavelet-based motion-encoding gradients.

PURPOSE: To 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. METHODS: A 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. RESULTS: In 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. CONCLUSION: The 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.

Magnetic Resonance Elastography-Based Technique to Assess the Biomechanics of the Skull-Brain Interface: Repeatability and Age-Sex Characteristics.

Increasing concerns have been raised about the long-term negative effects of subconcussive repeated head impact (RHI). To elucidate RHI injury mechanisms, many efforts have studied how head impacts affect the skull-brain biomechanics and have found that mechanical interactions at the skull-brain interface dampen and isolate brain motions by decoupling the brain from the skull. Despite intense interest, in vivo quantification of the functional state of the skull-brain interface remains difficult. This study developed a magnetic resonance elastography (MRE) based technique to non-invasively assess skull-brain mechanical interactions (i.e., motion transmission and isolation function) under dynamic loading. The full MRE displacement data were separated into rigid body motion and wave motion. The rigid body motion was used to calculate the brain-to-skull rotational motion transmission ratio (Rtr) to quantify skull-brain motion transmissibility, and the wave motion was used to calculate the cortical normalized octahedral shear strain (NOSS) (calculated based on a partial derivative computing neural network) to evaluate the isolation capability of the skull-brain interface. Forty-seven healthy volunteers were recruited to investigate the effects of age/sex on Rtr and cortical NOSS, and 17 of 47 volunteers received multiple scans to test the repeatability of the proposed techniques under different strain conditions. The results showed that both Rtr and NOSS were robust to MRE driver variations and had good repeatability, with intraclass correlation coefficient (ICC) values between 0.68 and 0.97 (fair to excellent). No age or sex dependence were observed with Rtr, whereas a significant positive correlation between age and NOSS was found in the cerebrum, frontal, temporal, and parietal lobes (all p < 0.05), but not in the occipital lobe (p = 0.99). The greatest change in NOSS with age was found in the frontal lobe, one of the most frequent locations of traumatic brain injury (TBI). Except for the temporal lobe (p = 0.0087), there was no significant difference in NOSS between men and women. This work provides motivation for utilizing MRE as a non-invasive tool for quantifying the biomechanics of the skull-brain interface. It evaluated the age and sex dependence and may lead to a better understanding of the protective role and mechanisms of the skull-brain interface in RHI and TBI, as well as improve the accuracy of computational models in simulating the skull-brain interface.

Head-to-head comparison of magnetic resonance elastography-based liver stiffness, fat fraction, and T1 relaxation time in identifying at-risk NASH.

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 [AUC LS : 0.89 (0.82, 0.95), AUC PDFF : 0.70 (0.58, 0.81), AUC T1 : 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 [AUC PDFF : 0.82 (0.72, 0.91), AUC LS : 0.73 (0.63, 0.84), AUC T1 : 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.

Differential effect of dementia etiology on cortical stiffness as assessed by MR elastography.

BACKGROUND: Aging and dementia involve the disruption of brain molecular pathways leading to the alterations in tissue composition and gross morphology of the brain. Phenotypic and biomarker overlap between various etiologies of dementia supports a need for new modes of information to more accurately distinguish these disorders. Brain mechanical properties, which can be measured noninvasively by MR elastography, represent one understudied feature that are sensitive to neurodegenerative processes. In this study, we used two stiffness estimation schemes to test the hypothesis that different etiologies of dementia are associated with unique patterns of mechanical alterations across the cerebral cortex. METHODS: MR elastography data were acquired for six clinical groups including amyloid-negative cognitively unimpaired (CU), amyloid-positive cognitively unimpaired (A + CU), amyloid-positive participants with mild cognitive impairment (A + MCI), amyloid-positive participants with Alzheimer's clinical syndrome (A + ACS), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Stiffness maps were computed using two neural network inversions with the objective to at least partially separate the parenchyma-specific and morphological effects of neurodegeneration on mechanical property estimates. A tissue-confined inversion algorithm was designed to obtain the best estimate of stiffness in the brain parenchyma itself, while a regionally-aware inversion algorithm was used to measure the tissue stiffness along with the surroundings. Mean stiffness of 15 bilateral gray matter cortical regions were considered for statistical analysis. First, we tested the hypothesis that cortical stiffness changes in the aging brain. Next, we tested the overall study hypothesis by first comparing stiffness in each clinical group to the CU group, and then comparing the clinical groups against one another. Finally, we assessed the spatial and statistical overlap between atrophy and stiffness changes for both inversions. RESULTS: Cortical brain regions become softer with age for both inversions with larger effects observed using regionally-aware stiffness. Stiffness decreases in the range 0.010-0.027 kPa per year were observed. Pairwise comparisons of each clinical group with cognitively unimpaired participants demonstrated 5 statistically significant differences in stiffness for tissue-confined measurements and 19 statistically different stiffness changes for the regionally-aware stiffness measurements. Pairwise comparisons between clinical groups further demonstrated unique patterns of stiffness differences. Analysis of the atrophy-versus-stiffness relationship showed that regionally-aware stiffness measurements exhibit higher sensitivity to neurodegeneration with findings that are not fully explained by partial volume effects or atrophy. CONCLUSIONS: Both tissue-confined and regionally-aware stiffness estimates exhibited unique and complementary stiffness differences in various etiologies of dementia. Our results suggest that mechanical alterations measured by MRE reflect both tissue-specific differences as well as environmental effects. Multi-inversion schemes in MRE may provide new insights into the relationships between neuropathology and brain biomechanics.

Longitudinal Changes in MR Elastography-based Biomarkers in Obese Patients Treated with Bariatric Surgery.

Obesity-related chronic inflammation contributes to nonalcoholic fatty liver disease (NAFLD) progression in obese patients (body mass index [BMI] >30 kg/m2).1 The early detection of inflammation with noninvasive imaging technology may help identify individuals with a high risk of developing NAFLD.

Impact of material homogeneity assumption on cortical stiffness estimates by MR elastography.

PURPOSE: Inversion algorithms used to convert acquired MR elastography wave data into material property estimates often assume that the underlying materials are locally homogeneous. Here we evaluate the impact of that assumption on stiffness estimates in gray-matter regions of interest in brain MR elastography. METHODS: We describe an updated neural network inversion framework using finite-difference model-derived data to train convolutional neural network inversion algorithms. Neural network inversions trained on homogeneous simulations (homogeneous learned inversions [HLIs]) or inhomogeneous simulations (inhomogeneous learned inversions [ILIs]) are generated with a variety of kernel sizes. These inversions are evaluated in a brain MR elastography simulation experiment and in vivo in a test-retest repeatability experiment including 10 healthy volunteers. RESULTS: In simulation and in vivo, HLI and ILI with small kernels produce similar results. As kernel size increases, the assumption of homogeneity has a larger effect, and HLI and ILI stiffness estimates show larger differences. At each inversion's optimal kernel size in simulation (7 × 7 × 7 for HLI, 11 × 11 × 11 for ILI), ILI is more sensitive to true changes in stiffness in gray-matter regions of interest in simulation. In vivo, there is no difference in the region-level repeatability of stiffness estimates between the inversions, although ILI appears to better maintain the stiffness map structure as kernel size increases, while decreasing the spatial variance in stiffness estimates. CONCLUSIONS: This study suggests that inhomogeneous inversions provide small but significant benefits even when large stiffness gradients are absent.

An under-recognized phenomenon: Myocardial volume change during the cardiac cycle.

BACKGROUND: Myocardial volume is assumed to be constant over the cardiac cycle in the echocardiographic models used by professional guidelines, despite evidence that suggests otherwise. The aim of this paper is to use literature-derived myocardial strain values from healthy patients to determine if myocardial volume changes during the cardiac cycle. METHODS: A systematic review for studies with longitudinal, radial, and circumferential strain from echocardiography in healthy volunteers ultimately yielded 16 studies, corresponding to 2917 patients. Myocardial volume in systole (MVs) and diastole (MVd) was used to calculate MVs/MVd for each study by applying this published strain data to three models: the standard ellipsoid geometric model, a thin-apex geometric model, and a strain-volume ratio. RESULTS: MVs/MVd<1 in 14 of the 16 studies, when computed using these three models. A sensitivity analysis of the two geometric models was performed by varying the dimensions of the ellipsoid and calculating MVs/MVd. This demonstrated little variability in MVs/MVd, suggesting that strain values were the primary determinant of MVs/MVd rather than the geometric model used. Another sensitivity analysis using the 97.5th percentile of each orthogonal strain demonstrated that even with extreme values, in the largest two studies of healthy populations, the calculated MVs/MVd was <1. CONCLUSIONS: Healthy human myocardium appears to decrease in volume during systole. This is seen in MRI studies and is clinically relevant, but this study demonstrates that this characteristic was also present but unrecognized in the existing echocardiography literature.

A new method for quantification and 3D visualization of brain tumor adhesion using slip interface imaging in patients with meningiomas.

OBJECTIVES: To develop an objective quantitative method to characterize and visualize meningioma-brain adhesion using MR elastography (MRE)-based slip interface imaging (SII). METHODS: This retrospective study included 47 meningiomas (training dataset: n = 35; testing dataset: n = 12) with MRE/SII examinations. Normalized octahedral shear strain (NOSS) values were calculated from the acquired MRE displacement data. The change in NOSS at the tumor boundary (ΔNOSSbdy) was computed, from which a 3D ΔNOSSbdy map of the tumor surface was created and the probability distribution of ΔNOSSbdy over the entire tumor surface was calculated. Statistical features were calculated from the probability histogram. After eliminating highly correlated features, the capability of the remaining feature for tumor adhesion classification was assessed using a one-way ANOVA and ROC analysis. RESULTS: The magnitude and location of the tumor adhesion can be visualized by the reconstructed 3D ΔNOSSbdy surface map. The entropy of the ΔNOSSbdy histogram was significantly different between adherent tumors and partially/completely non-adherent tumors in both the training (AUC: 0.971) and testing datasets (AUC: 0.900). Based on the cutoff values obtained from the training set, the ΔNOSSbdy entropy in the testing dataset yielded an accuracy of 0.83 for distinguishing adherent versus partially/non-adherent tumors, and 0.67 for distinguishing non-adherent versus completely/partially adherent tumors. CONCLUSIONS: SII-derived ΔNOSSbdy values are useful for quantification and classification of meningioma-brain adhesion. The reconstructed 3D ΔNOSSbdy surface map presents the state and location of tumor adhesion in a "clinician-friendly" manner, and can identify meningiomas with a high risk of adhesion to adjacent brain parenchyma. KEY POINTS: • MR elastography (MRE)-based slip interface imaging shows promise as an objective tool to preoperatively discriminate meningiomas with a high risk of intraoperative adhesion. • Measurement of the change of shear strain at meningioma boundaries can provide quantitative metrics depicting the state of adhesion at the tumor-brain interface. • The surface map of tumor adhesion shows promise in assisting precise adhesion localization, using a comprehensible, "clinician-friendly" 3D visualization.

Harnessing brain waves: a review of brain magnetic resonance elastography for clinicians and scientists entering the field.

Brain magnetic resonance elastography (MRE) is an imaging technique capable of accurately and non-invasively measuring the mechanical properties of the living human brain. Recent studies have shown that MRE has potential to provide clinically useful information in patients with intracranial tumors, demyelinating disease, neurodegenerative disease, elevated intracranial pressure, and altered functional states. The objectives of this review are: (1) to give a general overview of the types of measurements that have been obtained with brain MRE in patient populations, (2) to survey the tools currently being used to make these measurements possible, and (3) to highlight brain MRE-based quantitative biomarkers that have the highest potential of being adopted into clinical use within the next 5 to 10 years. The specifics of MRE methodology strategies are described, from wave generation to material parameter estimations. The potential clinical role of MRE for characterizing and planning surgical resection of intracranial tumors and assessing diffuse changes in brain stiffness resulting from diffuse neurological diseases and altered intracranial pressure are described. In addition, the emerging technique of functional MRE, the role of artificial intelligence in MRE, and promising applications of MRE in general neuroscience research are presented.

Simultaneous Noise Suppression and Incoherent Artifact Reduction in Ultrafast Ultrasound Vascular Imaging.

Ultrasound vascular imaging based on ultrafast plane wave imaging and singular value decomposition (SVD) clutter filtering has demonstrated superior sensitivity in blood flow detection. However, ultrafast ultrasound vascular imaging is susceptible to electronic noise due to the weak penetration of unfocused waves, leading to a lower signal-to-noise ratio (SNR) at larger depths. In addition, incoherent clutter artifacts originating from strong and moving tissue scatterers that cannot be completely removed create a strong mask on top of the blood signal that obscures the vessels. Herein, a method that can simultaneously suppress the background noise and incoherent artifacts is proposed. The method divides the tilted plane or diverging waves into two subgroups. Coherent spatial compounding is performed within each subgroup, resulting in two compounded data sets. An SVD-based clutter filter is applied to each data set, followed by a correlation between the two data sets to produce a vascular image. Uncorrelated noise and incoherent artifacts can be effectively suppressed with the correlation process, while the coherent blood signal can be preserved. The method was evaluated in wire-target simulations and phantom, in which around 7-10-dB SNR improvement was shown. Consistent results were found in a flow channel phantom with improved SNR by the proposed method (39.9 ± 0.2 dB) against conventional power Doppler (29.1 ± 0.6 dB). Last, we demonstrated the effectiveness of the method combined with block-wise SVD clutter filtering in a human liver, breast tumor, and inflammatory bowel disease data sets. The improved blood flow visualization may facilitate more reliable small vessel imaging for a wide range of clinical applications, such as cancer and inflammatory diseases.

A new method for assessing anal distensibility with a barostat and magnetic resonance imaging in healthy and constipated women.

OBJECTIVES: Defecation requires relaxation of the internal and external anal sphincters. High anal resting pressure is associated with painful constipation, defecatory disorders, and increased healthcare utilization in constipated patients; the mechanisms are unclear. Perhaps patients with a high anal resting pressure have a less distensible canal, which impedes defecation. METHODS: In 50 of 64 participants (33 healthy and 17 constipated women), anal pressures and distensibility were measured, respectively, with manometry and balloon distention combined with magnetic resonance imaging; rectal balloon expulsion time (BET) was also studied. RESULTS: The BET (P = .006) was longer, and the mean (SD) rectoanal pressure gradient (-58[40] vs -34[26] mm Hg, P = .03) was more negative in constipated than healthy women; anal resting pressure was not different. During anal distention, the balloon expanded rapidly at an opening pressure of 49 (18) mm Hg, which was lower (P < .0001) than resting pressure (90 [25] mm Hg). The resting pressure was correlated with the opening pressure (r = 0.57, P < .0001) and inversely (r = -0.38, P = .007) with maximum volume but not with anal distensibility (volume-pressure slope). In healthy women, the difference (opening-resting pressure) was correlated with anal relaxation during evacuation (r = 0.35, P = .04). Anal distensibility and sensory thresholds were not different between constipated and healthy women. CONCLUSIONS: Among healthy and constipated women, a greater anal resting pressure is correlated with greater opening pressure and lower maximum volume during distention, and, hence, provides a surrogate marker of anal distensibility. The difference (opening-resting pressure), which reflects anal relaxation during distention, is correlated with anal relaxation during evacuation. Anal resting pressure and distensibility were comparable in healthy and constipated women.

Systolic-to-diastolic myocardial volume ratio as a novel imaging marker of cardiomyopathy.

BACKGROUND: In patients with normal left ventricular ejection fraction, it may be difficult to distinguish between the normal and diseased heart. Novel assessments of ventricular function, such as extracellular volume imaging, myocardial perfusion imaging and myocardial contraction fraction are emerging to better assess disease burden in these cases. This study endeavored to determine whether the ratio of myocardial volume in systole to myocardial volume in diastole (MVs/MVd), differs between normal hearts and those with disease states characterized by normal ejection fraction. METHOD: Consecutive patients from 2008 to 2018 with hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and heart failure with preserved ejection fraction (HFpEF) who underwent cardiac magnetic resonance imaging (MRI) were selected for inclusion, along with a sex- and age-matched cohort of normal volunteers who also underwent cardiac MRI. Manual tracings were performed on each MRI to calculate MVs/MVd, which was then compared across subgroups. RESULTS: Included were 50 patients with HCM, 50 patients with cardiac amyloidosis, 26 patients with HFpEF, and 30 normal subjects. Age was 54.1 years (SD 16.7); mean MVs/MVd was 0.88 (SD 0.04) in the normal subgroup, 1.03 (SD 0.06) in HCM patients, 1.03 (SD 0.06) in cardiac amyloidosis patients, and 0.97 (SD 0.02) in HFpEF patients, with all pathology subgroups different from the normal subgroup (p < .0001 for each). The ratio of MVs/MVd discriminated diseased from normal with c statistic 0.989 (p < .001). CONCLUSIONS: This study suggests that a novel and easily-captured metric of ventricular function, MVs/MVd, can differentiate normal ventricular function from multiple cardiomyopathies with normal ejection fractions.

TURBINE-MRE: A 3D hybrid radial-Cartesian EPI acquisition for MR elastography.

PURPOSE: To 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. METHOD: The 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. RESULTS: The 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. CONCLUSION: We 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.

Cardiac MRI demonstrates compressibility in healthy myocardium but not in myocardium with reduced ejection fraction.

BACKGROUND: The professional guidelines assume that the myocardial volume in systole (MVs) is equal to that in diastole (MVd), despite some limited evidence that points to the contrary. The aim of this manuscript is to determine whether this is true in healthy myocardium using gold standard cardiac MRI, as well as transthoracic echocardiography (TTE). The secondary aim is to determine whether there are similar MV changes in patients with heart failure with reduced ejection fraction (HFrEF). METHOD: A prospectively derived cohort at Mayo Clinic of 115 adult subjects (mean age 42.8 years, 58% female) with no cardiac risk factors was identified. Cardiac MRI was obtained on all 115 patients, 51 of whom also consented to a TTE. MRI from a retrospectively derived cohort of 50 HFrEF patients was also collected. MVs and MVd was calculated using standard approaches with inclusion of the papillary muscles. RESULTS: In the healthy population, MRI demonstrated MVs/MVd = 0.87 (SD 0.04) and TTE demonstrated MVs/MVd = 0.79 (SD 0.07), suggesting compressibility (p < 0.0001). In the 51 healthy patients who received both imaging modalities, MVs/MVd was 8.0% higher in MRI than TTE (p < 0.0001), but both modalities had MVs/MVd < 1 (p < 0.0001). A Bland-Altman plot demonstrated that as the mean MVs/MVd increases, the difference in MVs/MVd MRI-TTE declines (r = -0.53, p < 0.0001). However, in HFrEF populations, MVs/MVd = 1.01 (0.03), suggesting myocardial incompressibility. CONCLUSION: Contrary to currently accepted standards, healthy myocardium is compressible but HFrEF myocardium is incompressible. The ratio MVs/MVd merits further study in an expanded normal cohort and in disease states.

Quantitative assessment of portal hypertension with bi-parametric dual-frequency hepatic MR elastography in mouse models.

OBJECTIVES: To determine the potential of bi-parametric dual-frequency hepatic MR elastography (MRE) for predicting portal pressure (PP) in mouse models of portal hypertension (PHTN) with the presence of varying hepatic fibrosis. METHODS: We studied 73 wild-type male mice, including 22 mice with hepatic congestion, 20 mice with cholestatic liver injury, and 31 age-matched sham mice. Hepatic shear stiffness (SS) and volumetric strain (VS) were calculated by 3D MRE acquired at 80 and 200 Hz. We measured PP immediately after MRE. Liver fibrosis was verified by hydroxyproline assay. We predicted PP by fitting generalized linear models with single- and dual-frequency SS and VS, respectively. The relationship between predicted and actual PP was evaluated by Spearman's correlation. We compared the prediction accuracy of portal hypertension for all models with DeLong tests at a significance level of 0.05. RESULTS: Animals with congestive or cholestatic liver disease developed significant PHTN and hepatic fibrosis to varying degrees. In both models, SS increased, while VS decreased significantly compared with shams. All bi-parametric models had high diagnostic accuracy for PHTN. The dual-frequency models (AUCs: 0.90 [81-95%], 0.91 [81-95%]) had substantially or significantly higher accuracy than single-frequency ones (AUCs: 0.83 [71-91%], and 0.78 [66-87%]). The predicted PP of dual-frequency models also showed stronger correlations with actual PP than single-frequency predictions. CONCLUSIONS: The bi-parametric dual-frequency model improved the diagnostic accuracy of liver MRE in diagnosing PHTN in preclinical models. This technical advance has the potential to monitor PHTN progression and treatment efficacy in the presence of varying fibrosis. KEY POINTS: • Bi-parametric hepatic MR elastography can predict portal pressure. • The prediction models of shear stiffness and volumetric strain with dual-frequency measurements demonstrate high diagnostic accuracy (AUCs > 0.9) in two different portal hypertension mouse models with varying fibrosis.

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.

Deploying MMEJ using MENdel in precision gene editing applications for gene therapy and functional genomics.

Gene-editing experiments commonly elicit the error-prone non-homologous end joining for DNA double-strand break (DSB) repair. Microhomology-mediated end joining (MMEJ) can generate more predictable outcomes for functional genomic and somatic therapeutic applications. We compared three DSB repair prediction algorithms - MENTHU, inDelphi, and Lindel - in identifying MMEJ-repaired, homogeneous genotypes (PreMAs) in an independent dataset of 5,885 distinct Cas9-mediated mouse embryonic stem cell DSB repair events. MENTHU correctly identified 46% of all PreMAs available, a ∼2- and ∼60-fold sensitivity increase compared to inDelphi and Lindel, respectively. In contrast, only Lindel correctly predicted predominant single-base insertions. We report the new algorithm MENdel, a combination of MENTHU and Lindel, that achieves the most predictive coverage of homogeneous out-of-frame mutations in this large dataset. We then estimated the frequency of Cas9-targetable homogeneous frameshift-inducing DSBs in vertebrate coding regions for gene discovery using MENdel. 47 out of 54 genes (87%) contained at least one early frameshift-inducing DSB and 49 out of 54 (91%) did so when also considering Cas12a-mediated deletions. We suggest that the use of MENdel helps researchers use MMEJ at scale for reverse genetics screenings and with sufficient intra-gene density rates to be viable for nearly all loss-of-function based gene editing therapeutic applications.