Entwicklung und Anwendung der in vivo abdominellen Magnetresonanzelastographie

Magnetic Resonance Elastography (MRE) is a well-established non-invasive imaging technique used to quantify the mechanical properties of tissues in vivo for the diagnosis of liver fibrosis. However, MRE is limited by its spatial resolution, sensitivity to motion artifacts, and insensitivity to metabolic function. Therefore, three studies of abdominal MRE were conducted to improve the quality of mechanical maps for characterizing liver tumors, to correct for motion artifacts induced by breathing, and to implement MRE on a PET/MRI scanner to correlate mechanical liver properties with metabolic functions in small animals through technical improvements in image acquisition and post-processing. High-resolution stiffness (shear wave speed in m/s), wave penetration (penetration rate in m/s), and fluidity (phase of the complex shear modulus in rad) maps were generated using multifrequency MRE, novel actuators, and tomoelastography post-processing. The first study characterized the stiffness and fluidity of a total of 141 liver tumors in 70 patients. The second study analyzed the motion of abdominal organs and its effect on their stiffness using different acquisition paradigms and image registration in 12 subjects. The third study examined the relationship of liver stiffness and wave penetration to central metabolic liver functions in 19 rabbits. Malignant liver tumors were distinguished from the surrounding liver (stiffness area under the curve [AUC]: 0.88 and fluidity AUC: 0.95) and benign tumors (stiffness AUC: 0.85 and fluidity AUC: 0.86) due to their increased stiffness and fluidity. In the second study, no significant differences in stiffness were observed despite significant differences in examination time, organ motion, and image quality with different image acquisition paradigms. Motion correction by image registration increased image sharpness, so that no significant difference was measurable between MRE in free breathing and breath-hold. Healthy rabbit livers showed heterogeneous liver stiffness, such that division into low and high stiffness (>1.6 m/s) groups resulted in significant differences in central metabolic functions. Stiffness and fluidity measured by multifrequency MRE hold promise as quantitative biomarkers for the diagnosis of malignant liver tumors. Abdominal MRE with free breathing, followed by image registration, is recommended as the best balance between fast examination time and good image quality. Additionally, the applicability of abdominal MRE in small animals in a clinical MRI was demonstrated, and correlations between mechanical liver properties and metabolic functions were found. This study demonstrates improvements in the quality of maps of biophysical parameters for both clinical and preclinical studies, making an important contribution to the clinical translation of multifrequency MRE as a non-invasive imaging modality for abdominal organs and pathologies.Die Magnetresonanzelastographie (MRE) ist eine nichtinvasive Bildgebungsmethode zur Quantifizierung mechanischer Gewebeeigenschaften in vivo bei der Diagnose von Leberfibrose. Limitationen bestehen aufgrund örtlicher Bildauflösung, Bewegungsempfindlichkeit und Insensitivität zu metabolischen Funktionen. Aufgrund technischer Verbesserung in der Bildaufnahme und der Bildauswertung wurde daher anhand von drei Studien zur abdominellen MRE die Bildqualität mechanischer Karten zur Charakterisierung von Lebertumoren verbessert, atmungsinduzierte Organbewegungen korrigiert und die MRE an klinischen PET/MRT implementiert, um an Kleintieren die mechanischen Lebereigenschaften mit metabolischen Funktionen zu korrelieren. Mittels multifrequenter MRE, neuartiger Aktoren und tomoelastographischer Auswertung wurden hochaufgelöste Karten der Steifigkeit (Scherwellengeschwindigkeit in m/s), Wellenpenetration (Wellenpenetrationsrate in m/s) und Fluidität (Phase des komplexen Schermoduls in rad) generiert. Die erste Studie charakterisierte die Steifigkeit und Fluidität von insgesamt 141 Lebertumoren an 70 Patienten. Eine zweite Studie analysierte die Bewegung und den Einfluss auf die Steifigkeit abdomineller Organe mittels unterschiedlicher Aufnahmeparadigmen und Bildregistrierung in 12 Probanden. In einer dritten Studie wurde der Zusammenhang von Lebersteifigkeit und Wellenpenetration zu zentralen metabolischen Leberfunktionen an 19 Kaninchen untersucht. Maligne Lebertumoren können durch erhöhte Steifigkeit und Fluidität (Steifigkeit AUC: 0.88 und Fluidität AUC: 0.95) gut von gutartigen Tumoren (Steifigkeit AUC: 0.85 und Fluidität AUC: 0.86) unterschieden werden. In der zweiten Studie wurden trotz verschiedener Aufnahmeparadigmen und Unterschiede in Untersuchungsdauer, Organbewegung und Bildqualität keine signifikanten Unterschiede in der Organsteifigkeit festgestellt. Die Bildregistrierung verbesserte die Bildschärfe, sodass kein signifikanter Unterschied zwischen freier Atmung und Atempause messbar war. Kaninchenlebern zeigten heterogene Steifigkeiten, sodass eine Zweiteilung in niedrige und hohe Steifigkeit (>1.6 m/s) signifikante Unterschiede in zentralen metabolischen Funktionen zeigte. Steifigkeit und Fluidität, die mittels der Mehrfrequenz-MRE gemessen werden, stellen vielversprechende quantitative Biomarker für die Diagnose maligner Lebertumoren dar. Abdominelle MRE in freier Atmung mit Bildregistrierung ist der beste Kompromiss aus schneller Untersuchungsdauer und guter Bildqualität. Die Anwendbarkeit an Kleintieren in einem klinischen MRT wurde gezeigt, inklusive Korrelationen zwischen mechanischen Lebereigenschaften und metabolischen Funktionen. Diese Arbeit konnte somit die Bildqualität mechanischer Karten sowohl für klinische als auch präklinische Untersuchungen verbessern und damit einen wichtigen Beitrag zur Translation der Multifrequenz-MRE als klinisch angewandte nichtinvasive Bildgebungsmethode abdomineller Organe und Pathologien leisten

Cerebral Ultrasound Time-Harmonic Elastography Reveals Softening of the Human Brain Due to Dehydration

Hydration influences blood volume, blood viscosity, and water content in soft tissues - variables that determine the biophysical properties of biological tissues including their stiffness. In the brain, the relationship between hydration and stiffness is largely unknown despite the increasing importance of stiffness as a quantitative imaging marker. In this study, we investigated cerebral stiffness (CS) in 12 healthy volunteers using ultrasound time-harmonic elastography (THE) in different hydration states: (i) during normal hydration, (ii) after overnight fasting, and (iii) within 1 h of drinking 12 ml of water per kg body weight. In addition, we correlated shear wave speed (SWS) with urine osmolality and hematocrit. SWS at normal hydration was 1.64 ± 0.02 m/s and decreased to 1.57 ± 0.04 m/s (p < 0.001) after overnight fasting. SWS increased again to 1.63 ± 0.01 m/s within 30 min of water drinking, returning to values measured during normal hydration (p = 0.85). Urine osmolality at normal hydration (324 ± 148 mOsm/kg) increased to 784 ± 107 mOsm/kg (p < 0.001) after fasting and returned to normal (288 ± 128 mOsm/kg, p = 0.83) after water drinking. SWS and urine osmolality correlated linearly (r = -0.68, p < 0.001), while SWS and hematocrit did not correlate (p = 0.31). Our results suggest that mild dehydration in the range of diurnal fluctuations is associated with significant softening of brain tissue, possibly due to reduced cerebral perfusion. To ensure consistency of results, it is important that cerebral elastography with a standardized protocol is performed during normal hydration

Spatial heterogeneity of hepatic fibrosis in primary sclerosing cholangitis vs. viral hepatitis assessed by MR elastography

Spatial heterogeneity of hepatic fibrosis in primary sclerosing cholangitis (PSC) in comparison to viral hepatitis was assessed as a potential new biomarker using MR elastography (MRE). In this proof-of-concept study, we hypothesized a rather increased heterogeneity in PSC and a rather homogeneous distribution in viral hepatitis. Forty-six consecutive subjects (PSC: n=20, viral hepatitis: n=26) were prospectively enrolled between July 2014 and April 2017. Subjects underwent multifrequency MRE (1.5 T) using drive frequencies of 35-60 Hz and generating shear-wave speed (SWS in m/s) maps as a surrogate of stiffness. The coefficient of variation (CV in %) was determined to quantify fibrosis heterogeneity. Mean SWS and CV were 1.70 m/s and 21% for PSC, and 1.84 m/s and 18% for viral hepatitis. Fibrosis heterogeneity was significantly increased for PSC (P=0.04) while no difference was found for SWS of PSC and viral hepatitis (P=0.17). Global hepatic stiffness was similar in PSC and viral hepatitis groups, but spatial heterogeneity may reveal spatial patterns of stiffness changes towards enhanced biophysics-based diagnosis by MRI

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

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

Cerebral tomoelastography based on multifrequency MR elastography in two and three dimensions

Magnetic resonance elastography (MRE) generates quantitative maps of the mechanical properties of biological soft tissues. However, published values obtained by brain MRE vary largely and lack detail resolution, due to either true biological effects or technical challenges. We here introduce cerebral tomoelastography in two and three dimensions for improved data consistency and detail resolution while considering aging, brain parenchymal fraction (BPF), systolic blood pressure, and body-mass-index. Multifrequency MRE with 2D- and 3D-tomoelastography postprocessing was applied to the brains of 31 volunteers (age range: 22-61 years) for analyzing the coefficient of variation (CV) and effects of biological factors. Eleven volunteers were rescanned after one day and one year to determine intraclass correlation coefficient (ICC) and identify possible long-term changes. White matter shear-wave-speed (SWS) was slightly higher in 2D-MRE (1.28±0.02m/s) than 3D-MRE (1.22±0.05m/s, p<0.0001), with less variation after one day in 2D (0.33±0.32%) than in 3D (0.96±0.66%, p=0.004), which was also reflected in a slightly lower CV and higher ICC in 2D (1.84%, 0.97 [0.88-0.99]) than in 3D (3.89%, 0.95 [0.76-0.99]). Remarkably, 3D-MRE was sensitive to a decrease in white matter SWS within only one year, whereas no change in white matter volume was observed during this follow-up period. Across volunteers, stiffness correlated with age and BPF, but not with blood pressure and body-mass-index. Cerebral tomoelastography provides high-resolution viscoelasticity maps with excellent consistency. Brain MRE in 2D shows less variation across volunteers in shorter scan times than 3D-MRE, while 3D-MRE appears to be more sensitive to subtle biological effects such as aging

On the relationship between metabolic capacities and in vivo viscoelastic properties of the liver

The liver is the central metabolic organ. It constantly adapts its metabolic capacity to current physiological requirements. However, the relationship between tissue structure and hepatic function is incompletely understood; this results in a lack of diagnostic markers in medical imaging that can provide information about the liver's metabolic capacity. Therefore, using normal rabbit livers, we combined magnetic resonance elastography (MRE) with proteomics-based kinetic modeling of central liver metabolism to investigate the potential role of MRE for predicting the liver's metabolic function in vivo. Nineteen New Zealand white rabbits were investigated by multifrequency MRE and positron emission tomography (PET). This yielded maps of shear wave speed (SWS), penetration rate (PR) and standardized uptake value (SUV). Proteomic analysis was performed after the scans. Hepatic metabolic functions were assessed on the basis of the HEPATOKIN1 model in combination with a model of hepatic lipid-droplet metabolism using liquid chromatography-mass spectrometry. Our results showed marked differences between individual livers in both metabolic functions and stiffness properties, though not in SUV. When livers were divided into 'stiff' and 'soft' subgroups (cutoff SWS = 1.6 m/s), stiff livers showed a lower capacity for triacylglycerol storage, while at the same time showing an increased capacity for gluconeogenesis and cholesterol synthesis. Furthermore, SWS was correlated with gluconeogenesis and PR with urea production and glutamine exchange. In conclusion, our study indicates a close relationship between the viscoelastic properties of the liver and metabolic function. This could be used in future studies to predict non-invasively the functional reserve capacity of the liver in patients

In vivo stiffness of multiple sclerosis lesions is similar to that of normal-appearing white matter

In 1868, French neurologist Jean-Martin Charcot coined the term multiple sclerosis (MS) after his observation that numerous white matter (WM) glial scars felt like sclerotic tissue. Nowadays, magnetic resonance elastography (MRE) can generate images with contrast of stiffness (CS) in soft in vivo tissues and may therefore be sensitive to MS lesions, provided that sclerosis is indeed a mechanical signature of this disease. We analyzed CS in a total of 147 lesions in patients with relapsing-remitting MS, compared with control regions in contralateral brain regions, and phantom data as well as performed numerical simulations to determine the delineation limits of multifrequency MRE (20 - 40 Hz) in MS. MRE analysis of simulated waves revealed a delineation limit of approximately 10% CS for detecting 9-mm lesions (mean size in our patient population). Due to inversion bias, this limit is reached when true CS is -11% for soft and 35% for stiff lesions. In vivo MRE identified 35 stiffer lesions and 17 softer lesions compared with surrounding WM (mean stiffness: 934±82 Pa). However, a similar pattern was found in the contralateral brain, suggesting that the range of stiffness changes in WM lesions due to MS is within the normal range of WM variability and normal heterogeneity-related CS. Consequently, Charcot's original intuition that MS is a focal sclerotic disease can neither be dismissed nor confirmed by in vivo MRE. However, the observation that MS lesions do not markedly differ in stiffness from surrounding brain tissue suggests that marked tissue sclerosis is not a mechanical signature of MS. STATEMENT OF SIGNIFICANCE: Multiple sclerosis (MS) was named by J.M. Charcot after the sclerotic changes in brain tissue he found in post-mortem autopsies. Since then, nothing has been revealed about the actual stiffening of MS lesions in vivo. Studying the viscoelastic properties of plaques in their natural environment is a major challenge that can only be overcome by MR elastography (MRE). Therefore, we used multifrequency MRE to answer the question whether MS lesions in patients with a relapsing-remitting disease course are mechanically different than surrounding tissue. Our findings suggest that the range of stiffness changes in white matter lesions due to MS is within the normal range of white matter variability and in vivo tissue sclerosis might not be a mechanical signature of MS

Superviscous properties of the in vivo brain at large scales

There is growing awareness that brain mechanical properties are important for neural development and health. However, published values of brain stiffness differ by orders of magnitude between static measurements and in vivo magnetic resonance elastography (MRE), which covers a dynamic range over several frequency decades. We here show that there is no fundamental disparity between static mechanical tests and in vivo MRE when considering large-scale properties, which encompass the entire brain including fluid filled compartments. Using gradient echo real-time MRE, we investigated the viscoelastic dispersion of the human brain in, so far, unexplored dynamic ranges from intrinsic brain pulsations at 1 Hz to ultralow-frequency vibrations at 5, 6.25, 7.8 and 10 Hz to the normal frequency range of MRE of 40 Hz. Surprisingly, we observed variations in brain stiffness over more than two orders of magnitude, suggesting that the in vivo human brain is superviscous on large scales with very low shear modulus of 42±13 Pa and relatively high viscosity of 6.6±0.3 Pa∙s according to the two-parameter solid model. Our data shed light on the crucial role of fluid compartments including blood vessels and cerebrospinal fluid (CSF) for whole brain properties and provide, for the first time, an explanation for the variability of the mechanical brain responses to manual palpation, local indentation, and high-dynamic tissue stimulation as used in elastography

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. © 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicin