Publications by authors named "Diego Hernando"

112 Publications

Limits of Fat Quantification in the Presence of Iron Overload.

J Magn Reson Imaging 2021 Mar 29. Epub 2021 Mar 29.

Department of Radiology, University of Wisconsin, Madison, Wisconsin, USA.

Background: Chemical shift encoded magnetic resonance imaging (CSE-MRI)-based tissue fat quantification is confounded by increased R2* signal decay rate caused by the presence of excess iron deposition.

Purpose: To determine the upper limit of R2* above which it is no longer feasible to quantify proton density fat fraction (PDFF) reliably, using CSE-MRI.

Study Type: Prospective.

Population: Cramér-Rao lower bound (CRLB) calculations, Monte Carlo simulations, phantom experiments, and a prospective study in 26 patients with known or suspected liver iron overload.

Field Strength/sequence: Multiecho gradient echo at 1.5 T and 3.0 T.

Assessment: CRLB calculations were used to develop an empirical relationship between the maximum R2* value above which PDFF estimation will achieve a desired number of effective signal averages. A single voxel multi-TR, multi-TE stimulated echo acquisition mode magnetic resonance spectroscopy acquisition was used as a reference standard to estimate PDFF. Reconstructed PDFF and R2* maps were analyzed by one analyst using multiple regions of interest drawn in all nine Couinaud segments.

Statistical Tests: None.

Results: Simulations, phantom experiments, and in vivo measurements demonstrated unreliable PDFF estimates with increased R2*, with PDFF errors as large as 20% at an R2* of 1000 s . For typical optimized Cartesian acquisitions (TE1 = 0.75 msec, ΔTE = 0.67 msec at 1.5 T, TE1 = 0.65 msec, ΔTE = 0.58 msec at 3.0 T), an empirical relationship between PDFF estimation errors and acquisition parameters was developed that suggests PDFF estimates are unreliable above an R2* of ~538 s and ~779 s at 1.5 T and 3 T, respectively. This empirical relationship was further investigated with phantom experiments and in vivo measurements, with PDFF errors at an R2* of 1000 s at 3.0 T as large as 10% with TE1 = 1.24 msec, ΔTE = 1.01 msec compared to 3% with TE1 = 0.65 msec, ΔTE = 0.58 msec.

Data Conclusion: We successfully developed a theoretically-based empirical formula that may provide an easily calculable guideline to identify R2* values above which PDFF is not reliable in research and clinical applications using CSE-MRI to quantify PDFF in the presence of iron overload.

Level Of Evidence: 1 TECHNICAL EFFICACY STAGE: 1.
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http://dx.doi.org/10.1002/jmri.27611DOI Listing
March 2021

Contrasting recruitment of skin-associated adipose depots during cold challenge of mouse and human.

J Physiol 2021 Mar 16. Epub 2021 Mar 16.

McArdle Laboratory for Cancer Research, University of Wisconsin-Madison.

Key Points: Several distinct strategies produce and conserve heat to maintain body temperature of mammals, each associated with unique physiologies, with consequence for wellness and disease susceptibility Highly regulated properties of skin offset the total requirement for heat production  We hypothesize that the adipose component of skin is primarily responsible for modulating heat flux; here we evaluate the relative regulation of adipose depots in mouse and human, to test their recruitment to heat production and conservation We found that insulating mouse dermal white adipose tissue accumulates in response to environmentally- and genetically-induced cool stress; this layer is one of two adipose depots closely apposed to mouse skin, where the subcutaneous mammary gland fat pads are actively recruited to heat production In contrast, the body-wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue ABSTRACT: Mammalian skin impacts metabolic efficiency system-wide, controlling the rate of heat loss and consequent heat production. Here we compare the unique fat depots associated with mouse and human skin, to determine whether they have corresponding function and regulation. For human, we assay a skin-associated fat (SAF) body-wide depot to distinguish it from the subcutaneous fat pads characteristic of abdomen and upper limbs. We show that the thickness of SAF is not related to general adiposity; it is much thicker (1.6-fold) in women than men, and highly subject-specific. We used molecular and cellular assays of β-adrenergic induced lipolysis and found that dermal white adipose tissue (dWAT) in mice is resistant to lipolysis; in contrast, the body-wide human SAF depot becomes lipolytic, generating heat in response to β-adrenergic stimulation. In mice challenged to make more heat to maintain body temperature (either environmentally or genetically), there is a compensatory increase in thickness of dWAT: A corresponding β-adrenergic stimulation of human skin adipose (in vivo or in explant) depletes adipocyte lipid content. We summarize the regulation of skin-associated adipocytes by age, sex, and adiposity, for both species. We conclude that the body-wide dWAT depot of mice shows unique regulation that enables it to be deployed for heat preservation; combined with the actively lipolytic subcutaneous mammary fat pads they enable thermal defense. The adipose tissue that covers human subjects produces heat directly, providing an alternative to the brown adipose tissues. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1113/JP280922DOI Listing
March 2021

Accuracies of Chemical Shift In/Opposed Phase and Chemical Shift Encoded Magnetic Resonance Imaging to Detect Intratumoral Fat in Hepatocellular Carcinoma.

J Magn Reson Imaging 2021 Feb 12. Epub 2021 Feb 12.

Department of Radiology, Third Affiliated Hospital of Sun Yat sen University (SYSU), Guangzhou, China.

Background: Magnetic Resonance Imaging (MRI) being a noninvasive modality may help in preoperative evaluation of intratumoral fat in hepatocellular carcinoma (HCC) using chemical shift encoded (CSE) MRI and in-/opposed-phase (IOP) imaging sequences.

Purpose: To compare the diagnostic accuracy of chemical shift encoded fat fraction at three different flip angles (FAs) using quantitative chemical shift encoded MRI (CSE-MRI) with in-/opposed phase (IOP) imaging to evaluate intratumoral fat in HCC.

Study Type: Retrospective.

Population: Eighty-six patients with 87 pathology proven HCCs.

Field Strength/sequence: IOP (LAVA-Flex) and CSE-MRI (IDEAL IQ) a three-dimensional spoiled gradient-echo pulse sequences acquired at 3 T.

Assessment: Regions of interest (ROIs) were manually drawn by two observers in the tumors to measure mean fat fractions. Surgical specimens were reassessed for intratumoral fat content. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were assessed for CSE-MRI sequence at FA 3°, 8°, and 9°.

Statistical Tests: Intraclass correlation coefficient (ICC) was expressed in terms of inter- and intra-observer agreements. Receiver operating characteristic curve analysis was performed for the diagnostic performance followed by combined metric of both. SNR/CNR were analyzed by Kruskal-Wallis test.

Results: Excellent inter- and intra-observer agreements (ICC >0.95, P < 0.001) were observed for both IOP and CSE-MRI. IOP (86.4%) showed higher sensitivity than CSE-MRI at FA 3° (72.5%), FA 8° (76.4%) and FA 9° (76.3%). In contrast, the specificity for CSE-MRI at FA 3° (86%), FA 8° (87%), and FA 9° (87%) were greater than IOP (72%). A combined metric of IOP and CSE-MRI derived fat fractions at FA 8° gave highest AUC of 87% and accuracy of 86%. SNR and CNR for CSE-MRI were significantly higher at FA 8° and FA 9° than FA 3° (P < 0.05).

Data Conclusion: IOP and quantitative CSE-MRI are both feasible methods to detect intratumoral fat in HCC with higher accuracy and SNR for CSE-MRI at FA 8° and 9°.

Level Of Evidence: 3 TECHNICAL EFFICACY: Stage 2.
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http://dx.doi.org/10.1002/jmri.27539DOI Listing
February 2021

Temperature-corrected proton density fat fraction estimation using chemical shift-encoded MRI in phantoms.

Magn Reson Med 2021 Jul 9;86(1):69-81. Epub 2021 Feb 9.

Department of Medical Physics, University of Wisconsin - Madison, Madison, Wisconsin, USA.

Purpose: Chemical shift-encoded MRI (CSE-MRI) is well-established to quantify proton density fat fraction (PDFF) as a quantitative biomarker of hepatic steatosis. However, temperature is known to bias PDFF estimation in phantom studies. In this study, strategies were developed and evaluated to correct for the effects of temperature on PDFF estimation through simulations, temperature-controlled experiments, and a multi-center, multi-vendor phantom study.

Theory And Methods: A technical solution that assumes and automatically estimates a uniform, global temperature throughout the phantom is proposed. Computer simulations modeled the effect of temperature on PDFF estimation using magnitude-, complex-, and hybrid-based CSE-MRI methods. Phantom experiments were performed to assess the temperature correction on PDFF estimation at controlled phantom temperatures. To assess the temperature correction method on a larger scale, the proposed method was applied to data acquired as part of a nine-site multi-vendor phantom study and compared to temperature-corrected PDFF estimation using an a priori guess for ambient room temperature.

Results: Simulations and temperature-controlled experiments show that as temperature deviates further from the assumed temperature, PDFF bias increases. Using the proposed correction method and a reasonable a priori guess for ambient temperature, PDFF bias and variability were reduced using magnitude-based CSE-MRI, across MRI systems, field strengths, protocols, and varying phantom temperature. Complex and hybrid methods showed little PDFF bias and variability both before and after correction.

Conclusion: Correction for temperature reduces temperature-related PDFF bias and variability in phantoms across MRI vendors, sites, field strengths, and protocols for magnitude-based CSE-MRI, even without a priori information about the temperature.
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http://dx.doi.org/10.1002/mrm.28669DOI Listing
July 2021

Linearity and Bias of Proton Density Fat Fraction as a Quantitative Imaging Biomarker: A Multicenter, Multiplatform, Multivendor Phantom Study.

Radiology 2021 Mar 19;298(3):640-651. Epub 2021 Jan 19.

From the Department of Radiology, Nationwide Children's Hospital, 700 Children's Dr, Columbus, OH 43235 (H.H.H., M.A.S.); Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); Department of Radiology (M.R.B., J.S.), Department of Medicine, Division of Gastroenterology (M.R.B.), and Center for Advanced Magnetic Resonance Development (M.R.B., J.S.), Duke University Medical Center, Durham, NC; Liver Imaging Group, Department of Radiology, University of California San Diego, San Diego, Calif (C.B.S., M.S.M., W.C.H., G.H.); Departments of Radiology (D.H., J.H.B., S.B.R.), Medical Physics (D.H., E.F.J., S.B.R.), Biomedical Engineering (S.B.R.), Medicine (S.B.R.), and Emergency Medicine (S.B.R.), University of Wisconsin, Madison, Wis; Department of Radiology, University of Michigan, Ann Arbor, Mich (D.M., T.L.C.); Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pa (S.D.S.); Department of Radiology, Mayo Clinic, Rochester, Minn (Y.S.); Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (J.A.T., A.T.T.); Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.A.T., A.T.T.); Department of Quantitative Health Science, Cleveland Clinic Foundation, Cleveland, Ohio (N.O.); and Calimetrix, LLC, Madison, Wis (J.H.B.).

Background Proton density fat fraction (PDFF) estimated by using chemical shift-encoded (CSE) MRI is an accepted imaging biomarker of hepatic steatosis. This work aims to promote standardized use of CSE MRI to estimate PDFF. Purpose To assess the accuracy of CSE MRI methods for estimating PDFF by determining the linearity and range of bias observed in a phantom. Materials and Methods In this prospective study, a commercial phantom with 12 vials of known PDFF values were shipped across nine U.S. centers. The phantom underwent 160 independent MRI examinations on 27 1.5-T and 3.0-T systems from three vendors. Two three-dimensional CSE MRI protocols with minimal T1 bias were included: vendor and standardized. Each vendor's confounder-corrected complex or hybrid magnitude-complex based reconstruction algorithm was used to generate PDFF maps in both protocols. The Siemens reconstruction required a configuration change to correct for water-fat swaps in the phantom. The MRI PDFF values were compared with the known PDFF values by using linear regression with mixed-effects modeling. The 95% CIs were calculated for the regression slope (ie, proportional bias) and intercept (ie, constant bias) and compared with the null hypothesis (slope = 1, intercept = 0). Results Pooled regression slope for estimated PDFF values versus phantom-derived reference PDFF values was 0.97 (95% CI: 0.96, 0.98) in the biologically relevant 0%-47.5% PDFF range. The corresponding pooled intercept was -0.27% (95% CI: -0.50%, -0.05%). Across vendors, slope ranges were 0.86-1.02 (vendor protocols) and 0.97-1.0 (standardized protocol) at 1.5 T and 0.91-1.01 (vendor protocols) and 0.87-1.01 (standardized protocol) at 3.0 T. The intercept ranges (absolute PDFF percentage) were -0.65% to 0.18% (vendor protocols) and -0.69% to -0.17% (standardized protocol) at 1.5 T and -0.48% to 0.10% (vendor protocols) and -0.78% to -0.21% (standardized protocol) at 3.0 T. Conclusion Proton density fat fraction estimation derived from three-dimensional chemical shift-encoded MRI in a commercial phantom was accurate across vendors, imaging centers, and field strengths, with use of the vendors' product acquisition and reconstruction software. © RSNA, 2021 See also the editorial by Dyke in this issue.
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http://dx.doi.org/10.1148/radiol.2021202912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924516PMC
March 2021

Free-breathing mapping of hepatic iron overload in children using 3D multi-echo UTE cones MRI.

Magn Reson Med 2021 May 11;85(5):2608-2621. Epub 2021 Jan 11.

Departments of Radiology and Electrical Engineering, Stanford University, Magnetic Resonance Systems Research Lab (MRSRL), Stanford, California, USA.

Purpose: To enable motion-robust, ungated, free-breathing mapping of hepatic iron overload in children with 3D multi-echo UTE cones MRI.

Methods: A golden-ratio re-ordered 3D multi-echo UTE cones acquisition was developed with chemical-shift encoding (CSE). Multi-echo complex-valued source images were reconstructed via gridding and coil combination, followed by confounder-corrected (=1/ ) mapping. A phantom containing 15 different concentrations of gadolinium solution (0-300 mM) was imaged at 3T. 3D multi-echo UTE cones with an initial TE of 0.036 ms and Cartesian CSE-MRI (IDEAL-IQ) sequences were performed. With institutional review board approval, 85 subjects (81 pediatric patients with iron overload + 4 healthy volunteers) were imaged at 3T using 3D multi-echo UTE cones with free breathing (FB cones), IDEAL-IQ with breath holding (BH Cartesian), and free breathing (FB Cartesian). Overall image quality of maps was scored by 2 blinded experts and compared by a Wilcoxon rank-sum test. For each pediatric subject, the paired maps were assessed to determine if a corresponding artifact-free 15 mm region-of-interest (ROI) could be identified at a mid-liver level on both images. Agreement between resulting quantification from FB cones and BH/FB Cartesian was assessed with Bland-Altman and linear correlation analyses.

Results: ROI-based regression analysis showed a linear relationship between gadolinium concentration and in IDEAL-IQ (y = 8.83x - 52.10, R = 0.995) as well as in cones (y = 9.19x - 64.16, R = 0.992). ROI-based Bland-Altman analysis showed that the mean difference (MD) was 0.15% and the SD was 5.78%. However, IDEAL-IQ measurements beyond 200 mM substantially deviated from a linear relationship for IDEAL-IQ (y = 5.85x + 127.61, R = 0.827), as opposed to cones (y = 10.87x - 166.96, R = 0.984). In vivo, FB cones had similar image quality with BH and FB Cartesian in 15 and 42 cases, respectively. FB cones had better image quality scores than BH and FB Cartesian in 3 and 21 cases, respectively, where BH/FB Cartesian exhibited severe ghosting artifacts. ROI-based Bland-Altman analyses were 2.23% (MD) and 6.59% (SD) between FB cones and BH Cartesian and were 0.21% (MD) and 7.02% (SD) between FB cones and FB Cartesian, suggesting a good agreement between FB cones and BH (FB) Cartesian . Strong linear relationships were observed between BH Cartesian and FB cones (y = 1.00x + 1.07, R = 0.996) and FB Cartesian and FB cones (y = 0.98x + 1.68, R = 0.999).

Conclusion: Golden-ratio re-ordered 3D multi-echo UTE Cones MRI enabled motion-robust, ungated, and free-breathing mapping of hepatic iron overload, with comparable measurements and image quality to BH Cartesian, and better image quality than FB Cartesian.
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http://dx.doi.org/10.1002/mrm.28610DOI Listing
May 2021

A pilot study of bladder voiding with real-time MRI and computational fluid dynamics.

PLoS One 2020 19;15(11):e0238404. Epub 2020 Nov 19.

Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States of America.

Lower urinary track symptoms (LUTS) affect many older adults. Multi-channel urodynamic studies provide information about bladder pressure and urinary flow but offer little insight into changes in bladder anatomy and detrusor muscle function. Here we present a novel method for real time MRI during bladder voiding. This was performed in a small cohort of healthy men and men with benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) to demonstrate proof of principle; The MRI urodynamic protocol was successfully implemented, and bladder wall displacement and urine flow dynamics were calculated. Displacement analysis on healthy controls showed the greatest bladder wall displacement in the dome of the bladder while men with BPH/LUTS exhibited decreased and asymmetric bladder wall motion. Computational fluid dynamics of voiding showed men with BPH/LUTS had larger recirculation regions in the bladder. This study demonstrates the feasibility of performing MRI voiding studies and their potential to provide new insight into lower urinary tract function in health and disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238404PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676741PMC
December 2020

B and B inhomogeneities in the liver at 1.5 T and 3.0 T.

Magn Reson Med 2021 04 26;85(4):2212-2220. Epub 2020 Oct 26.

Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Purpose: The purpose of this work is to characterize the magnitude and variability of B and B inhomogeneities in the liver in large cohorts of patients at both 1.5 T and 3.0 T.

Methods: Volumetric B and B maps were acquired over the liver of patients presenting for routine abdominal MRI. Regions of interest were drawn in the nine Couinaud segments of the liver, and the average value was recorded. Magnitude and variation of measured averages in each segment were reported across all patients.

Results: A total of 316 B maps and 314 B maps, acquired at 1.5 T and 3.0 T on a variety of GE Healthcare MRI systems in 630 unique exams, were identified, analyzed, and, in the interest of reproducible research, de-identified and made public. Measured B inhomogeneities ranged (5th-95th percentiles) from -31.7 Hz to 164.0 Hz for 3.0 T (-14.5 Hz to 81.3 Hz at 1.5 T), while measured B inhomogeneities (ratio of actual over prescribed flip angle) ranged from 0.59 to 1.13 for 3.0 T (0.83 to 1.11 at 1.5 T).

Conclusion: This study provides robust characterization of B and B inhomogeneities in the liver to guide the development of imaging applications and protocols. Field strength, bore diameter, and sex were determined to be statistically significant effects for both B and B uniformity. Typical clinical liver imaging at 3.0 T should expect B inhomogeneities ranging from approximately -100 Hz to 250 Hz (-50 Hz to 150 Hz at 1.5 T) and B inhomogeneities ranging from approximately 0.4 to 1.3 (0.7 to 1.2 at 1.5 T).
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http://dx.doi.org/10.1002/mrm.28549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869971PMC
April 2021

Comprehensive non-invasive analysis of lower urinary tract anatomy using MRI.

Abdom Radiol (NY) 2021 Apr 11;46(4):1670-1676. Epub 2020 Oct 11.

Departments of Radiology, School of Medicine and Public Health, University of Wisconsin, Madison, USA.

Purpose: Anatomic changes that coincide with aging including benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) negatively impact quality of life. Use of MRI with its exquisite soft tissue contrast, full field-of-view capabilities, and lack of radiation is uniquely suited for quantifying specific lower urinary tract features and providing comprehensive measurements such as total bladder wall volume (BWV), bladder wall thickness (BWT), and prostate volume (PV). We present a technique for generating 3D anatomical renderings from MRI to perform quantitative analysis of lower urinary tract anatomy.

Methods: T2-weighted fast-spin echo MRI of the pelvis in 117 subjects (59F;58 M) aged 30-69 (49.5 ± 11.3) without known lower urinary tract symptoms was retrospectively segmented using Materialise software. Virtual 3D models were used to measure BWV, BWT, and PV.

Results: BWV increased significantly between the 30-39 and 60-69 year age group in women (p = 0.01), but not men (p = 0.32). BWV was higher in men than women aged 30-39 and 40-49 (p = 0.02, 0.05, respectively) ,but not 50-59 or 60-69 (p = 0.18, 0.16, respectively). BWT was thicker in men than women across all age groups. Regional differences in BWT were observed both between men and women and between opposing bladder wall halves (anterior/posterior, dome/base, left/right) within each sex in the 50-59 and 60-69 year groups. PV increased from the 30-39 to 60-69 year groups (p = 0.05). BWT was higher in subjects with enlarged prostates (> 40cm) (p = 0.05).

Conclusion: Virtual 3D MRI models of the lower urinary tract reliably quantify sex-specific and age-associated changes of the bladder wall and prostate.
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http://dx.doi.org/10.1007/s00261-020-02808-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036233PMC
April 2021

Effect of noise and estimator type on bias for analysis of liver proton density fat fraction.

Magn Reson Imaging 2020 12 2;74:244-249. Epub 2020 Oct 2.

Department of Radiology, University of Wisconsin - Madison, Madison, WI, United States; Medical Physics, University of Wisconsin - Madison, Madison, WI, United States; Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, United States; Medicine, University of Wisconsin - Madison, Madison, WI, United States; Emergency Medicine, University of Wisconsin - Madison, Madison, WI, United States. Electronic address:

Purpose: Proton-density fat-fraction (PDFF) is typically measured from PDFF maps by calculating the mean PDFF value within a region of interest (ROI). However, the mean estimator has been shown to result in bias when signal-to-noise ratio (SNR) is low, resulting from a skewed distribution of PDFF noise statistics. Thus, the purpose of this work was to determine the relative performance of three estimation methods (mean, median, maximum likelihood estimators (MLE)) for analysis of liver PDFF maps.

Methods: Observational study of adult patients (n = 56) undergoing abdominal MRI. Both 2D-sequential CSE-MRI ('low-SNR') and 3D CSE-MRI ('high-SNR') acquisitions were obtained. Single-voxel MRS formed the independent reference measurement of hepatic PDFF. Intra-class correlation was tested on a subset of 'low-SNR' acquisitions. ROIs were semi-automatically co-registered across all acquisitions. Bland-Altman analysis and intra-class correlation coefficients were used for statistical analysis. A p-value of <0.05 was considered significant.

Results: For in vivo low-SNR acquisitions, the mean estimator had a larger error than either the median or MLE values (bias ~ -1% absolute PDFF). The intra-class correlation coefficient was significantly greater for median and maximum likelihood estimators (0.992 and 0.993, respectively) compared to the mean estimator (0.973).

Conclusion: Alternative ROI analysis strategies, such as MLE or median estimators, are useful to avoid SNR-related PDFF bias. Median may be the most clinically practical strategy given its ease of calculation.
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http://dx.doi.org/10.1016/j.mri.2020.09.027DOI Listing
December 2020

Complex confounder-corrected R2* mapping for liver iron quantification with MRI.

Eur Radiol 2021 Jan 12;31(1):264-275. Epub 2020 Aug 12.

Department of Radiology, University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, Rm 2474, 1111 Highland Ave, Madison, WI, 53705, USA.

Objectives: MRI-based R2* mapping may enable reliable and rapid quantification of liver iron concentration (LIC). However, the performance and reproducibility of R2* across acquisition protocols remain unknown. Therefore, the objective of this work was to evaluate the performance and reproducibility of complex confounder-corrected R2* across acquisition protocols, at both 1.5 T and 3.0 T.

Methods: In this prospective study, 40 patients with suspected iron overload and 10 healthy controls were recruited with IRB approval and informed written consent and imaged at both 1.5 T and 3.0 T. For each subject, acquisitions included four different R2* mapping protocols at each field strength, and an FDA-approved R2-based method performed at 1.5 T as a reference for LIC. R2* maps were reconstructed from the complex data acquisitions including correction for noise effects and fat signal. For each subject, field strength, and R2* acquisition, R2* measurements were performed in each of the nine liver Couinaud segments and the spleen. R2* measurements were compared across protocols and field strength (1.5 T and 3.0 T), and R2* was calibrated to LIC for each acquisition and field strength.

Results: R2* demonstrated high reproducibility across acquisition protocols (p > 0.05 for 96/108 pairwise comparisons across 2 field strengths and 9 liver segments, ICC > 0.91 for each field strength/segment combination) and high predictive ability (AUC > 0.95 for four clinically relevant LIC thresholds). Calibration of R2* to LIC was LIC = - 0.04 + 2.62 × 10 R2* at 1.5 T and LIC = 0.00 + 1.41 × 10 R2* at 3.0 T.

Conclusions: Complex confounder-corrected R2* mapping enables LIC quantification with high reproducibility across acquisition protocols, at both 1.5 T and 3.0 T.

Key Points: • Confounder-corrected R2* of the liver provides reproducible R2* across acquisition protocols, including different spatial resolutions, echo times, and slice orientations, at both 1.5 T and 3.0 T. • For all acquisition protocols, high correlation with R2-based liver iron concentration (LIC) quantification was observed. • The calibration between confounder-corrected R2* and LIC, at both 1.5 T and 3.0 T, is determined in this study.
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http://dx.doi.org/10.1007/s00330-020-07123-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755713PMC
January 2021

Design and evaluation of quantitative MRI phantoms to mimic the simultaneous presence of fat, iron, and fibrosis in the liver.

Magn Reson Med 2021 02 12;85(2):734-747. Epub 2020 Aug 12.

Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Purpose: To design, construct, and evaluate quantitative MR phantoms that mimic MRI signals from the liver with simultaneous control of three parameters: proton-density fat fraction (PDFF), , and T . These parameters are established biomarkers of hepatic steatosis, iron overload, and fibrosis/inflammation, respectively, which can occur simultaneously in the liver.

Methods: Phantoms including multiple vials were constructed. Peanut oil was used to modulate PDFF, MnCl and iron microspheres were used to modulate , and NiCl was used to modulate the T of water (T ). Phantoms were evaluated at both 1.5 T and 3 T using stimulated-echo acquisition-mode MRS and chemical shift-encoded MRI. Stimulated-echo acquisition-mode MRS data were processed to estimate T , T , , and for each vial. Chemical shift-encoded MRI data were processed to generate PDFF and maps, and measurements were obtained in each vial. Measurements were evaluated using linear regression and Bland-Altman analysis.

Results: High-quality PDFF and maps were obtained with homogeneous values throughout each vial. High correlation was observed between imaging PDFF with target PDFF (slope = 0.94-0.97, R = 0.994-0.997) and imaging with target (slope = 0.84-0.88, R = 0.935-0.943) at both 1.5 T and 3 T. The values of and were highly correlated with slope close to 1.0 at both 1.5 T (slope = 0.90, R = 0.988) and 3 T (slope = 0.99, R = 0.959), similar to the behavior observed in vivo. The value of T (500-1200 ms) was controlled with varying NiCl concentration, while T (300 ms) was independent of NiCl concentration.

Conclusion: Novel quantitative MRI phantoms that mimic the simultaneous presence of fat, iron, and fibrosis in the liver were successfully developed and validated.
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http://dx.doi.org/10.1002/mrm.28452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722215PMC
February 2021

Free-breathing liver fat and quantification using motion-corrected averaging based on a nonlocal means algorithm.

Magn Reson Med 2021 02 1;85(2):653-666. Epub 2020 Aug 1.

Radiology, University of Wisconsin-Madison, Madison, WI, USA.

Purpose: To propose a motion-robust chemical shift-encoded (CSE) method with high signal-to-noise (SNR) for accurate quantification of liver proton density fat fraction (PDFF) and .

Methods: A free-breathing multi-repetition 2D CSE acquisition with motion-corrected averaging using nonlocal means (NLM) was proposed. PDFF and quantified with 2D CSE-NLM were compared to two alternative 2D techniques: direct averaging and single acquisition (2D 1ave) in a digital phantom. Further, 2D NLM was compared in patients to 3D techniques (standard breath-hold, free-breathing and navigated), and the alternative 2D techniques. A reader study and quantitative analysis (Bland-Altman, correlation analysis, paired Student's t-test) were performed to evaluate the image quality and assess PDFF and measurements in regions of interest.

Results: In simulations, 2D NLM resulted in lower standard deviations (STDs) of PDFF (2.7%) and (8.2  ) compared to direct averaging (PDFF: 3.1%, : 13.6  ) and 2D 1ave (PDFF: 8.7%, : 33.2  ). In patients, 2D NLM resulted in fewer motion artifacts than 3D free-breathing and 3D navigated, less signal loss than 2D direct averaging, and higher SNR than 2D 1ave. Quantitatively, the STDs of PDFF and of 2D NLM were comparable to those of 2D direct averaging (p>0.05). 2D NLM reduced bias, particularly in (-5.73 to -0.36  ) that arises in direct averaging (-3.96 to 11.22  ) in the presence of motion.

Conclusions: 2D CSE-NLM enables accurate mapping of PDFF and in the liver during free-breathing.
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http://dx.doi.org/10.1002/mrm.28439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883322PMC
February 2021

Motion-robust, high-SNR liver fat quantification using a 2D sequential acquisition with a variable flip angle approach.

Magn Reson Med 2020 10 3;84(4):2004-2017. Epub 2020 Apr 3.

Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.

Purpose: Chemical shift encoded (CSE)-MRI enables quantification of proton-density fat fraction (PDFF) as a biomarker of liver fat content. However, conventional 3D Cartesian CSE-MRI methods require breath-holding. A motion-robust 2D Cartesian sequential method addresses this limitation but suffers from low SNR. In this work, a novel free breathing 2D Cartesian sequential CSE-MRI method using a variable flip angle approach with centric phase encoding (VFA-centric) is developed to achieve fat quantification with low bias, high SNR, and minimal blurring.

Methods: Numerical simulation was performed for variable flip angle schedule design and preliminary evaluation of VFA-centric method, along with several alternative flip angle designs. Phantom, adults (n = 8), and children (n = 27) were imaged at 3T. Multi-echo images were acquired and PDFF maps were estimated. PDFF standard deviation was used as a surrogate for SNR.

Results: In both simulation and phantom experiments, the VFA-centric method enabled higher SNR imaging with minimal bias and blurring artifacts. High correlation (slope = 1.00, intercept = 0.04, = 0.998) was observed in vivo between the proposed VFA-centric method obtained PDFF and reference PDFF (free breathing low-flip angle 2D sequential acquisition). Further, the proposed VFA-centric method (PDFF standard deviation = 1.5%) had a better SNR performance than the reference acquisition (PDFF standard deviation = 3.3%) with P < .001.

Conclusions: The proposed free breathing 2D Cartesian sequential CSE-MRI method with variable flip angle approach and centric-ordered phase encoding achieved motion robustness, low bias, high SNR compared to previous 2D sequential methods, and low blurring in liver fat quantification.
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http://dx.doi.org/10.1002/mrm.28263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366366PMC
October 2020

Stimulated-echo diffusion-weighted imaging with moderate b values for the detection of prostate cancer.

Eur Radiol 2020 Jun 16;30(6):3236-3244. Epub 2020 Feb 16.

Department of Medical Physics, University of Wisconsin Madison, Madison, WI, USA.

Objectives: Conventional spin-echo (SE) DWI leads to a fundamental trade-off depending on the b value: high b value provides better lesion contrast-to-noise ratio (CNR) by sacrificing signal-to-noise ratio (SNR), image quality, and quantitative reliability. A stimulated-echo (STE) DWI acquisition is evaluated for high-CNR imaging of prostate cancer while maintaining SNR and reliable apparent diffusion coefficient (ADC) mapping.

Methods: In this prospective, IRB-approved study, 27 patients with suspected prostate cancer (PCa) were scanned with three DWI sequences (SE b = 800 s/mm, SE b = 1500 s/mm, and STE b = 800 s/mm) after informed consent was obtained. ROIs were drawn on biopsy-confirmed cancer and non-cancerous tissue to perform quantitative SNR, CNR, and ADC measurements. Qualitative metrics (SNR, CNR, and overall image quality) were evaluated by three experienced radiologists. Metrics were compared pairwise between the three acquisitions using a t test (quantitative metrics) and Wilcoxon rank test (qualitative metrics).

Results: Quantitative measurements showed that STE DWI at b = 800 s/mm has significantly better SNR compared to SE DWI at b = 1500 s/mm (p < 0.0001) and comparable CNR to high-b value SE DWI at b = 1500 s/mm (p < 0.05) in the peripheral zone. Qualitative assessment showed preference to STE b = 800 s/mm in SNR and SE b = 1500 s/mm in CNR. The overall image quality and lesion detectability among most readers showed no significant preference between STE b = 800 s/mm and SE b = 1500 s/mm. Further, STE DWI had similar ADC contrast between lesion and normal tissue as SE DWI at b = 800 s/mm (p = 0.90).

Conclusion: STE DWI has the potential to provide high-SNR, high-CNR imaging of prostate cancer while also enabling reliable ADC mapping.

Key Points: • Quantitative analysis showed that STE DWI at b = 800 s/mmis able to achieve simultaneously high CNR, high SNR, and reliable ADC mapping, compared to SE b = 800 s/mmand SE b = 1500 s/mm. • Qualitative assessment by three readers showed that STE DWI at b = 800 s/mmhas significantly higher SNR than SE b = 1500 s/mm. No preference between SE b = 1500 s/mmand STE b = 800 s/mmwas determined in terms of CNR with no missed lesions were found in both acquisitions. • A single STE DWI acquisition at moderate b value (800-1000 s/mm) may provide sufficient image quality and quantitative reliability for prostate cancer imaging within a shorter scan time, in place of two DWI acquisitions (one with moderate b value and one with high b value).
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http://dx.doi.org/10.1007/s00330-020-06689-wDOI Listing
June 2020

Phase-based T mapping with gradient echo imaging.

Magn Reson Med 2020 08 24;84(2):609-619. Epub 2019 Dec 24.

Department of Radiology, University of Wisconsin, Madison, Wisconsin.

Purpose: Transverse relaxation time (T ) mapping with MRI has a plethora of clinical and research applications. Current T mapping techniques are based primarily on spin-echo (SE) relaxometry strategies that rely on the signal magnitude, and often suffer from lengthy acquisition times. In this work, we propose a phase-based T mapping technique where T information is encoded into the signal phase of rapid gradient echo (GRE) acquisitions.

Theory: Bloch equation simulations demonstrate that the phase of GRE acquisitions obtained with a very small inter-repetition RF phase increment has a strong monotonic dependence on T , resulting from coherent transverse magnetization. This T -dependent phase behavior forms the basis of the proposed T mapping technique. To isolate T -dependent phase from background phase, at least 2 data sets with different RF phase increments are acquired. The proposed method can also be combined with chemical shift encoded MRI to separate water and fat signals.

Methods: The feasibility of the proposed technique was validated in a phantom experiment. In vivo feasibility was demonstrated in the brain, knee, abdomen, and pelvis. Comparisons were made with SE-based T mapping, spectroscopy, and T values from the literature.

Results: The proposed method produced accurate T maps compared with SE-based T mapping in the phantom. Good qualitative agreement was observed in vivo between the proposed method and the reference. T measured in various anatomies agreed well with values reported in the literature.

Conclusion: A phase-based T mapping technique was developed and its feasibility demonstrated in phantoms and in vivo.
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http://dx.doi.org/10.1002/mrm.28138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180093PMC
August 2020

Magnetic resonance imaging of obesity and metabolic disorders: Summary from the 2019 ISMRM Workshop.

Magn Reson Med 2020 05 29;83(5):1565-1576. Epub 2019 Nov 29.

Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.

More than 100 attendees from Australia, Austria, Belgium, Canada, China, Germany, Hong Kong, Indonesia, Japan, Malaysia, the Netherlands, the Philippines, Republic of Korea, Singapore, Sweden, Switzerland, the United Kingdom, and the United States convened in Singapore for the 2019 ISMRM-sponsored workshop on MRI of Obesity and Metabolic Disorders. The scientific program brought together a multidisciplinary group of researchers, trainees, and clinicians and included sessions in diabetes and insulin resistance; an update on recent advances in water-fat MRI acquisition and reconstruction methods; with applications in skeletal muscle, bone marrow, and adipose tissue quantification; a summary of recent findings in brown adipose tissue; new developments in imaging fat in the fetus, placenta, and neonates; the utility of liver elastography in obesity studies; and the emerging role of radiomics in population-based "big data" studies. The workshop featured keynote presentations on nutrition, epidemiology, genetics, and exercise physiology. Forty-four proffered scientific abstracts were also presented, covering the topics of brown adipose tissue, quantitative liver analysis from multiparametric data, disease prevalence and population health, technical and methodological developments in data acquisition and reconstruction, newfound applications of machine learning and neural networks, standardization of proton density fat fraction measurements, and X-nuclei applications. The purpose of this article is to summarize the scientific highlights from the workshop and identify future directions of work.
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http://dx.doi.org/10.1002/mrm.28103DOI Listing
May 2020

T -corrected quantitative chemical shift-encoded MRI.

Magn Reson Med 2020 06 14;83(6):2051-2063. Epub 2019 Nov 14.

Department of Radiology, University of Wisconsin, Madison, Wisconsin.

Purpose: To develop and validate a T -corrected chemical-shift encoded MRI (CSE-MRI) method to improve noise performance and reduce bias for quantification of tissue proton density fat-fraction (PDFF).

Methods: A variable flip angle (VFA)-CSE-MRI method using joint-fit reconstruction was developed and implemented. In computer simulations and phantom experiments, sources of bias measured using VFA-CSE-MRI were investigated. The effect of tissue T on bias using low flip angle (LFA)-CSE-MRI was also evaluated. The noise performance of VFA-CSE-MRI was compared to LFA-CSE-MRI for liver fat quantification. Finally, a prospective pilot study in patients undergoing gadoxetic acid-enhanced MRI of the liver to evaluate the ability of the proposed method to quantify liver PDFF before and after contrast.

Results: VFA-CSE-MRI was accurate and insensitive to transmit B inhomogeneities in phantom experiments and computer simulations. With high flip angles, phase errors because of RF spoiling required modification of the CSE signal model. For relaxation parameters commonly observed in liver, the joint-fit reconstruction improved the noise performance marginally, compared to LFA-CSE-MRI, but eliminated T -related bias. A total of 25 patients were successfully recruited and analyzed for the pilot study. Strong correlation and good agreement between PDFF measured with VFA-CSE-MRI and LFA-CSE-MRI (pre-contrast) was observed before (R = 0.97; slope = 0.88, 0.81-0.94 95% confidence interval [CI]; intercept = 1.34, -0.77-1.92 95% CI) and after (R = 0.93; slope = 0.88, 0.78-0.98 95% CI; intercept = 1.90, 1.01-2.79 95% CI) contrast.

Conclusion: Joint-fit VFA-CSE-MRI is feasible for T -corrected PDFF quantification in liver, is insensitive to B inhomogeneities, and can eliminate T bias, but with only marginal SNR advantage for T values observed in the liver.
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http://dx.doi.org/10.1002/mrm.28062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047527PMC
June 2020

Pharmacokinetics of Ferumoxytol in the Abdomen and Pelvis: A Dosing Study with 1.5- and 3.0-T MRI Relaxometry.

Radiology 2020 01 12;294(1):108-116. Epub 2019 Nov 12.

Form the Departments of Radiology (S.A.W., T.S., U.M., S.D.S., C.A.C., S.K., D.H., S.B.R.), Biostatistics and Medical Informatics (K.M.W.), Biomedical Engineering (S.B.R.), Medical Physics (S.B.R.), Medicine (S.B.R.), and Emergency Medicine (S.B.R.), University of Wisconsin-Madison, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, E3/366, Madison, WI 53792; Clinic of Radiology and Nuclear Medicine, Basel University Hospital, Basel, Switzerland (T.S.); Department of Radiology, University of Yamanashi, Yamanashi, Japan (U.M.); and Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Germany (S.K.).

Background The off-label use of ferumoxytol (FE), an intravenous iron preparation for iron deficiency anemia, as a contrast agent for MRI is increasing; therefore, it is critical to understand its pharmacokinetics. Purpose To evaluate the pharmacokinetics of FE in the abdomen and pelvis, as assessed with quantitative 1.5- and 3.0-T MRI relaxometry. Materials and Methods R2*, an MRI technique used to estimate tissue iron content in the abdomen and pelvis, was performed at 1.5 and 3.0 T in 12 healthy volunteers between April 2015 and January 2016. Volunteers were randomly assigned to receive an FE dose of 2 mg per kilogram of body weight (FE) or 4 mg/kg (FE). MRI was repeated at 1.5 and 3.0 T for each volunteer at five time points: days 1, 2, 4, 7, and 30. A radiologist experienced in MRI relaxometry measured R2* in organs of the mononuclear phagocyte system (MPS) (ie, liver, spleen, and bone marrow), non-MPS anatomy (kidney, pancreas, and muscle), inguinal lymph nodes (LNs), and blood pool. A paired Student test was used to compare changes in tissue R2*. Results Volunteers (six female; mean age, 44.3 years ± 12.2 [standard deviation]) received either FE ( = 5) or FE ( = 6). Overall R2* trend analysis was temporally significant ( < .001). Time to peak R2* in the MPS occurred on day 1 for FE and between days 1 and 4 for FE ( < .001 to < .002). Time to peak R2* in non-MPS anatomy, LNs, and blood pool occurred on day 1 for both doses ( < .001 to < .09). Except for the spleen (at 1.5 T) and liver, MPS R2* remained elevated through day 30 for both doses ( = .02 to = .03). Except for the kidney and pancreas, non-MPS, LN, and blood pool R2* returned to baseline levels between days 2 and 4 at FE ( = .06 to = .49) and between days 4 and 7 at FE ( = .06 to = .63). There was no difference in R2* change between non-MPS and LN R2* at any time (range, 1-71 sec vs 0-50 sec; = .06 to = .97). Conclusion The pharmacokinetics of ferumoxytol in lymph nodes are distinct from those in mononuclear phagocyte system (MPS) organs, parallel non-MPS anatomy, and the blood pool. © RSNA, 2019
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http://dx.doi.org/10.1148/radiol.2019190489DOI Listing
January 2020

Determination of optimized set of b-values for Apparent Diffusion Coefficient mapping in liver Diffusion-Weighted MRI.

J Magn Reson 2020 01 31;310:106634. Epub 2019 Oct 31.

Laboratorio de Procesado de Imagen, Universidad de Valladolid, Valladolid, Spain.

In this manuscript we derive the Cramér-Rao Lower Bound (CRLB) of the monoexponential diffusion-weighted signal model under a realistic noise assumption, and propose a formulation to obtain optimized sets of b-values that maximize the noise performance of the Apparent Diffusion Coefficient (ADC) maps given a target ADC and a signal-to-noise ratio. Therefore, for various sets of parameters (S and ADC), signal-to-noise ratios (SNR) and noise distribution, we computed optimized sets of b-values using CRLB-based analysis in two different ways: (i) through a greedy algorithm where b-values from a pool of candidates were added iteratively to the set, and (ii) through a two b-value search algorithm were all two b-value combinations of the pool of candidates were tested. Further, optimized sets of b-values were computed from synthetic data, phantoms, and in-vivo liver diffusion-weighted imaging (DWI) experiments to validate the CRLB-based analysis. The optimized sets of b-values obtained through the proposed CRLB-based analysis showed good agreement with the optimized sets obtained experimentally from synthetic, phantoms, and in-vivo liver data. The variance of the ADC maps decreased when employing the optimized set of b-values compared to various sets of b-values proposed in the literature for in-vivo liver DWI, although differences of notable magnitude between noise models and optimization strategies were not found. In addition, the higher b-values decreased for lower SNR under the Rician noise distribution. Optimization of the set b-values is critical to maximize the noise performance (i.e., maximize the precision and minimize the variance) of the estimated ADC maps in diffusion-weighted MRI. Hence, the proposed approach may help to optimize and standardize liver diffusion-weighted MRI acquisitions by computing optimized set of b-values for a given set of parameters.
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http://dx.doi.org/10.1016/j.jmr.2019.106634DOI Listing
January 2020

Quantitative ferumoxytol-enhanced MRI in pregnancy: A feasibility study in the nonhuman primate.

Magn Reson Imaging 2020 01 23;65:100-108. Epub 2019 Oct 23.

Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA; Department of Radiology, University of Wisconsin, Madison, WI, USA; Department of Medical Physics, University of Wisconsin, Madison, WI, USA; Department of Electrical and Computer Engineering, University of Wisconsin, Madison, WI, USA. Electronic address:

Objectives: To assess the feasibility of ferumoxytol-enhanced MRI in pregnancy with a nonhuman primate model.

Materials And Methods: In this prospective study, eleven pregnant rhesus macaques at day 98 ± 5 of gestation were divided into three groups, untreated control (UC) (n = 3), saline control (SC) (n = 4) and interleukin 1 beta (IL-1β) treated (IT) (n = 4), which were administered with either saline or IL-1β into the amniotic fluid. All animals were imaged at multiple time points before and after ferumoxytol administration (4 mg/kg). Longitudinal R2* and susceptibility of tissues were obtained using region-of-interest analysis and the longitudinal changes were assessed using linear mixed models and Student's t-test.

Results: In fetuses, a slope of 0.3 s/day (P = 0.008), 0.00 ppm/day (P = 0.699) and - 0.2 s/day (P = 0.023) was observed in liver R2*, liver susceptibility, and lung R2*, respectively. In placentas, R2* and susceptibility increased immediately after ferumoxytol administration (P < 0.001) and decreased to baseline within two days. The mean change from baseline showed no significant difference between the SC group and the IT group at all scan time points. In maternal livers, R2* increased immediately after ferumoxytol administration, further increased at one-day, and then decreased but remained elevated (P < 0.001). The mean change from baseline showed no significant difference between the SC group and the IT group at all scan time points.

Conclusions: This work demonstrates the feasibility of quantitative ferumoxytol-enhanced MRI to measure dynamics of ferumoxytol delivery and washout in the placenta. Stable MRI measurements indicated no evidence of iron deposition in fetal tissues of nonhuman primates after maternal ferumoxytol exposure.
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http://dx.doi.org/10.1016/j.mri.2019.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956847PMC
January 2020

Impact of ferumoxytol magnetic resonance imaging on the rhesus macaque maternal-fetal interface†.

Biol Reprod 2020 02;102(2):434-444

Wisconsin National Primate Research Center (WNPRC), Madison, Wisconsin, USA.

Ferumoxytol is a superparamagnetic iron oxide nanoparticle used off-label as an intravascular magnetic resonance imaging (MRI) contrast agent. Additionally, ferumoxytol-uptake by macrophages facilitates detection of inflammatory sites by MRI through ferumoxytol-induced image contrast changes. Therefore, ferumoxytol-enhanced MRI holds great potential for assessing vascular function and inflammatory response, critical to determine placental health in pregnancy. This study sought to assess the fetoplacental unit and selected maternal tissues, pregnancy outcomes, and fetal well-being after ferumoxytol administration. In initial developmental studies, seven pregnant rhesus macaques were imaged with or without ferumoxytol administration. Pregnancies went to term with vaginal delivery and infants showed normal growth rates compared to control animals born the same year that did not undergo MRI. To determine the impact of ferumoxytol on the maternal-fetal interface (MFI), fetal well-being, and pregnancy outcome, four pregnant rhesus macaques at ~100 gestational day underwent MRI before and after ferumoxytol administration. Collection of the fetoplacental unit and selected maternal tissues was performed 2-3 days following ferumoxytol administration. A control group that did not receive ferumoxytol or MRI was used for comparison. Iron levels in fetal and MFI tissues did not differ between groups, and there was no significant difference in tissue histopathology with or without exposure to ferumoxytol, and no effect on placental hormone secretion. Together, these results suggest that the use of ferumoxytol and MRI in pregnant rhesus macaques does not negatively impact the MFI and can be a valuable experimental tool in research with this important animal model.
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http://dx.doi.org/10.1093/biolre/ioz181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016288PMC
February 2020

Ultrasonography of the Adult Male Urinary Tract for Urinary Functional Testing.

J Vis Exp 2019 08 14(150). Epub 2019 Aug 14.

Department of Urology, University of Wisconsin-Madison; U54 George M. O'Brien Center, University of Wisconsin-Madison;

The incidence of clinical benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) is increasing due to the aging population, resulting in a significant economic and quality of life burden. Transgenic and other mouse models have been developed to recreate various aspects of this multifactorial disease; however, methods to accurately quantitate urinary dysfunction and the effectiveness of new therapeutic options are lacking. Here, we describe a method that can be used to measure bladder volume and detrusor wall thickness, urinary velocity, void volume and void duration, and urethral diameter. This would allow for the evaluation of disease progression and treatment efficacy over time. Mice were anesthetized with isoflurane, and the bladder was visualized by ultrasound. For non-contrast imaging, a 3D image was taken of the bladder to calculate volume and evaluate shape; the bladder wall thickness was measured from this image. For contrast-enhanced imaging, a catheter was placed through the dome of the bladder using a 27-gauge needle connected to a syringe by PE50 tubing. A bolus of 0.5 mL of contrast was infused into the bladder until a urination event occurred. Urethral diameter was determined at the point of the Doppler velocity sample window during the first voiding event. Velocity was measured for each subsequent event yielding a flow rate. In conclusion, high frequency ultrasound proved to be an effective method for assessing bladder and urethral measurements during urinary function in mice. This technique may be useful in the assessment of novel therapies for BPH/LUTS in an experimental setting.
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http://dx.doi.org/10.3791/59802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328372PMC
August 2019

Sensitivity of quantitative relaxometry and susceptibility mapping to microscopic iron distribution.

Magn Reson Med 2020 02 18;83(2):673-680. Epub 2019 Aug 18.

Department of Radiology, University of Wisconsin, Madison, Wisconsin.

Purpose: Determine the impact of the microscopic spatial distribution of iron on relaxometry and susceptibility-based estimates of iron concentration.

Methods: Monte Carlo simulations and in vitro experiments of erythrocytes were used to create different microscopic distributions of iron. Measuring iron with intact erythrocyte cells created a heterogeneous distribution of iron, whereas lysing erythrocytes was used to create a homogeneous distribution of iron. Multi-echo spin echo and spoiled gradient echo acquisitions were then used to estimate relaxation parameters ( and ) and susceptibility.

Results: Simulations demonstrate that and measurements depend on the spatial distribution of iron even for the same iron concentration and volume susceptibility. Similarly, in vitro experiments demonstrate that and measurements depend on the microscopic spatial distribution of iron whereas the quantitative susceptibility mapping (QSM) susceptibility estimates reflect iron concentration without sensitivity to spatial distribution.

Conclusions: and for iron quantification depend on the spatial distribution or iron. QSM-based estimation of iron concentration is insensitive to the microscopic spatial distribution of iron, potentially providing a distribution independent measure of iron concentration.
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http://dx.doi.org/10.1002/mrm.27946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041893PMC
February 2020

MRI-based method for lower urinary tract dysfunction in adult male mice.

Am J Clin Exp Urol 2019 15;7(3):153-158. Epub 2019 Jun 15.

Mechanical Engineering, University of Wisconsin Madison, WI, USA.

Benign prostatic hyperplasia (BPH) develops in the majority of men as they age. As a result, lower urinary tract symptoms (LUTS) often develop, which significantly decrease quality of life. One model of studying BPH/LUTS in mice is to use a hormone-induced model of lower urinary tract dysfunction (LUTD), but current methods for studying endpoints require multiple analysis techniques that contribute to an overall lengthy process. However, developments in magnetic resonance imaging (MRI) have opened the door for more accurate and time efficient methods. The purpose of this study was to demonstrate the capabilities of MRI for the analysis of LUTD in mice. To do this, whole and partial urogenital tracts were extracted from mice and imaged on a 9.4 Tesla MRI system. Additionally, a device was designed and fabricated to aid in the imaging of up to 100 mouse urogenital tracts in a single imaging session. Images were processed for both qualitative representation of MRI resolution capabilities and quantitative measurements of urogenital tract components. Even the smallest anatomical structures of the urogenital tracts were resolved and quantified, including the ureters, urethra, ductus deferens, and fine nodules and textures on the seminal vesicles, bladder, and prostatic lobes. The visual representations and urogenital component quantifications demonstrated in this study may be of value in lesion detection, diagnosis, and LUTS symptom progression tracking.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627546PMC
June 2019

Evaporative cooling provides a major metabolic energy sink.

Mol Metab 2019 09 1;27:47-61. Epub 2019 Jul 1.

McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, United States. Electronic address:

Objective: Elimination of food calories as heat could help redress the excess accumulation of metabolic energy exhibited as obesity. Prior studies have focused on the induction of thermogenesis in beige and brown adipose tissues as the application of this principle, particularly because the β-adrenergic environment associated with thermogenic activation has been shown to have positive health implications. The counterpoint to this strategy is the regulation of heat loss; we propose that mammals with inefficient heat conservation will require more thermogenesis to maintain body temperature.

Methods: Surface temperature thermography and rates of trans-epidermal water loss were integrated to profile the total heat transfer of genetically-engineered and genetically variable mice.

Results: These data were incorporated with energy expenditure data to generate a biophysical profile to test the significance of increased rates of evaporative cooling.

Conclusions: We show that mouse skins vary considerably in their heat retention properties, whether because of naturally occurring variation (SKH-1 mice), or genetic modification of the heat-retaining lipid lamellae (SCD1, DGAT1 or Agouti A obese mice). In particular, we turn attention to widely different rates of evaporative cooling as the result of trans-epidermal water loss; higher rates of heat loss by evaporative cooling leads to increased demand for thermogenesis. We speculate that this physiology could be harnessed to create an energy sink to assist with strategies aimed at treating metabolic diseases.
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http://dx.doi.org/10.1016/j.molmet.2019.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717770PMC
September 2019

Evaluation of a motion-robust 2D chemical shift-encoded technique for R2* and field map quantification in ferumoxytol-enhanced MRI of the placenta in pregnant rhesus macaques.

J Magn Reson Imaging 2020 02 5;51(2):580-592. Epub 2019 Jul 5.

Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, USA.

Background: 3D chemical shift-encoded (CSE)-MRI techniques enable assessment of ferumoxytol concentration but are unreliable in the presence of motion.

Purpose: To evaluate a motion-robust 2D-sequential CSE-MRI for R2* and B0 mapping in ferumoxytol-enhanced MRI of the placenta.

Study Type: Prospective.

Animal Model: Pregnant rhesus macaques.

Field Strength/sequence: 3.0T/CSE-MRI.

Assessment: 2D-sequential CSE-MRI was compared with 3D respiratory-gated CSE-MRI in placental imaging of 11 anesthetized animals at multiple timepoints before and after ferumoxytol administration, and in ferumoxytol phantoms (0 μg/mL-440 μg/mL). Motion artifacts of CSE-MRI in 10 pregnant women without ferumoxytol administration were assessed retrospectively by three blinded readers (4-point Likert scale). The repeatability of CSE-MRI in seven pregnant women was also prospectively studied.

Statistical Tests: Placental R2* and boundary B0 field measurements (ΔB0) were compared between 2D-sequential and 3D respiratory-gated CSE-MRI using linear regression and Bland-Altman analysis.

Results: In phantoms, a slope of 0.94 (r = 0.99, concordance correlation coefficient ρ = 0.99), and bias of -4.8 s (limit of agreement [LOA], -41.4 s , +31.8 s ) in R2*, and a slope of 1.07 (r = 1.00, ρ = 0.99) and bias of 11.4 Hz (LOA -12.0 Hz, +34.8 Hz) in ΔB0 were obtained in 2D CSE-MRI compared with 3D CSE-MRI for reference R2* ≤390 s . In animals, a slope of 0.92 (r = 0.97, ρ = 0.98) and bias of -2.2 s (LOA -55.6 s , +51.3 s ) in R2*, and a slope of 1.05 (r = 0.95, ρ = 0.97) and bias of 0.4 Hz (LOA -9.0 Hz, +9.7 Hz) in ΔB0 were obtained. In humans, motion-impaired R2* maps in 3D CSE-MRI (Reader 1: 1.8 ± 0.6, Reader 2: 1.3 ± 0.7, Reader 3: 1.9 ± 0.6), while 2D CSE-MRI was motion-free (Reader 1: 2.9 ± 0.3, Reader 2: 3.0 ± 0, Reader 3: 3.0 ± 0). A mean difference of 0.66 s and coefficient of repeatability of 9.48 s for placental R2* were observed in the repeated 2D CSE-MRI.

Data Conclusion: 2D-sequential CSE-MRI provides accurate R2* and B0 measurements in ferumoxytol-enhanced placental MRI of animals in the presence of respiratory motion, and motion-robustness in human placental imaging.

Level Of Evidence: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:580-592.
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http://dx.doi.org/10.1002/jmri.26849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839098PMC
February 2020

Characterizing a short T * signal component in the liver using ultrashort TE chemical shift-encoded MRI at 1.5T and 3.0T.

Magn Reson Med 2019 12 3;82(6):2032-2045. Epub 2019 Jul 3.

Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin.

Purpose: Recent studies have suggested the presence of short-T * signals in the liver, which may confound chemical shift-encoded (CSE) fat quantification when using short echo times (TEs). The purpose of this study was to characterize the liver signal at short echo times and to determine its impact on liver fat quantification.

Methods: An ultrashort echo time (UTE) chemical shift-encoded MRI (CSE-MRI) technique and a multicomponent reconstruction were developed to characterize short-T * liver signals. Subsequently, liver fat fraction was quantified using a short-TE (first TE = 0.7 ms) and UTE CSE-MRI acquisitions and compared with a standard CSE-MRI (first TE = 1.2 ms).

Results: Short-T * signals were consistently observed in the liver of all healthy volunteers imaged at both 1.5T and 3.0T. At 3.0T, short-T * signal fractions of 9.6 ± 1.5%, 7.0 ± 1.7%, and 7.4 ± 1.7% with T * of 0.23 ± 0.05 ms, 0.20 ± 0.05 ms, and 0.10 ± 0.02 ms were measured in healthy volunteers, patients with liver cirrhotic disease, and patients with hepatic steatosis (but no cirrhosis), respectively. For proton density fat fraction (PDFF) estimation, 1.7% (P < .01) and 3.4% (P < .01) biases were observed in subjects imaged using short-TE CSE-MRI and using UTE CSE-MRI at 1.5T, respectively. The biases were reduced to 0.4% and -0.7%, respectively, by excluding short echoes less than 1 ms. A 3.2% bias (P < .01) was observed in subjects imaged using UTE CSE-MRI at 3.0T, which was reduced to 0.1% by excluding short echoes <1 ms.

Conclusions: A liver short-T * signal component was consistently observed and was shown to confound liver fat quantification when short echo times were used with CSE-MRI.
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http://dx.doi.org/10.1002/mrm.27876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717026PMC
December 2019

Prostate enlargement and altered urinary function are part of the aging process.

Aging (Albany NY) 2019 05;11(9):2653-2669

Department of Urology, University of Wisconsin - Madison, Madison, WI 53705, USA.

Prostate disease incidence, both benign and malignant, directly correlates with age. Men under 40 years of age are rarely diagnosed with benign or malignant prostate disease, while 90% of men over the age of 80 have histological evidence of benign disease (benign prostatic hyperplasia; BPH). Although rodent models have been invaluable in the study of disease progression and treatment efficacy, the effect of age is often not considered. In examining aged (24-month-old) mice, we observed changes within the lower urinary tract that is typically associated with lower urinary tract dysfunction (LUTD) similar to models of BPH. In this study, we identify LUTD using functional testing as well as various imaging technologies. We also characterize the histological differences within the lower urinary tract between young (2-month-old) and aged mice including proliferation, stromal remodeling, and collagen deposition. Additionally, we examined serum steroid hormone levels, as steroid changes drive LUTD in mice and are known to change with age. We conclude that, with age, changes in prostate function, consistent with LUTD, are a consequence. Therapeutic targeting of endocrine and prostatic factors including smooth muscle function, prostate growth and fibrosis are likely to reestablish normal urinary function.
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http://dx.doi.org/10.18632/aging.101938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535061PMC
May 2019

Clinical Implementation of a Focused MRI Protocol for Hepatic Fat and Iron Quantification.

AJR Am J Roentgenol 2019 Jul 27;213(1):90-95. Epub 2019 Mar 27.

Department of Radiology, University of Wisconsin School of Medicine and Public Health, E3/311 Clinical Science Center, 600 Highland Ave, Madison, WI 53792-3252.

The purpose of this article is to describe our institutional experience with the clinical implementation of a novel focused rapid chemical shift-encoded MRI protocol specifically intended to detect and quantify hepatic steatosis and iron overload, highlighting usage statistics and issues related to cost. Focused MRI examinations for specific clinical indications, such as this protocol for detection and quantification of hepatic steatosis and iron overload, are feasible in a busy clinical practice and add value for patients and referring providers.
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http://dx.doi.org/10.2214/AJR.18.20947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764903PMC
July 2019