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Background: Recent multicenter, multivendor MRI-based R2* vs. liver iron concentration (LIC) calibrations (i.e., MCMV calibrations) may facilitate broad clinical dissemination of R2*-based LIC quantification. However, these calibrations are based on a centralized offline R2* reconstruction, and their applicability with vendor-provided R2* maps is unclear., Purpose: To determine R2* ranges of agreement between the centralized and three MRI vendors' R2* reconstructions., Study Type: Prospective., Subjects: Two hundred and seven subjects (mean age 37.6 ± 19.6 years; 117 male) with known or suspected iron overload from four academic medical centers., Field Strength/sequence: Standardized multiecho spoiled gradient echo sequence at 1.5 T and 3.0 T for R2* mapping and a multiple spin-echo sequence at 1.5 T for LIC quantification. MRI vendors: GE Healthcare, Philips Healthcare, and Siemens Healthineers., Assessment: R2* maps were generated using both the centralized and vendor reconstructions, and ranges of agreement were determined. R2*-LIC linear calibrations were determined for each site, field strength, and reconstruction and compared with the MCMV calibrations., Statistical Tests: Bland-Altman analysis to determine ranges of agreement. Linear regression, analysis of covariance F tests, and Tukey's multiple comparison testing to assess reproducibility of calibrations across sites and vendors. A P value <0.05 was considered significant., Results: The upper limits of R2* ranges of agreement were approximately 500, 375, and 330 s -1 for GE, Philips, and Siemens reconstructions, respectively, at 1.5 T and approximately 700 and 800 s -1 for GE and Philips, respectively, at 3.0 T. Within the R2* ranges of agreement, vendor R2*-LIC calibrations demonstrated high reproducibility (no significant differences between slopes or intercepts; P ≥ 0.06) and agreed with the MCMV calibrations (overlapping 95% confidence intervals)., Data Conclusion: Based on the determined upper limits, R2* measurements obtained from vendor-provided R2* maps may be reliably and practically used to quantify LIC less than approximately 8-13 mg/g using the MCMV calibrations and similar acquisition parameters as this study., Evidence Level: 1 TECHNICAL EFFICACY: Stage 3., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Cardiac-induced liver motion can bias liver ADC measurements and compromise reproducibility. The purpose of this work was to enable motion-robust DWI on multiple MR scanners and assess reproducibility of the resulting liver ADC measurements., Methods: First moment-optimized diffusion imaging (MODI) was implemented on three MR scanners with various gradient performances and field strengths. MODI-DWI and conventional Stejskal-Tanner monopolar (MONO) DWI were acquired in eight (N = 8) healthy volunteers on each scanner, and DWI repetitions were combined using three different averaging methods. For each combination of scanner, acquisition, and averaging method, ADC measurements from each liver segment were collected. Systematic differences in ADC values between scanners and methods were assessed with linear mixed effects modeling, and reproducibility was quantified via reproducibility coefficients., Results: MODI reduced left-right liver lobe ADC bias from 0.43 × 10 -3  mm 2 /s (MONO) to 0.19 × 10 -3  mm 2 /s (MODI) when simple (unweighted) repetition averaging was used. The bias was reduced from 0.23 × 10 -3  mm 2 /s to 0.06 × 10 -3  mm 2 /s using weighted averaging, and 0.14 × 10 -3  mm 2 /s to 0.01 × 10 -3  mm 2 /s using squared weighted averaging. There was no significant difference in ADC measurements between field strengths or scanner gradient performance. MODI improved reproducibility coefficients compared to MONO: 0.84 × 10 -3  mm 2 /s vs. 0.63 × 10 -3  mm 2 /s (MODI vs. MONO) for simple averaging, 0.66 × 10 -3  mm 2 /s vs. 0.50 × 10 -3  mm 2 /s for weighted averaging, and 0.61 × 10 -3  mm 2 /s vs. 0.47 × 10 -3  mm 2 /s for squared weighted averaging., Conclusion: The feasibility of motion-robust liver DWI using MODI was demonstrated on multiple MR scanners. MODI improved interlobar agreement and reproducibility of ADC measurements in a healthy cohort., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: The purpose of this work was to obtain precise tri-exponential intravoxel incoherent motion (IVIM) quantification in the liver using 2D (b-value and first-order motion moment [M 1 ]) IVIM-DWI acquisitions and region of interest (ROI)-based fitting techniques., Methods: Diffusion MRI of the liver was performed in 10 healthy volunteers using three IVIM-DWI acquisitions: conventional monopolar, optimized monopolar, and optimized 2D (b-M 1 ). For each acquisition, bi-exponential and tri-exponential full, segmented, and over-segmented ROI-based fitting and a newly proposed blood velocity SDdistribution (BVD) fitting technique were performed to obtain IVIM estimates in the right and left liver lobes. Fitting quality was evaluated using corrected Akaike information criterion. Precision metrics (test-retest repeatability, inter-reader reproducibility, and inter-lobar agreement) were evaluated using Bland-Altman analysis, repeatability/reproducibility coefficients (RPCs), and paired sample t-tests. Precision was compared across acquisitions and fitting methods., Results: High repeatability and reproducibility was observed in the estimations of the diffusion coefficient (D tri  = [1.03 ± 0.11] × 10 -3  mm 2 /s; RPCs ≤ 1.34 × 10 -4  mm 2 /s), perfusion fractions (F 1  = 3.19 ± 1.89% and F 2  = 16.4 ± 2.07%; RPCs ≤ 2.51%), and blood velocity SDs (V b,1  = 1.44 ± 0.14 mm/s and V b,2  = 3.62 ± 0.13 mm/s; RPCs ≤ 0.41 mm/s) in the right liver lobe using the 2D (b-M 1 ) acquisition in conjunction with BVD fitting. Using these methods, significantly larger (p < 0.01) estimates of D tri and F 1 were observed in the left lobe in comparison to the right lobe, while estimates of V b,1 and V b,2 demonstrated high interlobar agreement (RPCs ≤ 0.45 mm/s)., Conclusions: The 2D (b-M 1 ) IVIM-DWI data acquisition in conjunction with BVD fitting enables highly precise tri-exponential IVIM quantification in the right liver lobe., (© 2022 International Society for Magnetic Resonance in Medicine.)

Purpose: To design a b value and first-order motion moment (M 1 ) optimized data acquisition for repeatable intravoxel incoherent motion (IVIM) quantification in the liver., Methods: Cramer-Rao lower bound optimization was performed to determine optimal monopolar and optimal 2D samplings of the b-M 1 space based on noise performance. Monte Carlo simulations were used to evaluate the bias and variability in estimates obtained using the proposed optimal samplings and conventional monopolar sampling. Diffusion MRI of the liver was performed in 10 volunteers using 3 IVIM acquisitions: conventional monopolar, optimized monopolar, and b-M 1 -optimized gradient waveforms (designed based on the optimal 2D sampling). IVIM parameter maps of diffusion coefficient, perfusion fraction, and blood velocity SD were obtained using nonlinear least squares fitting. Noise performance (SDs), stability (outlier percentage), and test-retest or scan-rescan repeatability (intraclass correlation coefficients) were evaluated and compared across acquisitions., Results: Cramer-Rao lower bound and Monte Carlo simulations demonstrated improved noise performance of the optimal 2D sampling in comparison to monopolar samplings. Evaluating the designed b-M 1 -optimized waveforms in healthy volunteers, significant decreases (p < 0.05) in the SDs and outlier percentages were observed for measurements of diffusion coefficient, perfusion fraction, and blood velocity SD in comparison to measurements obtained using monopolar samplings. Good-to-excellent repeatability (intraclass correlation coefficients ≥ 0.77) was observed for all 3 parameters in both the right and left liver lobes using the b-M 1 -optimized waveforms., Conclusions: 2D b-M 1 -optimized data acquisition enables repeatable IVIM quantification with improved noise performance. 2D acquisitions may advance the establishment of IVIM quantitative biomarkers for liver diseases., (© 2022 International Society for Magnetic Resonance in Medicine.)

Purpose: To evaluate the precision profile (repeatability and reproducibility) of quantitative STEAM-MRS and to determine the relationships between multiple MR biomarkers of chronic liver disease in subjects with iron overload at both 1.5 Tesla (T) and 3T., Methods: MRS data were acquired in patients with known or suspected liver iron overload. Two STEAM-MRS sequences (multi-TE and multi-TE-TR) were acquired at both 1.5T and 3T (same day), including test-retest acquisition. Each acquisition enabled estimation of R1, R2, and FWHM (each separately for water and fat); and proton density fat fraction. The test-retest repeatability and reproducibility across acquisition modes (multi-TE vs. multi-TE-TR) of the estimates were evaluated using intraclass correlation coefficients, linear regression, and Bland-Altman analyses. Multi-parametric relationships between parameters at each field strength, across field strengths, and with liver iron concentration were also evaluated using linear and nonlinear regression., Results: Fifty-six (n = 56) subjects (10 to 73 years, 37 males/19 females) were successfully recruited. Both STEAM-MRS sequences demonstrated good-to-excellent precision (intraclass correlation coefficient ≥ 0.81) for the quantification of R1 water , R2 water , FWHM water , and proton density fat fraction at both 1.5T and 3T. Additionally, several moderate (R 2 = 0.50 to 0.69) to high (R 2 ≥ 0.70) correlations were observed between biomarkers, across field strengths, and with liver iron concentration., Conclusions: Over a broad range of liver iron concentration, STEAM-MRS enables rapid and precise measurement of multiple biomarkers of chronic liver disease. By evaluating the multi-parametric relationships between biomarkers, this work may advance the comprehensive MRS-based assessment of chronic liver disease and may help establish biomarkers of chronic liver disease., (© 2021 International Society for Magnetic Resonance in Medicine.)

Functional magnetic resonance imaging (fMRI) has significant potential to evaluate changes in brain network activity after traumatic brain injury (TBI) and enable early prognosis of potential functional (e.g., motor, cognitive, behavior) deficits. In this study, resting-state and task-based fMRI (rs- and tb-fMRI) were utilized to examine network changes in a pediatric porcine TBI model that has increased predictive potential in the development of novel therapies. rs- and tb-fMRI were performed one day post-TBI in piglets. Activation maps were generated using group independent component analysis (ICA) and sparse dictionary learning (sDL). Activation maps were compared to pig reference functional connectivity atlases and evaluated using Pearson spatial correlation coefficients and mean ratios. Nonparametric permutation analyses were used to determine significantly different activation areas between the TBI and healthy control groups. Significantly lower Pearson values and mean ratios were observed in the visual, executive control, and sensorimotor networks for TBI piglets compared to controls. Significant differences were also observed within several specific individual anatomical structures within each network. In conclusion, both rs- and tb-fMRI demonstrate the ability to detect functional connectivity disruptions in a translational TBI piglet model, and these disruptions can be traced to specific affected anatomical structures.

Invasive spread of glioblastoma (GBM) is linked to changes in chondroitin sulfate (CS) proteoglycan (CSPG)-associated sulfated glycosaminoglycans (GAGs) that are selectively up-regulated in the tumor microenvironment (TME). We hypothesized that inhibiting CS-GAG signaling in the TME would stem GBM invasion. Rat F98 GBM cells demonstrated enhanced preferential cell invasion into oversulfated 3-dimensional composite of CS-A and CS-E [4- and 4,6-sulfated CS-GAG (COMP)] matrices compared with monosulfated (4-sulfated) and unsulfated hyaluronic acid matrices in microfluidics-based choice assays, which is likely influenced by differential GAG receptor binding specificities. Both F98 and human patient-derived glioma stem cells (GSCs) demonstrated a high degree of colocalization of the GSC marker CD133 and CSPGs. The small molecule sulfated GAG antagonist bis-2-methyl-4-amino-quinolyl-6-carbamide (surfen) reduced invasion and focal adhesions in F98 cells encapsulated in COMP matrices and blocked CD133 and antichondroitin sulfate antibody (CS-56) detection of respective antigens in F98 cells and human GSCs. Surfen-treated F98 cells down-regulated CSPG-binding receptor transcripts and protein, as well as total and activated ERK and protein kinase B. Lastly, rats induced with frontal lobe tumors and treated with a single intratumoral dose of surfen demonstrated reduced tumor burden and spread compared with untreated controls. These results present a first demonstration of surfen as an inhibitor of sulfated GAG signaling to stem GBM invasion.-Logun, M. T., Wynens, K. E., Simchick, G., Zhao, W., Mao, L., Zhao, Q., Mukherjee, S., Brat, D. J., Karumbaiah, L. Surfen-mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion.

Many neurological and psychiatric diseases in humans are caused by disruptions to large-scale functional properties of the brain, including functional connectivity. There has been growing interest in discovering the functional organization of brain networks in larger animal models. As a result, the use of translational pig models in neuroscience has significantly increased in the past decades. The gyrencephalic pig brain resembles the human brain more in anatomy, growth, and development than the brains of commonly used small laboratory animals such as rodents. In this work, resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) data were acquired from a group of pigs ( n  = 12). rs-fMRI data were analyzed for resting-state networks (RSNs) by using independent component analysis and sparse dictionary learning. Six RSNs (executive control, cerebellar, sensorimotor, visual, auditory, and default mode) were detected that resemble their counterparts in human brains, as measured by Pearson spatial correlations and mean ratios. Supporting evidence of the validity of these RSNs was provided through the evaluation and quantification of structural connectivity measures (mean diffusivity, fractional anisotropy, fiber length, and fiber density) estimated from the DTI data. This study shows that as a translational, large animal model, pigs demonstrate great potential for mapping connectome-scale functional connectivity in experimental modeling of human brain disorders.

Purpose: To assess the feasibility of quantifying liver iron concentration (LIC) using R2* and quantitative susceptibility mapping (QSM) at a high field strength of 7 Tesla (T)., Methods: Five different concentrations of Fe-dextran were injected into 12 mice to produce various degrees of liver iron overload. After mice were sacrificed, blood and liver samples were harvested. Ferritin enzyme-linked immunosorbent assay (ELISA) and inductively coupled plasma mass spectrometry were performed to quantify serum ferritin concentration and LIC. Multiecho gradient echo MRI was conducted to estimate R2* and the magnetic susceptibility of each liver sample through complex nonlinear least squares fitting and a morphology enabled dipole inversion method, respectively., Results: Average estimates of serum ferritin concentration, LIC, R2*, and susceptibility all show good linear correlations with injected Fe-dextran concentration; however, the standard deviations in the estimates of R2* and susceptibility increase with injected Fe-dextran concentration. Both R2* and susceptibility measurements also show good linear correlations with LIC (R 2  = 0.78 and R 2  = 0.91, respectively), and a susceptibility-to-LIC conversion factor of 0.829 ppm/(mg/g wet) is derived., Conclusion: The feasibility of quantifying LIC using MR-based  R2* and QSM at a high field strength of 7T is demonstrated. Susceptibility quantification, which is an intrinsic property of tissues and benefits from being field-strength independent, is more robust than R2* quantification in this ex vivo study. A susceptibility-to-LIC conversion factor is presented that agrees relatively well with previously published QSM derived results obtained at 1.5T and 3T., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: To explore, at a high field strength of 7T, the performance of various fat spectral models on the quantification of triglyceride composition and proton density fat fraction (PDFF) using chemical-shift encoded MRI (CSE-MRI)., Methods: MR data was acquired from CSE-MRI experiments for various fatty materials, including oil and butter samples and in vivo brown and white adipose mouse tissues. Triglyceride composition and PDFF were estimated using various a priori 6- or 9-peak fat spectral models. To serve as references, NMR spectroscopy experiments were conducted to obtain material specific fat spectral models and triglyceride composition estimates for the same fatty materials. Results obtained using the spectroscopy derived material specific models were compared to results obtained using various published fat spectral models., Results: Using a 6-peak fat spectral model to quantify triglyceride composition may lead to large biases at high field strengths. When using a 9-peak model, triglyceride composition estimations vary greatly depending on the relative amplitudes of the chosen a priori spectral model, while PDFF estimations show small variations across spectral models. Material specific spectroscopy derived spectral models produce estimations that better correlate with NMR spectroscopy estimations in comparison to those obtained using non-material specific models., Conclusion: At a high field strength of 7T, a material specific 9-peak fat spectral model, opposed to a widely accepted or generic human liver model, is necessary to accurately quantify triglyceride composition when using CSE-MRI estimation methods that assume the spectral model to be known as a priori information. CSE-MRI allows for the quantification of the spatial distribution of triglyceride composition for certain in vivo applications. Additionally, PDFF quantification is shown to be independent of the chosen a priori spectral model, which agrees with previously reported results obtained at lower field strengths (e.g. 3T)., (Copyright © 2018. Published by Elsevier Inc.)

The explosive spread of the Zika virus (ZIKV) through South and Central America has been linked to an increase in congenital birth defects, specifically microcephaly. Representative rodent models for investigating infections include direct central nervous system (CNS) injections late in pregnancy and transplacental transmission in immunodeficient mice. Microcephaly in humans may be the result of infection occurring early in pregnancy, therefore recapitulating that the human course of ZIKV infection should include normal embryo exposed to ZIKV during the first trimester. In ovo development of the chicken embryo closely mirrors human fetal neurodevelopment and, as a comparative model, could provide key insights into both temporal and pathophysiological effects of ZIKV. Chick embryos were directly infected early and throughout incubation with ZIKV isolated from a Mexican mosquito in January 2016. High doses of virus caused embryonic lethality. In a subset of lower dosed embryos, replicating ZIKV was present in various organs, including the CNS, throughout development. Surviving ZIKV-infected embryos presented a microcephaly-like phenotype. Chick embryos were longitudinally monitored by magnetic resonance imaging that documented CNS structural malformations, including enlarged ventricles (30% increase) and stunted cortical growth (decreased telencephalon by 18%, brain stem by 32%, and total brain volume by 18%), on both embryonic day 15 (E15) and E20 of development. ZIKV-induced microcephaly was observed with inoculations of as few as 2-20 viral particles. The chick embryo model presented ZIKV embryonic lethal effects and progressive CNS damage similar to microcephaly.