Repeatability of Quantitative Magnetic Resonance Imaging Biomarkers in the Tibia Bone Marrow of a Murine Myelofibrosis Model.

Quantitative MRI biomarkers are sought to replace painful and invasive sequential bone-marrow biopsies routinely used for myelofibrosis (MF) cancer monitoring and treatment assessment. Repeatability of MRI-based quantitative imaging biomarker (QIB) measurements was investigated for apparent diffusion coefficient (ADC), proton density fat fraction (PDFF), and magnetization transfer ratio (MTR) in a JAK2 V617F hematopoietic transplant model of MF. Repeatability coefficients (RCs) were determined for three defined tibia bone-marrow sections (2-9 mm; 10-12 mm; and 12.5-13.5 mm from the knee joint) across 15 diseased mice from 20-37 test-retest pairs. Scans were performed on consecutive days every two weeks for a period of 10 weeks starting 3-4 weeks after transplant. The mean RC with (95% confidence interval (CI)) for these sections, respectively, were for ADC: 0.037 (0.031, 0.050), 0.087 (0.069, 0.116), and 0.030 (0.022, 0.044) µm2/ms; for PDFF: 1.6 (1.3, 2.0), 15.5 (12.5, 20.2), and 25.5 (12.0, 33.0)%; and for MTR: 0.16 (0.14, 0.19), 0.11 (0.09, 0.15), and 0.09 (0.08, 0.15). Change-trend analysis of these QIBs identified a dynamic section within the mid-tibial bone marrow in which confident changes (exceeding RC) could be observed after a four-week interval between scans across all measured MRI-based QIBs. Our results demonstrate the capability to derive quantitative imaging metrics from mouse tibia bone marrow for monitoring significant longitudinal MF changes.

Evaluation of Apparent Diffusion Coefficient Repeatability and Reproducibility for Preclinical MRIs Using Standardized Procedures and a Diffusion-Weighted Imaging Phantom.

Relevant to co-clinical trials, the goal of this work was to assess repeatability, reproducibility, and bias of the apparent diffusion coefficient (ADC) for preclinical MRIs using standardized procedures for comparison to performance of clinical MRIs. A temperature-controlled phantom provided an absolute reference standard to measure spatial uniformity of these performance metrics. Seven institutions participated in the study, wherein diffusion-weighted imaging (DWI) data were acquired over multiple days on 10 preclinical scanners, from 3 vendors, at 6 field strengths. Centralized versus site-based analysis was compared to illustrate incremental variance due to processing workflow. At magnet isocenter, short-term (intra-exam) and long-term (multiday) repeatability were excellent at within-system coefficient of variance, wCV [±CI] = 0.73% [0.54%, 1.12%] and 1.26% [0.94%, 1.89%], respectively. The cross-system reproducibility coefficient, RDC [±CI] = 0.188 [0.129, 0.343] µm2/ms, corresponded to 17% [12%, 31%] relative to the reference standard. Absolute bias at isocenter was low (within 4%) for 8 of 10 systems, whereas two high-bias (>10%) scanners were primary contributors to the relatively high RDC. Significant additional variance (>2%) due to site-specific analysis was observed for 2 of 10 systems. Base-level technical bias, repeatability, reproducibility, and spatial uniformity patterns were consistent with human MRIs (scaled for bore size). Well-calibrated preclinical MRI systems are capable of highly repeatable and reproducible ADC measurements.

Multiparametric MRI to quantify disease and treatment response in mice with myeloproliferative neoplasms.

Histopathology, the standard method to assess BM in hematologic malignancies such as myeloproliferative neoplasms (MPNs), suffers from notable limitations in both research and clinical settings. BM biopsies in patients fail to detect disease heterogeneity, may yield a nondiagnostic sample, and cannot be repeated frequently in clinical oncology. Endpoint histopathology precludes monitoring disease progression and response to therapy in the same mouse over time, missing likely variations among mice. To overcome these shortcomings, we used MRI to measure changes in cellularity, macromolecular constituents, and fat versus hematopoietic cells in BM using diffusion-weighted imaging (DWI), magnetization transfer, and chemical shift-encoded fat imaging. Combining metrics from these imaging parameters revealed dynamic alterations in BM following myeloablative radiation and transplantation. In a mouse MPLW515L BM transplant model of MPN, MRI detected effects of a JAK2 inhibitor, ruxolitinib, within 5 days of initiating treatment and identified differing kinetics of treatment responses in subregions of the tibia. Histopathology validated the MRI results for BM composition and heterogeneity. Anatomic MRI scans also showed reductions in spleen volume during treatment. These findings establish an innovative, clinically translatable MRI approach to quantify spatial and temporal changes in BM in MPN.

Technical note: Temperature and concentration dependence of water diffusion in polyvinylpyrrolidone solutions.

OBJECTIVE: The goal of this work is to provide temperature and concentration calibration of water diffusivity in polyvinylpyrrolidone (PVP) solutions used in phantoms to assess system bias and linearity in apparent diffusion coefficient (ADC) measurements. METHOD: ADC measurements were performed for 40 kDa (K40) PVP of six concentrations (0%, 10%, 20%, 30%, 40%, and 50% by weight) at three temperatures (19.5°C, 22.5°C, and 26.4°C), with internal phantom temperature monitored by optical thermometer (±0.2°C). To achieve ADC measurement and fit accuracy of better than 0.5%, three orthogonal diffusion gradients were calibrated using known water diffusivity at 0°C and system gradient nonlinearity maps. Noise-floor fit bias was also controlled by limiting the maximum b-value used for ADC calculation of each sample. The ADC temperature dependence was modeled by Arrhenius functions of each PVP concentration. The concentration dependence was modeled by quadratic function for ADC normalized by the theoretical water diffusion values. Calibration coefficients were obtained from linear regression model fits. RESULTS: Measured phantom ADC values increased with temperature and decreasing PVP concentration, [PVP]. The derived Arrhenius model parameters for [PVP] between 0% and 50%, are reported and can be used for K40 ADC temperature calibration with absolute ADC error within ±0.016 µm2 /ms. Arrhenius model fit parameters normalized to water value scaled with [PVP] between 10% and 40%, and proportional change in activation energy increased faster than collision frequency. ADC normalization by water diffusivity, DW , from the Speedy-Angell relation accounted for the bulk of temperature dependence (±0.035 µm2 /ms) and yielded quadratic calibration for ADCPVP /DW  = (12.5 ± 0.7) ·10-5 ·[PVP]2 - (23.2 ± 0.3)·10-3 ·[PVP]+1, nearly independent of PVP molecular weight and temperature. CONCLUSION: The study provides ground-truth ADC values for K40 PVP solutions commonly used in diffusion phantoms for scanning at ambient room temperature. The described procedures and the reported calibration can be used for quality control and standardization of measured ADC values of PVP at different concentrations and temperatures.

Empirical validation of gradient field models for an accurate ADC measured on clinical 3T MR systems in body oncologic applications.

PURPOSE: To empirically corroborate vendor-provided gradient nonlinearity (GNL) characteristics and demonstrate efficient GNL bias correction for human brain apparent diffusion coefficient (ADC) across 3T MR systems and spatial locations. METHODS: Spatial distortion vector fields (DVF) were mapped in 3D using a surface fiducial array phantom for individual gradient channels on three 3T MR platforms from different vendors. Measured DVF were converted into empirical 3D GNL tensors and compared with their theoretical counterparts derived from vendor-provided spherical harmonic (SPH) coefficients. To illustrate spatial impact of GNL on ADC, diffusion weighted imaging using three orthogonal gradient directions was performed on a volunteer brain positioned at isocenter (as a reference) and offset superiorly by 10-17 cm (>10% predicted GNL bias). The SPH tensor-based GNL correction was applied to individual DWI gradient directions, and derived ADC was compared with low-bias reference for human brain white matter (WM) ROIs. RESULTS: Empiric and predicted GNL errors were comparable for all three studied 3T MR systems, with <1.0% differences in the median and width of spatial histograms for individual GNL tensor elements. Median (±width) of ADC (10-3mm2/s) histograms measured at isocenter in WM reference ROIs from three MR systems were: 0.73 ± 0.11, 0.71 ± 0.14, 0.74 ± 0.17, and at off-isocenters (before versus after GNL correction) were respectively 0.63 ± 0.14 versus 0.72 ± 0.11, 0.53 ± 0.16 versus 0.74 ± 0.18, and 0.65 ± 0.16 versus 0.76 ± 0.18. CONCLUSION: The phantom-based spatial distortion measurements validated vendor-provided gradient fields, and accurate WM ADC was recovered regardless of spatial locations and clinical MR platforms using system-specific tensor-based GNL correction for routine DWI.

Parametric Response Mapping of FLAIR MRI Provides an Early Indication of Progression Risk in Glioblastoma.

RATIONALE AND OBJECTIVES: Glioblastoma image evaluation utilizes Magnetic Resonance Imaging contrast-enhanced, T1-weighted, and noncontrast T2-weighted fluid-attenuated inversion recovery (FLAIR) acquisitions. Disease progression assessment relies on changes in tumor diameter, which correlate poorly with survival. To improve treatment monitoring in glioblastoma, we investigated serial voxel-wise comparison of anatomically-aligned FLAIR signal as an early predictor of GBM progression. MATERIALS AND METHODS: We analyzed longitudinal normalized FLAIR images (rFLAIR) from 52 subjects using voxel-wise Parametric Response Mapping (PRM) to monitor volume fractions of increased (PRMrFLAIR+), decreased (PRMrFLAIR-), or unchanged (PRMrFLAIR0) rFLAIR intensity. We determined response by rFLAIR between pretreatment and 10 weeks posttreatment. Risk of disease progression in a subset of subjects (N = 26) with stable disease or partial response as defined by Response Assessment in Neuro-Oncology (RANO) criteria was assessed by PRMrFLAIR between weeks 10 and 20 and continuously until the PRMrFLAIR+ exceeded a defined threshold. RANO defined criteria were compared with PRM-derived outcomes for tumor progression detection. RESULTS: Patient stratification for progression-free survival (PFS) and overall survival (OS) was achieved at week 10 using RANO criteria (PFS: p <0.0001; OS: p <0.0001), relative change in FLAIR-hyperintense volume (PFS: p = 0.0011; OS: p <0.0001), and PRMrFLAIR+ (PFS: p <0.01; OS: p <0.001). PRMrFLAIR+ also stratified responding patients' progression between weeks 10 and 20 (PFS: p <0.05; OS: p = 0.01) while changes in FLAIR-volume measurements were not predictive. As a continuous evaluation, PRMrFLAIR+ exceeding 10% stratified patients for PFA after 5.6 months (p<0.0001), while RANO criteria did not stratify patients until 15.4 months (p <0.0001). CONCLUSION: PRMrFLAIR may provide an early biomarker of disease progression in glioblastoma.

Retrospective Correction of ADC for Gradient Nonlinearity Errors in Multicenter Breast DWI Trials: ACRIN6698 Multiplatform Feasibility Study.

The presented analysis of multisite, multiplatform clinical oncology trial data sought to enhance quantitative utility of the apparent diffusion coefficient (ADC) metric, derived from diffusion-weighted magnetic resonance imaging, by reducing technical interplatform variability owing to systematic gradient nonlinearity (GNL). This study tested the feasibility and effectiveness of a retrospective GNL correction (GNC) implementation for quantitative quality control phantom data, as well as in a representative subset of 60 subjects from the ACRIN 6698 breast cancer therapy response trial who were scanned on 6 different gradient systems. The GNL ADC correction based on a previously developed formalism was applied to trace-DWI using system-specific gradient-channel fields derived from vendor-provided spherical harmonic tables. For quantitative DWI phantom images acquired in typical breast imaging positions, the GNC improved interplatform accuracy from a median of 6% down to 0.5% and reproducibility of 11% down to 2.5%. Across studied trial subjects, GNC increased low ADC (<1 µm2/ms) tumor volume by 16% and histogram percentiles by 5%-8%, uniformly shifting percentile-dependent ADC thresholds by ∼0.06 µm2/ms. This feasibility study lays the grounds for retrospective GNC implementation in multiplatform clinical imaging trials to improve accuracy and reproducibility of ADC metrics used for breast cancer treatment response prediction.

Repeatability and Reproducibility of ADC Histogram Metrics from the ACRIN 6698 Breast Cancer Therapy Response Trial.

Mean tumor apparent diffusion coefficient (ADC) of breast cancer showed excellent repeatability but only moderate predictive power for breast cancer therapy response in the ACRIN 6698 multicenter imaging trial. Previous single-center studies have shown improved predictive performance for alternative ADC histogram metrics related to low ADC dense tumor volume. Using test/retest (TT/RT) 4 b-value diffusion-weighted imaging acquisitions from pretreatment or early-treatment time-points on 71 ACRIN 6698 patients, we evaluated repeatability for ADC histogram metrics to establish confidence intervals and inform predictive models for future therapy response analysis. Histograms were generated using regions of interest (ROIs) defined separately for TT and RT diffusion-weighted imaging. TT/RT repeatability and intra- and inter-reader reproducibility (on a 20-patient subset) were evaluated using wCV and Bland-Altman limits of agreement for histogram percentiles, low-ADC dense tumor volumes, and fractional volumes (normalized to total histogram volume). Pearson correlation was used to reveal connections between metrics and ROI variability across the sample cohort. Low percentiles (15th and 25th) were highly repeatable and reproducible, wCV < 8.1%, comparable to mean ADC values previously reported. Volumetric metrics had higher wCV values in all cases, with fractional volumes somewhat better but at least 3 times higher than percentile wCVs. These metrics appear most sensitive to ADC changes around a threshold of 1.2 µm2/ms. Volumetric results were moderately to strongly correlated with ROI size. In conclusion, Lower histogram percentiles have comparable repeatability to mean ADC, while ADC-thresholded volumetric measures currently have poor repeatability but may benefit from improvements in ROI techniques.

Magnetic resonance electrical property mapping at 21.1 T: a study of conductivity and permittivity in phantoms, ex vivo tissue and in vivo ischemia.

Electrical properties (EP), namely conductivity and permittivity, can provide endogenous contrast for tissue characterization. Using electrical property tomography (EPT), maps of EP can be generated from conventional MRI data. This report investigates the feasibility and accuracy of EPT at 21.1 T for multiple RF coils and modes of operation using phantoms. Additionally, it demonstrates the EP of the in vivo rat brain with and without ischemia. Helmholtz-based EPT was implemented in its Full-form, which demands the complex [Formula: see text] field, and a simplified form requiring either just the [Formula: see text] field phase for conductivity or the [Formula: see text] field magnitude for permittivity. Experiments were conducted at 21.1 T using birdcage and saddle coils operated in linear or quadrature transceive mode, respectively. EPT approaches were evaluated using a phantom, ex and in vivo Sprague-Dawley rats under naïve conditions and ischemic stroke via transient middle cerebral artery occlusion. Different conductivity reconstruction approaches applied to the phantom displayed average errors of 12%-73% to the target acquired from dielectric probe measurements. Permittivity reconstructions showed higher agreement and an average 3%-8% error to the target depending on reconstruction approach. Conductivity and permittivity of ex and in vivo rodent brain were measured. Elevated EP in the ischemia region correlated with the increased sodium content and the influx of water intracellularly following ischemia in the lesion were detected. The Full-form technique generated from the linear birdcage provided the best accuracy for EP of the phantom. Phase-based conductivity and magnitude-based permittivity mapping provided reasonable estimates but also demonstrated the limitations of Helmholtz-based EPT at 21.1 T. Permittivity reconstruction was improved significantly over lower fields, suggesting a novel metric for in vivo brain studies. EPT applied to ischemic rat brain proved sensitivity to physiological changes, motivating the future application of more advanced reconstruction approaches.

Time and Frequency Domain Response of HTS Resonators for Use as NMR Transmit Coils.

Replacing normal metal NMR coils with thin-film high-temperature superconductor (HTS) resonators can significantly improve the sensitivity of analytical NMR. To study the use of these resonators for excitation as well as detection, we investigated the radio frequency properties of the HTS NMR coils in both frequency and time domain at a variety of transmit power levels. Experiments were conducted on a double-sided, counter wound spiral resonator designed to detect NMR signals from 13C nuclei at 14.1 T. Power-dependent nonlinearity was observed in the transmission coefficient and quality factor. The ability of the HTS resonators to accurately generate short pulses was studied in the time domain over the range power levels. The results of this study show that some form of Q switching is needed to get good transmit performance from HTS coils for 13C. For that purpose, the effect of adding a shorted transmission line stub to improve the pulse shapes and reduce phase transients was studied.

Structural connectivity within neural ganglia: A default small-world network.

Diffusion tensor imaging (DTI) provides a unique contrast based on the restricted directionality of water movement in an anisotropic environment. As such, DTI-based tractography can be used to characterize and quantify the structural connectivity within neural tissue. Here, DTI-based connectivity within isolated abdominal ganglia of Aplysia californica (ABG) is analyzed using network theory. In addition to quantifying the regional physical proprieties of the fractional anisotropy and apparent diffusion coefficient, DTI tractography was used to probe inner-connections of local communities, yielding unweighted, undirected graphs that represent community structures. Local and global efficiency, characteristic path lengths and clustering analysis are performed on both experimental and simulated data. The relevant intensity by which these specific nodes communicate is probed through weighted clustering coefficient measurements. Both small-worldness and novel small-world metrics were used as tools to verify the small-world properties for the experimental results. The aim of this manuscript is to categorize the properties exhibited by structural networks in a model neural tissue to derive unique mean field information that quantitatively describe macroscopic connectivity. For ABG, findings demonstrate a default structural network with preferential specific small-world properties when compared to simulated lattice and random networks that are equivalent in order and degree.