Quantitative magnetic resonance imaging biomarkers for cortical pathology in multiple sclerosis at 7 T.

Substantial cortical gray matter tissue damage, which correlates with clinical disease severity, has been revealed in multiple sclerosis (MS) using advanced magnetic resonance imaging (MRI) methods at 3 T and the use of ultra-high field, as well as in histopathology studies. While clinical assessment mainly focuses on lesions using T 1 - and T 2 -weighted MRI, quantitative MRI (qMRI) methods are capable of uncovering subtle microstructural changes. The aim of this ultra-high field study is to extract possible future MR biomarkers for the quantitative evaluation of regional cortical pathology. Because of their sensitivity to iron, myelin, and in part specifically to cortical demyelination, T 1 , T 2 , R 2 * , and susceptibility mapping were performed including two novel susceptibility markers; in addition, cortical thickness as well as the volumes of 34 cortical regions were computed. Data were acquired in 20 patients and 16 age- and sex-matched healthy controls. In 18 cortical regions, large to very large effect sizes (Cohen's d ≥ 1) and statistically significant differences in qMRI values between patients and controls were revealed compared with only four regions when using more standard MR measures, namely, volume and cortical thickness. Moreover, a decrease in all susceptibility contrasts ( χ , χ + , χ - ) and R 2 * values indicates that the role of cortical demyelination might outweigh inflammatory processes in the form of iron accumulation in cortical MS pathology, and might also indicate iron loss. A significant association between susceptibility contrasts as well as R 2 * of the caudal middle frontal gyrus and disease duration was found (adjusted R2 : 0.602, p = 0.0011). Quantitative MRI parameters might be more sensitive towards regional cortical pathology compared with the use of conventional markers only and therefore may play a role in early detection of tissue damage in MS in the future.

On the separation of susceptibility sources in quantitative susceptibility mapping: Theory and phantom validation with an in vivo application to multiple sclerosis lesions of different age.

PURPOSE: In biological tissue, phase contrast is determined by multiple substances such as iron, myelin or calcifications. Often, these substances occur co-located within the same measurement volume. However, quantitative susceptibility mapping can solely measure the average susceptibility per voxel. To provide new insight in disease progression and mechanisms in neurological diseases, where multiple processes such as demyelination and iron accumulation occur simultaneously in the same location, a separation of susceptibility sources is desirable to disentangle the underlying susceptibility proportions. METHODS: The basic concept of separating the susceptibility effects from sources with different sign within one voxel is to include information on relaxation rate ΔR2∗ in the quantitative susceptibility mapping reconstruction pipeline. The presented reconstruction algorithm is implemented as a constrained minimization problem and solved using conjugate gradients. The algorithm is evaluated using a software phantom and validated in MRI measurements with a phantom containing mixtures of microscopic positive and negative susceptibility sources. Data from three multiple sclerosis patients are used to show in vivo feasibility. RESULTS: In numerical simulations, the feasibility of disentangling susceptibility sources within the same voxel was confirmed provided the critera of the static dephasing regime were fulfilled. In phantom experiments, the magnitude decay kernel, which is an essential reconstruction parameter of the algorithm, was determined to be Dm=194.5T-1s-1ppm-1, and susceptibility sources could be separated in MRI measurement data. CONCLUSIONS: In conclusion, in this study a detailed description of the implementation of an algorithm for the separation of positive and negative susceptibility sources within the same volume element as well as its limitations is presented and validated quantitatively in both simulation and phantom experiments for the first time. An application to multiple sclerosis lesions shows promising results for in vivo usability.

A novel phantom with dia- and paramagnetic substructure for quantitative susceptibility mapping and relaxometry.

PURPOSE: A phantom is presented in this study that allows for an experimental evaluation of QSM reconstruction algorithms. The phantom contains susceptibility producing particles with dia- and paramagnetic properties embedded in an MRI visible medium and is suitable to assess the performance of algorithms that attempt to separate isotropic dia- and paramagnetic susceptibility at the sub-voxel level. METHODS: The phantom was built from calcium carbonate (diamagnetic) and tungsten carbide particles (paramagnetic) embedded in gelatin and surrounded by agarose gel. Different mass fractions and mixing ratios of both susceptibility sources were used. Gradient echo data were acquired at 1.5 T, 3 T and 7 T. Susceptibility maps were calculated using the MEDI toolbox and relaxation rates ΔR2∗ were determined using exponential fitting. RESULTS: Relaxation rates as well as susceptibility values generally coincide with the theoretical values for particles fulfilling the assumptions of the the static dephasing regime with stronger deviations for relaxation rates at higher field strength and for high susceptibility values. MRI raw data are available for free academic use as supplementary material. CONCLUSIONS: In this study, a susceptibility phantom is presented that might find its application in the development and quantitative validation of current and future QSM reconstruction algorithms which aim to separate the influence of isotropic dia- and paramagnetic substructure in quantitative susceptibility mapping.

Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry.

Friedreich's ataxia (FRDA) is a rare genetic disorder leading to degenerative processes. So far, no effective treatment has been found. Therefore, it is important to assist the development of medication with imaging biomarkers reflecting disease status and progress. Ten FRDA patients (mean age 37 ± 14 years; four female) and 10 age- and sex-matched controls were included. Acquisition of magnetic resonance imaging (MRI) data for quantitative susceptibility mapping, R1 , R2 relaxometry and diffusion imaging was performed at 7 Tesla. Results of volume of interest (VOI)-based analyses of the quantitative data were compared with a voxel-based morphometry (VBM) evaluation. Differences between patients and controls were assessed using the analysis of covariance (ANCOVA; p < 0.01) with age and sex as covariates, effect size of group differences, and correlations with disease characteristics with Spearman correlation coefficient. For the VBM analysis, a statistical threshold of 0.001 for uncorrected and 0.05 for corrected p-values was used. Statistically significant differences between FRDA patients and controls were found in five out of twelve investigated structures, and statistically significant correlations with disease characteristics were revealed. Moreover, VBM revealed significant white matter atrophy within regions of the brainstem, and the cerebellum. These regions overlapped partially with brain regions for which significant differences between healthy controls and patients were found in the VOI-based quantitative MRI evaluation. It was shown that two independent analyses provided overlapping results. Moreover, positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments.

On the influence of two coexisting species of susceptibility-producing structures on the R2∗ relaxation rate.

PURPOSE: Tissue microstructure can influence quantitative magnetic resonance imaging such as relaxation rate measurements. Consequently, relaxation rate mapping can provide useful information on tissue microstructure. In this work, the theory on relaxation mechanisms of the change of the relaxation rate ∆R2⁎ in the presence of spherical susceptibility sources in a spin bearing medium is validated in simulations and phantom experiments for the coexistence of two species of susceptibility sources. METHODS: The influence of coexisting spherical perturbers with magnetic susceptibilitys of different signs was evaluated in Monte Carlo simulations including diffusion effects in the surrounding medium. Simulations were compared with relaxometry measurements at 1.5 Tesla and at 3 Tesla. The phantoms used to validate the simulations were built from agarose gel containing calcium carbonate and tungsten carbide particles of different size and concentration. RESULTS: The Monte Carlo simulations showed, that the change in relaxation rate only depends on the overall amount of susceptibility producing structures in the simulation volume and no difference was found, if mixtures of positive and negative particles were simulated. Phantom measurements within the static dephasing regime showed linear additivity of the effects from positive and negative susceptibility sources that were present within the same voxel. CONCLUSIONS: In summary, both the simulations and the phantom measurements showed that changes in the relaxation rate ΔR2⁎ add up linearly for spherical particles with different susceptibilities within the same voxel if the conditions for the static dephasing regime are fulfilled. If particles with different susceptibilities have both different sizes and violate the conditions of the static dephasing regime, effects on relaxation rates might no longer be linear.

Rapid and accurate dictionary-based T2 mapping from multi-echo turbo spin echo data at 7 Tesla.

BACKGROUND: Using lower refocusing flip angles in multi-echo turbo spin echo (ME-TSE) sequences at ultra-high magnetic field leads to non-monoexponential signal decay and overestimation of T2 values due to stimulated and secondary echoes. PURPOSE: To investigate the feasibility of a fast and accurate reconstruction of quantitative T2 values using an ME-TSE sequence with reduced refocusing flip angles at 7 Tesla, a dictionary-based reconstruction method was developed and is presented in this work. STUDY TYPE: Prospective. SUBJECTS: Phantom measurements with relaxation phantom, four healthy volunteers. FIELD STRENGTH/SEQUENCE: 7 Tesla MRI, multi-echo turbo spin echo (ME-TSE), spin echo (SE), and B1 mapping. ASSESSMENT: Based on Bloch simulations and the extended phase graph model, signal decay curves were calculated to account for nonrectangular slice profile, B1 inhomogeneity, and reduced refocusing flip angles and stored in a dictionary. Data obtained with an ME-TSE sequence at 7 Tesla were matched to this dictionary to obtain T2 values. To compare the proposed method to reference T2 values, a spin echo sequence with different echo times was used. STATISTICAL TESTS: Welch's t-test was used to compare T2 values in phantom measurements. RESULTS: T2 values obtained with the proposed ME-TSE method coincided with the T2 values from the spin echo experiment in phantom measurements (P = 0.89 for 120° flip angle, P = 0.75 for 180° flip angle). Only for very low B1 transmit fields, a slight overestimation of T2 values was observed. In vivo measurements showed lower T2 values in gray matter (55 ± 2 millisecond) and white matter (39 ± 5 millisecond) compared with literature values of 3 Tesla data. DATA CONCLUSIONS: The proposed dictionary-based ME-TSE approach provided accurate T2 values in short measurement time at 7 Tesla with low specific absorption rate burden due to the reduction of refocusing flip angles. Therefore, it can provide new opportunities in clinical high-field MRI to further improve radiographic diagnosis by using quantitative imaging. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1253-1262.

Technical Note: On the size of susceptibility-induced MR image distortions in prostate and cervix in the context of MR-guided radiation therapy.

PURPOSE: To investigate the extent of MR image distortions in the pelvis caused by susceptibility-induced field inhomogeneities in MR images in the context of a study on MR-guided radiotherapy. METHODS: Using a high-bandwidth double-echo gradient echo sequence, field maps and distortion maps of the pelvis were calculated and evaluated for 219 exams (92 of female and 127 of male patients) to investigate patient-related image distortions caused by susceptibility differences in an ongoing study on MR-guided radiotherapy. The evaluation of distortions in the regions "rectum", "prostate", "cervix", and in a reference region in the gluteus maximus was based on masks drawn by two readers. RESULTS: Distortions in the prostate and cervix were smaller than 0.03 px (0.1 mm) for 99% of voxels, and reached a maximum value of 0.09 px (0.3 mm). In the reference region, maximum distortions were smaller than in the prostate and cervix. CONCLUSIONS: Using a geometric uncertainty of 0.2 px (0.6 mm) in margin definition for organs that are close to the rectum like the prostate and the cervix would be a cautious choice to account for susceptibility-induced distortions that can arise during MR-based treatment guidance for the imaging setting used in this study. Since distortions are inversely proportional to the readout bandwidth of the sequence, safety margins need to be adapted adequately. Additional sources of image distortions like gradient nonlinearities are not included in our margin recommendations and should be considered separately.

Mask-Adapted Background Field Removal for Artifact Reduction in Quantitative Susceptibility Mapping of the Prostate.

We propose an alternative processing method for quantitative susceptibility mapping of the prostate that reduces artifacts and enables better visibility and quantification of calcifications and other lesions. Three-dimensional gradient-echo magnetic resonance data were obtained from 26 patients at 3 T who previously received a planning computed tomography of the prostate. Phase images were unwrapped using Laplacian-based phase unwrapping. The background field was removed with the V-SHARP method using tissue masks for the entire abdomen (Method 1) and masks that excluded bone and the rectum (Method 2). Susceptibility maps were calculated with the iLSQR method. The quality of susceptibility maps was assessed by one radiologist and two physicists who rated the data for visibility of lesions and data quality on a scale from 1 (poor) to 4 (good). The readers rated susceptibility maps computed with Method 2 to be, on average, better for visibility of lesions with a score of 2.9 ± 1.1 and image quality with a score of 2.8 ± 0.8 compared with maps computed with Method 1 (2.4 ± 1.2/2.3 ± 1.0). Regarding strong artifacts, these could be removed using adapted masks, and the susceptibility values seemed less biased by the artifacts. Thus, using an adapted mask for background field removal when calculating susceptibility maps of the prostate from phase data reduces artifacts and improves visibility of lesions.

Suitable reference tissues for quantitative susceptibility mapping of the brain.

PURPOSE: Since quantitative susceptibility mapping (QSM) quantifies magnetic susceptibility relative to a reference value, a suitable reference tissue has to be available to compare different subjects and stages of disease. METHODS: To find such a suitable reference tissue for QSM of the brain, melanoma patients with and without brain metastases were measured. Twelve reference regions were chosen and assessed for stability of susceptibility values with respect to multiple intra-individual and inter-individual measurements, age, and stage of disease. RESULTS: Cerebrospinal fluid (CSF), the internal capsule and one region in the splenium of the corpus callosum are the regions with the smallest standard deviations of the mean susceptibility value. The mean susceptibility is 0.010 ± 0.014 ppm for CSF in the atrium of the lateral ventricles (csfpost ), -0.060 ± 0.019 ppm for the posterior limb of the internal capsule (ci2), and -0.008 ± 0.019 ppm for the splenium of the corpus callosum. csfpost and ci2 show nearly no dependence on age or stage of disease, whereas some other regions, e.g., the red nucleus, show moderate dependence on age or disease. CONCLUSION: The internal capsule and CSF appear to be the most suitable reference regions for QSM of the brain in the melanoma patients studied. Both showed virtually no dependence on age or disease and small variations among patients. Magn Reson Med 78:204-214, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Potential of quantitative susceptibility mapping for detection of prostatic calcifications.

PURPOSE: To evaluate whether quantitative susceptibility (QSM) may be used as an alternative to computed tomography (CT) to detect calcification in prostate cancer patients. MATERIALS AND METHODS: Susceptibility map calculation was performed using 3D gradient echo magnetic resonance imaging (MRI) data from 26 patients measured at 3T who previously received a planning CT of the prostate. Phase images were unwrapped using Laplacian-based phase unwrapping, the background field was removed with the V-SHARP method, and susceptibility maps were calculated with the iLSQR method. Two blinded readers were asked to identify peri- and intraprostatic calcifications. RESULTS: Average mean and minimum susceptibility values (referenced to iliopsoas muscle) of calcifications were -0.249 ± 0.179 ppm and -0.551 ± 0.323 ppm, and average mean and maximum intensities in CT images were 319 ± 164 HU and 679 ± 392 HU. Twenty-one and 17 out of 22 prostatic calcifications were identified using susceptibility maps and magnitude images, respectively, as well as more than half of periprostatic phleboliths depicted by CT. Calcifications in the prostate and its periphery were quantitatively differentiable from noncalcified prostate tissue in CT (mean values for calcifications / for noncalcified tissue: 71 to 649 / -1 to 83 HU) and in QSM (mean values for calcifications / for noncalcified tissue: -0.641 to 0.063 / -0.046 to 0.181 ppm). Moreover, there was a significant correlation between susceptibility values and CT image intensities for calcifications (P < 0.004). CONCLUSION: Prostatic calcifications could be well identified with QSM. Susceptibility maps can be easily obtained from clinical prostate MR protocols that include a 3D gradient echo sequence, rendering it a promising technique for detection and quantification of intraprostatic calcifications. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:889-898.