Quantitative susceptibility mapping (QSM) as a means to measure brain iron? A post mortem validation study

AbstractQuantitative susceptibility mapping (QSM) is a novel technique which allows determining the bulk magnetic susceptibility distribution of tissue in vivo from gradient echo magnetic resonance phase images. It is commonly assumed that paramagnetic iron is the predominant source of susceptibility variations in gray matter as many studies have reported a reasonable correlation of magnetic susceptibility with brain iron concentrations in vivo. Instead of performing direct comparisons, however, all these studies used the putative iron concentrations reported in the hallmark study by Hallgren and Sourander (1958) for their analysis. Consequently, the extent to which QSM can serve to reliably assess brain iron levels is not yet fully clear. To provide such information we investigated the relation between bulk tissue magnetic susceptibility and brain iron concentration in unfixed (in situ) post mortem brains of 13 subjects using MRI and inductively coupled plasma mass spectrometry. A strong linear correlation between chemically determined iron concentration and bulk magnetic susceptibility was found in gray matter structures (r=0.84, p<0.001), whereas the correlation coefficient was much lower in white matter (r=0.27, p<0.001). The slope of the overall linear correlation was consistent with theoretical considerations of the magnetism of ferritin supporting that most of the iron in the brain is bound to ferritin proteins. In conclusion, iron is the dominant source of magnetic susceptibility in deep gray matter and can be assessed with QSM. In white matter regions the estimation of iron concentrations by QSM is less accurate and more complex because the counteracting contribution from diamagnetic myelinated neuronal fibers confounds the interpretation

Structural and Functional Reorganization of the Brain in Migraine Without Aura

It remains unknown whether migraine headache has a progressive component in its pathophysiology. Quantitative MRI may provide valuable insight into abnormal changes in the migraine interictum and assist in identifying disrupted brain networks. We carried out a data-driven study of structural integrity and functional connectivity of the resting brain in migraine without aura. MRI scanning was performed in 36 patients suffering from episodic migraine without aura and 33 age-matched healthy subjects. Voxel-wise analysis of regional brain volume was performed by registration of the T1-weighted MRI scans into a common study brain template using the tensor-based morphometry (TBM) method. Changes in functional synchronicity of the brain networks were assessed using probabilistic independent component analysis (ICA). TBM revealed that migraine is associated with reduced volume of the medial prefrontal cortex (mPFC). Among 375 functional brain networks, resting-state connectivity was decreased between two components spanning the visual cortex, posterior insula, and parietal somatosensory cortex. Our study reveals structural and functional alterations of the brain in the migraine interictum that may stem from underlying disease risk factors and the “silent” aura phenomenon. Longitudinal studies will be needed to investigate whether interictal brain changes are progressive and associated with clinical disease trajectories

Recommended Implementation of Quantitative Susceptibility Mapping for Clinical Research in The Brain: A Consensus of the ISMRM Electro-Magnetic Tissue Properties Study Group

This article provides recommendations for implementing quantitative susceptibility mapping (QSM) for clinical brain research. It is a consensus of the ISMRM Electro-Magnetic Tissue Properties Study Group. While QSM technical development continues to advance rapidly, the current QSM methods have been demonstrated to be repeatable and reproducible for generating quantitative tissue magnetic susceptibility maps in the brain. However, the many QSM approaches available give rise to the need in the neuroimaging community for guidelines on implementation. This article describes relevant considerations and provides specific implementation recommendations for all steps in QSM data acquisition, processing, analysis, and presentation in scientific publications. We recommend that data be acquired using a monopolar 3D multi-echo GRE sequence, that phase images be saved and exported in DICOM format and unwrapped using an exact unwrapping approach. Multi-echo images should be combined before background removal, and a brain mask created using a brain extraction tool with the incorporation of phase-quality-based masking. Background fields should be removed within the brain mask using a technique based on SHARP or PDF, and the optimization approach to dipole inversion should be employed with a sparsity-based regularization. Susceptibility values should be measured relative to a specified reference, including the common reference region of whole brain as a region of interest in the analysis, and QSM results should be reported with - as a minimum - the acquisition and processing specifications listed in the last section of the article. These recommendations should facilitate clinical QSM research and lead to increased harmonization in data acquisition, analysis, and reporting

Two-dimensional local Fourier image reconstruction via domain decomposition Fourier continuation method

The MRI image is obtained in the spatial domain from the given Fourier coefficients in the frequency domain. It is costly to obtain the high resolution image because it requires higher frequency Fourier data while the lower frequency Fourier data is less costly and effective if the image is smooth. However, the Gibbs ringing, if existent, prevails with the lower frequency Fourier data. We propose an efficient and accurate local reconstruction method with the lower frequency Fourier data that yields sharp image profile near the local edge. The proposed method utilizes only the small number of image data in the local area. Thus the method is efficient. Furthermore the method is accurate because it minimizes the global effects on the reconstruction near the weak edges shown in many other global methods for which all the image data is used for the reconstruction. To utilize the Fourier method locally based on the local non-periodic data, the proposed method is based on the Fourier continuation method. This work is an extension of our previous 1D Fourier domain decomposition method to 2D Fourier data. The proposed method first divides the MRI image in the spatial domain into many subdomains and applies the Fourier continuation method for the smooth periodic extension of the subdomain of interest. Then the proposed method reconstructs the local image based on L-2 minimization regularized by the L-1 norm of edge sparsity to sharpen the image near edges. Our numerical results suggest that the proposed method should be utilized in dimension-by-dimension manner instead of in a global manner for both the quality of the reconstruction and computational efficiency. The numerical results show that the proposed method is effective when the local reconstruction is sought and that the solution is free of Gibbs oscillations.11Nsciescopu

An illustrated comparison of processing methods for phase MRI and QSM: removal of background field contributions from sources outside the region of interest

The elimination of so-called background fields is an essential step in phase MRI and quantitative susceptibility mapping (QSM). Background fields, which are caused by sources outside the region of interest (ROI), are often one to two orders of magnitude stronger than tissue-related field variations from within the ROI, hampering quantitative interpretation of field maps. This paper reviews the current literature on background elimination algorithms for QSM and provides insights into similarities and differences between the many algorithms proposed. We discuss the basic theoretical foundations and derive fundamental limitations of background field elimination

An illustrated comparison of processing methods for MR phase imaging and QSM: combining array coil signals and phase unwrapping

Phase imaging benefits from strong susceptibility effects at very high field and the high signal-to-noise ratio (SNR) afforded by multi-channel coils. Combining the information from coils is not trivial, however, as the phase that originates in local field effects (the source of interesting contrast) is modified by the inhomogeneous sensitivity of each coil. This has historically been addressed by referencing individual coil sensitivities to that of a volume coil, but alternative approaches are required for ultra-high field systems in which no such coil is available. An additional challenge in phase imaging is that the phase that develops up to the echo time is " wrapped" into a range of 2p radians. Phase wraps need to be removed in order to reveal the underlying phase distribution of interest. Beginning with a coil combination using a homogeneous reference volume coil -the Roemer approach -which can be applied at 3 T and lower field strengths, we review alternative methods for combining single-echo and multi-echo phase images where no such reference coil is available. These are applied to high-resolution data acquired at 7 T and their effectiveness assessed via an index of agreement between phase values over channels and the contrast-to-noise ratio in combined images. The virtual receiver coil and COMPOSER approaches were both found to be computationally efficient and effective. The main features of spatial and temporal phase unwrapping methods are reviewed, placing particular emphasis on recent developments in temporal phase unwrapping and Laplacian approaches. The features and performance of these are illustrated in application to simulated and high-resolution in vivo data. Temporal unwrapping was the fastest of the methods tested and the Laplacian the most robust in images with low SNR. (C) 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd

Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination

Siponimod (Sp) is a Sphingosine 1-phosphate (S1P) receptor modulator, and it suppresses S1P- mediated autoimmune lymphocyte transport and inflammation. Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis (MS) exhibits inflammation-driven acute and chronic phases, spinal cord lesions, brain and spinal cord atrophy, and white matter injury. The objective of the study was to investigate whether Sp treatment could attenuate inflammation-induced pathology in the TMEV model by inhibiting microglial activation and preventing the atrophy of central nervous tissue associated with neurodegeneration. Clinical disability score (CDS), body weight (BW), and rotarod retention time measures were used to assess Sp’s impact on neurodegeneration and disease progression in 4 study groups of 102 animals, including 44 Sp-treated (SpT), 44 vehicle-treated, 6 saline-injected, and 8 age-matched healthy controls (HC). Next, 58 (22 SpT, 22 vehicle, 6 saline injected, and 8 HC) out of the 102 animals were further evaluated to assess the effect of Sp on brain region-specific and spinal cord volume changes, as well as microglial activation. Sp increased CDS and decreased BW and rotarod retention time in TMEV mice, but did not significantly affect most brain region volumes, except for lateral ventricle volume. Sp suppressed ventricular enlargement, suggesting reduced TMEV-induced inflammation in LV. No significant differences in spine volume changes were observed between Sp- and vehicle-treated animals, but there were differences between HC and TMEV groups, indicating TMEV-induced inflammation contributed to increased spine volume. Spine histology revealed no significant microglial density differences between groups in gray matter, but HC animals had higher type 1 morphology and lower type 2 morphology percentages in gray and white matter regions. This suggests that Sp did not significantly affect microglial density but may have modulated neuroinflammation in the spinal cord. Sp may have some effects on neuroinflammation and ventricular enlargement. However, it did not demonstrate a significant impact on neurodegeneration, spinal volume, or lesion volume in the TMEV mouse model. Further investigation is required to fully understand Sp’s effect on microglial activation and its relevance to the pathophysiology of MS. The differences between the current study and previous research using other MS models, such as EAE, highlight the differences in pathological processes in these two disease models

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Monoclonal Antibody Tumor Disposition

The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection of patients for treatment with anti-cancer mAb. Here, we report the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with tumor penetration of the contrast agent gadobutrol used as a surrogate, to improve physiologically based pharmacokinetic model (PBPK) predictions of cetuximab pharmacokinetics in epidermal growth factor receptor (EGFR) positive xenografts. In the initial investigations, mice bearing Panc-1, NCI-N87, and LS174T xenografts underwent DCE-MRI imaging with the contrast agent gadobutrol, followed by intravenous dosing of an 125Iodine-labeled, non-binding mAb (8C2). Tumor concentrations of 8C2 were determined following the euthanasia of mice (3 h&ndash;6 days after 8C2 dosing). Potential predictor relationships between DCE-MRI kinetic parameters and 8C2 PBPK parameters were evaluated through covariate modeling. The addition of the DCE-MRI parameter Ktrans alone or Ktrans in combination with the DCE-MRI parameter Vp on the PBPK parameters for tumor blood flow (QTU) and tumor vasculature permeability (&sigma;TUV) led to the most significant improvement in the characterization of 8C2 pharmacokinetics in individual tumors. To test the utility of the DCE-MRI covariates on a priori prediction of the disposition of mAb with high-affinity tumor binding, a second group of tumor-bearing mice underwent DCE-MRI imaging with gadobutrol, followed by the administration of 125Iodine-labeled cetuximab (a high-affinity anti-EGFR mAb). The MRI-PBPK covariate relationships, which were established with the untargeted antibody 8C2, were implemented into the PBPK model with considerations for EGFR expression and cetuximab-EGFR interaction to predict the disposition of cetuximab in individual tumors (a priori). The incorporation of the Ktrans MRI parameter as a covariate on the PBPK parameters QTU and &sigma;TUV decreased the PBPK model prediction error for cetuximab tumor pharmacokinetics from 223.71 to 65.02%. DCE-MRI may be a useful clinical tool in improving the prediction of antibody pharmacokinetics in solid tumors. Further studies are warranted to evaluate the utility of the DCE-MRI approach to additional mAbs and additional drug modalities

Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals

Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE: rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+6.1ppb) and H63D (+6.9ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: −5.3ppb, right: −6.7ppb, p<0.05). Female MS patients had lower susceptibility in the caudate (−6.0ppb) and putamen (left: −3.9ppb, right: −4.6ppb) than men, but only when they had a wild-type allele (p<0.05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors. Keywords: Iron related genes, Quantitative susceptibility mapping, QSM, Iron, Multiple sclerosi

QSM reconstruction challenge 2.0: A realistic in silico head phantom for MRI data simulation and evaluation of susceptibility mapping procedures

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