Iron and Neurodegeneration in Multiple Sclerosis

Increased iron deposition might be implicated in multiple sclerosis (MS). Recent development of MRI enabled to determine brain iron levels in a quantitative manner, which has put more interest on studying the role of iron in MS. Evidence for abnormal iron homeostasis in MS comes also from analyses of iron and iron-related proteins in CSF and blood and postmortem MS brain sections. However, it is not yet clear if iron accumulation is implicated in MS pathology or merely reflects an epiphenomenon. Further interest has been generated by the idea of chronic cerebrospinal venous insufficiency that might be associated with brain iron accumulation due to a reduction in venous outflow, but its existence and etiologic role in MS are currently controversially debated. In future studies, combined approaches applying quantitative MRI together with CSF and serum analyses of iron and iron-related proteins in a clinical followup setting might help to elucidate the implication of iron accumulation in MS

Hybrid data fidelity term approach for quantitative susceptibility mapping

PURPOSE: Susceptibility maps are usually derived from local magnetic field estimations by minimizing a functional composed of a data consistency term and a regularization term. The data-consistency term measures the difference between the desired solution and the measured data using typically the L2-norm. It has been proposed to replace this L2-norm with the L1-norm, due to its robustness to outliers and reduction of streaking artifacts arising from highly noisy or strongly perturbed regions. However, in regions with high SNR, the L1-norm yields a suboptimal denoising performance. In this work, we present a hybrid data fidelity approach that uses the L1-norm and subsequently the L2-norm to exploit the strengths of both norms. METHODS: We developed a hybrid data fidelity term approach for QSM (HD-QSM) based on linear susceptibility inversion methods, with total variation regularization. Each functional is solved with ADMM. The HD-QSM approach is a two-stage method that first finds a fast solution of the L1-norm functional and then uses this solution to initialize the L2-norm functional. In both norms we included spatially variable weights that improve the quality of the reconstructions. RESULTS: The HD-QSM approach produced good quantitative reconstructions in terms of structural definition, noise reduction, and avoiding streaking artifacts comparable with nonlinear methods, but with higher computational efficiency. Reconstructions performed with this method achieved first place at the lowest RMS error category in stage 1 of the 2019 QSM Reconstruction Challenge. CONCLUSIONS: The proposed method allows robust and accurate QSM reconstructions, obtaining superior performance to state-of-the-art methods

Accelerated mapping of magnetic susceptibility using 3D planes-on-a-paddlewheel (POP) EPI at ultra-high field strength

With the advent of ultra-high field MRI scanners in clinical research, susceptibility based MRI has recently gained increasing interest because of its potential to assess subtle tissue changes underlying neurological pathologies/disorders. Conventional, but rather slow, three-dimensional (3D) spoiled gradient-echo (GRE) sequences are typically employed to assess the susceptibility of tissue. 3D echo-planar imaging (EPI) represents a fast alternative but generally comes with echo-time restrictions, geometrical distortions and signal dropouts that can become severe at ultra-high fields. In this work we assess quantitative susceptibility mapping (QSM) at 7T using non-Cartesian 3D EPI with a planes-on-a-paddlewheel (POP) trajectory, which is created by rotating a standard EPI readout train around its own phase encoding axis. We show that the threefold accelerated non-Cartesian 3D POP EPI sequence enables very fast, whole brain susceptibility mapping at an isotropic resolution of 1mm and that the high image quality has sufficient signal-to-noise ratio in the phase data for reliable QSM processing. The susceptibility maps obtained were comparable with regard to QSM values and geometric distortions to those calculated from a conventional 4min 3D GRE scan using the same QSM processing pipeline

Time-optimized high-resolution readout-segmented diffusion tensor imaging

Readout-segmented echo planar imaging with 2D navigator-based reacquisition is an uprising technique enabling the sampling of high-resolution diffusion images with reduced susceptibility artifacts. However, low signal from the small voxels and long scan times hamper the clinical applicability. Therefore, we introduce a regularization algorithm based on total variation that is applied directly on the entire diffusion tensor. The spatially varying regularization parameter is determined automatically dependent on spatial variations in signal-to-noise ratio thus, avoiding over- or under-regularization. Information about the noise distribution in the diffusion tensor is extracted from the diffusion weighted images by means of complex independent component analysis. Moreover, the combination of those features enables processing of the diffusion data absolutely user independent. Tractography from in vivo data and from a software phantom demonstrate the advantage of the spatially varying regularization compared to un-regularized data with respect to parameters relevant for fiber-tracking such as Mean Fiber Length, Track Count, Volume and Voxel Count. Specifically, for in vivo data findings suggest that tractography results from the regularized diffusion tensor based on one measurement (16 min) generates results comparable to the un-regularized data with three averages (48 min). This significant reduction in scan time renders high resolution (1×1×2.5 mm3) diffusion tensor imaging of the entire brain applicable in a clinical context

Susceptibility induced gray–white matter MRI contrast in the human brain

AbstractMR phase images have shown significantly improved contrast between cortical gray and white matter regions compared to magnitude images obtained with gradient echo sequences. A variety of underlying biophysical mechanisms (including iron, blood, myelin content, macromolecular chemical exchange, and fiber orientation) have been suggested to account for this observation but assessing the individual contribution of these factors is limited in vivo.For a closer investigation of iron and myelin induced susceptibility changes, postmortem MRI of six human corpses (age range at death: 56–80years) was acquired in situ. Following autopsy, the iron concentrations in the frontal and occipital cortex as well as in white matter regions were chemically determined. The magnetization transfer ratio (MTR) was used as an indirect measure for myelin content. Susceptibility effects were assessed separately by determining R2* relaxation rates and quantitative phase shifts. Contributions of myelin and iron to local variations of the susceptibility were assessed by univariate and multivariate linear regression analysis.Mean iron concentration was lower in the frontal cortex than in frontal white matter (26±6 vs. 45±6mg/kg wet tissue) while an inverse relation was found in the occipital lobe (cortical gray matter: 41±10 vs. white matter: 34±10mg/kg wet tissue). Multiple regression analysis revealed iron and MTR as independent predictors of the effective transverse relaxation rate R2* but solely MTR was identified as source of MR phase contrast. R2* was correlated with iron concentrations in cortical gray matter only (r=0.42, p<0.05).In conclusion, MR phase contrast between cortical gray and white matter can be mainly attributed to variations in myelin content, but not to iron concentration. Both, myelin and iron impact the effective transverse relaxation rate R2* significantly. Magnitude contrast is limited because it only reflects the extent but not the direction of the susceptibility shift

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

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

SHARQnet – Sophisticated harmonic artifact reduction in quantitative susceptibility mapping using a deep convolutional neural network

Quantitative susceptibility mapping (QSM) reveals pathological changes in widespread diseases such as Parkinson's disease, Multiple Sclerosis, or hepatic iron overload. QSM requires multiple processing steps after the acquisition of magnetic resonance imaging (MRI) phase measurements such as unwrapping, background field removal and the solution of an ill-posed field-to-source-inversion. Current techniques utilize iterative optimization procedures to solve the inversion and background field correction, which are computationally expensive and lead to suboptimal or over-regularized solutions requiring a careful choice of parameters that make a clinical application of QSM challenging. We have previously demonstrated that a deep convolutional neural network can invert the magnetic dipole kernel with a very efficient feed forward multiplication not requiring iterative optimization or the choice of regularization parameters. In this work, we extended this approach to remove background fields in QSM. The prototype method, called SHARQnet, was trained on simulated background fields and tested on 3T and 7T brain datasets. We show that SHARQnet outperforms current background field removal procedures and generalizes to a wide range of input data without requiring any parameter adjustments. In summary, we demonstrate that the solution of ill-posed problems in QSM can be achieved by learning the underlying physics causing the artifacts and removing them in an efficient and reliable manner and thereby will help to bring QSM towards clinical applications