Characterization of microparticles of iron oxide for magnetic resonance imaging.

Microparticles of iron oxide (MPIOs) are increasingly used for contrast generation in magnetic resonance imaging (MRI). In particular, Dynabeads® MyOne™ Tosylactivated MPIOs have enabled sensitive and targeted molecular imaging, e.g., to detect vascular inflammation. For the first time we measured the relaxivities as well as the molar susceptibility χM of these MPIOs at 7 T in agarose gels. They are r1 = 0.69 ± 0.03 s-1/mM, r2 = 220 ± 6 s-1/mM, r2* = 679 ± 14 s-1/mM, and χM = 0.66 ± 0.05 ppm/mM, when expressed with respect to the iron concentration. These material parameters are essential to optimize MRI protocols and progress toward quantitative imaging. To address the heterogeneous nature of the MPIO distributions over the size of a typical MRI voxel, we coupled the MPIOs to a fluorophore to create a bimodal phantom that can be imaged by both Light Sheet microscopy and MRI. In this phantom, the MPIOs produced contrast similar to that found in vivo . The submicron resolution of Light Sheet microscopy images provided a precise measurement of the MPIO spatial distribution in phantoms also imaged by MRI. MPIO aggregates occupying less than one MRI voxel were responsible for alterations in R2* and magnetic susceptibility χ across several MRI voxels. In these cases, the sum of R2* or χ over the affected MRI volume correlated better with the microscopically determined number of MPIOs. These findings were confirmed with simulations performed in the static dephasing regime. The microscopically determined MPIO distribution was also entered directly into the simulation framework, indicating that the bimodal phantom is a useful tool to test theoretical models against experimental measurements.

Safety and effectiveness of percutaneous sclerotherapy for venous disorders of the labia majora in patients with vascular malformations.

OBJECTIVE: The aim of this study was to evaluate the safety and clinical outcomes of percutaneous sclerotherapy of venous disorders of the labia majora in patients with vascular malformations of the lower limbs. METHODS: Thirty percutaneous sclerotherapy treatments were performed over a 6-year period among 17 female patients with symptomatic venous malformation (VM) or secondary varicosis of the labia majora. Four patients were treated with sclerotherapy alone, 13 patients had additional procedures to control the VM before sclerotherapy. Polidocanol was used as sclerosant. Indications for sclerotherapy included pain, bleeding, thrombophlebitis, and swelling. Genitourinary symptoms were recorded. The number of treatments and procedure-related complications were registered. Complications were classified according to the Society of Interventional Radiology (SIR) classification system (grade A-E). The 3-month postintervention follow-up included magnetic resonance imaging, clinical examination, and a symptom-related questionnaire. If no reintervention was necessary, consultation was scheduled biannually. RESULTS: All patients had local swelling and pain; only a fraction of the patients had further symptoms with bleeding or thrombophlebitis (47% each). Eight patients required reintervention. No major complications were observed; minor complications such as postprocedural swelling occurred in 29% (SIR grade A), pain occurred in 17% (SIR grade B), and skin blistering developed in 5% (SIR grade B). Upon follow-up examination after a median of 40 months, 76% showed complete relief of symptoms, and 23% reported partial relief. All patients reported a substantial reduction in pain (75% >5 points in visual analogue scale) and swelling (88% complete cessation). CONCLUSIONS: Percutaneous sclerotherapy is a safe and effective treatment option of VM and secondary varicosis of the labia majora.

Characterization of Iron Accumulation in Deep Gray Matter in Myotonic Dystrophy Type 1 and 2 Using Quantitative Susceptibility Mapping and R2* Relaxometry: A Magnetic Resonance Imaging Study at 3 Tesla.

Quantitative mapping of the magnetic susceptibility and the effective transverse relaxation rate (R2*) are suitable to assess the iron content in distinct brain regions. In this prospective, explorative study the iron accumulation in deep gray matter nuclei (DGM) in myotonic dystrophy type 1 (DM1) and 2 (DM2) and its clinical and neuro-cognitive relevance using susceptibility and R2* mapping was examined. Twelve classical DM1, four childhood-onset DM1 (DM1c.o.), twelve DM2 patients and twenty-nine matched healthy controls underwent MRI at 3 Tesla, neurological and neuro-cognitive tests. Susceptibility, R2* and volumes were determined for eleven DGM structures and compared between patients and controls. Twelve classical DM1, four childhood-onset DM1, and 12 DM2 patients as well as 29 matched healthy controls underwent MRI at 3 Tesla, and neurological and neuro-cognitive tests. Susceptibility, R2* and volumes were determined for 11 DGM structures and compared between patients and controls. Iron accumulation in DGM reflected by R2* or susceptibility was found in the putamen and accumbens of DM1 and in DM2, but was more widespread in DM1 (caudate, pallidum, hippocampus, subthalamic nucleus, thalamus, and substantia nigra). Opposed changes of R2* or susceptibility were detected in caudate, putamen and accumbens in the childhood-onset DM1 patients compared to classical DM1. R2* or susceptibility alterations in DGM were significantly associated with clinical symptoms including muscular weakness (DM1), daytime sleepiness (DM1), depression (DM2), and with specific cognitive deficits in DM1 and DM2.

The influence of brain iron and myelin on magnetic susceptibility and effective transverse relaxation - A biochemical and histological validation study.

Quantitative susceptibility mapping (QSM) and effective transverse relaxation rate (R2*) mapping are both highly sensitive to variations in brain iron content. Clinical Magnetic Resonance Imaging (MRI) studies report changes of susceptibilities and relaxation rates in various neurological diseases which are often equated with changes in regional brain iron content. However, these mentioned metrics lack specificity for iron, since they are also influenced by the presence of myelin. In this study, we assessed the extent to which QSM and R2* reflect iron concentration as well as histological iron and myelin intensities. Six unfixed human post-mortem brains were imaged in situ with a 7 T MRI scanner. After formalin fixation, the brains were sliced axially and punched. 671 tissue punches were subjected to ferrozine iron quantification. Subsequently, brain slices were embedded in paraffin, and histological double-hemispheric axial brain slices were stained for Luxol fast blue (myelin) and diaminobenzidine (DAB)-enhanced Turnbull blue (iron). 3331 regions of interest (ROIs) were drawn on the histological stainings to assess myelin and iron intensities, which were compared with MRI data in corresponding ROIs. QSM more closely reflected quantitative ferrozine iron values (r = 0.755 vs. 0.738), whereas R2* correlated better with iron staining intensities (r = 0.619 vs. 0.445). Myelin intensities correlated negatively with QSM (r = -0.352), indicating a diamagnetic effect of myelin on susceptibility. Myelin intensities were higher in the thalamus than in the basal ganglia. A significant relationship was nonetheless observed between quantitative iron values and QSM, confirming the applicability of the latter in this brain region for iron quantification.

Quantitative Susceptibility Mapping Indicates a Disturbed Brain Iron Homeostasis in Neuromyelitis Optica - A Pilot Study.

Dysregulation of brain iron homeostasis is a hallmark of many neurodegenerative diseases and can be associated with oxidative stress. The objective of this study was to investigate brain iron in patients with Neuromyelitis Optica (NMO) using quantitative susceptibility mapping (QSM), a quantitative iron-sensitive MRI technique. 12 clinically confirmed NMO patients (6 female and 6 male; age 35.4y±14.2y) and 12 age- and sex-matched healthy controls (7 female and 5 male; age 33.9±11.3y) underwent MRI of the brain at 3 Tesla. Quantitative maps of the effective transverse relaxation rate (R2*) and magnetic susceptibility were calculated and a blinded ROI-based group comparison analysis was performed. Normality of the data and differences between patients and controls were tested by Kolmogorov-Smirnov and t-test, respectively. Correlation with age was studied using Spearman's rank correlation and an ANCOVA-like analysis. Magnetic susceptibility values were decreased in the red nucleus (p<0.01; d>0.95; between -15 and -22 ppb depending on reference region) with a trend toward increasing differences with age. R2* revealed significantly decreased relaxation in the optic radiations of five of the 12 patients (p<0.0001; -3.136±0.567 s(-1)). Decreased relaxation in the optic radiation is indicative for demyelination, which is in line with previous findings. Decreased magnetic susceptibility in the red nucleus is indicative for a lower brain iron concentration, a chemical redistribution of iron into less magnetic forms, or both. Further investigations are necessary to elucidate the pathological cause or consequence of this finding.

Quantitative assessment of microvasculopathy in arcAß mice with USPIO-enhanced gradient echo MRI.

Magnetic resonance imaging employing administration of iron oxide-based contrast agents is widely used to visualize cellular and molecular processes in vivo. In this study, we investigated the ability of [Formula: see text] and quantitative susceptibility mapping to quantitatively assess the accumulation of ultrasmall superparamagnetic iron oxide (USPIO) particles in the arcAß mouse model of cerebral amyloidosis. Gradient-echo data of mouse brains were acquired at 9.4 T after injection of USPIO. Focal areas with increased magnetic susceptibility and [Formula: see text] values were discernible across several brain regions in 12-month-old arcAß compared to 6-month-old arcAß mice and to non-transgenic littermates, indicating accumulation of particles after USPIO injection. This was concomitant with higher [Formula: see text] and increased magnetic susceptibility differences relative to cerebrospinal fluid measured in USPIO-injected compared to non-USPIO-injected 12-month-old arcAß mice. No differences in [Formula: see text] and magnetic susceptibility were detected in USPIO-injected compared to non-injected 12-month-old non-transgenic littermates. Histological analysis confirmed focal uptake of USPIO particles in perivascular macrophages adjacent to small caliber cerebral vessels with radii of 2-8 µm that showed no cerebral amyloid angiopathy. USPIO-enhanced [Formula: see text] and quantitative susceptibility mapping constitute quantitative tools to monitor such functional microvasculopathies.

Brain iron quantification by MRI in mitochondrial membrane protein-associated neurodegeneration under iron-chelating therapy.

Therapeutic trials for Neurodegeneration with Brain Iron Accumulation have aimed at a reduction of cerebral iron content. A 13-year-old girl with mitochondrial membrane protein-associated neurodegeneration treated with an iron-chelating agent was monitored by R2 relaxometry, R2* relaxometry, and quantitative susceptibility mapping to estimate the brain iron content. The highly increased brain iron content slowly decreased in the substantia nigra but remained stable for globus pallidus. The estimated iron content was higher by R2* compared to R2 and quantitative susceptibility mapping, a finding not previously observed in the brain of healthy volunteers. A hypothesis explaining this discrepancy is offered.

Longitudinal Assessment of Amyloid Pathology in Transgenic ArcAß Mice Using Multi-Parametric Magnetic Resonance Imaging.

Magnetic resonance imaging (MRI) can be used to monitor pathological changes in Alzheimer's disease (AD). The objective of this longitudinal study was to assess the effects of progressive amyloid-related pathology on multiple MRI parameters in transgenic arcAß mice, a mouse model of cerebral amyloidosis. Diffusion-weighted imaging (DWI), T1-mapping and quantitative susceptibility mapping (QSM), a novel MRI based technique, were applied to monitor structural alterations and changes in tissue composition imposed by the pathology over time. Vascular function and integrity was studied by assessing blood-brain barrier integrity with dynamic contrast-enhanced MRI and cerebral microbleed (CMB) load with susceptibility weighted imaging and QSM. A linear mixed effects model was built for each MRI parameter to incorporate effects within and between groups (i.e. genotype) and to account for changes unrelated to the disease pathology. Linear mixed effects modelling revealed a strong association of all investigated MRI parameters with age. DWI and QSM in addition revealed differences between arcAß and wt mice over time. CMBs became apparent in arcAß mice with 9 month of age; and the CMB load reflected disease stage. This study demonstrates the benefits of linear mixed effects modelling of longitudinal imaging data. Moreover, the diagnostic utility of QSM and assessment of CMB load should be exploited further in studies of AD.

Quantitative susceptibility mapping differentiates between blood depositions and calcifications in patients with glioblastoma.

OBJECTIVES: The application of susceptibility weighted imaging (SWI) in brain tumor imaging is mainly used to assess tumor-related "susceptibility based signals" (SBS). The origin of SBS in glioblastoma is still unknown, potentially representing calcifications or blood depositions. Reliable differentiation between both entities may be important to evaluate treatment response and to identify glioblastoma with oligodendroglial components that are supposed to present calcifications. Since calcifications and blood deposits are difficult to differentiate using conventional MRI, we investigated whether a new post-processing approach, quantitative susceptibility mapping (QSM), is able to distinguish between both entities reliably. MATERIALS AND METHODS: SWI, FLAIR, and T1-w images were acquired from 46 patients with glioblastoma (14 newly diagnosed, 24 treated with radiochemotherapy, 8 treated with radiochemotherapy and additional anti-angiogenic medication). Susceptibility maps were calculated from SWI data. All glioblastoma were evaluated for the appearance of hypointense or hyperintense correlates of SBS on the susceptibility maps. RESULTS: 43 of 46 glioblastoma presented only hyperintense intratumoral SBS on susceptibility maps, indicating blood deposits. Additional hypointense correlates of tumor-related SBS on susceptibility maps, indicating calcification, were identified in 2 patients being treated with radiochemotherapy and in one patient being treated with additional anti-angiogenic medication. Histopathologic reports revealed an oligodendroglial component in one patient that presented calcifications on susceptibility maps. CONCLUSIONS: QSM provides a quantitative, local MRI contrast, which reliably differentiates between blood deposits and calcifications. Thus, quantitative susceptibility mapping appears promising to identify rare variants of glioblastoma with oligodendroglial components non-invasively and may allow monitoring the role of calcification in the context of different therapy regimes.

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

Quantitative 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.

Detection of cerebral microbleeds with quantitative susceptibility mapping in the ArcAbeta mouse model of cerebral amyloidosis.

Cerebral microbleeds (CMBs) are findings in patients with neurological disorders such as cerebral amyloid angiopathy and Alzheimer's disease, and are indicative of an underlying vascular pathology. A diagnosis of CMBs requires an imaging method that is capable of detecting iron-containing lesions with high sensitivity and spatial accuracy in the presence of potentially confounding tissue abnormalities. In this study, we investigated the feasibility of quantitative magnetic susceptibility mapping (QSM), a novel technique based on gradient-recalled echo (GRE) phase data, for the detection of CMBs in the arcAß mouse, a mouse model of cerebral amyloidosis. Quantitative susceptibility maps were generated from phase data acquired with a high-resolution T(2)(*)-weighted GRE sequence at 9.4 T. We examined the influence of different regularization parameters on susceptibility computation; a proper adjustment of the regularization parameter minimizes streaking artifacts and preserves fine structures. In the present study, it is shown that QSM provides increased detection sensitivity of CMBs and improved contrast when compared with GRE magnitude imaging. Furthermore, QSM corrects for the blooming effect observed in magnitude and phase images and depicts both the localization and spatial extent of CMBs with high accuracy. Therefore, QSM may become an important tool for diagnosing CMBs in neurological diseases.

Quantitative imaging of intrinsic magnetic tissue properties using MRI signal phase: an approach to in vivo brain iron metabolism?

Quantitative susceptibility mapping (QSM) based on gradient echo (GRE) magnetic resonance phase data is a novel technique for non-invasive assessment of magnetic tissue susceptibility differences. The method is expected to be an important means to determine iron distributions in vivo and may, thus, be instrumental for elucidating the physiological role of iron and disease-related iron concentration changes associated with various neurological and psychiatric disorders. This study introduces a framework for QSM and demonstrates calculation of reproducible and orientation-independent susceptibility maps from GRE data acquired at 3T. The potential of these susceptibility maps to perform anatomical imaging is investigated, as well as the ability to measure the venous blood oxygen saturation level in large vessels, and to assess the local tissue iron concentration. In order to take into account diamagnetic susceptibility contributions induced by myelin, a correction scheme for susceptibility based iron estimation is demonstrated. The findings suggest that susceptibility contrast, and therewith also phase contrast, are not only linked to the storage iron concentration but are also significantly influenced by other sources such as myelin. After myelin correction the linear dependence between magnetic susceptibilities and previously published iron concentrations from post mortem studies was significantly improved. Finally, a comparison between susceptibility maps and processed phase images indicated that caution should be exercised when drawing conclusions about iron concentrations when directly assessing processed phase information.

Differentiation between diamagnetic and paramagnetic cerebral lesions based on magnetic susceptibility mapping.

PURPOSE: Identification of calcifications and hemorrhages is essential for the etiological diagnosis of cerebral lesions. The purpose of this work was to develop a robust method for characterization of para- and diamagnetic intracerebral lesions based on clinical gradient-echo magnetic resonance phase data acquired at 1.5 Tesla. METHODS: The magnetic susceptibility distribution of biological tissue produces a distinct magnetic field pattern, which is directly reflected in gradient-echo magnetic resonance phase images. Compared to brain parenchyma, iron-laden tissues are more paramagnetic, whereas mineralized tissues usually possess more diamagnetic susceptibilities. Magnetic resonance phase data were inverted to the underlying susceptibility distribution utilizing additional geometrical information about the lesions, which was obtained from the gradient-echo magnitude signal void corresponding to the lesions. Clinical magnetic resonance exams of three patients with multiple brain lesions (total n = 70) were processed and evaluated. For one patient, the results were validated by an additionally available computed tomography scan. Numerical simulations were conducted to evaluate the robustness of the method. RESULTS: The obtained susceptibility maps showed impressive delineation of lesions, vessels, and potentially iron-laden tissue. Compensation of the nonlocal field perturbations was clearly discernable on the susceptibility maps. In all cases, discrimination of para- from diamagnetic lesions was achieved and the results were confirmed by the additional computed tomography. The numerical simulations demonstrated that robust determination of the total magnetic moment of lesions is possible. Thus, the proposed method is able to yield quantitative values for the minimum magnetic susceptibility of lesions. CONCLUSIONS: A method has been developed for noninvasive, semiautomatic characterization of brain lesions based on magnetic resonance imaging data. Initial clinical results demonstrated that the proposed technique can be applied to diagnosis of lesions with calcifications or hemorrhages. If confirmed by larger studies, it bears the potential to obviate the need for confirmation with computed tomography.

Investigation of the influence of carbon dioxide concentrations on cerebral physiology by susceptibility-weighted magnetic resonance imaging (SWI).

Breathing carbogen (5% CO2 / 95% O2) dramatically increases cerebral blood flow (CBF), which induces a blood oxygenation level dependent (BOLD) related vascular signal change due to the concomitantly increased oxyhemoglobin concentration in the veins. However, carbogen often causes discomfort due to its forced strong and deep breathing which also may lead to severe motion artifacts in magnetic resonance imaging. In this study, susceptibility-weighted imaging (SWI) was performed with CO2 levels of 0, 1.67%, 3.33% and 5% to measure the induced BOLD signal changes in venous vessels and brain tissue. Susceptibility-weighted imaging data from 15 healthy subjects and one patient with a brain tumor were acquired. The signal magnitude of cortical veins increased relative to pure oxygen by 3.5+/-3.8%, 10.3+/-4.5%, and 22.7+/-8.8% for CO2 concentrations of 1.67%, 3.33%, and 5%, respectively. Significant signal changes were detected in segmented white matter for 5% CO2, and gray matter for both 3.3% and 5% CO2. The influence of motion artifacts was clearly traceable by the broadening of the signal distribution in segmented tissue. Heterogeneous signal changes were observed in the patient for the same tumor regions at both 3.33% and 5% CO2. Signal phase values of white and gray matter changed only very slightly with increasing CO2. Based on our findings we recommend the reduction of CO2 concentration to about 3% when using a mixture of O2 and CO2. All subjects also reported highly improved breathing comfort at 3.3% CO2 as compared to 5%. The marginal phase change of white and gray matter supports the assumption that deoxygenated blood alone does not explain the commonly observed phase difference between the two tissues.

Detection of multiple intracranial hemorrhages in a child with acute lymphocytic leukemia (ALL) by susceptibility weighted imaging (SWI).

Susceptibility weighted imaging (SWI) combines magnitude and phase information from a high-resolution, fully velocity compensated, three-dimensional (3D) gradient echo sequence. We report on the use of this MRI technique in a young patient with acute lymphocytic leukemia (ALL) and demonstrate a higher detection rate of hemorrhagic lesion in comparison with other T2*-weighted sequences.

Susceptibility weighted imaging: data acquisition, image reconstruction and clinical applications.

Susceptibility-weighted imaging (SWI) is a novel method, that combines magnitude and phase information from a high-resolution, fully velocity compensated 3D T2-weighted gradient echo sequence. Phase images are unwrapped and high pass filtered to highlight phase changes associated with venous vessels and converted into a mask that is multiplied with the corresponding phase image. This technique has been applied thus far to the imaging of tumors, vascular malformations, trauma, stroke, micro-hemorrhages, and as a functional imaging method. The purpose of this paper is to present an overview of the current status of the technique and to illustrate its potential.

Demonstration of paramagnetic and diamagnetic cerebral lesions by using susceptibility weighted phase imaging (SWI).

Susceptibility-weighted MR imaging (SWI) has become a non-invasive diagnostic modality for functional MR imaging (fMRI) of the brain and also for the imaging of tumors, injuries, malformations or microhemorrhages. SWI often enables detection of otherwise subtle abnormalities or provides additional relevant information when combined with routine MR imaging. The purpose of this article is to illustrate the potential of SWI in the discrimination of paramagnetic and diamagnetic brain lesions in neuroradiological applications.