Positive visualization of implanted devices with susceptibility gradient mapping using the original resolution.

In magnetic resonance imaging, implantable devices are usually visualized with a negative contrast. Recently, positive contrast techniques have been proposed, such as susceptibility gradient mapping (SGM). However, SGM reduces the spatial resolution making positive visualization of small structures difficult. Here, a development of SGM using the original resolution (SUMO) is presented. For this, a filter is applied in k-space and the signal amplitude is analyzed in the image domain to determine quantitatively the susceptibility gradient for each pixel. It is shown in simulations and experiments that SUMO results in a better visualization of small structures in comparison to SGM. SUMO is applied to patient datasets for visualization of stent and prostate brachytherapy seeds. In addition, SUMO also provides quantitative information about the number of prostate brachytherapy seeds. The method might be extended to application for visualization of other interventional devices, and, like SGM, it might also be used to visualize magnetically labelled cells.

Monitoring of bevacizumab-induced antiangiogenic treatment effects by "steady state" ultrasmall superparamagnetic iron oxide particles magnetic resonance imaging using robust multiecho ΔR2* relaxometry.

RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate whether "steady state" magnetic resonance imaging (MRI) using a robust multiecho ΔR2* MR relaxometry technique is suitable for the early assessment of a clinically approved antiangiogenic treatment regimen using bevacizumab (Avastin). METHODS: A673 rhabdomyosarcoma-bearing mice were treated with bevacizumab (n = 6) or saline as control, respectively (n = 6). MRI using a multigradient echo sequence was performed before and after 2 doses of 100 µg bevacizumab at baseline and day 7. Ultrasmall superparamagnetic iron oxide particles (SH U 555 C) induced changes of the transverse relaxation rate R2* (ΔR2*) were measured in regions of interest. From these results, the vascular volume fraction was estimated, providing a surrogate marker for the microvessel density (MVD). The actual MVD was determined by immunohistochemistry and correlated with the MRI results. RESULTS: Bevacizumab treatment resulted in a significant reduction of the ΔR2* values compared with the control group (bevacizumab: 10.47 ± 0.78 seconds(-1) vs. control: 17.91 ± 2.63 seconds(-1); P = 0.01), reflecting the significant decrease of the vascular volume fraction by 33% (bevacizumab: 2.21% ± 0.15% vs. control: 3.31% ± 0.22%; P = 0.001). Immunohistochemistry confirmed the MR results showing an approximately 25% reduction of the MVD after treatment (bevacizumab: 7.11 ± 0.3 vs. control: 9.45 ± 0.38; P = 0.001). CONCLUSION: Multiecho ΔR2* MR relaxometry allows an early and quantitative assessment of tumor vascularization changes in response to an antiangiogenic treatment with a clinically approved vascular endothelial growth factor inhibitor. With the availability of long circulating ultrasmall superparamagnetic iron oxide particles s for clinical use, this imaging technique could be instantly translated to antiangiogenic treatment monitoring in clinical studies.

Fast T(2) relaxometry with an accelerated multi-echo spin-echo sequence.

A new method has been developed to reduce the number of phase-encoding steps in a multi-echo spin-echo imaging sequence allowing fast T(2) mapping without loss of spatial resolution. In the proposed approach, the k-space data at each echo time were undersampled and a reconstruction algorithm that exploited the temporal correlation of the MR signal in k-space was used to reconstruct alias-free images. A specific application of this algorithm with multiple-receiver acquisition, offering an alternative to existing parallel imaging methods, has also been introduced. The fast T(2) mapping method has been validated in human brain T(2) measurements in a group of nine volunteers with acceleration factors up to 3.4. The results demonstrated that the proposed method exhibited excellent linear correlation with the regular T(2) mapping with full sampling and achieved better image reconstruction and T(2) mapping with respect to SNR and reconstruction artifacts than the selected reference acceleration techniques. The new method has also been applied for quantitative tracking of injected magnetically labeled breast cancer cells in the rat brain with acceleration factors of 1.8 and 3.0. The proposed technique can provide an effective approach for accelerated T(2) quantification, especially for experiments with single-channel coil when parallel imaging is not applicable.

Quantification of the magnetic resonance signal response to dynamic (C)O(2)-enhanced imaging in the brain at 3 T: R*(2) BOLD vs. balanced SSFP.

PURPOSE: To compare two magnetic resonance (MR) contrast mechanisms, R*(2) BOLD and balanced SSFP, for the dynamic monitoring of the cerebral response to (C)O(2) respiratory challenges. MATERIALS AND METHODS: Carbogen and CO(2)-enriched air were delivered to 9 healthy volunteers and 1 glioblastoma patient. The cerebral response was recorded by two-dimensional (2D) dynamic multi-gradient-echo and passband-balanced steady-state free precession (bSSFP) sequences, and local changes of R*(2) and signal intensity were investigated. Detection sensitivity was analyzed by statistical tests. An exponential signal model was fitted to the global response function delivered by each sequence, enabling quantitative comparison of the amplitude and temporal behavior. RESULTS: The bSSFP signal changes during carbogen and CO(2)/air inhalation were lower compared with R*(2) BOLD (ca. 5% as opposed to 8-13%). The blood-oxygen-level-dependent (BOLD) response amplitude enabled differentiation between carbogen and CO(2)/air by a factor of 1.4-1.6, in contrast to bSSFP, where differentiation was not possible. Furthermore, motion robustness and detection sensitivity were higher for R*(2) BOLD. CONCLUSION: Both contrast mechanisms are well suited to dynamic (C)O(2)-enhanced MR imaging, although the R*(2) BOLD mechanism was demonstrated to be superior in several respects for the chosen application. This study suggests that the R*(2) BOLD and bSSFP-response characteristics are related to different physiologic mechanisms.

Tumor blood volume determination by using susceptibility-corrected DeltaR2* multiecho MR.

PURPOSE: To evaluate a susceptibility-corrected multiecho magnetic resonance (MR) relaxometry technique for an accurate and robust determination of DeltaR2* as a noninvasive surrogate parameter of the perfused tumor blood volume. MATERIALS AND METHODS: All experiments were approved by the institutional animal care committee. In a glass tube phantom with different superparamagnetic iron oxide (SPIO) particle concentrations and at tumor mice xenografts with DU-4475, HT-1080, and MDA-MB-435 tumors (n = 15 total, n = 5 per model) with different degrees of neovascularization after injection of different ultrasmall SPIO (USPIO) doses changes of the transverse relaxation rate (DeltaR2*) were determined by using a fixed echo time (TE) of 22 msec and a susceptibility-corrected multigradient-echo technique. The mean DeltaR2* value and the vascular volume fraction (VVF) of each tumor was determined and compared with independent in vivo fluorescent tumor perfusion measurements and histologic analysis helped determine microvessel density (MVD). Statistical differences were tested by using analysis of variance and linear correlations. RESULTS: For the phantom study, DeltaR2* maps calculated with a fixed TE of 22 msec showed a higher standard deviation of the noise index compared with the susceptibility-corrected multiecho technique. For the xenograft model, mean tumor DeltaR2* values (+/- standard error of the mean) showed significant differences between the various tumors (eg, DU-4475: 12.3 sec(-1) +/- 2.67, HT-1080: 36.47 sec(-1) +/- 5.84, and MDA-MB-435: 64.01 sec(-1) +/- 8.87 at 80 mumol of iron per kilogram; P < .05). DeltaR2* values increased dose dependently and in a linear fashion, resulting in reproducibly stable VVF measurements. Fluorescent tumor perfusion measurements and MVD counts corroborated the MR results. CONCLUSION: Susceptibility-corrected multiecho MR relaxometry allows a highly accurate and robust determination of DeltaR2* and VVF with an excellent dynamic range for tumor characterization at clinically relevant doses of USPIO.

Utilizing different methods for visualizing susceptibility from a single multi-gradient echo dataset.

PURPOSE: Objects that cause a susceptibility gradient can generate regions of hypo-intensity in MRI. MR techniques developed for positive enhancement of such objects require sequence parameter optimization. Thus comparison of images acquired successively using different techniques is difficult since different parameter settings result in variations in signal and noise. A new method is presented that allows production of positive contrast images, a relaxation rate R*2-map and negative contrast images from a single dataset by post-processing. METHODS: Positive contrast techniques considered include the "white marker" technique, inversion-recovery on-resonance (IRON) and susceptibility gradient mapping (SGM). The new method was tested in phantoms of iron-oxide agent gel solutions and prostate marker seeds. Images produced by post-processing were compared with those obtained directly. The post-processing technique was applied in vivo for the visualization of iron-oxide contrast agent uptake in a balloon-injured swine carotid model. RESULTS: The images produced in the post-processing step allowed determination of optimal parameter settings for each technique. SGM was found to provide the greatest positive contrast, whilst the T*2-weighted images provide more sensitivity to regions that exhibited weaker susceptibility effects. CONCLUSIONS: Combined T*2-weighted imaging and SGM using the same complex image data was found to provide complementary information and high sensitivity to detect distortion inducing agents.

Iterative off-resonance and signal decay estimation and correction for multi-echo MRI.

Signal dephasing due to field inhomogeneity and signal decay due to transverse relaxation lead to perturbations of the Fourier encoding commonly applied in magnetic resonance imaging. Hence, images acquired with long readouts suffer from artifacts such as blurring, distortion, and intensity variation. These artifacts can be removed in reconstruction, usually based on separately collected information in form of field and relaxation maps. In this work, a recently proposed gridding-based algorithm for off-resonance correction is extended to also address signal decay. It is integrated into a new fixed-point iteration, which permits the joint estimation of an image and field and relaxation maps from multi-echo acquisitions. This approach is then applied in simulations and in vivo experiments and demonstrated to improve both images and maps. The rapid convergence of the fixed-point iteration in combination with the efficient gridding-based correction promises to render the running time of such a joint estimation acceptable.

Ultrashort T2* relaxometry for quantitation of highly concentrated superparamagnetic iron oxide (SPIO) nanoparticle labeled cells.

A new method was developed to measure ultrashort T(2)* relaxation in tissues containing a focal area of superparamagnetic iron oxide (SPIO) nanoparticle-labeled cells in which the T(2)* decay is too short to be accurately measured using regular gradient echo T(2)* mapping. The proposed method utilizes the relatively long T(2) relaxation of SPIO-labeled cells and acquires a series of spin echo images with the readout echo shifted to sample the T(2)* decay curve. MRI experiments in phantoms and rats with SPIO-labeled tumors demonstrated that it can detect ultrashort T(2)* down to 1 ms or less. The measured T(2)* values were about 10% higher than those from the ultrashort TE (UTE) technique. The shorter the TE, the less the measurements deviated from the UTE T(2)* mapping. Combined with the regular T(2)* mapping, this technique is expected to provide quantitation of highly concentrated iron-labeled cells from direct cell transplantation.

Susceptibility gradient mapping (SGM): a new postprocessing method for positive contrast generation applied to superparamagnetic iron oxide particle (SPIO)-labeled cells.

Local susceptibility gradients result in a dephasing of the precessing magnetic moments and thus in a fast decay of the NMR signals. In particular, cells labeled with superparamagnetic iron oxide particles (SPIOs) induce hypointensities, making the in vivo detection of labeled cells from such a negative image contrast difficult. In this work, a new method is proposed to selectively turn this negative contrast into a positive contrast. The proposed method calculates the susceptibility gradient and visualizes it in a parametric map directly from a regular gradient-echo image dataset. The susceptibility gradient map is determined in a postprocessing step, requiring no dedicated pulse sequences or adaptation of the sequence before and during image acquisition. Phantom experiments demonstrated that local susceptibility differences can be quantified. In vivo experiments showed the feasibility of the method for tracking of SPIO-labeled cells. The method bears the potential also for usage in other applications, including the detection of contrast agents and interventional devices as well as metal implants.

Magnetic resonance imaging and spectroscopy.

Magnetic resonance imaging (MRI) and spectroscopy (MRS) are noninvasive techniques that allow the characterization of morphology, physiology and metabolism in vivo. MRI and MRS have become techniques of choice in many pre-clinical and clinical applications. In this chapter, the basic principles and the instrumentation of MRI and MRS are described. Furthermore, the factors that influence the sensitivity are discussed and examples for the limit of contrast agent detection are given.

In vivo MRI using positive-contrast techniques in detection of cells labeled with superparamagnetic iron oxide nanoparticles.

Positive-contrast techniques are being developed to increase the detection of magnetically labeled cells in tissues. We evaluated a post-processing positive-contrast technique, susceptibility-gradient mapping (SGM), and compared this approach with two pulse sequences, a gradient-compensation-based "White Marker" technique and an off-resonance-based approach, inversion recovery on-resonance water suppression (IRON), for the detection of superparamagnetic iron oxide (SPIO) nanoparticle-labeled C6 glioma cells implanted in the flanks of nude rats. The SGM, White Marker and IRON positive-contrast images were acquired when the labeled C6 glioma tumors were approximately 5 mm (small), approximately 10 mm (medium) and approximately 20 mm (large) in diameter along the largest dimension to evaluate their sensitivity to the dilution of the SPIO nanoparticles as the tumor cells proliferated. In vivo MRI demonstrated that all three positive-contrast techniques can produce hyperintensities in areas around the labeled flank tumors against a dark background. The number of positive voxels detected around small and medium tumors was significantly greater with the SGM technique than with the White Marker and IRON techniques. For large tumors, the SGM resulted in a similar number of positive voxels to the White Marker technique, and the IRON approach failed to generate positive-contrast images with a 200 Hz suppression band. This study also reveals that hemorrhage appears as hyperintensities on positive-contrast images and may interfere with the detection of SPIO-labeled cells.

R2 and R2* mapping for sensing cell-bound superparamagnetic nanoparticles: in vitro and murine in vivo testing.

PURPOSE: To prospectively determine the cellular iron uptake by using R2 and R2* mapping with multiecho readout gradient-echo and spin-echo sequences. MATERIALS AND METHODS: All experiments were approved by the institutional animal care committee. Lung carcinoma cells were lipofected with superparamagnetic iron oxides (SPIOs). Agarose gel phantoms containing (a) 1 x 10(5) CCL-185 cells per milliliter of agarose gel with increasing SPIO load (0.01-5.00 mg of iron per milliliter in the medium), (b) different amounts (5.0 x 10(3) to 2.5 x 10(5) cells per milliliter of agarose gel) of identically loaded cells, and (c) free (non-cell-bound) SPIOs at the iron concentrations described for (b) were analyzed with 3.0-T R2 and R2* relaxometry. Iron uptake was analyzed with light microscopy, quantified with atomic emission spectroscopy (AES), and compared with MR data. For in vivo relaxometry, agarose gel pellets containing SPIO-labeled cells, free SPIO, unlabeled control cells, and pure agarose gel were injected into three nude mice each. Linear and nonlinear regression analyses were performed. RESULTS: Light microscopy and AES revealed efficient SPIO particle uptake (mean uptake: 0.22 pg of iron per cell +/- 0.1 [standard deviation] for unlabeled cells, 31.17 pg of iron per cell +/- 4.63 for cells incubated with 0.5 mg/mL iron). R2 and R2* values were linearly correlated with cellular iron load, number of iron-loaded cells, and content of freely dissolved iron (r(2) range, 0.92-0.99; P < .001). For cell-bound SPIO, R2* effects were significantly greater than R2 effects (P < .01); for free SPIO, R2 and R2* effects were similar. In vivo relaxometry enabled accurate prediction of the number of labeled cells. R2' (R2* - R2) mapping enabled differentiation between cell-bound and free iron in vitro and in vivo. CONCLUSION: Quantitative R2 and R2* mapping enables noninvasive estimations of cellular iron load and number of iron-labeled cells. Cell-bound SPIOs can be differentiated from free SPIOs with R2' imaging.

In vivo magnetic resonance imaging of iron oxide-labeled, arterially-injected mesenchymal stem cells in kidneys of rats with acute ischemic kidney injury: detection and monitoring at 3T.

PURPOSE: To evaluate MRI for a qualitative and quantitative in vivo tracking of intraaortal injected iron oxide-labeled mesenchymal stem cells (MSC) into rats with acute kidney injury (AKI). MATERIALS AND METHODS: In vitro MRI and R2* measurement of nonlabeled and superparamagnetic iron oxide (SPIO)-labeled MSC (MSC(SPIO)) was performed in correlation to cellular iron content and cytological examination (Prussian blue, electron microscopy). In vivo MRI and R2* evaluation were performed before and after ischemic/reperfusion AKI (N = 14) and intraaortal injection of 1.5 x 10(6) MSC(SPIO) (N = 7), fetal calf serum (FCS) (medium, N = 6), and SPIO alone (N = 1) up to 14 days using a clinical 3T scanner. Signal to noise ratios (SNR), R2* of kidneys, liver, spleen, and bone marrow, renal function (creatinine [CREA], blood urea nitrogen [BUN]), and kidney volume were measured and tested for statistical significance (Student's t-test, P < 0.05) in comparison histology (hematoxylin and eosin [H&E], Prussian blue, periodic acid-Schiff [PAS], CD68). RESULTS: In vitro, MSC(SPIO) showed a reduction of SNR and T2* with R2* approximately number of MSC(SPIO) (R2 = 0.98). In vivo MSC(SPIO) administration resulted in a SNR decrease (35 +/- 15%) and R2* increase (101 +/- 18.3%) in renal cortex caused by MSC(SPIO) accumulation in contrast to control animals (P < 0.01). Liver, spleen, and bone marrow (MSC(SPIO)) showed a delayed SNR decline/R2* increase (P < 0.05) resulting from MSC(SPIO) migration. The increase of kidney volume and the decrease in renal function (P < 0.05) was reduced in MSC-treated animals. CONCLUSION: Qualitative and quantitative in vivo cell-tracking and monitoring of organ distribution of intraaortal injected MSC(SPIO) in AKI is feasible in MRI at 3T.

Online recording of ethane traces in human breath via infrared laser spectroscopy.

A method is described for rapidly measuring the ethane concentration in exhaled human breath. Ethane is considered a volatile marker for lipid peroxidation. The breath samples are analyzed in real time during single exhalations by means of infrared cavity leak-out spectroscopy. This is an ultrasensitive laser-based method for the analysis of trace gases on the sub-parts per billion level. We demonstrate that this technique is capable of online quantifying of ethane traces in exhaled human breath down to 500 parts per trillion with a time resolution of better than 800 ms. This study includes what we believe to be the first measured expirograms for trace fractions of ethane. The expirograms were recorded after a controlled inhalation exposure to 1 part per million of ethane. The normalized slope of the alveolar plateau was determined, which shows a linear increase over the first breathing cycles and ends in a mean value between 0.21 and 0.39 liter-1. The washout process was observed for a time period of 30 min and was modelled by a threefold exponential decay function, with decay times ranging from 12 to 24, 341 to 481, and 370 to 1770 s. Our analyzer provides a promising noninvasive tool for online monitoring of the oxidative stress status.