Investigation of atherosclerotic plaques with MRI at 3 T using ultrasmall superparamagnetic particles of iron oxide

This study aims to investigate the uptake of the experimental ultrasmall superparamagnetic particles of iron oxide (USPIO) contrast agent DDM43/34 (Schering AG, Berlin, Germany) by aortic atherosclerotic plaques using magnetic resonance imaging (MRI) at 3 T. Six Watanabe heritable hyperlipidemic rabbits were injected with USPIO at doses of 0.1–1.0 mmol/kg Fe. Parasagittal magnetic resonance angiography (MRA) scans were acquired using 3D gradient-echo sequences before and after USPIO administration, then again after 6 h, 1 day, 2 days and 5 days. At later time points, when the USPIO concentration was too low to enhance blood signal, additional MRA scans were acquired during the infusion of gadopentate dimeglumine (Magnevist; Schering AG). In the images, widespread susceptibility artifacts demonstrated readily detectable USPIO uptake in the liver, bone marrow and lymphatic vessels. Surprisingly, however, no such effects could be associated specifically with the aortic vessel wall, in contrast to previous studies that showed strong uptake with similar pulse sequences. Histological analysis was performed on aortic slices from two animals, demonstrating that aortic plaques were active but showed very little USPIO uptake, consistent with MRI findings. We conclude that, despite the exciting potential of plaque detection using USPIO, some caution is advised since the absence of susceptibility effects does not necessarily imply the absence of plaque, even at 3 T, which offers increased sensitivity to susceptibility. Future work will investigate the dependence of such results on stage of plaque development, magnetic field strength and choice of contrast agent.     

MR imaging of murine arthritis using ultrasmall superparamagnetic iron oxide particles.

The objective of this work was to determine the ability of magnetic resonance (MR) imaging with ultrasmall superparamagnetic iron oxide (USPIO) particles to provide quantitative measures of inflammation in autoimmune arthritis.Mice were injected intravenously or intra-articularly with USPIO followed by magnetic resonance and histological assessment of the knee joint. Comparisons were made between MR microimages and histology in na?ve mice and mice with collagen-induced arthritis.Following intravenous administration, accumulation of USPIO was observed in the popliteal lymph nodes, but not the joint. Administration of USPIO intra-articularly resulted in signal loss in the joint. The MR signal intensity could be quantified and correlated with iron staining in the synovial lining. A marked increase in USPIO uptake and a corresponding decrease in signal intensity were observed in arthritic, compared to na?ve mice. Areas of focal signal loss corresponded to foci of iron staining by histology.These studies may provide a basis for the clinical application of USPIO in arthritis for assessing disease severity and monitoring response to therapy.     

Magnetic resonance imaging with superparamagnetic iron oxide particles for the detection of myocardial reperfusion

The effect of superparamagnetic iron oxide particles on magnetic resonance myocardial signal intensity was examined in order to define the ability of this agent to identify normal, ischemic, and reperfused myocardium. Data were obtained from 6 normal rats (group 1) and from 6 heterotopic isogenic rat heart transplants (group 2) at 4.7 T with a multislice spin-echo sequence. Images were acquired in (a) normal rats before and after the infusion of 36 μmol Fe/kg of AMI-25 (group 1) and (b) rat heart transplants during control, global myocardial ischemia (before and after the injection of 72 μmol Fe/kg of AMI-25), and following reperfusion (group 2). Myocardial signal intensity decreased by 36 ± 4%, p < 0.001, following contrast infusion in normal hearts (group 1). The intensity remained constant in the rat heart transplants (group 2) during coronary occlusion, both before and after the infusion of AMI-25 and decreased by 61 ± 7%, p < 0.001, upon reperfusion. The larger effect of AMI-25 in reperfused as compared to normal myocardium suggests the presence of ischemia-induced hyperemia. There was no significant difference (analysis of variance) among intensities from different myocardial regions in either group at any stage of the experiment. We conclude that the use of AMI-25 permits identification of normal, ischemic, and reperfused myocardium and may therefore be helpful for the early detection of reperfusion following thrombolytic therapy for acute myocardial infarction.     

Magnetization transfer MRI of mouse brain reveals areas of high neural density

Extending applications of magnetization transfer contrast (MTC) in magnetic resonance imaging (MRI) of the human central nervous system, this work quantitatively describes MTC of the murine brain. As a novel finding, complementing T₁- and T₂-weighted MRI, MTC allows for the distinction of densely packed gray matter from normal gray and white matter. Examples include the Purkinje cell layer and the granular cell layer in the mouse cerebellum as well as the delineation of the CA3 subfield of the hippocampus relative to surrounding hippocampal gray matter and white matter tracts such as the hippocampal fimbria. Using a kainate lesion model, the CA3 hyperintensities in MTC and T₁-weighted MRI are assigned to the densely packed somata of pyramidal cells.     

MRI with superparamagnetic iron oxide: efficacy in the detection and characterization of focal hepatic lesions

The purpose of this study was to evaluate the potential of superparamagnetic iron oxide particles (SPIO) as tissue specific contrast agent in magnetic resonance (MR) imaging in detection and characterization of focal hepatic lesions. We investigated 45 patients with focal hepatic lesions. T1-weighted SE (TR 650/TE 15 ms) and T2-weighted SE (TR 2015-2030/TE 45 and 90 ms) unenhanced images were obtained. After SPIO application we performed T1-weighted images with and T2-weighted images with and without fat suppression using the same image parameters. Liver signal intensity decreased by 74% (min 47%, max 83%) on T2-weighted images after application of the contrast agent. Benign lesions (FNH, adenoma) showed an average signal drop of 40% (min 20%, max 47%) whereas malignant lesions showed no significant change of signal intensity on post-contrast images. The mean tumor-to-liver contrast-to-noise ratio (C/N) was improved in all post-contrast sequences irrespective of the lesion type. An additional increase of tumor-to-liver contrast by use of fat suppression technique could be established in the slightly T2-weighted sequence (TE 45 ms). In metastases, divided in different size groups, we could determine a significant size relation of tumor-to-liver C/N. After SPIO application the number of detected lesions increased distinctly, especially small foci are more easily demonstrated. SPIO particles are a efficacious contrast agent for MR examinations of the liver. For tumor characterization T1- and T2-weighted pre- and post-contrast images are necessary. The T1-weighted sequences are helpful to differentiate benign lesions such as cysts and hemangiomas from malignant lesions. Detection and differential diagnoses of hepatic lesions are improved by use of the SPIO-particles.     

Studies of anisotropy mechanisms in polyphosphate-treated magnetic iron oxide particles

The coercive force of small, acicular ( 2000 Å length, 8:1 length-to-diameter ratio) spinel-type iron oxide particles increases substantially following surface treatment with sodium polyphosphate. Regardless of Fe²⁺/Fe³⁺ cation ratio, H_c always attains a peak value when the polyphosphate/iron oxide weight ratio P/Fe is in the range 0.5–0.6, denoted (P/Fe)_max. The maximum change in H_c is observed when Fe²⁺/Fe³⁺ ≈ 0.10–0.15. When P/Fe0.5–0.6, however, both magnitude and sign of the change in coercive force show strong dependence on the Fe²⁺ content of the oxide, suggesting that the H_c changes are caused by a magnetostrictive mechanism at these high treatment ratios. Calculated anisotropy field distributions of treated specimens show that both the mean anisotropy field δH_kδ_G and predicted H_c reach a peak when particles are treated at (P/Fe)_max, where the distribution becomes very broad. At high treatment ratios both δH_kδ_G and predicted H_c decrease to values below that of the untreated oxide. Mössbauer studies of treated and untreated particles show no significant change in the environment of surface iron ions following treatement at P/FE = 0.5, but indicate a small increase in the Fe³⁺ concentration of the particle core. When P/Fe = 2.5, however, the Fe²⁺ concentration of the core increases markedly.     

Traveling Internal Plane-wave Synthesis (TIPS) for uniform B1 in high field MRI

A new target-field approach to generating uniform radio frequency (RF) fields within the human body for high field MRI is described. The method involves producing a set of external fields which, after interaction with a dielectric object, superimpose to produce a traveling plane wave, exposing all spins to the same RF amplitude (B1) over a cycle of the harmonic field. Conceptually this is similar to conventional RF shimming, but uses a different RF source design, input data, and objective function. The method requires a detailed knowledge of the coupling between exterior field modes, produced by an array of RF sources, and field modes within the body. Given an estimate of the coupling matrix, the linear superposition of external modes that produces a desired internal target field can be determined. The new method is termed Traveling Internal Plane-wave Synthesis (TIPS). A simple design of a coil array is described that can, in principle, generate the required field modes. Simulations demonstrate that radio frequency magnetic fields of nearly uniform (< 1% variation) magnitude can be produced within dielectric objects larger than a wavelength in size. If the dielectric medium has non-zero conductivity, traveling waves are attenuated as they traverse the object, but field uniformity within planar slices is preserved. For general 3D imaging, a superposition of plane waves can provide field focusing to balance conductive losses, thereby achieving nearly uniform-magnitude B1+ magnetic fields over a volume of interest.     

MRI detection of tumor in mouse lung using partial liquid ventilation with a perfluorocarbon-in-water emulsion

Transverse relaxation time (T(2*))-weighted (1)H-MRI of mouse lungs has been performed using partial liquid ventilation (PLV) with a perfluorocarbon (PFC)-in-water emulsion as a contrast modality for lung MRI. Significant sensitivity enhancement in MRI of mouse lungs has been demonstrated with the protocol. The results show that the T(2*) value in lung is approximately proportional to the infusion dose up to a dose of 5 ml/kg body weight (BW) (4.5 g PFC/kg BW) and becomes essentially constant beyond this dosage. T(2*) maps of lungs have been calculated and T(2*) in lungs is in the range of 10-35 ms with this technique, which is an order of magnitude greater than the T(2*) value of mouse lungs without using a PFC-in-water emulsion. T(2*)-weighted (1)H-MR images of mouse lungs have been obtained with good quality under our experimental conditions. We have applied this technique to detect tumors in mouse lungs. Our technique can detect small lung tumors of B16 melanoma, about 1 mm in diameter, in mice. With its significant MR sensitivity enhancement and technical simplicity, T(2*)-weighted (1)H-MRI using PLV with PFC-in-water emulsion offers a promising approach to investigate lung cancers using rodent models.     

Reproducibility and biases in high field brain diffusion MRI: An evaluation of acquisition and analysis variables

Diffusion tensor imaging (DTI) of in-vivo human brain provides insights into white matter anatomical connectivity, but little is known about measurement difference biases and reliability of data obtained with last generation high field scanners (> 3 T) as function of MRI acquisition and analyses variables. Here we assess the impact of acquisition (voxel size: 1.8 × 1.8 × 1.8, 2 × 2 × 2 and 2.5 × 2.5 × 2.5 mm³, b-value: 700, 1000 and 1300 s/mm²) and analysis variables (within-session averaging and co-registration methods) on biases and test-retest reproducibility of some common tensor derived quantities like fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivity in a group of healthy subjects at 4 T in three regions: arcuate fasciculus, corpus callosum and cingulum. Averaging effects are also evaluated on a full-brain voxel based approach. The main results are: i) group FA and MD reproducibility errors across scan sessions are on average double of those found in within-session repetitions (≈ 1.3 %), regardless of acquisition protocol and region; ii) within-session averaging of two DTI acquisitions does not improve reproducibility of any of the quantities across sessions at the group level, regardless of acquisition protocol; iii) increasing voxel size biased MD, axial and radial diffusivities to higher values and FA to lower values; iv) increasing b-value biased all quantities to lower values, axial diffusivity showing the strongest effects; v) the two co-registration methods evaluated gave similar bias and reproducibility results. Altogether these results show that reproducibility of FA and MD is comparable to that found at lower fields, not significantly dependent on pre-processing and acquisition protocol manipulations, but that the specific choice of acquisition parameters can significantly bias the group measures of FA, MD, axial and radial diffusivities.     

How size evaluation of lymph node is protocol dependent in MRI when using ultrasmall superparamagnetic iron oxide nanoparticles

In this study, the volume of susceptibility artifact was evaluated in T1 and T2-weighted spin echo (SE) and gradient echo (GRE) images at various parameters using registration and subtraction methods. In order to state an important misinterpretation problem in lymphography, it was demonstrated that a lymph node size may be enlarged approximately 10 times when a T2*-weighted GRE protocol is used. To overcome this problem a technical consideration using multisequence (GRE and SE) paradigm was suggested to ensure both lymph node detection and metastasis identification in lymphatic system. The paradigm was also extended by post-processing manipulation of the SE images using a registration and subtraction approach for detection of lymphatic lesions.     

Improved detection of time windows of brain responses in fMRI using modified temporal clustering analysis

Temporal clustering analysis (TCA) has been proposed recently as a method to detect time windows of brain responses in functional MRI (fMRI) studies when the timing and location of the activation are completely unknown. Modifications to the TCA technique are introduced in this report to further improve the sensitivity in detecting brain activation. The modified TCA is based on the integrated signal intensity of a temporal cluster at each time point, while the original TCA is based only on the size of a temporal cluster at each time point. A temporal cluster at each time point is defined, in both TCA methods, as a group of pixels reaching their maximum (or minimum) values at the same time. Both computer simulation and in vivo fMRI experiments have been performed. Compared with the original TCA, the modified TCA shows a significant improvement in the sensitivity to detect activation peaks for determining time windows of brain responses.     

Non-uniformity correction of human brain imaging at high field by RF field mapping of B1+ and B1-

A new method of non-uniform image correction is proposed. Image non-uniformity is originated from the spatial distribution of RF transmission and reception fields, represented as B(1)(+) and B(1)(-), respectively. In our method, B(1)(+) mapping was performed invivo by a phase method. In B(1)(-) mapping, images with multiple TEs were acquired with a multi-echo adiabatic spin echo (MASE) sequence which enables homogeneous excitation. By T(2) fitting of these images an M(0) map (M(0)(MASE)) was obtained, in which signal intensity was expressed as the product of B(1)(-) and M?(1-e?(TR/T1)) . The ratio of this M(0)(MASE) map to the B(1)(+) map showed a similar spatial pattern in different human brains. These ratios of M(0)(MASE) to B(1)(+) in 24 subjects were averaged and then fitted with a spatially polynomial function to obtain a ratio map of B(1)(-)/B(1)(+)(α). Uniform image was achieved in spin echo (SE), MASE and inversion recovery turboFLASH (IRTF) images using measured B(1)(+) and calculated B(1)(-) by αB(1)(+). Water fractions in gray and white matters obtained from the M(0) images corrected by this method were in good agreement with previously reported values. From these experimental results, the proposed method of non-uniformity correction is validated at 4.7 T imaging.     

Improved Measurement of the Cabibbo-Kobayashi-Maskawa angle alpha using B0(B) --> rho+rho- decays

We present results from an analysis of B(0)B(0)--> rho(+)rho(-) using 232 x 10(6) Gamma (4S) --> BB decays collected with the BABAR detector at the PEP-II asymmetric-energy B factory at SLAC. We measure the longitudinal polarization fraction f(L) = 0.978 +/- 0.014(stat) + 0.021 / -0.029(syst) and the CP-violating parameters S(L)= -0.33 +/- 0.24(stat) + 0.08 / -0.14(syst) and C(L)= -0.03 +/- 0.18(stat) +/- 0.09(syst). Using an isospin analysis of B --> rhorho decays, we determine the unitarity triangle parameter alpha. The solution compatible with the standard model is alpha = (100 +/- 13) degrees.     

Application of stereological methods to estimate post-mortem brain surface area using 3 T MRI

The Cavalieri and Vertical Sections methods of design based stereology were applied in combination with 3 tesla (i.e. 3 T) Magnetic Resonance Imaging (MRI) to estimate cortical and subcortical volume, area of the pial surface, area of the grey–white matter boundary, and thickness of the cerebral cortex. The material comprises eight human cadaveric cerebri which had been separated into sixteen cerebral hemisphere specimens prior to embedding in agar gel. The results from MRI were compared with corresponding ‘gold standard’ values subsequently obtained by application of the same methodology using physical sectioning of the specimens.     

Multifunctional iron platinum stealth immunomicelles: targeted detection of human prostate cancer cells using both fluorescence and magnetic resonance imaging

Superparamagnetic iron oxide nanoparticles (SPIONs) are the most common type of contrast agents used in contrast agent-enhanced magnetic resonance imaging (MRI). Still, there is a great deal of room for improvement, and nanoparticles with increased MRI relaxivities are needed to increase the contrast enhancement in MRI applied to various medical conditions including cancer. We report the synthesis of superparamagnetic iron platinum nanoparticles (SIPPs) and subsequent encapsulation using PEGylated phospholipids to create stealth immunomicelles (DSPE-SIPPs) that can be specifically targeted to human prostate cancer cell lines and detected using both MRI and fluorescence imaging. SIPP cores and DSPE-SIPPs were 8.5 ± 1.6 nm and 42.9 ± 8.2 nm in diameter, respectively, and the SIPPs had a magnetic moment of 120 A m²/kg iron. J591, a monoclonal antibody against prostate specific membrane antigen (PSMA), was conjugated to the DSPE-SIPPs (J591-DSPE-SIPPs), and specific targeting of J591-DSPE-SIPPs to PSMA-expressing human prostate cancer cell lines was demonstrated using fluorescence confocal microscopy. The transverse relaxivity of the DSPE-SIPPs, measured at 4.7 Tesla, was 300.6 ± 8.5 s^?1 mM^?1, which is 13-fold better than commercially available SPIONs (23.8 ± 6.9 s^?1 mM^?1) and ~3-fold better than reported relaxivities for Feridex^® and Resovist^®. Our data suggest that J591-DSPE-SIPPs specifically target human prostate cancer cells in vitro, are superior contrast agents in T ₂-weighted MRI, and can be detected using fluorescence imaging. To our knowledge, this is the first report on the synthesis of multifunctional SIPP micelles and using SIPPs for the specific detection of prostate cancer.     

Improved field emission stability and uniformity of printed carbon nanotubes prepared using high energy-milled glass frit

Stable and uniform electron field emitters were fabricated by the screen-printing of a carbon nanotube (CNT) paste. The CNT paste was prepared by mixing thin multi-walled CNTs, organic binder and glass frits in terpineol followed by three-roll milling. The paste was screen-printed onto an indium tin oxide (ITO)-coated glass substrate and exposed to firing. The emitters formed by the adhesive tape treatment of the printed pastes generally showed non-uniform heights of emitting tips due to the large-sized glass frit distributed in the paste. On the other hand, small glass frits with a uniform particle size distribution could be obtained by high energy milling. In addition, the CNT paste prepared using the high energy-milled glass frits showed very uniform tip heights. The uniform CNT tip height was found to play an important role in acquiring the long-term emission stability and uniformity of field emitters.     

Fast T1 mapping of the brain at high field using Look-Locker and fast imaging

This study aims to develop and evaluate a new method for fast high resolution T1 mapping of the brain based on the Look-Locker technique. Single-shot turboflash sequence with high temporal acceleration is used to sample the recovery of inverted magnetization. Multi-slice interleaved acquisition within one inversion slab is used to reduce the number of inversion pulses and hence SAR. Accuracy of the proposed method was studied using simulation and validated in phantoms. It was then evaluated in healthy volunteers and stroke patients. In-vivo results were compared to values obtained by inversion recovery fast spin echo (IR-FSE) and literatures. With the new method, T₁ values in phantom experiments agreed with reference values with median error < 3%. For in-vivo experiments, a T1 map was acquired in 3.35 s and the T1 maps of the whole brain were acquired in 2 min with two-slice interleaving, with a spatial resolution of 1.1 × 1.1 × 4 mm³. The T₁ values obtained were comparable to those measured with IR-FSE and those reported in literatures. These results demonstrated the feasibility of the proposed method for fast T1 mapping of the brain in both healthy volunteers and stroke patients at 3T.     

MRI evaluation of brain iron in earlier- and later-onset Parkinson's disease and normal subjects

Tissue iron levels in the extrapyramidal system of earlier- and later-onset Parkinson's disease (PD) subjects were evaluated in vivo using a magnetic resonance imaging (MRI) method. The method involves scanning subjects in both high- and low-field MRI instruments, measuring tissue relaxation rate (R2), and calculating the field-dependent R2 increase (FDRI) which is the difference between the R2 measured with the two MRI instruments. In tissue, only ferritin iron is known to increase R2 in a field-dependent manner and the FDRI measure is a specific measure of this tissue iron pool. Two groups of male subjects with PD and two age-matched groups of normal control males were studied. The two groups of six subjects with PD consisted of subjects with earlier- or later-onset (before or after age 60) PD. FDRI was measured in five subcortical structures: the substantia nigra reticulata (SNR), substantia nigra compacta (SNC), globus pallidus, putamen, and caudate nucleus, and in one comparison region; the frontal white matter. Earlier-onset PD subjects had significant (p < 0.05) increases in FDRI in the SNR, SNC, putamen, and globus pallidus, while later-onset PD subjects had significantly decreased FDRI in the SNR when compared to their respective age-matched controls. Controlling for illness duration or structure size did not meaningfully alter the results. Published post-mortem studies on SN iron levels indicate decreased ferritin levels and increased free iron levels in the SN of older PD subjects, consistent with the decreased FDRI observed in our later-onset PD sample, which was closely matched in age to the post-mortem PD samples. The FDRI results suggest that disregulation of iron metabolism occurs in PD and that this disregulation may differ in earlier- versus later-onset PD.     

High resolution NMR spectroscopy of rat brain in vivo through indirect zero-quantum-coherence detection

The time evolution of zero-quantum-coherences (ZQCs) is insensitive to magnetic field inhomogeneity. Using a 2D indirect ZQC detection method it is shown that high-resolution (1)H NMR spectra can be obtained from rat brain in vivo at 11.74T that are immune to magnetic field inhomogeneity. Simulations based on the density matrix formalism, as well as in vitro measurements are used to demonstrate the features of 2D ZQC NMR spectra. Unique spectral information which is normally not directly available from regular (1)H NMR spectra can be extracted and used for compound identification or improved prior knowledge during spectral fitting.