Target-Specific Magnetic Resonance Imaging of Human Prostate Adenocarcinoma Using NaDyF4-NaGdF4 Core-Shell Nanoparticles.

We illustrate the development of NaDyF4-NaGdF4 core-shell nanoparticles (NPs) for targeting prostate cancer cells using a preclinical 9.4 T magnetic resonance imaging (MRI) of live animals. The NPs composed of paramagnetic Dy3+ and Gd3+ (T2- and T1-contrast agents, respectively) demonstrate proton relaxivities of r1 = 20.2 mM-1 s-1 and r2 = 32.3 mM-1 s-1 at clinical 3 T and r1 = 9.4 mM-1 s-1 and r2 = 144.7 mM-1 s-1 at preclinical 9.4 T. The corresponding relaxivity values per NP are r1 = 19.4 × 105 mMNP-1 s-1 and r2 = 33.0 × 105 mMNP-1 s-1 at 3 T and r1 = 9.0 × 105 mMNP-1 s-1 and r2 = 147.0 × 105 mMNP-1 s-1 at 9.4 T. In vivo active targeting of human prostate tumors grown in nude mice revealed docking of anti-prostate-specific membrane antigen (PSMA) antibody-tagged NPs at tumor sites post-24 h of their intravenous injection. On the other hand, in vivo passive targeting showed preferential accumulation of NPs at tumor sites only within 2 h of their injection, ascribed to the enhanced permeation and retention effect of the tumor. A biodistribution study employing the harvested organs of mice, post-24 h injection of NPs, quantified active targeting as nearly twice as efficient as passive targeting. These outcomes provide potential opportunities for noninvasive diagnosis using NaDyF4-NaGdF4 core-shell NPs for target-specific MRI.

Simple compensation method for improved half-pulse excitation profile with rephasing gradient.

PURPOSE: To improve the slice profile quality obtained by RF half-pulse excitation for 2D-UTE applications. METHODS: The overall first-order and zero-order phase errors along the slice-selection direction were obtained with the help of an optimization task to minimize the out-of-slice signal contamination from the calibration 1-dimenisonal (1D) profile data. The time-phase-error evolution was approximated from the k-space readout data, which were acquired primarily for correction of the readout trajectories during data regridding to the rectilinear grids. The correction of the slice profile was achieved by rephasing gradient pulses applied immediately after the end of excitation. The total prescan calibration typically took less than 2 minutes. RESULTS: The improved image quality using the proposed calibration method was demonstrated both on phantoms and on ankle images obtained from healthy volunteers. It was demonstrated that calibration can be performed either as a separate water phantom measurement or directly as a prescan procedure. CONCLUSION: The slice-profile distortion from the half-pulse excitation could substantially affect the overall fidelity of 2D-UTE images. The presented experiments proved that the image quality could be substantially increased by application of the proposed slice-correction method.

Influence of k-space trajectory corrections on proton density mapping with ultrashort echo time imaging: Application for imaging of short T2 components in white matter.

PURPOSE: To evaluate the impact of MR gradient system imperfections and limitations for the quantitative mapping of short T2* signals performed by ultrashort echo time (UTE) acquisition approach. MATERIALS AND METHODS: The measurement of short T2* signals from a phantom and a healthy volunteer study (8 subjects of average age 28 ±â€¯4 years) were performed on a 3T scanner. The characteristics of the gradient system were obtained using calibration method performed directly on the measured subject or phantom. This information was used to calculate the actual sampling trajectory with the help of a parametric eddy current model. The actual sample positions were used to reconstruct corrected images and compared with uncorrected data. RESULTS: Comparison of both approaches, i.e., without and with correction of k-space sampling trajectories revealed substantial improvement when correction was applied. The phantom experiments demonstrate substantial in-plane signal intensity variations for uncorrected sampling trajectories. In the case of the volunteer study, this led to significant differences in relative proton density (RPD) estimation between the uncorrected and corrected data (P = 0.0117 by Wilcoxon matched-pairs test) and provides for about ~15% higher values for short T2* components of white matter (WM) in the case of uncorrected images. CONCLUSION: The imperfection of the applied gradients could induce errors in k-space data sampling which further propagates into the fidelity of the UTE images and jeopardizes precision of quantification. However, the study proved that measurement of gradient errors together with correction of sample positions can contribute to increased accuracy and unbiased characterization of short T2* signals.

Early and progressive microstructural brain changes in mice overexpressing human α-Synuclein detected by diffusion kurtosis imaging.

Diffusion kurtosis imaging (DKI) is sensitive in detecting α-Synuclein (α-Syn) accumulation-associated microstructural changes at late stages of the pathology in α-Syn overexpressing TNWT-61 mice. The aim of this study was to perform DKI in young TNWT-61 mice when α-Syn starts to accumulate and to compare the imaging results with an analysis of motor and memory impairment and α-Syn levels. Three-month-old (3mo) and six-month-old (6mo) mice underwent DKI scanning using the Bruker Avance 9.4T magnetic resonance imaging system. Region of interest (ROI) analyses were performed in the gray matter; tract-based spatial statistics (TBSS) analyses were performed in the white matter. In the same mice, α-Syn expression was evaluated using quantitative immunofluorescence. Mean kurtosis (MK) was the best differentiator between TNWT-61 mice and wildtype (WT) mice. We found increases in MK in 3mo TNWT-61 mice in the striatum and thalamus but not in the substantia nigra (SN), hippocampus, or sensorimotor cortex, even though the immunoreactivity of human α-Syn was similar or even higher in the latter regions. Increases in MK in the SN were detected in 6mo mice. These findings indicate that α-Syn accumulation-associated changes may start in areas with a high density of dopaminergic nerve terminals. We also found TBSS changes in white matter only at 6mo, suggesting α-Syn accumulation-associated changes start in the gray matter and later progress to the white matter. MK is able to detect microstructural changes induced by α-Syn overexpression in TNWT-61 mice and could be a useful clinical tool for detecting early-stage Parkinson's disease in human patients.

K-space trajectory mapping and its application for ultrashort Echo time imaging.

MR images are affected by system delays and gradient field imperfections which induce discrepancies between prescribed and actual k-space trajectories. This could be even more critical for non-Cartesian data acquisitions where even a small deviation from the assumed k-space trajectory results in severe image degradation and artifacts. Knowledge of the actual k-space trajectories is therefore crucial and can be incorporated in the reconstruction of high quality non-Cartesian images. A novel MR method for the calibration of actual gradient waveforms was developed using a combination of phase encoding increments and subsequent detection of the exact time point at which the corresponding trajectory is crossing the k-space origin. The measured sets of points were fitted to a parametrical model to calculate the complete actual acquisition trajectory. Measurements performed on phantoms and volunteers, positioned both in- and off-isocenter of the magnet, clearly demonstrate the improvement in reconstructed ultrashort echo time (UTE) images, when information from calibration of k-space sampling trajectories is employed in the MR image reconstruction procedure. The unique feature of the proposed method is its robustness and simple experimental setup, making it suitable for quick acquisition trajectory calibration procedures e.g. for non-Cartesian radial fast imaging.

Late-stage α-synuclein accumulation in TNWT-61 mouse model of Parkinson's disease detected by diffusion kurtosis imaging.

Diffusion kurtosis imaging (DKI) by measuring non-Gaussian diffusion allows an accurate estimation of the distribution of water molecule displacement and may correctly characterize microstructural brain changes caused by neurodegeneration. The aim of this study was to evaluate the ability of DKI to detect changes induced by α-synuclein (α-syn) accumulation in α-syn over-expressing transgenic mice (TNWT-61) in both gray matter (GM) and white matter (WM) using region of interest (ROI) and tract-based spatial statistics analyses, respectively, and to explore the relationship between α-syn accumulation and DKI metrics in our regions of interest. Fourteen-month-old TNWT-61 mice and wild-type (WT) littermates underwent in vivo DKI scanning using the Bruker Avance 9.4 Tesla magnetic resonance imaging system. ROI analysis in the GM regions substantia nigra, striatum, hippocampus, sensorimotor cortex, and thalamus and tract-based spatial statistics analysis in WM were performed. Immunohistochemistry for α-syn was performed in TNWT-61 mice and correlated with DKI findings. We found increased kurtosis and decreased diffusivity values in GM regions such as the thalamus and sensorimotor cortex, and in WM regions such as the external and internal capsule, mamillothalamic tract, anterior commissure, cingulum, and corpus callosum in TNWT-61 mice as compared to WT mice. Furthermore, we report for the first time that α-syn accumulation is positively correlated with kurtosis and negatively correlated with diffusivity in the thalamus. The study provides evidence of an association between the amount of α-syn and the magnitude of DKI metric changes in the ROIs, with the potential of improving the clinical diagnosis of Parkinson's disease. We propose diffusion kurtosis imaging as a sensitive method for detecting human α-synuclein accumulation-induced changes in brain tissue, which may be reflective of Parkinson disease stage. Boxplots show the averaged mean kurtosis (orange) and mean diffusivity (blue) under the results of the analysis (*p < 0.05) in brains of wild-type (WT) and α-synuclein over-expressing (TNWT-61) mice. This approach might represent a novel biomarker for the early diagnosis of Parkinson's disease. Read the Editorial Highlight for this article on page 1117.

Diffusion Kurtosis Imaging Detects Microstructural Alterations in Brain of α-Synuclein Overexpressing Transgenic Mouse Model of Parkinson's Disease: A Pilot Study.

Evidence suggests that accumulation and aggregation of α-synuclein contribute to the pathogenesis of Parkinson's disease (PD). The aim of this study was to evaluate whether diffusion kurtosis imaging (DKI) will provide a sensitive tool for differentiating between α-synuclein-overexpressing transgenic mouse model of PD (TNWT-61) and wild-type (WT) littermates. This experiment was designed as a proof-of-concept study and forms a part of a complex protocol and ongoing translational research. Nine-month-old TNWT-61 mice and age-matched WT littermates underwent behavioral tests to monitor motor impairment and MRI scanning using 9.4 Tesla system in vivo. Tract-based spatial statistics (TBSS) and the DKI protocol were used to compare the whole brain white matter of TNWT-61 and WT mice. In addition, region of interest (ROI) analysis was performed in gray matter regions such as substantia nigra, striatum, hippocampus, sensorimotor cortex, and thalamus known to show higher accumulation of α-synuclein. For the ROI analysis, both DKI (6 b-values) protocol and conventional (2 b-values) diffusion tensor imaging (cDTI) protocol were used. TNWT-61 mice showed significant impairment of motor coordination. With the DKI protocol, mean, axial, and radial kurtosis were found to be significantly elevated, whereas mean and radial diffusivity were decreased in the TNWT-61 group compared to that in the WT controls with both TBSS and ROI analysis. With the cDTI protocol, the ROI analysis showed decrease in all diffusivity parameters in TNWT-61 mice. The current study provides evidence that DKI by providing both kurtosis and diffusivity parameters gives unique information that is complementary to cDTI for in vivo detection of pathological changes that underlie PD-like symptomatology in TNWT-61 mouse model of PD. This result is a crucial step in search for a candidate diagnostic biomarker with translational potential and relevance for human studies.

Functional MRI of the thoracic spinal cord during vibration sensation.

PURPOSE: To demonstrate that it is possible to acquire accurate functional magnetic resonance images from thoracic spinal cord neurons. MATERIALS AND METHODS: The lower thoracic spinal dermatomes (T7-T11) on the right side of the body were mechanically stimulated by vibration for 15 participants. Neuronal responses to vibration sensation were measured in the thoracic spinal cord using a HASTE sequence on a 3 Tesla MRI system. RESULTS: Signal increases were observed in the corresponding lower thoracic spinal cord segments ipsilateral to the side of stimulation in the dorsal aspect of the spinal cord. CONCLUSION: This is the first study to provide proof of principle that functional imaging of the entire thoracic spinal cord is possible, by detecting neuronal activity in the thoracic spinal cord during sensory stimulation using spinal fMRI.

Subzone based multi-frequency magnetic resonance elastography using a Rayleigh damped material model.

MR Elastography (MRE) is a relatively novel imaging technique using conventional MRI methods to assess the mechanical properties of tissues. In time-harmonic MRE, a Rayleigh, or proportional, Damping (RD) model incorporates attenuation behavior proportionally related to both elastic and inertial forces, thus providing a more sophisticated description of the elastic energy dissipation occurring in the biological tissue. The overall damping ratio can be extracted from the combined effect of these two components, while an additional measure, called Rayleigh Composition, can be calculated by the ratio between the two components. Thus, RD elastography is capable of not only reconstructing the viscoelastic properties of the material, but also providing additional information about damping behavior and structure. A 3D subzone based reconstruction algorithm using a RD material model has been developed and optimized to reconstruct the viscoelastic properties, damping behavior and elastic energy attenuation mechanism of tissue-simulating damping phantoms across multiple frequencies. Results have shown that all three iterative reconstructed parameters are in relatively close agreement for both the tofu and gelatin materials in both phantom configurations across the frequency range. Preliminary results from in-vivo healthy brain are also presented and discussed.

NaDyF4 Nanoparticles as T2 Contrast Agents for Ultrahigh Field Magnetic Resonance Imaging.

A major limitation of the commonly used clinical MRI contrast agents (CAs) suitable at lower magnetic field strengths (<3.0 T) is their inefficiency at higher fields (>7 T), where next-generation MRI scanners are going. We present dysprosium nanoparticles (ß-NaDyF4 NPs) as T2 CAs suitable at ultrahigh fields (9.4 T). These NPs effectively enhance T2 contrast at 9.4 T, which is 10-fold higher than the clinically used T2 CA (Resovist). Evaluation of the relaxivities at 3 and 9.4 T show that the T2 contrast enhances with an increase in NP size and field strength. Specifically, the transverse relaxivity (r2) values at 9.4 T were ∼64 times higher per NP (20.3 nm) and ∼6 times higher per Dy(3+) ion compared to that at 3 T, which is attributed to the Curie spin relaxation mechanism. These results and confirming phantom MR images demonstrate their effectiveness as T2 CAs in ultrahigh field MRIs.

A volume microstrip RF coil for MRI microscopy.

Quantitative magnetic resonance imaging (MRI) studies of small samples such as a single cell or cell clusters require application of radiofrequency (RF) coils that provide homogenous B(1) field distribution and high signal-to-noise ratio (SNR). We present a novel design of an MRI RF volume microcoil based on a microstrip structure. The coil consists of two parallel microstrip elements conducting RF currents in the opposite directions, thus creating homogenous RF field within the space between the microstrips. The construction of the microcoil is simple, efficient and cost-effective. Theoretical calculations and finite element method simulations were used to optimize the coil geometry to achieve optimal B(1) and SNR distributions within the sample and predict parameters of the coil. The theoretical calculations were confirmed with MR images of a 1-mm-diameter capillary and a plant obtained with the double microstrip RF microcoil at 11.7 T. The in-plane resolution of MR images was 24 µm × 24 µm.

Convertible pneumatic actuator for magnetic resonance elastography of the brain.

Here we present a novel pneumatic actuator design for brain magnetic resonance elastography (MRE). Magnetic resonance elastography is a phase contrast technique capable of tracing strain wave propagation and utilizing this information for the calculation of mechanical properties of materials and living tissues. In MRE experiments, the acoustic waves are generated in a synchronized way with respect to image acquisition, using various types of mechanical actuators. The unique feature of the design is its simplicity and flexibility, which allows reconfiguration of the actuator for different applications ranging from in vivo brain MRE to experiments with phantoms. Phantom and in vivo data are presented to demonstrate actuator performance.

Bloch simulations with intra-voxel spin dephasing.

A common problem in simulations of MRI-experiments based on the numerical solution of the Bloch equations is the finite number of isochromats used in the calculations. This usually results in false or spurious signals and is a source of various differences between calculated and experimentally obtained data. In this paper, we are proposing a technique representing each sample voxel by a central and three additional isochromats, slightly shifted in orthogonal directions from center, thus providing a linear approximation of intra-voxel dephasing. This approach allows for further improvement and precision of the calculated NMR signal and virtually avoids the problem related to an finite set of isochromats. Here we provide details of the algorithm together with examples of simulations which prove the efficiency of this approach.

On the diffusion constant of water in wheat.

Diffusion-weighted magnetic resonance imaging (MRI) was used to obtain diffusion constants for water in the embryo and endosperm of wheat. Our experiments showed a significant difference between the diffusion constant for the two components. It was also shown that water diffusion in both the endosperm and embryo deviates from the typically observed Gaussian behavior in bulk fluids, showing a time-dependent diffusion constant. Diffusion constants for the embryo and endosperm were shown to differ by an order of magnitude. Using a model for restricted diffusion, information on the endosperm pore size and the embryo cell dimensions could be obtained.

Single-point imaging with a variable phase encoding interval.

A modified single-point imaging (SPI) technique using a variable phase encoding interval is proposed. This method is based on the minimization of the phase encoding interval for further signal-to-noise ratio (SNR) optimization. This is particularly beneficial when the maximum gradient amplitude limits an optimal phase encoding interval, and the resulting SNR suffers from T(2)-related signal attenuation. Theoretical calculation of the SNR and simulation of the point spread function (PSF) for the different experimental parameters are presented. Experiments using a rubber sample (T(2)* approximately 73 micros) and a tooth (bi-exponential relaxation: T(2,1)*=111 micros and T(2,1)*=872 micros) showed a significant increase in SNR (>3 and >2, respectively) when compared with images acquired with conventional SPI.

Simple phase method for measurement of magnetic field gradient waveforms.

Magnetic field gradients play a fundamental role in MR imaging and localized spectroscopy. The MRI experiment, in particular fast MRI, relies on precise gradient switching, which has become more demanding with the constantly growing number of fast imaging techniques. Here we present a simple MR method to measure the behavior of a magnetic field gradient waveform in an MR scanner. The method employs excitation of a thin slice, followed by application of the studied gradient and simultaneous FID acquisition. Measurements of different gradient waveforms were performed with a spherical phantom filled with doped water and positioned at the isocenter of the gradient set. The presented experiments demonstrate the capability of the technique to measure different gradient waveforms with an estimated error of less than 200 microT/m.

Early detection and quantification of murine melanoma bone metastases with magnetic resonance imaging.

OBJECTIVE: Bone metastases occur in approximately 80% of patients with advanced cancer and cause significant morbidity. There are currently no established means by which to identify the early growth of micro-metastatic cells or their effects on bone at a time when curative therapy might be initiated. We postulated that high-resolution magnetic resonance imaging (MRI) could detect and quantify the growth and destructive effects of bone micrometastases. DESIGN: Using a mouse model for metastasis of malignant melanoma, we have examined the ability of MRI to quantify cortical bone destruction and the percentage of the medullary cavity occupied by tumour, trabecular bone, and marrow. The results from MRI were compared to histomorphometry (the reference standard) and to radiographs. RESULTS: In vivo gradient-echo and spin-echo MRI demonstrated that metastatic melanoma replaced the marrow space but that the cortical bone integrity was preserved (P < or = 0.001). The smallest detectable micrometastasis had an area of 0.323 mm(2). In contrast, we observed no trends after quantifying the radiograph data. CONCLUSION: These approaches delineated the limits of MRI in its ability to quantify tumour burden and the effect on bone in this model. Given the increasing use of MRI as a non-invasive clinical diagnostic method, the present findings may be applicable in detecting bone metastases in the clinical setting at an early and potentially treatable stage.

Magnetic resonance imaging of trabecular and cortical bone in mice: comparison of high resolution in vivo and ex vivo MR images with corresponding histology.

Measurements of bone morphometry and remodeling have been shown to reflect bone strength and can be used to diagnose degenerative bone disease. In this study, in vivo and ex vivo magnetic resonance imaging (MRI) techniques to assess trabecular and cortical bone properties have been compared to each other and to histology as a novel means for the quantification of bone. Femurs of C57Bl/6 mice were examined both in vivo and ex vivo on an 11.7 T MRI scanner, followed by histologic processing and morphometry. A thresholding analysis technique was applied to the MRI images to generate contour lines and to delineate the boundaries between bone and marrow. Using MRI, an optimal correlation with histology was obtained with an in vivo longitudinal sectioned short echo time gradient-echo versus an in vivo long echo time spin-echo sequence or an ex vivo pulse sequence. Gradient-echo images were acquired with a maximum in-plane resolution of 35 microm. Our results demonstrated that in both the in vivo and ex vivo data sets, the percent area of marrow increases and percent area of trabecular bone and cortical bone thickness decreases moving from the epiphyseal growth plate to the diaphysis. These changes, observed with MRI, correlate with the histological data. Investigations using in vivo MRI gradient-echo sequences consistently gave the best correlation with histology. Our quantitative evaluation using both ex vivo and in vivo MRI was found to be an effective means to visualize non-invasively the normal variation in trabecular and cortical bone as compared to a histological "gold standard" The experiments validated in vivo MRI as a potential high resolution technique for investigating both soft tissue, such as marrow, and bone without radiation exposure.

Single point imaging with suppressed sound pressure levels through gradient-shape adjustment.

Acoustic noise produced during single point imaging (SPI) experiments was modulated by changes in the spatial encoding gradients. Parameters of both linear and sine-shaped gradient ramps were modified to minimize the acoustic noise levels. Acoustic noise measurements during SPI were measured on three different gradient systems and revealed that for small gradient-bore systems a considerable acoustic noise reduction of more than 20 dB can easily be achieved. SPI in conjunction with an optimized gradient waveform can be a superb alternative to the previously introduced single point ramped imaging with T(1) enhancement (SPRITE) method when sound levels and overheating of gradients are a concern.

Magnetic resonance imaging of seeds by use of single point acquisition.

In general, magnetic resonance imaging (MRI) is used to obtain a spatial representation of the water distribution in an object. Water in soft materials (living matter) often shows a high degree of translational mobility, giving rise to relatively long magnetic relaxation times. This allows the use of conventional MRI techniques such as the spin-echo, to acquire an image. However, when hydration levels become low, water becomes less mobile, resulting in much shorter magnetic relaxation times and a corresponding signal loss. To avoid problems arising from rapid decaying signals, we investigated the use of single point imaging (SPI) in the study of seeds. We were able to obtain SPI images of nonimbibed and imbibed seeds. Using SPI with shaped gradients significantly reduced the acoustic noise level.