Quantification of the rotating frame relaxation time T2ρ: Comparison of balanced spin-lock and continuous-wave Malcolm-Levitt preparations.

For the quantification of rotating frame relaxation times, the T2ρ relaxation pathway plays an essential role. Nevertheless, T2ρ imaging has been studied only to a small extent compared with T1ρ, and preparation techniques for T2ρ have so far been adapted from T1ρ methods. In this work, two different preparation concepts are compared specifically for the use of T2ρ mapping. The first approach involves transferring the balanced spin-locking (B-SL) concept of T1ρ imaging. The second and newly proposed approach is a continuous-wave Malcolm-Levitt (CW-MLEV) pulse train with zero echo times and was motivated from T2 preparation strategies. The modules are tested in Bloch simulations for their intrinsic sensitivity to field inhomogeneities and validated in phantom experiments. In addition, myocardial T2ρ mapping was performed in mice as an exemplary application. Our results demonstrate that the CW-MLEV approach provides superior robustness and thus suggest that established methods of T1ρ imaging are not best suited for T2ρ experiments. In the presence of field inhomogeneities, the simulations indicated an increased banding compensation by a factor of 4.1 compared with B-SL. Quantification of left ventricular T2ρ time in mice yielded more consistent results, and values in the range of 59.2-61.1 ms (R2 = 0.986-0.992) were observed at 7 T.

Rotary excitation of non-sinusoidal pulsed magnetic fields: Towards non-invasive direct detection of cardiac conduction.

PURPOSE: There is a need for high resolution non-invasive imaging methods of physiologic magnetic fields. The purpose of this work is to develop a MRI detection approach for non-sinusoidal magnetic fields based on the rotary excitation (REX) mechanism which was previously successfully applied for the detection of oscillating magnetic fields in the sub-nT range. METHODS: The new detection concept was examined by means of Bloch simulations, evaluating the interaction effect of spin-locked magnetization and low-frequency pulsed magnetic fields. The REX detection approach was validated under controlled conditions in phantom experiments at 3 T. Gaussian and sinc-shaped stimuli were investigated. In addition, the detection of artificial fields resembling a cardiac QRS complex, which is the most prominent peak visible on a magnetocardiogram, was tested. RESULTS: Bloch simulations demonstrated that the REX method has a high sensitivity to pulsed fields in the resonance case, which is met when the spin-lock frequency coincides with a non-zero Fourier component of the stimulus field. In the experiments, we found that magnetic stimuli of different durations and waveforms can be distinguished by their characteristic REX response spectrum. The detected REX amplitude was proportional to the stimulus peak amplitude (R2 > 0.98) and the lowest field detection was 1 nT. Furthermore, the detection of QRS-like fields with varying QRS durations yielded significant results in a phantom setup (p < 0.001). CONCLUSION: REX detection can be transferred to non-sinusoidal pulsed magnetic fields and could provide a non-invasive, quantitative tool for spatially resolved assessment of cardiac biomagnetism. Potential applications include the direct detection and characterization of cardiac conduction.

Quantification correction for free-breathing myocardial T1ρ mapping in mice using a recursively derived description of a T1ρ* relaxation pathway.

BACKGROUND: Fast and accurate T1ρ mapping in myocardium is still a major challenge, particularly in small animal models. The complex sequence design owing to electrocardiogram and respiratory gating leads to quantification errors in in vivo experiments, due to variations of the T1ρ relaxation pathway. In this study, we present an improved quantification method for T1ρ using a newly derived formalism of a T1ρ* relaxation pathway. METHODS: The new signal equation was derived by solving a recursion problem for spin-lock prepared fast gradient echo readouts. Based on Bloch simulations, we compared quantification errors using the common monoexponential model and our corrected model. The method was validated in phantom experiments and tested in vivo for myocardial T1ρ mapping in mice. Here, the impact of the breath dependent spin recovery time Trec on the quantification results was examined in detail. RESULTS: Simulations indicate that a correction is necessary, since systematically underestimated values are measured under in vivo conditions. In the phantom study, the mean quantification error could be reduced from - 7.4% to - 0.97%. In vivo, a correlation of uncorrected T1ρ with the respiratory cycle was observed. Using the newly derived correction method, this correlation was significantly reduced from r = 0.708 (p < 0.001) to r = 0.204 and the standard deviation of left ventricular T1ρ values in different animals was reduced by at least 39%. CONCLUSION: The suggested quantification formalism enables fast and precise myocardial T1ρ quantification for small animals during free breathing and can improve the comparability of study results. Our new technique offers a reasonable tool for assessing myocardial diseases, since pathologies that cause a change in heart or breathing rates do not lead to systematic misinterpretations. Besides, the derived signal equation can be used for sequence optimization or for subsequent correction of prior study results.

Fast myocardial T1ρ mapping in mice using k-space weighted image contrast and a Bloch simulation-optimized radial sampling pattern.

PURPOSE: T1ρ dispersion quantification can potentially be used as a cardiac magnetic resonance index for sensitive detection of myocardial fibrosis without the need of contrast agents. However, dispersion quantification is still a major challenge, because T1ρ mapping for different spin lock amplitudes is a very time consuming process. This study aims to develop a fast and accurate T1ρ mapping sequence, which paves the way to cardiac T1ρ dispersion quantification within the limited measurement time of an in vivo study in small animals. METHODS: A radial spin lock sequence was developed using a Bloch simulation-optimized sampling pattern and a view-sharing method for image reconstruction. For validation, phantom measurements with a conventional sampling pattern and a gold standard sequence were compared to examine T1ρ quantification accuracy. The in vivo validation of T1ρ mapping was performed in N = 10 mice and in a reproduction study in a single animal, in which ten maps were acquired in direct succession. Finally, the feasibility of myocardial dispersion quantification was tested in one animal. RESULTS: The Bloch simulation-based sampling shows considerably higher image quality as well as improved T1ρ quantification accuracy (+ 56%) and precision (+ 49%) compared to conventional sampling. Compared to the gold standard sequence, a mean deviation of - 0.46 ± 1.84% was observed. The in vivo measurements proved high reproducibility of myocardial T1ρ mapping. The mean T1ρ in the left ventricle was 39.5 ± 1.2 ms for different animals and the maximum deviation was 2.1% in the successive measurements. The myocardial T1ρ dispersion slope, which was measured for the first time in one animal, could be determined to be 4.76 ± 0.23 ms/kHz. CONCLUSION: This new and fast T1ρ quantification technique enables high-resolution myocardial T1ρ mapping and even dispersion quantification within the limited time of an in vivo study and could, therefore, be a reliable tool for improved tissue characterization.

2D Projection Maps of WSS and OSI Reveal Distinct Spatiotemporal Changes in Hemodynamics in the Murine Aorta during Ageing and Atherosclerosis.

Growth, ageing and atherosclerotic plaque development alter the biomechanical forces acting on the vessel wall. However, monitoring the detailed local changes in wall shear stress (WSS) at distinct sites of the murine aortic arch over time has been challenging. Here, we studied the temporal and spatial changes in flow, WSS, oscillatory shear index (OSI) and elastic properties of healthy wildtype (WT, n = 5) and atherosclerotic apolipoprotein E-deficient (Apoe-/-, n = 6) mice during ageing and atherosclerosis using high-resolution 4D flow magnetic resonance imaging (MRI). Spatially resolved 2D projection maps of WSS and OSI of the complete aortic arch were generated, allowing the pixel-wise statistical analysis of inter- and intragroup hemodynamic changes over time and local correlations between WSS, pulse wave velocity (PWV), plaque and vessel wall characteristics. The study revealed converse differences of local hemodynamic profiles in healthy WT and atherosclerotic Apoe-/- mice, and we identified the circumferential WSS as potential marker of plaque size and composition in advanced atherosclerosis and the radial strain as a potential marker for vascular elasticity. Two-dimensional (2D) projection maps of WSS and OSI, including statistical analysis provide a powerful tool to monitor local aortic hemodynamics during ageing and atherosclerosis. The correlation of spatially resolved hemodynamics and plaque characteristics could significantly improve our understanding of the impact of hemodynamics on atherosclerosis, which may be key to understand plaque progression towards vulnerability.

Evaluation of Plaque Characteristics and Inflammation Using Magnetic Resonance Imaging.

Atherosclerosis is an inflammatory disease of large and medium-sized arteries, characterized by the growth of atherosclerotic lesions (plaques). These plaques often develop at inner curvatures of arteries, branchpoints, and bifurcations, where the endothelial wall shear stress is low and oscillatory. In conjunction with other processes such as lipid deposition, biomechanical factors lead to local vascular inflammation and plaque growth. There is also evidence that low and oscillatory shear stress contribute to arterial remodeling, entailing a loss in arterial elasticity and, therefore, an increased pulse-wave velocity. Although altered shear stress profiles, elasticity and inflammation are closely intertwined and critical for plaque growth, preclinical and clinical investigations for atherosclerosis mostly focus on the investigation of one of these parameters only due to the experimental limitations. However, cardiovascular magnetic resonance imaging (MRI) has been demonstrated to be a potent tool which can be used to provide insights into a large range of biological parameters in one experimental session. It enables the evaluation of the dynamic process of atherosclerotic lesion formation without the need for harmful radiation. Flow-sensitive MRI provides the assessment of hemodynamic parameters such as wall shear stress and pulse wave velocity which may replace invasive and radiation-based techniques for imaging of the vascular function and the characterization of early plaque development. In combination with inflammation imaging, the analyses and correlations of these parameters could not only significantly advance basic preclinical investigations of atherosclerotic lesion formation and progression, but also the diagnostic clinical evaluation for early identification of high-risk plaques, which are prone to rupture. In this review, we summarize the key applications of magnetic resonance imaging for the evaluation of plaque characteristics through flow sensitive and morphological measurements. The simultaneous measurements of functional and structural parameters will further preclinical research on atherosclerosis and has the potential to fundamentally improve the detection of inflammation and vulnerable plaques in patients.

Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch.

PURPOSE: Wall shear stress (WSS) and pulse wave velocity (PWV) are important parameters to characterize blood flow in the vessel wall. Their quantification with flow-sensitive phase-contrast (PC) cardiovascular magnetic resonance (CMR), however, is time-consuming. Furthermore, the measurement of WSS requires high spatial resolution, whereas high temporal resolution is necessary for PWV measurements. For these reasons, PWV and WSS are challenging to measure in one CMR session, making it difficult to directly compare these parameters. By using a retrospective approach with a flexible reconstruction framework, we here aimed to simultaneously assess both PWV and WSS in the murine aortic arch from the same 4D flow measurement. METHODS: Flow was measured in the aortic arch of 18-week-old wildtype (n = 5) and ApoE-/- mice (n = 5) with a self-navigated radial 4D-PC-CMR sequence. Retrospective data analysis was used to reconstruct the same dataset either at low spatial and high temporal resolution (PWV analysis) or high spatial and low temporal resolution (WSS analysis). To assess WSS, the aortic lumen was labeled by semi-automatically segmenting the reconstruction with high spatial resolution. WSS was determined from the spatial velocity gradients at the lumen surface. For calculation of the PWV, segmentation data was interpolated along the temporal dimension. Subsequently, PWV was quantified from the through-plane flow data using the multiple-points transit-time method. Reconstructions with varying frame rates and spatial resolutions were performed to investigate the influence of spatiotemporal resolution on the PWV and WSS quantification. RESULTS: 4D flow measurements were conducted in an acquisition time of only 35 min. Increased peak flow and peak WSS values and lower errors in PWV estimation were observed in the reconstructions with high temporal resolution. Aortic PWV was significantly increased in ApoE-/- mice compared to the control group (1.7 ± 0.2 versus 2.6 ± 0.2 m/s, p < 0.001). Mean WSS magnitude values averaged over the aortic arch were (1.17 ± 0.07) N/m2 in wildtype mice and (1.27 ± 0.10) N/m2 in ApoE-/- mice. CONCLUSION: The post processing algorithm using the flexible reconstruction framework developed in this study permitted quantification of global PWV and 3D-WSS in a single acquisition. The possibility to assess both parameters in only 35 min will markedly improve the analyses and information content of in vivo measurements.

Fast self-navigated wall shear stress measurements in the murine aortic arch using radial 4D-phase contrast cardiovascular magnetic resonance at 17.6 T.

PURPOSE: 4D flow cardiovascular magnetic resonance (CMR) and the assessment of wall shear stress (WSS) are non-invasive tools to study cardiovascular risks in vivo. Major limitations of conventional triggered methods are the long measurement times needed for high-resolution data sets and the necessity of stable electrocardiographic (ECG) triggering. In this work an ECG-free retrospectively synchronized method is presented that enables accelerated high-resolution measurements of 4D flow and WSS in the aortic arch of mice. METHODS: 4D flow and WSS were measured in the aortic arch of 12-week-old wildtype C57BL/6 J mice (n = 7) with a radial 4D-phase-contrast (PC)-CMR sequence, which was validated in a flow phantom. Cardiac and respiratory motion signals were extracted from the radial CMR signal and were used for the reconstruction of 4D-flow data. Rigid motion correction and a first order B0 correction was used to improve the robustness of magnitude and velocity data. The aortic lumen was segmented semi-automatically. Temporally averaged and time-resolved WSS and oscillatory shear index (OSI) were calculated from the spatial velocity gradients at the lumen surface at 14 locations along the aortic arch. Reproducibility was tested in 3 animals and the influence of subsampling was investigated. RESULTS: Volume flow, cross-sectional areas, WSS and the OSI were determined in a measurement time of only 32 min. Longitudinal and circumferential WSS and radial stress were assessed at 14 analysis planes along the aortic arch. The average longitudinal, circumferential and radial stress values were 1.52 ± 0.29 N/m2, 0.28 ± 0.24 N/m2 and - 0.21 ± 0.19 N/m2, respectively. Good reproducibility of WSS values was observed. CONCLUSION: This work presents a robust measurement of 4D flow and WSS in mice without the need of ECG trigger signals. The retrospective approach provides fast flow quantification within 35 min and a flexible reconstruction framework.

Positive chemical exchange contrast in MRI using Refocused Acquisition of Chemical Exchange Transferred Excitations (RACETE).

PURPOSE: A new chemical exchange MRI method is proposed which allows for direct detection of exchanging solute protons with concurrent water background suppression. METHODS: The proposed method, RACETE (Refocused Acquisition of Chemical Exchange Transferred Excitations), is based on a stimulated-echo-technique, where the first two excitation pulses are replaced by a train of N solute-selective excitation-transfer modules. This excitation cycle is then followed by a stimulated echo acquisition via selective refocusing of exchanged solute protons now present in the solvent pool. RESULTS: The obtained magnitude and phase phantom images demonstrate that with only one RACETE-imaging experiment two different chemical exchange active substances with mMol-concentrations can be detected and distinguished simultaneously. CONCLUSION: The proposed RACETE-approach allows for true positive chemical exchange contrast imaging with the proven ability to exploit magnitude as well as phase image data.

Assessment of local pulse wave velocity distribution in mice using k-t BLAST PC-CMR with semi-automatic area segmentation.

BACKGROUND: Local aortic pulse wave velocity (PWV) is a measure for vascular stiffness and has a predictive value for cardiovascular events. Ultra high field CMR scanners allow the quantification of local PWV in mice, however these systems are yet unable to monitor the distribution of local elasticities. METHODS: In the present study we provide a new accelerated method to quantify local aortic PWV in mice with phase-contrast cardiovascular magnetic resonance imaging (PC-CMR) at 17.6 T. Based on a k-t BLAST (Broad-use Linear Acquisition Speed-up Technique) undersampling scheme, total measurement time could be reduced by a factor of 6. The fast data acquisition enables to quantify the local PWV at several locations along the aortic blood vessel based on the evaluation of local temporal changes in blood flow and vessel cross sectional area. To speed up post processing and to eliminate operator bias, we introduce a new semi-automatic segmentation algorithm to quantify cross-sectional areas of the aortic vessel. The new methods were applied in 10 eight-month-old mice (4 C57BL/6J-mice and 6 ApoE (-/-)-mice) at 12 adjacent locations along the abdominal aorta. RESULTS: Accelerated data acquisition and semi-automatic post-processing delivered reliable measures for the local PWV, similiar to those obtained with full data sampling and manual segmentation. No statistically significant differences of the mean values could be detected for the different measurement approaches. Mean PWV values were elevated for the ApoE (-/-)-group compared to the C57BL/6J-group (3.5 ± 0.7 m/s vs. 2.2 ± 0.4 m/s, p < 0.01). A more heterogeneous PWV-distribution in the ApoE (-/-)-animals could be observed compared to the C57BL/6J-mice, representing the local character of lesion development in atherosclerosis. CONCLUSION: In the present work, we showed that k-t BLAST PC-MRI enables the measurement of the local PWV distribution in the mouse aorta. The semi-automatic segmentation method based on PC-CMR data allowed rapid determination of local PWV. The findings of this study demonstrate the ability of the proposed methods to non-invasively quantify the spatial variations in local PWV along the aorta of ApoE (-/-)-mice as a relevant model of atherosclerosis.

MRI-based quantification of renal perfusion in mice: Improving sensitivity and stability in FAIR ASL.

PURPOSE: The importance of the orientation of the selective inversion slice in relation to the anatomy in flow-sensitive alternating inversion recovery arterial spin labeling (FAIR ASL) kidney perfusion measurements is demonstrated by comparing the standard FAIR scheme to a scheme with an improved slice selective control experiment. METHODS: A FAIR ASL method is used. The selective inversion preparation slice is set perpendicular to the measurement slice to decrease the unintended labeling of arterial spins in the control experiment. A T1*-based quantification method compensates for the effects of the imperfect inversion on the edge of the selective inversion slice. The quantified perfusion values are compared to the standard experiment with parallel orientation of imaging and selective inversion slice. RESULTS: Perfusion maps acquired with the perpendicular inversion slice orientation show higher sensitivity compared to the parallel orientation. The T1*-based quantification method removes artifacts arising from imperfect inversion slice profiles. The stability is improved. CONCLUSION: Adjusting the labeling technique to the anatomy is of high importance. Improved sensitivity and reproducibility could be demonstrated. The proposed method provides a solution to the problem of FAIR ASL measurements of renal perfusion in coronal view.

High isotropic resolution magnetic resonance imaging of the mandibular canal at 1.5 T: a comparison of gradient and spin echo sequences.

OBJECTIVES: The precision of localizing the mandibular canal prior to surgical intervention depends on the achievable resolution, whereas identification of the nerve depends on the image contrast. In our study, we developed new protocols based on gradient and spin echo sequences. The results from both sequences were quantitatively compared for their agreement to identify the most suitable approach. METHODS: By limiting the field of view to one side of the mandible, three-dimensional acquisitions with T1 weighted gradient and spin echo sequences were performed with 0.5 × 0.5 × 0.5 mm3 resolution within 6.5 min covering the mandibular canal from the mandibular to the mental foramen. Aliasing artefacts were suppressed by different techniques. A manual segmentation of the mandibular canal from seven healthy volunteers was performed on this section by three different observers. The surface distance of the segmented volumes was computed between both sequences as well as between the different observers as a measure of equality. RESULTS: The quantitative comparison of the segmentation resulted in an average surface distance of 0.26 ± 0.05 mm between both sequences and an interobserver difference of 0.26 ± 0.08 mm for gradient and 0.29 ± 0.07 mm for spin echo data. By repeated evaluation, a difference of 0.15 ± 0.02 mm for gradient and 0.18 ± 0.03 mm for spin echo data was observed, indicating a slightly higher variability for spin echo images. CONCLUSIONS: Both sequences can be used to achieve high-resolution images with good contrast and can be used for precise localization of the mandibular canal. Despite a slightly increased difference for the spin echo data, the advantage of an easy and robust setup remains.

Free breathing 1H MRI of the human lung with an improved radial turbo spin-echo.

OBJECTIVE: To optimize a radial turbo spin-echo sequence for motion-robust morphological lung magnetic resonance imaging (MRI) in free respiration. MATERIALS AND METHODS: A versatile multi-shot radial turbo spin-echo (rTSE) sequence is presented, using a modified golden ratio-based reordering designed to prevent coherent streaking due to data inconsistencies from physiological motion and the decaying signal. The point spread function for a moving object was simulated using a model for joint respiratory and cardiac motion with a concomitant T2 signal decay and with rTSE acquisition using four different reordering techniques. The reordering strategies were compared in vivo using healthy volunteers and the sequence was tested for feasibility in two patients with lung cancer and pneumonia. RESULTS: Simulations and in vivo measurements showed very weak artifacts, aside from motion blur, using the proposed reordering. Due to the opportunity for longer scan times in free respiration, a high signal-to-noise ratio (SNR) was achieved, facilitating identification of the disease as compared to standard half-Fourier-acquisition single-shot turbo spin-echo (HASTE) scans. Additionally, post-processing allowed modifying the T2 contrast retrospectively, further improving the diagnostic fidelity. CONCLUSION: The proposed radial TSE sequence allowed for high-resolution imaging with limited obscuring artifacts. The radial k-space traversal allowed for versatile post-processing that may help to improve the diagnosis of subtle diseases.

Optimization of the AC-gradient method for velocity profile measurement and application to slow flow.

This work presents a spectroscopic method to measure slow flow. Within a single shot the velocity distribution is acquired. This allows distinguishing rapidly between single velocities within the sampled volume with a high sensitivity. The technique is based on signal acquisition in the presence of a periodic gradient and a train of refocussing RF pulses. The theoretical model for trapezoidal bipolar pulse shaped gradients under consideration of diffusion and the outflow effect is introduced. A phase correction technique is presented that improves the spectral accuracy. Therefore, flow phantom measurements are used to validate the new sequence and the simulation based on the theoretical model. It was demonstrated that accurate parabolic flow profiles can be acquired and flow variations below 200 µm/s can be detected. Three post-processing methods that eliminate static background signal are also presented for applications in which static background signal dominates. Finally, this technique is applied to flow measurement of a small alder tree demonstrating a typical application of in vivo plant measurements.

Spatial phase encoding exploiting the Bloch-Siegert shift effect.

OBJECTIVE: The present work introduces an alternative to the conventional B0-gradient spatial phase encoding technique. By applying far off-resonant radiofrequency (RF) pulses, a spatially dependent phase shift is introduced to the on-resonant transverse magnetization. This so-called Bloch-Siegert (BS) phase shift has been recently used for B1(+)-mapping. The current work presents the theoretical background for the BS spatial encoding technique (BS-SET) using RF-gradients. MATERIALS AND METHODS: Since the BS-gradient leads to nonlinear encoding, an adapted reconstruction method was developed to obtain undistorted images. To replace conventional phase encoding gradients, BS-SET was implemented in a two-dimensional (2D) spin echo sequence on a 0.5 T portable MR scanner. RESULTS: A 2D spin echo (SE) measurement imaged along a single dimension using the BS-SET was compared to a conventional SE 2D measurement. The proposed reconstruction method yielded undistorted images. CONCLUSIONS: BS-gradients were demonstrated as a feasible option for spatial phase encoding. Furthermore, undistorted BS-SET images could be obtained using the proposed reconstruction method.

Treatment of malignant effusion by oncolytic virotherapy in an experimental subcutaneous xenograft model of lung cancer.

BACKGROUND: Malignant pleural effusion (MPE) is associated with advanced stages of lung cancer and is mainly dependent on invasion of the pleura and expression of vascular endothelial growth factor (VEGF) by cancer cells. As MPE indicates an incurable disease with limited palliative treatment options and poor outcome, there is an urgent need for new and efficient treatment options. METHODS: In this study, we used subcutaneously generated PC14PE6 lung adenocarcinoma xenografts in athymic mice that developed subcutaneous malignant effusions (ME) which mimic pleural effusions of the orthotopic model. Using this approach monitoring of therapeutic intervention was facilitated by direct observation of subcutaneous ME formation without the need of sacrificing mice or special imaging equipment as in case of MPE. Further, we tested oncolytic virotherapy using Vaccinia virus as a novel treatment modality against ME in this subcutaneous PC14PE6 xenograft model of advanced lung adenocarcinoma. RESULTS: We demonstrated significant therapeutic efficacy of Vaccinia virus treatment of both advanced lung adenocarcinoma and tumor-associated ME. We attribute the efficacy to the virus-mediated reduction of tumor cell-derived VEGF levels in tumors, decreased invasion of tumor cells into the peritumoral tissue, and to viral infection of the blood vessel-invading tumor cells. Moreover, we showed that the use of oncolytic Vaccinia virus encoding for a single-chain antibody (scAb) against VEGF (GLAF-1) significantly enhanced mono-therapy of oncolytic treatment. CONCLUSIONS: Here, we demonstrate for the first time that oncolytic virotherapy using tumor-specific Vaccinia virus represents a novel and promising treatment modality for therapy of ME associated with advanced lung cancer.

Imaging of intratumoral inflammation during oncolytic virotherapy of tumors by 19F-magnetic resonance imaging (MRI).

BACKGROUND: Oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. Unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. Here, we evaluate (19)F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy. METHODOLOGY/PRINCIPAL FINDINGS: The Vaccinia virus strain GLV-1h68 was used as an oncolytic agent for the treatment of different tumor models. Systemic application of PFC emulsions followed by (1)H/(19)F MRI of mock-infected and GLV-1h68-infected tumor-bearing mice revealed a significant accumulation of the (19)F signal in the tumor rim of virus-treated mice. Histological examination of tumors confirmed a similar spatial distribution of the (19)F signal hot spots and CD68(+)-macrophages. Thereby, the CD68(+)-macrophages encapsulate the GFP-positive viral infection foci. In multiple tumor models, we specifically visualized early inflammatory cell recruitment in Vaccinia virus colonized tumors. Furthermore, we documented that the (19)F signal correlated with the extent of viral spreading within tumors. CONCLUSIONS/SIGNIFICANCE: These results suggest (19)F MRI as a non-invasive methodology to document the tumor-associated host immune response as well as the extent of intratumoral viral replication. Thus, (19)F MRI represents a new platform to non-invasively investigate the role of the host immune response for therapeutic outcome of oncolytic virotherapy and individual patient response.

Rapid spectroscopic velocity quantification using periodically oscillating gradients.

In this work two spectroscopic methods are described which allow rapid flow velocity quantification in the presence of a parabolic velocity distribution. This method requires only a single excitation and is based on flow encoding by periodically oscillating gradients. In the shown spin echo variant additional refocusing pulses correct for field inhomogeneities. A theoretical model is introduced, which describes the course of the derived spectra even in high flow region, where a significant part of the encoded spins leaves the sensitive area of the coil during data acquisition (outflow-effect). It was demonstrated that both methods can quantify flow velocities within the velocity range of 1mm/s up to 36 cm/s in the presence of a parabolic flow velocity distribution. The maximum velocity of the parabolic distribution is indicated in this method by a peak in the acquired spectrum from which the velocity could be quantified. Flow velocity quantification by periodically oscillating gradients seems a reasonable and fast alternative to established imaging techniques.

SAR-reduced spin-echo-based Bloch-Siegert B(1)(+) mapping: BS-SE-BURST.

Fast and accurate B(1)(+) mapping is possible using phase-based Bloch-Siegert (BS) methods. Importantly, the off-resonant pulses needed for BS B(1)(+) mapping methods can easily be implemented in multiple MR sequences. BS-based B(1)(+) mapping has thus been introduced for gradient echo (BS-FLASH), spin-echo (BS-SE), and Carr, Purcell, Meiboom, Gill (CPMG)-based multi-SE and turbo-SE sequences. When using SE and multi-SE/turbo-SE-based BS sequences, however, the high intrinsic specific absorption rates must be considered in clinical situations. This study introduces a fast BS B(1)(+) mapping method based on a SE-BURST sequence (BS-SE-BURST). With SE-BURST sequences, multiple low-magnitude excitation pulses are applied prior to the refocusing pulse. Thus, multiple and different phase-encoded echoes can be acquired per excitation cycle. Compared with a SE sequence, this excitation strategy results in a similar signal-to-noise ratio (SNR) per unit time but with reduced specific absorption rate. The proposed BS-SE-BURST sequence was implemented on a conventional 3 T whole body MRI scanner and applied successfully.

Murine atherosclerotic plaque imaging with the USPIO Ferumoxtran-10.

In this study we intended to image plaque inflammation in a murine model of atherosclerosis with MRI and Ferumoxtran-10 (Sinerem, Guerbet, France). 8 apoE-/- mice were injected 500 micromol Fe/kg or 1000 micromol Fe/kg Ferumoxtran-10. 2 apoE-/- mice were injected NaCl. After a post-contrast time of 24 to 336 hours the mice were scarificed and the aortas were imaged ex vivo. All measurements were performed on a 17.6 Tesla Bruker AVANCE 750WB MR scanner (Bruker, Germany). Spin-echo sequences and gradient-echo sequences with variable TE were performed and T2* maps were generated. Prussian-blue and hematoxilin-eosin histology were obtained afterwards and iron-uptake was quantified by counting iron positive areas. 2 apoE-/- mice were imaged in vivo before and 48 hours after 1000 micromol Fe/kg. Atheroma iron uptake was not elevated after 24 hours compared to controls. 48 hours after 1000 micromol Fe/kg but not 500 micromol Fe/kg histology revealed a 1.3- fold increase in plaque iron content compared to NaCl injected mice. Normalized T2*-times decreased from 0.86+/-0.02 in controls to 0.66+/-0.15 after a dose of 500 micromol Fe/ml and 0.59+/-0.14 in mice injected with 1000 micromol Fe/Kg (p=0.038). These results translated into a mean of 122% increase in CNR, as measured by in vivo MRI. We have demonstrated that Ferumoxtran-10 is taken up by atherosclerotic plaques in untreated apoE-/- mice and this alters plaque signal properties.