Eight-channel transceiver RF coil array tailored for (1)H/(19)F MR of the human knee and fluorinated drugs at 7.0 T

The purpose of this study was to evaluate the feasibility of an eight-channel dual-tuned transceiver surface RF coil array for combined (1) H/(19) F MR of the human knee at 7.0 T following application of (19) F-containing drugs. The (1) H/(19) F RF coil array includes a posterior module with two (1) H loop elements and two anterior modules, each consisting of one (1) H and two (19) F elements. The decoupling of neighbor elements is achieved by a shared capacitor. Electromagnetic field simulations were performed to afford uniform transmission fields and to be in accordance with RF safety guidelines. Localized (19) F MRS was conducted with 47 and 101 mmol/L of flufenamic acid (FA) - a (19) F-containing non-steroidal anti-inflammatory drug - to determine T1 and T2 and to study the (19) F signal-to-dose relationship. The suitability of the proposed approach for (1) H/(19) F MR was examined in healthy subjects. Reflection coefficients of each channel were less than -17 dB and coupling between channels was less than -11 dB. QL /QU was less than 0.5 for all elements. MRS results demonstrated signal stability with 1% variation. T1 and T2 relaxation times changed with concentration of FA: T1 /T2 = 673/31 ms at 101 mmol/L and T1 /T2 = 616/26 ms at 47 mmol/L. A uniform signal and contrast across the patella could be observed in proton imaging. The sensitivity of the RF coil enabled localization of FA ointment administrated to the knee with an in-plane spatial resolution of (1.5 × 1.5) mm(2) achieved in a total scan time of approximately three minutes, which is well suited for translational human studies. This study shows the feasibility of combined (1) H/(19) F MRI of the knee at 7.0 T and proposes T1 and T2 mapping methods for quantifying fluorinated drugs in vivo. Further technological developments are necessary to promote real-time bioavailability studies and quantification of (19) F-containing medicinal compounds in vivo

Solving the time- and frequency-multiplexed problem of constrained radiofrequency induced hyperthermia

Targeted radiofrequency (RF) heating induced hyperthermia has a wide range of applications, ranging from adjunct anti-cancer treatment to localized release of drugs. Focal RF heating is usually approached using time-consuming nonconvex optimization procedures or approximations, which significantly hampers its application. To address this limitation, this work presents an algorithm that recasts the problem as a semidefinite program and quickly solves it to global optimality, even for very large (human voxel) models. The target region and a desired RF power deposition pattern as well as constraints can be freely defined on a voxel level, and the optimum application RF frequencies and time-multiplexed RF excitations are automatically determined. 2D and 3D example applications conducted for test objects containing pure water (r(target) = 19 mm, frequency range: 500–2000 MHz) and for human brain models including brain tumors of various size (r(1) = 20 mm, r(2) = 30 mm, frequency range 100–1000 MHz) and locations (center, off-center, disjoint) demonstrate the applicability and capabilities of the proposed approach. Due to its high performance, the algorithm can solve typical clinical problems in a few seconds, making the presented approach ideally suited for interactive hyperthermia treatment planning, thermal dose and safety management, and the design, rapid evaluation, and comparison of RF applicator configurations

Fluorine-19 MRI at 21.1 T: enhanced spin-lattice relaxation of perfluoro-15-crown-5-ether and sensitivity as demonstrated in ex vivo murine neuroinflammation

OBJECTIVE: Fluorine MR would benefit greatly from enhancements in signal-to-noise ratio (SNR). This study examines the sensitivity gain of (19)F MR that can be practically achieved when moving from 9.4 to 21.1 T. MATERIALS AND METHODS: We studied perfluoro-15-crown-5-ether (PFCE) at both field strengths (B(0)), as a pure compound, in the form of nanoparticles (NP) as employed to study inflammation in vivo, as well as in inflamed tissue. Brains, lymph nodes (LNs) and spleens were obtained from mice with experimental autoimmune encephalomyelitis (EAE) that had been administered PFCE NPs. All samples were measured at both B(0) with 2D-RARE and 2D-FLASH using (19)F volume radiofrequency resonators together. T(1) and T(2) of PFCE were measured at both B(0) strengths. RESULTS: Compared to 9.4 T, an SNR gain of > 3 was observed for pure PFCE and > 2 for PFCE NPs at 21.1 T using 2D-FLASH. A dependency of (19)F T(1) and T(2) relaxation on B(0) was demonstrated. High spatially resolved (19)F MRI of EAE brains and LNs at 21.1 T revealed signals not seen at 9.4 T. DISCUSSION: Enhanced SNR and T(1) shortening indicate the potential benefit of in vivo (19)F MR at higher B(0) to study inflammatory processes with greater detail

ERK1 as a therapeutic target for dendritic cell vaccination against high-grade gliomas

Glioma regression requires the recruitment of potent anti-tumor immune cells into the tumor microenvironment. Dendritic cells (DCs) play a role in immune responses to these tumors. The fact that DC vaccines do not effectively combat high-grade gliomas, however, suggests that DCs need to be genetically modified especially to promote their migration to tumor relevant sites. Previously, we identified extracellular signal-regulated kinase (ERK1) as a regulator of DC immunogenicity and brain autoimmunity. In the present study, we made use of modern magnetic resonance methods to study the role of ERK1 in regulating DC migration and tumor progression in a model of high-grade glioma. We found that ERK1-deficient mice are more resistant to the development of gliomas, and tumor growth in these mice is accompanied by a higher infiltration of leukocytes. ERK1-deficient DCs exhibit an increase in migration that is associated with sustained Cdc42 activation and increased expression of actin-associated cytoskeleton-organizing proteins. We also demonstrated that ERK1 deletion potentiates DC vaccination and provides a survival advantage in high-grade gliomas. Considering the therapeutic significance of these results, we propose ERK1-deleted DC vaccines as an additional means of eradicating resilient tumor cells and preventing tumor recurrence

Visualizing brain inflammation with a shingled-leg radio-frequency head probe for (19)F/(1)H MRI

Magnetic resonance imaging (MRI) provides the opportunity of tracking cells in vivo. Major challenges in dissecting cells from the recipient tissue and signal sensitivity constraints albeit exist. In this study, we aimed to tackle these limitations in order to study inflammation in autoimmune encephalomyelitis. We constructed a very small dual-tunable radio frequency (RF) birdcage probe tailored for (19)F (fluorine) and (1)H (proton) MR mouse neuroimaging. The novel design eliminated the need for extra electrical components on the probe structure and afforded a uniform -field as well as good SNR. We employed fluorescently-tagged (19)F nanoparticles and could study the dynamics of inflammatory cells between CNS and lymphatic system during development of encephalomyelitis, even within regions of the brain that are otherwise not easily visualized by conventional probes. (19)F/(1)H MR Neuroimaging will allow us to study the nature of immune cell infiltration during brain inflammation over an extensive period of time

High temporal resolution parametric MRI monitoring of the initial ischemia/reperfusion phase in experimental acute kidney injury

Ischemia/reperfusion (I/R) injury, a consequence of kidney hypoperfusion or temporary interruption of blood flow is a common cause of acute kidney injury (AKI). There is an unmet need to better understand the mechanisms operative during the initial phase of ischemic AKI. Non-invasive parametric magnetic resonance imaging (MRI) may elucidate spatio-temporal pathophysiological changes in the kidney by monitoring the MR relaxation parameters T* and T, which are known to be sensitive to blood oxygenation. The aim of our study was to establish the technical feasibility of fast continuous T*/T mapping throughout renal I/R. MRI was combined with a remotely controlled I/R model and a segmentation model based semi-automated quantitative analysis. This technique enabled the detailed assessment of changes in all kidney regions during ischemia and early reperfusion. Significant changes in T* and T were observed shortly after induction of renal ischemia and during the initial reperfusion phase. Our study demonstrated for the first time that continuous and high temporal resolution parametric MRI is feasible for monitoring and characterization of I/R induced AKI in rats. This technique may help in the identification of the timeline of key events responsible for development of renal damage in hypoperfusion-induced AKI

Enhanced fluorine-19 MRI sensitivity using a cryogenic radiofrequency probe: technical developments and ex vivo demonstration in a mouse model of neuroinflammation

Neuroinflammation can be monitored using fluorine-19 ((19)F)-containing nanoparticles and (19)F MRI. Previously we studied neuroinflammation in experimental autoimmune encephalomyelitis (EAE) using room temperature (RT) (19)F radiofrequency (RF) coils and low spatial resolution (19)F MRI to overcome constraints in signal-to-noise ratio (SNR). This yielded an approximate localization of inflammatory lesions. Here we used a new (19)F transceive cryogenic quadrature RF probe ((19) F-CRP) that provides the SNR necessary to acquire superior spatially-resolved (19)F MRI. First we characterized the signal-transmission profile of the (19) F-CRP. The (19) F-CRP was then benchmarked against a RT (19)F/(1)H RF coil. For SNR comparison we used reference compounds including (19)F-nanoparticles and ex vivo brains from EAE mice administered with (19)F-nanoparticles. The transmit/receive profile of the (19) F-CRP diminished with increasing distance from the surface. This was counterbalanced by a substantial SNR gain compared to the RT coil. Intraparenchymal inflammation in the ex vivo EAE brains was more sharply defined when using 150 μm isotropic resolution with the (19) F-CRP, and reflected the known distribution of EAE histopathology. At this spatial resolution, most (19)F signals were undetectable using the RT coil. The (19) F-CRP is a valuable tool that will allow us to study neuroinflammation with greater detail in future in vivo studies

B(1) inhomogeneity correction of RARE MRI at low SNR: quantitative in vivo (19)F MRI of mouse neuroinflammation with a cryogenically-cooled transceive surface radiofrequency probe

PURPOSE: Low SNR in fluorine-19 (19F) MRI benefits from cryogenically-cooled transceive surface RF probes (CRPs), but strong B(1) inhomogeneities hinder quantification. Rapid acquisition with refocused echoes (RARE) is an SNR-efficient method for MRI of neuroinflammation with perfluorinated compounds but lacks an analytical signal intensity equation to retrospectively correct B(1) inhomogeneity. Here, a workflow was proposed and validated to correct and quantify (19)F-MR signals from the inflamed mouse brain using a (19)F-CRP. METHODS: In vivo (19)F-MR images were acquired in a neuroinflammation mouse model with a quadrature (19)F-CRP using an imaging setup including 3D-printed components to acquire co-localized anatomical and (19)F images. Model-based corrections were validated on a uniform (19)F phantom and in the neuroinflammatory model. Corrected (19)F-MR images were benchmarked against reference images and overlaid on in vivo (1)H-MR images. Computed concentration uncertainty maps using Monte Carlo simulations served as a measure of performance of the B(1) corrections. RESULTS: Our study reports on the first quantitative in vivo (19)F-MR images of an inflamed mouse brain using a (19)F-CRP, including in vivo T(1) calculations for (19)F-nanoparticles during pathology and B(1) corrections for (19)F-signal quantification. Model-based corrections markedly improved (19)F-signal quantification from errors > 50% to < 10% in a uniform phantom (p < 0.001). Concentration uncertainty maps ex vivo and in vivo yielded uncertainties that were generally < 25%. Monte Carlo simulations prescribed SNR ≥ 10.1 to reduce uncertainties < 10%, and SNR ≥ 4.25 to achieve uncertainties < 25%. CONCLUSION: Our model-based correction method facilitated (19)F signal quantification in the inflamed mouse brain when using the SNR-boosting (19)F-CRP technology, paving the way for future low-SNR (19)F-MRI applications in vivo

First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod

Theranostic imaging methods could greatly enhance our understanding of the distribution of CNS-acting drugs in individual patients. Fluorine-19 magnetic resonance imaging ((19)F MRI) offers the opportunity to localize and quantify fluorinated drugs non-invasively, without modifications and without the application of ionizing or other harmful radiation. Here we investigated siponimod, a sphingosine 1-phosphate (S(1)P) receptor antagonist indicated for secondary progressive multiple sclerosis (SPMS), to determine the feasibility of in vivo (19)F MR imaging of a disease modifying drug. METHODS: The (19)F MR properties of siponimod were characterized using spectroscopic techniques. Four MRI methods were investigated to determine which was the most sensitive for (19)F MR imaging of siponimod under biological conditions. We subsequently administered siponimod orally to 6 mice and acquired (19)F MR spectra and images in vivo directly after administration, and in ex vivo tissues. RESULTS: The (19)F transverse relaxation time of siponimod was 381 ms when dissolved in dimethyl sulfoxide, and substantially reduced to 5 ms when combined with serum, and to 20 ms in ex vivo liver tissue. Ultrashort echo time (UTE) imaging was determined to be the most sensitive MRI technique for imaging siponimod in a biological context and was used to map the drug in vivo in the stomach and liver. Ex vivo images in the liver and brain showed an inhomogeneous distribution of siponimod in both organs. In the brain, siponimod accumulated predominantly in the cerebrum but not the cerebellum. No secondary (19)F signals were detected from metabolites. From a translational perspective, we found that acquisitions done on a 3.0 T clinical MR scanner were 2.75 times more sensitive than acquisitions performed on a preclinical 9.4 T MR setup when taking changes in brain size across species into consideration and using equivalent relative spatial resolution. CONCLUSION: Siponimod can be imaged non-invasively using (19)F UTE MRI in the form administered to MS patients, without modification. This study lays the groundwork for more extensive preclinical and clinical investigations. With the necessary technical development, (19)F MRI has the potential to become a powerful theranostic tool for studying the time-course and distribution of CNS-acting drugs within the brain, especially during pathology

Multiband diffusion-weighted MRI of the eye and orbit free of geometric distortions using a RARE-EPI hybrid

Diffusion-weighted imaging (DWI) provides information on tissue microstructure. Single-shot echo planar imaging (EPI) is the most common technique for DWI applications in the brain, but is prone to geometric distortions and signal voids. Rapid acquisition with relaxation enhancement [RARE, also known as fast spin echo (FSE)] imaging presents a valuable alternative to DWI with high anatomical accuracy. This work proposes a multi-shot diffusion-weighted RARE-EPI hybrid pulse sequence, combining the anatomical integrity of RARE with the imaging speed and radiofrequency (RF) power deposition advantage of EPI. The anatomical integrity of RARE-EPI was demonstrated and quantified by center of gravity analysis for both morphological images and diffusion-weighted acquisitions in phantom and in vivo experiments at 3.0 T and 7.0 T. The results indicate that half of the RARE echoes in the echo train can be replaced by EPI echoes whilst maintaining anatomical accuracy. The reduced RF power deposition of RARE-EPI enabled multiband RF pulses facilitating simultaneous multi-slice imaging. This study shows that diffusion-weighted RARE-EPI has the capability to acquire high fidelity, distortion-free images of the eye and the orbit. It is shown that RARE-EPI maintains the immunity to B0 inhomogeneities reported for RARE imaging. This benefit can be exploited for the assessment of ocular masses and pathological changes of the eye and the orbit