In vivo monitoring of renal tubule volume fraction using dynamic parametric MRI.

PURPOSE: The increasing incidence of kidney diseases is a global concern, and current biomarkers and treatments are inadequate. Changes in renal tubule luminal volume fraction (TVF) serve as a rapid biomarker for kidney disease and improve understanding of renal (patho)physiology. This study uses the amplitude of the long T2 component as a surrogate for TVF in rats, by applying multiexponential analysis of the T2-driven signal decay to examine micromorphological changes in renal tissue. METHODS: Simulations were conducted to identify a low mean absolute error (MAE) protocol and an accelerated protocol customized for the in vivo study of T2 mapping of the rat kidney at 9.4 T. We then validated our bi-exponential approach in a phantom mimicking the relaxation properties of renal tissue. This was followed by a proof-of-principle demonstration using in vivo data obtained during a transient increase of renal pelvis and tubular pressure. RESULTS: Using the low MAE protocol, our approach achieved an accuracy of MAE < 1% on the mechanical phantom. The T2 mapping protocol customized for in vivo study achieved an accuracy of MAE < 3%. Transiently increasing pressure in the renal pelvis and tubules led to significant changes in TVF in renal compartments: ΔTVFcortex = 4.9%, ΔTVFouter_medulla = 4.5%, and ΔTVFinner_medulla = -14.6%. CONCLUSION: These results demonstrate that our approach is promising for research into quantitative assessment of renal TVF in in vivo applications. Ultimately, these investigations have the potential to help reveal mechanism in acute renal injury that may lead to chronic kidney disease, which will support research into renal disorders.

Dynamic parametric MRI and deep learning: Unveiling renal pathophysiology through accurate kidney size quantification.

Renal pathologies often manifest as alterations in kidney size, providing a valuable avenue for employing dynamic parametric MRI as a means to derive kidney size measurements for the diagnosis, treatment, and monitoring of renal disease. Furthermore, this approach holds significant potential in supporting MRI data-driven preclinical investigations into the intricate mechanisms underlying renal pathophysiology. The integration of deep learning algorithms is crucial in achieving rapid and precise segmentation of the kidney from temporally resolved parametric MRI, facilitating the use of kidney size as a meaningful (pre)clinical biomarker for renal disease. To explore this potential, we employed dynamic parametric T2 mapping of the kidney in rats in conjunction with a custom-tailored deep dilated U-Net (DDU-Net) architecture. The architecture was trained, validated, and tested on manually segmented ground truth kidney data, with benchmarking against an analytical segmentation model and a self-configuring no new U-Net. Subsequently, we applied our approach to in vivo longitudinal MRI data, incorporating interventions that emulate clinically relevant scenarios in rats. Our approach achieved high performance metrics, including a Dice coefficient of 0.98, coefficient of determination of 0.92, and a mean absolute percentage error of 1.1% compared with ground truth. The DDU-Net enabled automated and accurate quantification of acute changes in kidney size, such as aortic occlusion (-8% ± 1%), venous occlusion (5% ± 1%), furosemide administration (2% ± 1%), hypoxemia (-2% ± 1%), and contrast agent-induced acute kidney injury (11% ± 1%). This approach can potentially be instrumental for the development of dynamic parametric MRI-based tools for kidney disorders, offering unparalleled insights into renal pathophysiology.

MRI of kidney size matters.

OBJECTIVE: To highlight progress and opportunities of measuring kidney size with MRI, and to inspire research into resolving the remaining methodological gaps and unanswered questions relating to kidney size assessment. MATERIALS AND METHODS: This work is not a comprehensive review of the literature but highlights valuable recent developments of MRI of kidney size. RESULTS: The links between renal (patho)physiology and kidney size are outlined. Common methodological approaches for MRI of kidney size are reviewed. Techniques tailored for renal segmentation and quantification of kidney size are discussed. Frontier applications of kidney size monitoring in preclinical models and human studies are reviewed. Future directions of MRI of kidney size are explored. CONCLUSION: MRI of kidney size matters. It will facilitate a growing range of (pre)clinical applications, and provide a springboard for new insights into renal (patho)physiology. As kidney size can be easily obtained from already established renal MRI protocols without the need for additional scans, this measurement should always accompany diagnostic MRI exams. Reconciling global kidney size changes with alterations in the size of specific renal layers is an important topic for further research. Acute kidney size measurements alone cannot distinguish between changes induced by alterations in the blood or the tubular volume fractions-this distinction requires further research into cartography of the renal blood and the tubular volumes.

High-Fidelity 3D Stray Magnetic Field Mapping of Smartphones to Address Safety Considerations with Active Implantable Electronic Medical Devices.

Case reports indicate that magnets in smartphones could be a source of electromagnetic interference (EMI) for active implantable medical devices (AIMD), which could lead to device malfunction, compromising patient safety. Recognizing this challenge, we implemented a high-fidelity 3D magnetic field mapping (spatial resolution 1 mm) setup using a three-axis Hall probe and teslameter, controlled by a robot (COSI Measure). With this setup, we examined the stray magnetic field of an iPhone 13 Pro, iPhone 12, and MagSafe charger to identify sources of magnetic fields for the accurate risk assessment of potential interferences with AIMDs. Our measurements revealed that the stray fields of the annular array of magnets, the wide-angle camera, and the speaker of the smartphones exceeded the 1 mT limit defined by ISO 14117:2019. Our data-driven safety recommendation is that an iPhone 13 Pro should be kept at least 25 mm away from an AIMD to protect it from unwanted EMI interactions. Our study addresses safety concerns due to potential device-device interactions between smartphones and AIMDs and will help to define data-driven safety guidelines. We encourage vendors of electronic consumer products (ECP) to provide information on the magnetic fields of their products and advocate for the inclusion of smartphones in the risk assessment of EMI with AIMDs.

B1 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 (19 F) MRI benefits from cryogenically-cooled transceive surface RF probes (CRPs), but strong B1 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 B1 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 B1 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 T1 calculations for 19 F-nanoparticles during pathology and B1 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.

Simultaneous T2 and T2∗ mapping of multiple sclerosis lesions with radial RARE-EPI.

PURPOSE: The characteristic MRI features of multiple sclerosis (MS) lesions make it conceptually appealing to pursue parametric mapping techniques that support simultaneous generation of quantitative maps of 2 or more MR contrast mechanisms. We present a modular rapid acquisition with relaxation enhancement (RARE)-EPI hybrid that facilitates simultaneous T2 and T2∗ mapping (2in1-RARE-EPI). METHODS: In 2in1-RARE-EPI the first echoes in the echo train are acquired with a RARE module, later echoes are acquired with an EPI module. To define the fraction of echoes covered by the RARE and EPI module, an error analysis of T2 and T2∗ was conducted with Monte Carlo simulations. Radial k-space (under)sampling was implemented for acceleration (R = 2). The feasibility of 2in1-RARE-EPI for simultaneous T2 and T2∗ mapping was examined in a phantom study mimicking T2 and T2∗ relaxation times of the brain. For validation, 2in1-RARE-EPI was benchmarked versus multi spin-echo (MSE) and multi gradient-echo (MGRE) techniques. The clinical applicability of 2in1-RARE-EPI was demonstrated in healthy subjects and MS patients. RESULTS: There was a good agreement between T2 / T2∗ values derived from 2in1-RARE-EPI and T2 / T2∗ reference values obtained from MSE and MGRE in both phantoms and healthy subjects. In patients, MS lesions in T2 and T2∗ maps deduced from 2in1-RARE-EPI could be just as clearly delineated as in reference maps calculated from MSE/MGRE. CONCLUSION: This work demonstrates the feasibility of radially (under)sampled 2in1-RARE-EPI for simultaneous T2 and T2∗ mapping in MS patients.

B1 inhomogeneity correction of RARE MRI with transceive surface radiofrequency probes.

PURPOSE: The use of surface radiofrequency (RF) coils is common practice to boost sensitivity in (pre)clinical MRI. The number of transceive surface RF coils is rapidly growing due to the surge in cryogenically cooled RF technology and ultrahigh-field MRI. Consequently, there is an increasing need for effective correction of the excitation field ( B1+ ) inhomogeneity inherent in these coils. Retrospective B1 correction permits quantitative MRI, but this usually requires a pulse sequence-specific analytical signal intensity (SI) equation. Such an equation is not available for fast spin-echo (Rapid Acquisition with Relaxation Enhancement, RARE) MRI. Here we present, test, and validate retrospective B1 correction methods for RARE. METHODS: We implemented the commonly used sensitivity correction and developed an empirical model-based method and a hybrid combination of both. Tests and validations were performed with a cryogenically cooled RF probe and a single-loop RF coil. Accuracy of SI quantification and T1 contrast were evaluated after correction. RESULTS: The three described correction methods achieved dramatic improvements in B1 homogeneity and significantly improved SI quantification and T1 contrast, with mean SI errors reduced from >40% to >10% following correction in all cases. Upon correction, images of phantoms and mouse heads demonstrated homogeneity comparable to that of images acquired with a volume resonator. This was quantified by SI profile, SI ratio (error < 10%), and percentage of integral uniformity (PIU > 80% in vivo and ex vivo compared to PIU > 87% with the reference RF coil). CONCLUSION: This work demonstrates the efficacy of three B1 correction methods tailored for transceive surface RF probes and RARE MRI. The corrected images are suitable for quantification and show comparable results between the three methods, opening the way for T1 measurements and X-nuclei quantification using surface transceiver RF coils. This approach is applicable to other MR techniques for which no analytical SI exists.

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 19F 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 (B0), 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 B0 with 2D-RARE and 2D-FLASH using 19F volume radiofrequency resonators together. T1 and T2 of PFCE were measured at both B0 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 19F T1 and T2 relaxation on B0 was demonstrated. High spatially resolved 19F MRI of EAE brains and LNs at 21.1 T revealed signals not seen at 9.4 T. DISCUSSION: Enhanced SNR and T1 shortening indicate the potential benefit of in vivo 19F MR at higher B0 to study inflammatory processes with greater detail.

CX3CR1-dependent recruitment of mature NK cells into the central nervous system contributes to control autoimmune neuroinflammation.

Fractalkine receptor (CX3CR1)-deficient mice develop very severe experimental autoimmune encephalomyelitis (EAE), associated with impaired NK cell recruitment into the CNS. Yet, the precise implications of NK cells in autoimmune neuroinflammation remain elusive. Here, we investigated the pattern of NK cell mobilization and the contribution of CX3CR1 to NK cell dynamics in the EAE. We show that in both wild-type and CX3CR1-deficient EAE mice, NK cells are mobilized from the periphery and accumulate in the inflamed CNS. However, in CX3CR1-deficient mice, the infiltrated NK cells displayed an immature phenotype contrasting with the mature infiltrates in WT mice. This shift in the immature/mature CNS ratio contributes to EAE exacerbation in CX3CR1-deficient mice, since transfer of mature WT NK cells prior to immunization exerted a protective effect and normalized the CNS NK cell ratio. Moreover, mature CD11b(+) NK cells show higher degranulation in the presence of autoreactive 2D2 transgenic CD4(+) T cells and kill these autoreactive cells more efficiently than the immature CD11b(-) fraction. Together, these data suggest a protective role of mature NK cells in EAE, possibly through direct modulation of T cells inside the CNS, and demonstrate that mature and immature NK cells are recruited into the CNS by distinct chemotactic signals.

Synthesis of europium-doped VSOP, customized enhancer solution and improved microscopy fluorescence methodology for unambiguous histological detection.

BACKGROUND: Intrinsic iron in biological tissues frequently precludes unambiguous the identification of iron oxide nanoparticles when iron-based detection methods are used. Here we report the full methodology for synthesizing very small iron oxide nanoparticles (VSOP) doped with europium (Eu) in their iron oxide core (Eu-VSOP) and their unambiguous qualitative and quantitative detection by fluorescence. METHODS AND RESULTS: The resulting Eu-VSOP contained 0.7 to 2.7% Eu relative to iron, which was sufficient for fluorescent detection while not altering other important particle parameters such as size, surface charge, or relaxivity. A customized enhancer solution with high buffer capacity and nearly neutral pH was developed to provide an antenna system that allowed fluorescent detection of Eu-VSOP in cells and histologic tissue slices as well as in solutions even under acidic conditions as frequently obtained from dissolved organic material. This enhancer solution allowed detection of Eu-VSOP using a standard fluorescence spectrophotometer and a fluorescence microscope equipped with a custom filter set with an excitation wavelength (λex) of 338 nm and an emission wavelength (λem) of 616 nm. CONCLUSION: The fluorescent detection of Eu-doped very small iron oxide nanoparticles (Eu-VSOP) provides a straightforward tool to unambiguously characterize VSOP biodistribution and toxicology at tissue, and cellular levels, providing a sensitive analytical tool to detect Eu-doped IONP in dissolved organ tissue and biological fluids with fluorescence instruments.

Inflammation-induced brain endothelial activation leads to uptake of electrostatically stabilized iron oxide nanoparticles via sulfated glycosaminoglycans.

Based on our previous data on the presence of very small superparamagnetic iron oxide nanoparticles (VSOP) on brain endothelial structures during experimental autoimmune encephalomyelitis (EAE), we investigated the mechanisms of VSOP binding on inflamed brain endothelial cells in vivo and in vitro. After intravenous application, VSOP were detected in brain endothelial cells of EAE animals at peak disease and prior to clinical onset. In vitro, inflammatory stimuli increased VSOP uptake by brain endothelial bEnd.3 cells, which we confirmed in primary endothelial cells and in bEnd.3 cells cultured under shear stress. Transmission electron microscopy and blocking experiments revealed that during inflammation VSOP were endocytosed by bEnd.3. Modified sulfated glycosaminoglycans (GAG) on inflamed brain endothelial cells were the primary binding site for VSOP, as GAG degradation and inhibition of GAG sulfation reduced VSOP uptake. Thus, VSOP-based MRI is sensitive to visualize early neuroinflammatory processes such as GAG modifications on brain endothelial cells.

Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica.

BACKGROUND: In contrast to multiple sclerosis (MS), lesions in neuromyelitis optica (NMO) frequently contain neutrophils. However, the phenotypic profile of neutrophils in these two distinct pathologies remains unknown. OBJECTIVE: Our aim is to better understand the potential contribution of neutrophils to NMO and MS pathology. METHODS: We performed the first functional analysis of blood neutrophils in NMO and MS, including evaluation of neutrophil immune response (fMLP receptor, TLR2), chemotaxis and migration (CXCR1, CD62L, CD43), regulation of complement (CD46, CD55, CD59), respiratory burst, phagocytosis and degranulation. RESULTS: Compared with healthy controls (HC), neutrophils in NMO and MS show an activated phenotype characterized by an increased surface expression of TLR2 and fMLP receptor. However, contrary to MS neutrophils, NMO neutrophils show reduced adhesion and migratory capacity as well as decreased reduced production of reactive oxygen species (respiratory burst) and degranulation. CONCLUSION: Although NMO and MS neutrophils display an activated phenotype in comparison with HC, NMO neutrophils show a compromised functionality when compared with MS patients. These results suggest a distinct functional profile of neutrophils in MS and NMO.

A revised strategy for monitoring BKV-specific cellular immunity in kidney transplant patients.

Reactivation of Polyomavirus BKV is a severe complication in kidney transplant patients. Current treatment requires close monitoring, and modification of immunosuppressive drugs. As an important additional tool, the monitoring of BKV immunity has been based on detection of cytokine-secreting T cells upon BKV-antigen challenge. However, low frequent BKV-specific T cells are often barely detectable and their roles in BKV clearance remain unclear. Here, we analyzed the effects of immunosuppressive agents on BKV-specific T cells in vitro. Significant reductions in expression of several markers, and reduced killing functions upon treatment with calcineurin but not mTOR inhibitors were detected. However, effects of these drugs on expression of surface markers and GranzymeB were substantially less striking than effects on cytokine expression. Consequently, we applied a novel detection strategy for BKV-specific T cells in immunosuppressed kidney transplant patients using these more robust markers, and showed significantly improved sensitivity compared with the conventional IFNγ-based method. Using this strategy and 17-color flow cytometry, we found BKV-specific helper and cytolytic CD4+ T-cell subsets that differed in their memory phenotype, which corresponded with BKV clearance in kidney transplant patients. Thus, our results offer an improved detection strategy for BKV-specific T cells in kidney transplant patients, and shed light on the contributions of these cells to BKV clearance.

Tissue structure and inflammatory processes shape viscoelastic properties of the mouse brain.

Magnetic resonance elastography (MRE) is an imaging method that reveals the mechanical properties of tissue, modelled as a combination of " viscosity" and " elasticity" . We recently showed reduced brain viscoelasticity in multiple sclerosis (MS) patients compared with healthy controls, and in the relapsing-remitting disease model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which these intrinsic tissue properties become altered remain unclear. This study investigates whether distinct regions in the mouse brain differ in their native viscoelastic properties, and how these properties are affected during chronic EAE in C57Bl/6 mice and in mice lacking the cytokine interferon-gamma. IFN-γ(-/-) mice exhibit a more severe EAE phenotype, with amplified inflammation in the cerebellum and brain stem. Brain scans were performed in the sagittal plane using a 7 T animal MRI scanner, and the anterior (cerebral) and posterior (cerebellar) regions analyzed separately. MRE investigations were accompanied by contrast-enhanced MRI scans, and by histopathology and gene expression analysis ex vivo. Compared with the cerebrum, the cerebellum in healthy mice has a lower viscoelasticity, i.e. it is intrinsically " softer" . This was seen both in the wild-type mice and the IFNγ(-/-) mice. During chronic EAE, C57Bl/6 mice did not show altered brain viscoelasticity. However, as expected, the IFNγ(-/-) mice showed a more severe EAE phenotype, and these mice did show altered brain elasticity during the course of disease. The magnitude of the elasticity reduction correlated with F4/80 gene expression, a marker for macrophages/microglia in inflamed central nervous system tissue. Together these results demonstrate that MRE is sensitive enough to discriminate between viscoelastic properties in distinct anatomical structures in the mouse brain, and to confirm a further relationship between cellular inflammation and mechanical alterations of the brain. This study underscores the utility of MRE to monitor pathological tissue alterations in vivo.

Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation.

The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation.

Accelerated Simultaneous T2 and T2* Mapping of Multiple Sclerosis Lesions Using Compressed Sensing Reconstruction of Radial RARE-EPI MRI.

(1) Background: Radial RARE-EPI MRI facilitates simultaneous T2 and T2* mapping (2in1-RARE-EPI). With modest undersampling (R = 2), the speed gain of 2in1-RARE-EPI relative to Multi-Spin-Echo and Multi-Gradient-Recalled-Echo references is limited. Further reduction in scan time is crucial for clinical studies investigating T2 and T2* as imaging biomarkers. We demonstrate the feasibility of further acceleration, utilizing compressed sensing (CS) reconstruction of highly undersampled 2in1-RARE-EPI. (2) Methods: Two-fold radially-undersampled 2in1-RARE-EPI data from phantoms, healthy volunteers (n = 3), and multiple sclerosis patients (n = 4) were used as references, and undersampled (Rextra = 1-12, effective undersampling Reff = 2-24). For each echo time, images were reconstructed using CS-reconstruction. For T2 (RARE module) and T2* mapping (EPI module), a linear least-square fit was applied to the images. T2 and T2* from CS-reconstruction of undersampled data were benchmarked against values from CS-reconstruction of the reference data. (3) Results: We demonstrate accelerated simultaneous T2 and T2* mapping using undersampled 2in1-RARE-EPI with CS-reconstruction is feasible. For Rextra = 6 (TA = 01:39 min), the overall MAPE was ≤8% (T2*) and ≤4% (T2); for Rextra = 12 (TA = 01:06 min), the overall MAPE was <13% (T2*) and <5% (T2). (4) Conclusion: Substantial reductions in scan time are achievable for simultaneous T2 and T2* mapping of the brain using highly undersampled 2in1-RARE-EPI with CS-reconstruction.

Monitoring kidney size to interpret MRI-based assessment of renal oxygenation in acute pathophysiological scenarios.

AIM: Tissue hypoxia is an early key feature of acute kidney injury. Assessment of renal oxygenation using magnetic resonance imaging (MRI) markers T2 and T2 * enables insights into renal pathophysiology. This assessment can be confounded by changes in the blood and tubular volume fractions, occurring upon pathological insults. These changes are mirrored by changes in kidney size (KS). Here, we used dynamic MRI to monitor KS for physiological interpretation of T2 * and T2 changes in acute pathophysiological scenarios. METHODS: KS was determined from T2 *, T2 mapping in rats. Six interventions that acutely alter renal tissue oxygenation were performed directly within the scanner, including interventions that change the blood and/or tubular volume. A biophysical model was used to estimate changes in O2 saturation of hemoglobin from changes in T2 * and KS. RESULTS: Upon aortic occlusion KS decreased; this correlated with a decrease in T2 *, T2 . Upon renal vein occlusion KS increased; this negatively correlated with a decrease in T2 *, T2 . Upon simultaneous occlusion of both vessels KS remained unchanged; there was no correlation with decreased T2 *, T2 . Hypoxemia induced mild reductions in KS and T2 *, T2 . Administration of an X-ray contrast medium induced sustained KS increase, with an initial increase in T2 *, T2 followed by a decrease. Furosemide caused T2 *, T2 elevation and a minor increase in KS. Model calculations yielded physiologically plausible calibration ratios for T2 *. CONCLUSION: Monitoring KS allows physiological interpretation of acute renal oxygenation changes obtained by T2 *, T2 . KS monitoring should accompany MRI-oximetry, for new insights into renal pathophysiology and swift translation into human studies.

Advanced Radio Frequency Applicators for Thermal Magnetic Resonance Theranostics of Brain Tumors.

Thermal Magnetic Resonance (ThermalMR) is a theranostic concept that combines diagnostic magnetic resonance imaging (MRI) with targeted thermal therapy in the hyperthermia (HT) range using a radiofrequency (RF) applicator in an integrated system. ThermalMR adds a therapeutic dimension to a diagnostic MRI device. Focused, targeted RF heating of deep-seated brain tumors, accurate non-invasive temperature monitoring and high-resolution MRI are specific requirements of ThermalMR that can be addressed with novel concepts in RF applicator design. This work examines hybrid RF applicator arrays combining loop and self-grounded bow-tie (SGBT) dipole antennas for ThermalMR of brain tumors, at magnetic field strengths of 7.0 T, 9.4 T and 10.5 T. These high-density RF arrays improve the feasible transmission channel count, and provide additional degrees of freedom for RF shimming not afforded by using dipole antennas only, for superior thermal therapy and MRI diagnostics. These improvements are especially relevant for ThermalMR theranostics of deep-seated brain tumors because of the small surface area of the head. ThermalMR RF applicators with the hybrid loop+SGBT dipole design outperformed applicators using dipole-only and loop-only designs, with superior MRI performance and targeted RF heating. Array variants with a horse-shoe configuration covering an arc (270°) around the head avoiding the eyes performed better than designs with 360° coverage, with a 1.3 °C higher temperature rise inside the tumor while sparing healthy tissue. Our EMF and temperature simulations performed on a virtual patient with a clinically realistic intracranial tumor provide a technical foundation for implementation of advanced RF applicators tailored for ThermalMR theranostics of brain tumors.

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 (19F 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 (S1P) receptor antagonist indicated for secondary progressive multiple sclerosis (SPMS), to determine the feasibility of in vivo 19F MR imaging of a disease modifying drug. Methods: The 19F MR properties of siponimod were characterized using spectroscopic techniques. Four MRI methods were investigated to determine which was the most sensitive for 19F MR imaging of siponimod under biological conditions. We subsequently administered siponimod orally to 6 mice and acquired 19F MR spectra and images in vivo directly after administration, and in ex vivo tissues. Results: The 19F 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 19F 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 19F 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, 19F 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.