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Purpose: Low SNR in fluorine-19 ( 19 F) 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., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: The use of rigid multi-exponential models (with a priori predefined numbers of components) is common practice for diffusion-weighted MRI (DWI) analysis of the kidney. This approach may not accurately reflect renal microstructure, as the data are forced to conform to the a priori assumptions of simplified models. This work examines the feasibility of less constrained, data-driven non-negative least squares (NNLS) continuum modelling for DWI of the kidney tubule system in simulations that include emulations of pathophysiological conditions., Methods: Non-linear least squares (LS) fitting was used as reference for the simulations. For performance assessment, a threshold of 5% or 10% for the mean absolute percentage error (MAPE) of NNLS and LS results was used. As ground truth, a tri-exponential model using defined volume fractions and diffusion coefficients for each renal compartment (tubule system: D tubules , f tubules ; renal tissue: D tissue , f tissue ; renal blood: D blood , f blood ;) was applied. The impact of: (I) signal-to-noise ratio (SNR) =40-1,000, (II) number of b-values (n=10-50), (III) diffusion weighting (b-range small =0-800 up to b-range large =0-2,180 s/mm 2 ), and (IV) fixation of the diffusion coefficients D tissue and D blood was examined. NNLS was evaluated for baseline and pathophysiological conditions, namely increased tubular volume fraction (ITV) and renal fibrosis (10%: grade I, mild) and 30% (grade II, moderate)., Results: NNLS showed the same high degree of reliability as the non-linear LS. MAPE of the tubular volume fraction ( f tubules ) decreased with increasing SNR. Increasing the number of b-values was beneficial for f tubules precision. Using the b-range large led to a decrease in MAPE ftubules compared to b-range small . The use of a medium b-value range of b=0-1,380 s/mm 2 improved f tubules precision, and further b max increases beyond this range yielded diminishing improvements. Fixing D blood and D tissue significantly reduced MAPE ftubules and provided near perfect distinction between baseline and ITV conditions. Without constraining the number of renal compartments in advance, NNLS was able to detect the (fourth) fibrotic compartment, to differentiate it from the other three diffusion components, and to distinguish between 10% vs. 30% fibrosis., Conclusions: This work demonstrates the feasibility of NNLS modelling for DWI of the kidney tubule system and shows its potential for examining diffusion compartments associated with renal pathophysiology including ITV fraction and different degrees of fibrosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-1360). TN, AP, TG, ES, SW, KC report funding provided by the German Research Foundation [Gefoerdert durch die Deutsche Forschungsgemeinschaft (DFG), Projektnummer 394046635, SFB 1365, RENOPROTECTION. Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Project number 394046635, SFB 1365, RENOPROTECTION]. The other authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Here we describe a simple and inexpensive protocol for preparing ex vivo rodent phantoms for use in MR imaging studies. The experimental animals are perfused and fixed with formaldehyde, and then wrapped with gauze and sealed with liquid latex. This yields a phantom that preserves all organs in situ, and which avoids the need to keep fixed animals and organs in containers that have dimensions very different from living animals. This is especially important for loading in MR detectors, and specifically the RF coils, they are usually used with. The phantom can be safely stored and conveniently reused, and can provide MR scientists with a realistic phantom with which to establish protocols in preparation for preclinical in vivo studies-for renal, brain, and body imaging. The phantom also serves as an ideal teaching tool, for trainees learning how to perform preclinical MRI investigations of the kidney and other target organs, while avoiding the need for handling living animals, and reducing the total number of animals required.This protocol chapter is part of the PARENCHIMA initiative "MRI Biomarkers for CKD " (CA16103), a community-driven Action of the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.

Inflammation is one underlying contributing factor in the pathology of acute and chronic kidney disorders. Phagocytes such as monocytes, neutrophils and dendritic cells are considered to play a deleterious role in the progression of kidney disease but may also contribute to organ homeostasis. The kidney is a target of life-threatening autoimmune disorders such as the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Neutrophils and monocytes express ANCA antigens and play an important role in the pathogenesis of AAV. Noninvasive in vivo methods that can quantify the distribution of inflammatory cells in the kidney as well as other organs in vivo would be vital to identify the causality and significance of inflammation during disease progression. Here we describe an noninvasive technique to study renal inflammation in rodents in vivo using fluorine ( 19 F) MRI. In this protocol we chose a murine ANCA-AAV model of renal inflammation and made use of nanoparticles prepared from perfluoro-5-crown-15-ether (PFCE) for renal 19 F MRI.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This experimental protocol chapter is complemented by two separate chapters describing the basic concept and data analysis.

Kidney-associated pathologies would greatly benefit from noninvasive and robust methods that can objectively quantify changes in renal function. In the past years there has been a growing incentive to develop new applications for fluorine ( 19 F) MRI in biomedical research to study functional changes during disease states. 19 F MRI represents an instrumental tool for the quantification of exogenous 19 F substances in vivo. One of the major benefits of 19 F MRI is that fluorine in its organic form is absent in eukaryotic cells. Therefore, the introduction of exogenous 19 F signals in vivo will yield background-free images, thus providing highly selective detection with absolute specificity in vivo. Here we introduce the concept of 19 F MRI, describe existing challenges, especially those pertaining to signal sensitivity, and give an overview of preclinical applications to illustrate the utility and applicability of this technique for measuring renal function in animal models.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.

Background: Magnetic resonance imaging (MRI) is indispensable for diagnosing neurological conditions such as multiple sclerosis (MS). MRI also supports decisions regarding the choice of disease-modifying drugs (DMDs). Determining in vivo tissue concentrations of DMDs has the potential to become an essential clinical tool for therapeutic drug monitoring (TDM). The aim here was to examine the feasibility of fluorine-19 ( 19 F) MR methods to detect the fluorinated DMD teriflunomide (TF) during normal and pathological conditions. Methods: We used 19 F MR spectroscopy to detect TF in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS) in vivo . Prior to the in vivo investigations we characterized the MR properties of TF in vitro . We studied the impact of pH and protein binding as well as MR contrast agents. Results: We could detect TF in vivo and could follow the 19 F MR signal over different time points of disease. We quantified TF concentrations in different tissues using HPLC/MS and showed a significant correlation between ex vivo TF levels in serum and the ex vivo 19 F MR signal. Conclusion: This study demonstrates the feasibility of 19 F MR methods to detect TF during neuroinflammation in vivo . It also highlights the need for further technological developments in this field. The ultimate goal is to add 19 F MR protocols to conventional 1 H MRI protocols in clinical practice to guide therapy decisions., Competing Interests: Competing Interests: C.P. received presentation fees from Sanofi-Aventis. J.M.M. received presentation fees from Novartis. M.R. is founder and CEO of Lipidomix GmbH. T.N. is founder and CEO of MRI.TOOLS GmbH and received travel funds from Siemens Healthcare. S.W. received research grants from Novartis and Genzyme and presentation fees from Novartis., (© The author(s).)

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 ( B 1 + ) inhomogeneity inherent in these coils. Retrospective B 1 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 B 1 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 T 1 contrast were evaluated after correction., Results: The three described correction methods achieved dramatic improvements in B 1 homogeneity and significantly improved SI quantification and T 1 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 B 1 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 T 1 measurements and X-nuclei quantification using surface transceiver RF coils. This approach is applicable to other MR techniques for which no analytical SI exists., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

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.

Objective: This study examines the influence of the environmental factor temperature on the 19 F NMR characteristics of fluorinated compounds in phantom studies and in tissue., Materials and Methods: 19 F MR mapping and MR spectroscopy techniques were used to characterize the 19 F NMR characteristics of perfluoro-crown ether (PFCE), isoflurane, teriflunomide, and flupentixol. T 1 and T 2 mapping were performed, while temperature in the samples was changed (T = 20-60 °C) and monitored using fiber optic measurements. In tissue, T 1 of PFCE nanoparticles was determined at physiological temperatures and compared with the T 1- measured at room temperature., Results: Studies on PFCE, isoflurane, teriflunomide, and flupentixol showed a relationship between temperature and their physicochemical characteristics, namely, chemical shift, T 1 and T 2 . T 1 of PFCE nanoparticles was higher at physiological body temperatures compared to room temperature., Discussion: The impact of temperature on the 19 F NMR parameters of fluorinated compounds demonstrated in this study not only opens a trajectory toward 19 F MR-based thermometry, but also indicates the need for adapting MR sequence parameters according to environmental changes such as temperature. This will be an absolute requirement for detecting fluorinated compounds by 19 F MR techniques in vivo.

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.

Tryptophan (TRP) depletion was used to study serotonin because the ratio of TRP to large neutral amino acids (TRP/LNAA) determines the quantity of TRP that enters the brain. Because TRP is not universally available, a modified technique of TRP depletion was developed where a 1/4 strength preparation of an amino acid mixture (AAM) replaces TRP as the placebo. Seven healthy subjects could not differentiate between the preparations in this double-blind, placebo-controlled study. Urinary 6-hydroxymelatonin sulfate (6-MS) was monitored as a biochemical marker of serotonin. The TRP/LNAA ratio (GG = 0.001) and 6-MS secretion (GG = 0.024) were decreased, but placebo TRP levels (GG = 0.062) were not altered significantly. This modified technique facilitates the use of TRP depletion in clinical research.