Tumor Contrast Enhancement and Whole-Body Elimination of the Manganese-Based Magnetic Resonance Imaging Contrast Agent Mn-PyC3A Objectives The goals of this study were to compare the efficacy of the new manganese-based magnetic resonance imaging (MRI) contrast agent Mn-PyC3A to the commercial gadolinium-based agents Gd-DOTA and to Gd-EOB-DTPA to detect tumors in murine models of breast cancer and metastatic liver disease, respectively, and to quantify the fractional excretion and elimination of Mn-PyC3A in rats. Methods T1-weighted contrast-enhanced MRI with 0.1 mmol/kg Mn-PyC3A was compared with 0.1 mmol/kg Gd-DOTA in a breast cancer mouse model (n = 8) and to 0.025 mmol/kg Gd-EOB-DTPA in a liver metastasis mouse model (n = 6). The fractional excretion, 1-day biodistribution, and 7-day biodistribution in rats after injection of 2.0 mmol/kg [52Mn]Mn-PyC3A or Gd-DOTA were quantified by 52Mn gamma counting or Gd elemental analysis. Imaging data were compared with a paired t test; biodistribution data were compared with an unpaired t test. Results The postinjection-preinjection increases in tumor-to-muscle contrast-to-noise ratio (ΔCNR) 3 minutes after injection of Mn-PyC3A and Gd-DOTA (mean ± standard deviation) were 17 ± 3.8 and 20 ± 4.4, respectively (P = 0.34). Liver-to-tumor ΔCNR values at 8 minutes postinjection of Mn-PyC3A and Gd-EOB-DTPA were 28 ± 9.0 and 48 ± 23, respectively (P = 0.11). Mn-PyC3A is eliminated with 85% into the urine and 15% into the feces after administration to rats. The percentage of the injected doses (%ID) of Mn and Gd recovered in tissues after 1 day were 0.32 ± 0.12 and 0.57 ± 0.12, respectively (P = 0.0030), and after 7 days were 0.058 ± 0.051 and 0.19 ± 0.052, respectively (P < 0.0001). Conclusions Mn-PyC3A provides comparable tumor contrast enhancement to Gd-DOTA in a mouse breast cancer model and is more completely eliminated than Gd-DOTA; partial hepatobiliary elimination of Mn-PyC3A enables conspicuous delayed phase visualization of liver metastases. Received for publication April 16, 2019; and accepted for publication, after revision, May 22, 2019. Conflicts of interest and sources of funding: This work was supported by grants from the National Institutes of Health (K25HL128899, R21EB022804, R44DK113906, P41RR014075, R01EB009062, and S10OD010650) and the Department of Energy (DESC0015773). P.C. and E.M.G. hold equity and consult to Reveal Pharmaceuticals, a company that is working to develop a manganese-based MRI contrast agent. The other authors report no conflicts of interest. Correspondence to: Eric M. Gale, PhD, Athinoula A. Martinos Center for Biomedical Imaging, 149 Thirteenth St, Suite 2301, Charlestown, MA 02129. E-mail: egale@nmr.mgh.harvard.edu. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Breast Magnetic Resonance Spectroscopy at 3 T in Biopsy-Proven Breast Cancers: Does Choline Peak Correlate With Prognostic Factors? Objectives The role of functional techniques, such as magnetic resonance spectroscopy (1H-MRS), as noninvasive tools to increase breast MR imaging reliability has been widely investigated during the last 2 decades. Considering the growing interest in tumor biology and its influence on functional parameters, the aim of this study was to investigate the relationship between 1H-MRS parameters and breast cancer biomarkers and to evaluate whether the results of 1H-MRS at 3 T can correlate with established breast cancer prognostic factors in our clinical experience. Materials and Methods One hundred two patients with biopsy-proven breast cancer underwent 3 T breast MR imaging. Single-voxel 1H-MRS was performed after the T1-weighted sequence, using a PRESS water-suppressed sequence (BREASE). Data were collected from a single rectangular volume of interest that encompassed the lesion. Magnetic resonance images and spectra of 102 Breast Imaging Reporting and Data System 6 lesions were prospectively evaluated by 2 radiologists in consensus. 1H-MRS results were considered positive if the choline peak signal-to-noise ratio was 2 or higher. 1H-MRS findings were then compared with morphological features and to histological findings, such as lesion size, nuclear grade, Ki-67, hormone receptor status, and Her2 expression. Results Elevated levels of total choline were detectable in 68/102 cases (66.67%) and undetectable in 34/102 (33.33%). A statistically significant association between the presence of choline peak and higher tumor grading (P < 0.0001), greater Ki-67 value (P < 0.0001), and larger lesion size (P < 0.0001) was found. No statistically significant associations were observed between choline peak and the luminal subgroups, even if higher levels of choline were more frequent in nonluminal A lesions. Conclusions Our study confirms that 3 T breast 1H-MRS can be a valid additional tool to obtain further information about breast cancer biology and to predict tumor aggressiveness, because the detection of elevated levels of total choline in the spectrum is associated with a biologically aggressive breast cancer phenotype (large dimensions, grade 3, high values of Ki-67). Our results need to be validated in standardized larger-scale studies. Received for publication April 29, 2019; and accepted for publication, after revision, June 15, 2019. Conflicts of interest and sources of funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors, including National Institutes of Health, Wellcome Trust, and Howard Hughes Medical Institute. The authors report no conflicts of interest. Correspondence to: Francesca Galati, MD, PhD, Department of Radiological, Oncological and Pathological Sciences, “Sapienza”–University of Rome, V.le Regina Elena, 324, 00161 Rome, Italy. E-mail: francesca.galati3@gmail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Modulating Diffusion-Weighted Magnetic Resonance Imaging for Screening in Oncologic Tertiary Prevention: A Prospective Ex Vivo and In Vivo Study Introduction Diffusion-weighted imaging (DWI) is an important part of oncological magnetic resonance imaging (MRI) examinations, especially for tertiary cancer prevention in terms of early detection of recurrent disease. However, abdominal studies can be challenged by motion artifacts, poor signal-to-noise ratios, and visibility of retroperitoneal structures, which necessitates sequence optimization depending on the investigated region. This study aims at prospectively evaluating an adapted DWI sequence ex vivo and in vivo in oncologic patients undergoing abdominal MRI. Methods This institutional review board–approved, prospective study included phantom measurements, volunteer examinations, and oncologic patient examinations of the abdomen. Fifty-seven MRI examinations in 54 patients (mean age, 58 years; range, 21–90 years) were included into the analysis. The MRI examination were performed at a 1.5 T MRI scanner (MAGNETOM Aera; Siemens Healthcare, Erlangen, Germany) and included both a standard EPI-DWI (s-DWI; b = 50, 900 s/mm2) and an adapted DWI (opt-DWI; EPI-DWI with b = 0, 50, 900, 1500 s/mm2, acquisition with higher spatial resolution and optimized processing for the abdomen including motion correction, adaptive image combination, and background suppression). For b = 900 s/mm2, the ratio of signal intensity in the normal tissue and the standard deviation of the noise in the surrounding air was quantitatively calculated; image quality and tissue differentiation parameters were rated by 2 independent, blinded readers using a 5-point Likert scale. Statistics included Wilcoxon signed-rank test and kappa statistic (P < 0.05/0.0125 after Bonferroni correction). Results The DWI phantom demonstrated an optimized contour sharpness and inlay differentiation for opt-DWI. The apparent ratio of normal tissue signal/standard deviation of background noise at b = 900 s/mm2 of the right/left hemiabdomen was significantly increased in opt-DWI (mean, 71.9 ± 23.5/86.0 ± 43.3) versus s-DWI (mean, 51.4 ± 15.4/63.4 ± 36.5; P < 0.001). Image quality parameters (contour sharpness and tissue differentiation of upper abdominal and retroperitoneal structures) were significantly increased in opt-DWI versus s-DWI (P < 0.001). Interreader reliability test showed good agreement (kappa = 0.768; P < 0.001). Discussion This study prospectively evaluated the potential of adapted DWI for screening in tertiary prevention of oncologic patients. An optimized DWI protocol with advanced processing achieved improved image quality in quantitative and qualitative analyses. Oncological optimization of DWI should be performed before its application in cancer patients to improve both screening and follow-up examinations, to better unleash the diagnostic potential of DWI. Received for publication April 2, 2019; and accepted for publication, after revision, May 25, 2019. Conflicts of interest and sources of funding: S.B. received speaker's fee from Siemens, pending patents in DWI; T.A.K. is a cofounder of HQ Imaging GmbH, pending patents in DWI. F.B.L. is a cofound of HQ Imaging GmbH. T.B., D.N, and R.S. are employees of Siemens. No funding was declared. Correspondence to: Constantin Dreher, MD, Department of Radiology (E010), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. E-mail: c.dreher@dkfz.de. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Measuring Dynamic CT Perfusion Based on Time-Resolved Quantitative DECT Iodine Maps: Comparison to Conventional Perfusion at 80 kVp for Pancreatic Carcinoma Objectives Using dual-energy computed tomography (DECT) for quantifying iodine content after injection of contrast agent could provide a quantitative basis for dynamic computed tomography (CT) perfusion measurements by means of established mathematical models of contrast agent kinetics, thus improving results by combining the strength of both techniques, which was investigated in this study. Materials and Methods A dynamic DECT acquisition over 51 seconds performed at 80/Sn140 kVp in 17 patients with pancreatic carcinoma was used to calculate iodine-enhancement images for each time point by means of 3-material decomposition. After motion correction, perfusion maps of blood flow were calculated using the maximum-slope model from both 80 kVp image data and iodine-enhancement images. Blood flow was measured in regions of interest placed in healthy pancreatic tissue and carcinoma for both of the derived perfusion maps. To assess image quality of input data, an adjusted contrast-to-noise ratio was calculated for 80 kVp images and iodine-enhancement images. Susceptibility of perfusion results to residual patient breathing motion during acquisition was investigated by measuring blood flow in fatty tissue surrounding the pancreas, where blood flow should be negligible compared with the pancreas. Results For both 80 kVp and iodine-enhancement images, blood flow was significantly higher in healthy tissue (114.2 ± 37.4 mL/100 mL/min or 115.1 ± 36.2 mL/100 mL/min, respectively) than in carcinoma (46.5 ± 26.6 mL/100 mL/min or 49.7 ± 24.7 mL/100 mL/min, respectively). Differences in blood flow between 80 kVp image data and iodine-enhancement images were statistically significant in healthy tissue, but not in carcinoma. For 80 kVp images, adjusted contrast-to-noise ratio was significantly higher (1.3 ± 1.1) than for iodine-enhancement images (1.1 ± 0.9). When evaluating fatty tissue surrounding the pancreas for estimating influence of patient motion, measured blood flow was significantly lower for iodine-enhancement images (30.7 ± 12.0 mL/100 mL/min) than for 80 kVp images (39.0 ± 19.1 mL/100 mL/min). Average patient radiation exposure was 8.01 mSv for dynamic DECT acquisition, compared with 4.60 mSv for dynamic 80 kVp acquisition. Discussion Iodine enhancement images can be used to calculate CT perfusion maps of blood flow, and compared with 80 kVp images, results showed only a small difference of 1 mL/100 mL/min in blood flow in healthy tissue, whereas patient radiation exposure was increased for dynamic DECT. Perfusion maps calculated based on iodine-enhancement images showed lower blood flow in fatty tissues surrounding the pancreas, indicating reduced susceptibility to residual patient breathing motion during the acquisition. Received for publication March 27, 2019; and accepted for publication, after revision, May 17, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Wolfram Stiller, PhD, Diagnostic and Interventional Radiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. E-mail: wolfram.stiller@med.uni-heidelberg.de. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Improved Liver Diffusion-Weighted Imaging at 3 T Using Respiratory Triggering in Combination With Simultaneous Multislice Acceleration Objectives The aim of this study was to retrospectively compare optimized respiratory-triggered diffusion-weighted imaging with simultaneous multislice acceleration (SMS-RT-DWI) of the liver with a standard free-breathing echo-planar DWI (s-DWI) protocol at 3 T with respect to the imaging artifacts inherent to DWI. Materials and Methods Fifty-two patients who underwent a magnetic resonance imaging study of the liver were included in this retrospective study. Examinations were performed on a 3 T whole-body magnetic resonance system (MAGNETOM Skyra; Siemens Healthcare, Erlangen, Germany). In all patients, both s-DWI and SMS-RT-DWI of the liver were obtained. Images were qualitatively evaluated by 2 independent radiologists with regard to overall image quality, liver edge sharpness, sequence-related artifacts, and overall scan preference. For quantitative evaluation, signal-to-noise ratio was measured from signal-to-noise ratio maps. The mean apparent diffusion coefficient (ADC) was measured in each liver quadrant. The Wilcoxon rank-sum test was used for analysis of the qualitative parameters and the paired Student t test for quantitative parameters. Results Overall image quality, liver edge sharpness, and sequence-related artifacts of SMS-RT-DWI received significantly better ratings compared with s-DWI (P < 0.05 for all). For 90.4% of the examinations, both readers overall preferred SMS-RT-DWI to s-DWI. Acquisition time for SMS-RT-DWI was 34% faster than s-DWI. Signal-to-noise ratio values were significantly higher for s-DWI at b50 but did not statistically differ at b800, and they were more homogenous for SMS-RT-DWI, with a significantly lower standard deviation at b50. Mean ADC values decreased from the left to right hepatic lobe as well as from cranial to caudal for s-DWI. With SMS-RT-DWI, mean ADC values were homogeneous throughout the liver. Conclusions Optimized, multislice, respiratory-triggered DWI of the liver at 3 T substantially improves image quality with a reduced scan acquisition time compared with s-DWI. Received for publication April 15, 2019; and accepted for publication, after revision, May 22, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Andrej Tavakoli, MD, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. E-mail: s.tavakoli@gmx.de. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Three Tesla 3D High-Resolution Vessel Wall MRI of the Orbit may Differentiate Arteritic From Nonarteritic Anterior Ischemic Optic Neuropathy Background Anterior ischemic optic neuropathy (AION) is the most common cause of acute optic neuropathy in older patients. Distinguishing between arteritic AION (A-AION) and nonarteritic (NA-AION) is paramount for improved patient management. Purpose The aim of this study was to evaluate 3-dimensional high-resolution vessel wall (HR-VW) magnetic resonance imaging (MRI) at 3 T to discriminate A-AION from NA-AION. Materials and Methods This prospective single-center study was approved by a national research ethics board and included 27 patients (17 A-AION and 10 NA-AION) with 36 AIONs from December 2014 to August 2017 who underwent 3 T HR-VW MRI. Two radiologists blinded to clinical data individually analyzed the imaging separately and in random order. Discrepancies were resolved by consensus with a third neuroradiologist. The primary diagnostic criterion was the presence of inflammatory changes of the ophthalmic artery. Secondary diagnostic criteria included the presence of an enhancement of the optic nerve or its sheath, the optic disc, or inflammatory changes of posterior ciliary or extracranial arteries. A Fisher exact test was used to compare A-AION from NA-AION patients. Results Inflammatory changes of the ophthalmic artery were present in all patients with A-AION but in none of NA-AION (P < 0.0001). Its sensitivity, specificity, positive predictive value, and negative predictive value were 100%. Inflammatory changes of posterior ciliary arteries were significantly more likely in A-AOIN (82% vs 0%, P < 0.0001). Interreader and intrareader agreements were almost perfect (κ = 0.82–1). Conclusions High-resolution vessel wall MRI seems highly accurate when distinguishing A-AION from NA-AION and might be useful to improve patient management. Received for publication April 8, 2019; and accepted for publication, after revision, June 1, 2019. Conflicts of interest and sources of funding: none declared. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com). Correspondence to: Augustin Lecler, MD, PhD, Department of Neuroradiology, Foundation Adolphe de Rothschild Hospital, 29 Rue Manin, 75019 Paris, France. E-mail: alecler@for.paris. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Ultrasound Time-Harmonic Elastography of the Aorta: Effect of Age and Hypertension on Aortic Stiffness Objectives The aim of this study was to investigate ultrasound time-harmonic elastography for quantifying aortic stiffness in vivo in the context of aging and arterial hypertension. Materials and Methods Seventy-four participants (50 healthy participants and 24 participants with long-standing hypertension) were prospectively included between January 2018 and October 2018, and underwent ultrasound time-harmonic elastography of the upper abdominal aorta. Compound maps of shear-wave speed (SWS) as a surrogate of tissue stiffness were generated from multifrequency wave fields covering the full field-of-view of B-mode ultrasound. Blood pressure and pulse wave velocity were measured beforehand. Interobserver and intraobserver agreement was determined in 30 subjects. Reproducibility of time-harmonic elastography was assessed in subgroups with repeated measurements after 20 minutes and after 6 months. Linear regression analysis, with subsequent age adjustment of SWS obtained, receiver operating characteristic analysis, and intraclass correlation coefficients (ICCs) were used for statistical evaluation. Results Linear regression analysis revealed a significant effect of age on SWS with an increase by 0.024 m/s per year (P < 0.001). Age-adjusted SWS was significantly greater in hypertensives (0.24 m/s; interquartile range [IQR], 0.17–0.40 m/s) than in healthy participants (0.07 m/s; IQR, −0.01 to 0.06 m/s; P < 0.001). A cutoff value of 0.15 m/s was found to differentiate best between groups (area under the receiver operating characteristic curve, 0.966; 95% confidence interval, 0.93–1.0; P < 0.001; 83% sensitivity and 98% specificity). Interobserver and intraobserver variability was excellent (ICC, 0.987 and 0.937, respectively). Reproducibility was excellent in the short term (ICC, 0.968; confidence interval, 0.878–0.992) and good in the long term (ICC, 0.844; confidence interval, 0.491–0.959). Conclusions Ultrasound time-harmonic elastography of the upper abdominal aorta allows quantification of aortic wall stiffness in vivo and shows significantly higher values in patients with arterial hypertension. Received for publication February 6, 2019; and accepted for publication, after revision, May 10, 2019. Conflicts of interest and sources of funding: This study was in part funded by a research grant from the German Research Foundation (Bonn, Germany) to Thomas Elgeti (grant number: EL606/2-1). The authors gratefully acknowledge support from the German Research Foundation (GRK2260 BIOQIC, SFB1340 Matrix-in-Vision). Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com). Correspondence to: Thomas Elgeti, MD, Department of Radiology, Charité–Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany. E-mail: thomas.elgeti@charite.de. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Free-Breathing Fast Low-Angle Shot Quiescent-Interval Slice-Selective Magnetic Resonance Angiography for Improved Detection of Vascular Stenoses in the Pelvis and Abdomen: Technical Development Objectives Balanced steady-state free precession-based quiescent-interval slice-selective (bSSFP QISS) magnetic resonance angiography (MRA) is accurate for the noncontrast evaluation of peripheral arterial disease (PAD); however, drawbacks include the need for breath-holding when imaging the abdomen and pelvis, and sensitivity to off-resonance artifacts. The purpose of this study was to evaluate the image quality and diagnostic accuracy in the pelvis and abdomen of free-breathing fast low-angle shot-based QISS (FLASH QISS) techniques in comparison to bSSFP QISS in patients with PAD, using computed tomographic angiography as the reference. Materials and Methods Twenty-seven patients (69 ± 10 years, 17 men) with PAD were enrolled in this institutional review board–approved, Health Insurance Portability and Accountability Act–compliant prospective study between April and December 2018. Patients underwent noncontrast MRA using standard bSSFP QISS and prototype free-breathing radial-FLASH and Cartesian-FLASH QISS at 3 T. A subset of patients (n = 22) also underwent computed tomographic angiography as the reference standard. Nine arterial segments per patient were evaluated spanning the abdomen, pelvis, and upper thigh regions. Objective (signal intensity ratio and relative standard deviation) and subjective image quality (4-point scale) and stenosis (>50%) were evaluated by 2 readers and compared using one-way analysis of variance, Wilcoxon, and McNemar tests, respectively. Results A total of 179 vascular segments were available for analysis by all QISS techniques. No significant difference was observed among bSSFP, radial-FLASH, and Cartesian-FLASH QISS techniques in signal intensity ratio (P = 0.428) and relative standard deviation (P = 0.220). Radial-FLASH QISS demonstrated the best image quality (P < 0.0001) and the highest interreader agreement (κ = 0.721). The sensitivity values of bSSFP, radial-FLASH, and Cartesian-FLASH QISS for the detection of greater than 50% stenosis were 76.0%, 84.0%, and 80.0%, respectively, whereas specificity values were 97.6%, 94.0%, and 92.8%, respectively. Moreover, FLASH QISS consistently reduced off-resonance artifacts compared with bSSFP QISS. Conclusions Free-breathing FLASH QISS MRA techniques provide improved image quality and sensitivity, high specificity, and reduced off-resonance artifacts for vascular stenosis detection in the abdomen and pelvis. Received for publication April 19, 2019; and accepted for publication, after revision, May 19, 2019. Conflicts of interest and sources of funding: U. Joseph Schoepf is a consultant for and/or receives research support from Astellas, Bayer, Elucid Bioimaging, Guerbet, HeartFlow Inc, and Siemens Healthcare. Akos Varga-Szemes receives institutional research and travel support from Siemens Healthcare and is a consultant for Elucid Bioimaging. Robert R. Edelman receives grant support and royalties from Siemens Healthcare. Ioannis Koktzoglou receives research support from Siemens Healthcare. This study was supported by NIH NHLBI R01 HL130093 (R.R.E.). Correspondence to: Robert R. Edelman, MD, Department of Radiology, NorthShore University HealthSystem, Walgreen Bldg, G534, 2650 Ridge Ave, Evanston, IL 60201. E-mail: redelman999@gmail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Back to the Future: Lipiodol in Lymphography—From Diagnostics to Theranostics Lipiodol is an iodinated poppy seed oil first synthesized in 1901. Originally developed for therapeutic purposes, it has mainly become a diagnostic contrast medium since the 1920s. At the end of the 20th century, Lipiodol underwent a transition back to a therapeutic agent, as exemplified by its increasing use in lymphangiography and lymphatic interventions. Nowadays, indications for lymphangiography include chylothorax, chylous ascites, chyluria, and peripheral lymphatic fistula or lymphoceles. In these indications, Lipiodol alone has a therapeutic effect with clinical success in 51% to 100% of cases. The 2 main access sites to the lymphatic system for lymphangiography are cannulation of lymphatic vessels in the foot (transpedal) and direct puncture of (mainly inguinal) lymph nodes (transnodal). In case of failure of lymphangiography alone to occlude the leaking lymphatic vessel as well as in indications such as protein-losing enteropathy, postoperative hepatic lymphorrhea, or plastic bronchitis, lymphatic vessels can also be embolized directly by injecting a mixture of Lipiodol and surgical glues (most commonly in thoracic duct embolization). The aim of this article is to review the historical role of Lipiodol and the evolution of its clinical application in lymphangiography over time until the current state-of-the-art lymphatic imaging techniques and interventions. Received for publication February 18, 2019; and accepted for publication, after revision, April 2, 2019. Conflicts of interest and sources of funding: C.C.P. is part of the speakers bureau of and/or received educational grants from Philips Healthcare, Bayer Vital, Boston Scientific, Guerbet, and Medserena; G.M. and C.M.S. are both part of the speakers bureau at Guerbet; M.I. is part of the speakers bureau at and received research grants from Guerbet. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com). Correspondence to: Claus Christian Pieper, MD, Department of Radiology, University Hospital Bonn, Sigmund-Freud Strasse 25, 53127 Bonn, Germany. E-mail: claus.christian.pieper@ukbonn.de; pieper.lymphatic@gmail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Gadolinium Deposition in the Brain in a Large Animal Model: Comparison of Linear and Macrocyclic Gadolinium-Based Contrast Agents Objective Recent studies reported a signal intensity increase in the deep cerebellar nuclei (DCN) on magnetic resonance images caused by gadolinium deposition after the injection of gadolinium-based contrast agents (GBCAs). There is an ongoing debate if the propensity of a GBCA to deposit gadolinium is primarily determined by its class as either linear or macrocyclic. In the current study, we aimed to compare the amount and the distribution of retained gadolinium of linear and macrocyclic GBCAs in the DCN after a single injection at a dose comparable to a human patient's in a large animal model. Materials and Methods Eighteen sheep were randomly assigned in 6 groups of 3 animals, which received a single injection of 0.1 mmol/kg body weight of either the macrocyclic GBCAs gadobutrol, gadoteridol, or gadoterate meglumine; the linear GBCAs gadobenate dimeglumine or gadodiamide; or saline. Animals were euthanized 10 weeks after injection. Local distribution and concentration of gadolinium and colocalization to other metals (iron, zinc, copper) in the DCN was assessed by laser ablation-inductively coupled plasma-mass spectrometry. Results Average gadolinium concentration for the macrocyclic GBCAs and the saline group was below the limit of quantification (5.7 ng/g tissue). In contrast, 14 (for gadobenate) and 27 (for gadodiamide) times more gadolinium than the limit of quantification was found for the linear GBCAs gadobenate (mean, 83 ng/g) or gadodiamide (mean, 155 ng/g brain tissue). Gadolinium distribution colocalized with other metals for linear GBCAs and a specific accumulation in the DCN was found. Discussion The current study supports the hypothesis that the amount of gadolinium deposited in the brain is primarily determined by its class as either macrocyclic or linear. The accumulation of gadolinium in the DCN for linear GBCAs explains the hyperintensities in the DCN found in previous patient studies with linear GBCAs. Received for publication January 26, 2019; and accepted for publication, after revision, March 27, 2019. Alexander Radbruch and Henning Richter contributed equally to this study. The study was not supported by any funding. Alexander Radbruch lectures for Guerbet and Bayer, and he is also part of the Advisory Boards for GE, Bracco, and Guerbet. This study was supported by Bayer and Guerbet. For the remaining authors, no conflicts of interest are declared. Correspondence to: Alexander Radbruch, MD, JD, Department of Diagnostic and Interventional Radiology and Neuroradiology, University Clinic Essen, Hufelandstraße 55, 45147 Essen, Germany. E-mail: a.radbruch@dkfz.de. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.