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Objectives: Hysterosalpingography (HSG) is widely used for evaluating the fallopian tubes; however, controversies regarding the use of water- or oil-based iodine-based contrast media (CM) remain. The aim of this work was (1) to discuss reported pregnancy rates related to the CM type used, (2) to validate the used CM in published literature, (3) to discuss possible complications and side effects of CM in HSG, and (4) to develop guidelines on the use of oil-based CM in HSG., Methods: A systematic literature search was conducted for original RCT studies or review/meta-analyses on using water-based and oil-based CM in HSG with fertility outcomes and complications. Nine randomized controlled trials (RCTs) and 10 reviews/meta-analyses were analyzed. Grading of the literature was performed based on the Oxford Centre for Evidence-Based Medicine (OCEBM) 2011 classification., Results: An approximately 10% higher pregnancy rate is reported for oil-based CM. Side effects are rare, but oil-based CM have potentially more side effects on the maternal thyroid function and the peritoneum., Conclusions: 1. HSG with oil-based CM gives approximately 10% higher pregnancy rates. 2. External validity is limited, as in five of nine RCTs, the CM used is no longer on the market. 3. Oil-based CM have potentially more side effects on the maternal thyroid function and on the peritoneum. 4. Guideline: Maternal thyroid function should be tested before HSG with oil-based CM and monitored for 6 months after., Clinical Relevance Statement: Oil-based CM is associated with an approximately 10% higher chance of pregnancy compared to water-based CM after HSG. Although side effects are rare, higher iodine concentration and slower clearance of oil-based CM may induce maternal thyroid function disturbance and peritoneal inflammation and granuloma formation., Key Points: • It is unknown which type of contrast medium, oil-based or water-based, is the optimal for HSG. • Oil-based contrast media give a 10% higher chance of pregnancy after HSG, compared to water-based contrast media. • From the safety perspective, oil-based CM can cause thyroid dysfunction and an intra-abdominal inflammatory response in the patient., (© 2024. The Author(s).)

Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the "EU Joint Programme - Neurodegenerative Disease Research (JPND)" consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration-time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

The Contrast Media Safety Committee of the European Society of Urogenital Radiology has, together with the Preanalytical Phase Working Group of the EFLM Science Committee, reviewed the literature and updated its recommendations to increase awareness and provide insight into these interferences. CLINICAL RELEVANCE STATEMENT: Contrast Media may interfere with clinical laboratory tests. Awareness of potential interference may prevent unwanted misdiagnosis. KEY POINTS: • Contrast Media may interfere with clinical laboratory tests; therefore awareness of potential interference may prevent unwanted misdiagnosis. • Clinical Laboratory tests should be performed prior to radiological imaging with contrast media or alternatively, blood or urine collection should be delayed, depending on kidney function., (© 2023. The Author(s).)

The Contrast Media Safety Committee of the European Society of Urogenital Radiology has, together with the Preanalytical Phase Working Group of the EFLM Science Committee, reviewed the literature and updated its recommendations to increase awareness and provide insight into these interferences., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Abstract: Brain and cardiac MRIs are fundamental noninvasive imaging tools, which can provide important clinical information and can be performed without or with gadolinium-based contrast agents (GBCAs), depending on the clinical indication. It is currently a topic of debate whether it would be feasible to extract information such as standard gadolinium-enhanced MRI while injecting either less or no GBCAs. Artificial intelligence (AI) is a great source of innovation in medical imaging and has been explored as a method to synthesize virtual contrast MR images, potentially yielding similar diagnostic performance without the need to administer GBCAs. If possible, there would be significant benefits, including reduction of costs, acquisition time, and environmental impact with respect to conventional contrast-enhanced MRI examinations. Given its promise, we believe additional research is needed to increase the evidence to make these AI solutions feasible, reliable, and robust enough to be integrated into the clinical framework. Here, we review recent AI studies aimed at reducing or replacing gadolinium in brain and cardiac imaging while maintaining diagnostic image quality., Competing Interests: Conflicts of interest and sources of funding: A.J.v.d.M. receives consultancy fees from Guerbet (for the gadopiclenol, Expert Group Netherlands). G.Z. reported the following: Subtle Medical (co-founder, equity, spouse employment), GE Healthcare (funding support), Biogen (consultant), and Nvidia (GPU donation). All the other authors have no conflicts of interest to declare. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Deep learning approaches are playing an ever-increasing role throughout diagnostic medicine, especially in neuroradiology, to solve a wide range of problems such as segmentation, synthesis of missing sequences, and image quality improvement. Of particular interest is their application in the reduction of gadolinium-based contrast agents, the administration of which has been under cautious reevaluation in recent years because of concerns about gadolinium deposition and its unclear long-term consequences. A growing number of studies are investigating the reduction (low-dose approach) or even complete substitution (zero-dose approach) of gadolinium-based contrast agents in diverse patient populations using a variety of deep learning methods. This work aims to highlight selected research and discusses the advantages and limitations of recent deep learning approaches, the challenges of assessing its output, and the progress toward clinical applicability distinguishing between the low-dose and zero-dose approach., Competing Interests: Conflicts of interest and sources of funding: R.H. is funded by a research grant (BONFOR; O-194.0002.1) of the Medical Faculty of the University of Bonn. A.E. and T.P. are funded by the German Research Foundation under Germany's Excellence Strategy (EXC-2047/1, 390685813 and EXC-2151, 390873048). All authors are cofounders of relios.vision., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The purpose of this study was to implement a state-of-the-art convolutional neural network used to synthesize artificial T1-weighted (T1w) full-dose images from corresponding noncontrast and low-dose images (using various settings of input sequences) and test its performance on a patient population acquired prospectively., Materials and Methods: In this monocentric, institutional review board-approved study, a total of 138 participants were included who received an adapted imaging protocol with acquisition of a T1w low dose after administration of 10% of the standard dose and acquisition of a T1w full dose after administration of the remaining 90% of the standard dose of a gadolinium-containing contrast agent. A total of 83 participants formed the training sample (51.7 ± 16.5 years, 36 women), 25 the validation sample (55.3 ± 16.4 years, 11 women), and 30 the test sample (55.0 ± 15.0 years, 9 women). Four input settings were differentiated: only the T1w noncontrast and T1w low-dose images (standard setting), only the T1w noncontrast and T1w low-dose images with a prolonged postinjection time of 5 minutes (5-minute setting), multiple noncontrast sequences (T1w, T2w, diffusion) and the T1w low-dose images (extended setting), and only noncontrast sequences (T1w, T2w, diffusion) were used (zero-dose setting). For each setting, a deep neural network was trained to synthesize artificial T1w full-dose images, which were assessed on the test sample using an objective evaluation based on quantitative metrics and a subjective evaluation through a reader-based study. Three readers scored the overall image quality, the interchangeability in regard to the clinical conclusion compared with the true T1w full-dose sequence, the contrast enhancement of lesions, and their conformity to the respective references in the true T1w full dose., Results: Quantitative analysis of the artificial T1w full-dose images of the standard setting provided a peak signal-to-noise ratio of 33.39 ± 0.62 (corresponding to an average improvement of the low-dose sequences of 5.2 dB) and a structural similarity index measure of 0.938 ± 0.005. In the 4-fold cross-validation, the extended setting yielded similar performance to the standard setting in terms of peak signal-to-noise ratio ( P = 0.20), but a slight improvement in structural similarity index measure ( P < 0.0001). For all settings, the reader study found comparable overall image quality between the original and artificial T1w full-dose images. The proportion of scans scored as fully or mostly interchangeable was 55%, 58%, 43%, and 3% and the average counts of false positives per case were 0.42 ± 0.83, 0.34 ± 0.71, 0.82 ± 1.15, and 2.00 ± 1.07 for the standard, 5-minute, extended, and zero-dose setting, respectively. Using a 5-point Likert scale (0 to 4, 0 being the worst), all settings of synthesized full-dose images showed significantly poorer contrast enhancement of lesions compared with the original full-dose sequence (difference of average degree of contrast enhancement-standard: -0.97 ± 0.83, P = <0.001; 5-minute: -0.93 ± 0.91, P = <0.001; extended: -0.96 ± 0.97, P = <0.001; zero-dose: -2.39 ± 1.14, P = <0.001). The average scores of conformity of the lesions compared with the original full-dose sequence were 2.25 ± 1.21, 2.22 ± 1.27, 2.24 ± 1.25, and 0.73 ± 0.93 for the standard, 5-minute, extended, and zero-dose setting, respectively., Conclusions: The tested deep learning algorithm for synthesis of artificial T1w full-dose sequences based on images after administration of only 10% of the standard dose of a gadolinium-based contrast agent showed very good quantitative performance. Despite good image quality in all settings, both false-negative and false-positive signals resulted in significantly limited interchangeability of the synthesized sequences with the original full-dose sequences., Competing Interests: Conflicts of interest and sources of funding: R.H., T.P., E.K., D.P., A.E., A.R., K.D.: cofounder, stockholder of relios.vision. For the other authors, none were declared. R.H. is funded by a research grant (BONFOR; O-194.0002.1) from the Medical Faculty of the University of Bonn. A.E. and T.P. are funded by the German Research Foundation under Germany's Excellence Strategy (EXC-2047/1, 390685813 and EXC-2151, 390873048)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Gadolinium (Gd) deposition in the brain, first and foremost in the dentate nucleus in the cerebellum, following contrast enhanced MRI, rose awareness of potential adverse effects of gadolinium-based contrast agent (GBCA) administration. According to previous in vitro experiments, a conceivable side-effect of Gd deposition could be an alteration of gene expression. In the current study, we aimed to investigate the influence of GBCA administration on gene expression in the cerebellum of mice using a combination of elemental bioimaging and transcriptomics. In this prospective animal study, three groups of eight mice each were intravenously injected with either linear GBCA gadodiamide, macrocyclic GBCA gadoterate (1 mmol GBCA/kg body weight) or saline (NaCl 0.9%). Animals were euthanized four weeks after injection. Subsequently, Gd quantification via laser ablation-ICP-MS and whole genome gene expression analysis of the cerebellum were performed. Four weeks after single application of GBCAs to 24-31 days old female mice, traces of Gd were detectable in the cerebellum for both, the linear and macrocyclic group. Subsequent transcriptome analysis by RNA sequencing using principal component analysis did not reveal treatment-related clustering. Also differential expression analysis did not reveal any significantly differentially expressed genes between treatments., (© 2023. The Author(s).)

Gadolinium (Gd) deposition has been found in both animal and human tissues after injections of Gd-based contrast agents (GBCAs). Without the knowledge of which tissues are most affected, it is difficult to determine whether Gd accumulation could lead to any pathological changes. The current study aims at investigating histological sections of three patients who were exposed to GBCAs during their lifetime, and identify areas of Gd accumulation. Tissue sections of three autopsy cases were investigated by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to assess the distribution of Gd, and the deposition within tissue sections was quantified. Additional application of laser ablation-inductively coupled plasma-optical emission spectroscopy (LA-ICP-OES) enabled a sensitive detection of calcium (Ca) in the vessel walls, which is usually impeded in LA-ICP-MS due to the isobaric interference with argon. Complementary LA-ICP-MS and LA-ICP-OES analysis revealed that Gd was co-localized with zinc and Ca, in the area where smooth muscle actin was present. Notably, high levels of Gd were found in the tunica media of arterial walls, which requires further research into potential Gd-related toxicity in this specific location., (© The Author(s) 2022. Published by Oxford University Press.)

Need for a Review: Guidelines for management and prevention of contrast media extravasation have not been updated recently. In view of emerging research and changing working practices, this review aims to inform update on the current guidelines., Areas Covered: In this paper, we review the literature pertaining to the pathophysiology, diagnosis, risk factors and treatments of contrast media extravasation. A suggested protocol and guidelines are recommended based upon the available literature., Key Points: • Risk of extravasation is dependent on scanning technique and patient risk factors. • Diagnosis is mostly clinical, and outcomes are mostly favourable. • Referral to surgery should be based on clinical severity rather than extravasated volume., (© 2022. The Author(s).)

Background There is an ongoing scientific debate about the degree and clinical importance of gadolinium deposition in the brain and other organs after administration of gadolinium-based contrast agents (GBCAs). While most published data focus on gadolinium deposition in the brain, other organs are rarely investigated. Purpose To compare gadolinium tissue concentrations in various organs 10 weeks after one injection (comparable to a clinically applied dose) of linear and macrocyclic GBCAs in a large-animal model. Materials and Methods In this prospective animal study conducted from March to May 2018, 36 female Swiss-Alpine sheep (age range, 4-10 years) received one injection (0.1 mmol/kg) of macrocyclic GBCAs (gadobutrol, gadoteridol, and gadoterate meglumine), linear GBCAs (gadodiamide and gadobenate dimeglumine), or saline. Ten weeks after injection, sheep were sacrificed and tissues were harvested. Gadolinium concentrations were quantified with inductively coupled plasma mass spectrometry (ICP-MS). Histologic staining was performed. Data were analyzed with nonparametric tests. Results At 10 weeks after injection, linear GBCAs resulted in highest mean gadolinium concentrations in the kidney (502 ng/g [95% CI: 270, 734]) and liver (445 ng/g [95% CI: 202, 687]), while low concentrations were found in the deep cerebellar nuclei (DCN) (30 ng/g [95% CI: 20, 41]). Tissue concentrations of linear GBCAs were three to 21 times higher compared with those of macrocyclic GBCAs. Administered macrocyclic GBCAs resulted in mean gadolinium concentrations of 86 ng/g (95% CI: 31, 141) ( P = .08) in the kidney, 21 ng/g (95% CI: 4, 39) ( P = .15) in liver tissue, and 10 ng/g (95% CI: 9, 12) ( P > .99) in the DCN, which were not significantly elevated when compared with concentrations in control animals. No histopathologic alterations were observed irrespective of tissue concentrations within any examined organ. Conclusion Ten weeks after one injection of a clinically relevant dose of gadolinium-based contrast agents, the liver and kidney appeared to be reservoirs of gadolinium; however, despite gadolinium presence, no tissue injury was detected. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Clément in this issue.

Objectives: To reduce the dose of intravenous iodine-based contrast media (ICM) in CT through virtual contrast-enhanced images using generative adversarial networks., Methods: Dual-energy CTs in the arterial phase of 85 patients were randomly split into an 80/20 train/test collective. Four different generative adversarial networks (GANs) based on image pairs, which comprised one image with virtually reduced ICM and the original full ICM CT slice, were trained, testing two input formats (2D and 2.5D) and two reduced ICM dose levels (-50% and -80%). The amount of intravenous ICM was reduced by creating virtual non-contrast series using dual-energy and adding the corresponding percentage of the iodine map. The evaluation was based on different scores (L1 loss, SSIM, PSNR, FID), which evaluate the image quality and similarity. Additionally, a visual Turing test (VTT) with three radiologists was used to assess the similarity and pathological consistency., Results: The -80% models reach an SSIM of > 98%, PSNR of > 48, L1 of between 7.5 and 8, and an FID of between 1.6 and 1.7. In comparison, the -50% models reach a SSIM of > 99%, PSNR of > 51, L1 of between 6.0 and 6.1, and an FID between 0.8 and 0.95. For the crucial question of pathological consistency, only the 50% ICM reduction networks achieved 100% consistency, which is required for clinical use., Conclusions: The required amount of ICM for CT can be reduced by 50% while maintaining image quality and diagnostic accuracy using GANs. Further phantom studies and animal experiments are required to confirm these initial results., Key Points: • The amount of contrast media required for CT can be reduced by 50% using generative adversarial networks. • Not only the image quality but especially the pathological consistency must be evaluated to assess safety. • A too pronounced contrast media reduction could influence the pathological consistency in our collective at 80%., (© 2021. The Author(s).)

Materials and Methods: Our local ethics committee approved this retrospective monocenter study.First, a dual-time approach was assessed, for which the CNN was provided sequences of the MRI that initially depicted new MM (diagnosis MRI) as well as of a prediagnosis MRI: inclusion of only contrast-enhanced T1-weighted images (CNNdual&#95;ce) was compared with inclusion of also the native T1-weighted images, T2-weighted images, and FLAIR sequences of both time points (CNNdual&#95;all).Second, results were compared with the corresponding single time approaches, in which the CNN was provided exclusively the respective sequences of the diagnosis MRI.Casewise diagnostic performance parameters were calculated from 5-fold cross-validation., Results: In total, 94 cases with 494 MMs were included. Overall, the highest diagnostic performance was achieved by inclusion of only the contrast-enhanced T1-weighted images of the diagnosis and of a prediagnosis MRI (CNNdual&#95;ce, sensitivity = 73%, PPV = 25%, F1-score = 36%). Using exclusively contrast-enhanced T1-weighted images as input resulted in significantly less false-positives (FPs) compared with inclusion of further sequences beyond contrast-enhanced T1-weighted images (FPs = 5/7 for CNNdual&#95;ce/CNNdual&#95;all, P < 1e-5). Comparison of contrast-enhanced dual and mono time approaches revealed that exclusion of prediagnosis MRI significantly increased FPs (FPs = 5/10 for CNNdual&#95;ce/CNNce, P < 1e-9).Approaches with only native sequences were clearly inferior to CNNs that were provided contrast-enhanced sequences., Conclusions: Automated MM detection on contrast-enhanced T1-weighted images performed with high sensitivity. Frequent FPs due to artifacts and vessels were significantly reduced by additional inclusion of prediagnosis MRI, but not by inclusion of further sequences beyond contrast-enhanced T1-weighted images. Future studies might investigate different change detection architectures for computer-aided detection., Competing Interests: Conflicts of interest and sources of funding: A.R. received personal fees for consulting and talks (within the last 3 years) from Bayer, Guerbet, and Novartis, and financial study support from Bayer and Guerbet. K.D.H. received personal fees for talks from GE and financial study support from Bayer and Guerbet. The other authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Recently, gadolinium from linear GBCAs has been reported to deposit in various regions of the body. Besides gadolinium, other lanthanides are used in medical care. In the current study, we investigated deposition of lanthanum in two patients who received lanthanum carbonate as a phosphate binder due to chronic kidney injury and compared it to additionally found Gd deposition., Methods: Tissue specimens of two patients with long-term application of lanthanum carbonate as well as possible GBCA application were investigated. Spatial distribution of gadolinium and lanthanum was determined by quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging of tissue sections. The deposition of gadolinium and lanthanum in different organs was compared, and the ratio of Gd concentration to La concentration (Gd-to-La-ratio) was investigated on an individual pixel base within the images., Results: Deposition of Gd and La was found in all investigated tissues of both patients. Gd and La exhibited high spatial correlation for all samples, with the main deposition being located in the middle coat (tunica media) of blood vessels. The Gd-to-La-ratio was similar in the tissues investigated (between 8 ± 4 (mean ± standard deviation) and 10 ± 2), except for the thyroid vasculature and surrounding tissue (90 ± 17) as well as the cerebellum (270 ± 18). Here, the ratio was significantly increased towards higher Gd concentration., Conclusion: The results of this study demonstrate long-term deposition of La and comparable localization of additionally found Gd in various tissues of the body. La deposition was relatively low, considering the total administered amount of lanthanum carbonate of up to 11.5 kg, indicating a low absorption and/or high excretion of lanthanum. However, the total amount of deposited La is significant and raises questions about possible adverse side effects. The ratio-approach allows for the usage of the additionally generated Gd data, without detailed knowledge about possible GBCA applications. The significantly decreased Gd-to-La-ratio in the brain might be explained by the lanthanum being released and taken up as free La 3+ ion in the stomach that impedes a crossing of the blood-brain-barrier while the intravenously injected GBCAs might dechelate first when they have already crossed the blood-brain-barrier., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Objectives: In recent years, complaints of patients about burning pain in arms and legs after the injection of gadolinium-based contrast agents (GBCAs) have been reported. In the current study, we investigated changes of small fibers in the epidermis as a potential cause of the patient complaints in a mouse model., Methods: Six groups of 8 mice were intravenously injected with either a macrocyclic GBCA (gadoteridol, gadoterate meglumine, gadobutrol), a linear GBCA (gadodiamide or gadobenate dimeglumine) (1 mmol/kg body weight), or saline (NaCl 0.9%). Four weeks after injection, animals were euthanized, and footpads were assessed using immunofluorescence staining. Intraepidermal nerve fiber density (IENFD) was calculated, and the median number of terminal axonal swellings (TASs) per IENFD was determined., Results: Nonparametric Wilcoxon signed-rank test revealed significantly lower IENFDs for all GBCAs compared with the control group (P < 0.0001) with the linear GBCAs showing significantly lower IENFDs than the macrocyclic GBCAs (P < 0.0001). The linear GBCAs presented significantly more TAS per IENFD than the control group (P < 0.0001), whereas no significant increase of TAS per IENFD compared with the control group was found for macrocyclic GBCAs (P < 0.237)., Interpretation: It is unclear whether or at what dosage the decrease of IENFDs and the increase of TAS per IENFD found in the current animal model will appear in humans and if it translates into clinical symptoms. However, given the highly significant findings of the current study, more research in this field is required.

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.

Objective: Over the last years several studies reported an increased signal intensity (SI) of the dentate nucleus (DN) on unenhanced T1-weighted images after repeated application of gadolinium-based contrast agents (GBCAs), suggesting gadolinium deposition. The aim of this study was to investigate with diffusion-weighted MRI possible tissue abnormalities of the DN in multiple sclerosis (MS) patients., Material and Methods: We retrospectively identified seventeen patients with at least six contrast-enhanced MRI examinations by using the linear GBCA gadopentate dimeglumine and twenty-three patients with the exclusive use of the macrocyclic contrast agent gadoterate meglumine followed by another 3 Tesla MRI scan including unenhanced T1-weighted and diffusion-weighted images., Results: In the linear GBCA group, we found significant differences of the DN-to-pons SI ratio on unenhanced T1-weighted images (1.13 ± 0.05) when compared to the macrocyclic GBCA group (0.97 ± 0.03; p < 0.001). However, we found no significant differences between apparent diffusion coefficient (ADC) values of the DN in both groups (linear GBCA group: 0.82 ± 0.04 × 10 -3  mm/s 2 ; marcocyclic GBCA group: 0.79 ± 0.04 × 10 -3  mm/s 2 ; p = 0.15)., Conclusions: Our results do not suggest that there is any difference in ADC values in the T1-hyperintense DN, which does not indicate a difference in tissue integrity between patients exposed to macrocyclic or linear GBCAs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The "glymphatic system" (GS), a brain-wide network of cerebrospinal fluid microcirculation, supplies a pathway through and out of the central nervous system (CNS); malfunction of the system is implicated in a variety of neurological disorders. In this exploratory study, we analyzed the potential of a new imaging approach that we coined delayed T2-weighted gadolinium-enhanced imaging to visualize the GS in vivo., Methods: Heavily T2-weighted fluid-attenuated inversion recovery (hT2w-FLAIR) magnetic resonance imaging was obtained before, and 3 hours and 24 hours after intravenous gadolinium-based contrast agent (GBCA) application in 33 neurologically healthy patients and 7 patients with an impaired blood-brain barrier (BBB) due to cerebral metastases. Signal intensity (SI) was determined in various cerebral fluid spaces, and white matter hyperintensities were quantified by applying the Fazekas scoring system., Findings: Delayed hT2w-FLAIR showed GBCA entry into the CNS via the choroid plexus and the ciliary body, with GBCA drainage along perineural sheaths of cranial nerves and along perivascular spaces of penetrating cortical arteries. In all patients and all sites, a significant SI increase was found for the 3 hours and 24 hours time points compared with baseline. Although no significant difference in SI was found between neurologically healthy patients and patients with an impaired BBB, a significant positive correlation between Fazekas scoring system and SI increase in the perivascular spaces 3 hours post injection was shown., Interpretation: Delayed T2-weighted gadolinium-enhanced imaging can visualize the GBCA pathway into and through the GS. Presence of GBCAs within the GS might be regarded as part of the natural excretion process and should not be mixed up with gadolinium deposition. Rather, the correlation found between deep white matter hyperintensities, an imaging sign of vascular dementia, and GS functioning demonstrated feasibility to exploit the pathway of GBCAs through the GS for diagnostic purposes.

Recent studies showed gadolinium depositions following serial administrations of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging examinations in various parts of the brain with the dentate nucleus (DN) being most affected. Even though no clinical correlates of the deposits are known yet, an intensive debate developed if this might be harmful. The aim of the current study was to specify the gadolinium distribution in brain tissue of patients who received serial injections of GBCAs in the low-µm range and to explore any potential pathological tissue changes caused by gadolinium deposits. Thirteen autopsy cases-eight receiving GBCA administrations, five serving as controls-were identified and analyzed. For all patients, total gadolinium quantification after acidic digestion by means of inductively coupled plasma-mass spectrometry (ICP-MS) was performed. Six cases were utilized for the spatially resolved quantification of gadolinium within the cerebellum and the basal ganglia by means of high-resolution laser ablation (LA)-ICP-MS. Histopathological and immunohistochemical examinations were performed to determine tissue reactions. LA-ICP-MS revealed gadolinium depositions in the walls of small blood vessels of the DN in all GBCA exposed patients, while no gadolinium was found in the control group. Additionally, the detection of phosphorus and metals like copper, zinc and iron provides evidence that transmetalation reactions might have occurred. No significant pathological changes of the brain tissue in the vicinity of the DN with respect to micro-/astrogliosis and neuronal loss were found in any of the patients. This notably holds true even for a patient who died from nephrogenic systemic fibrosis exhibiting extremely high gadolinium concentrations within the DN. The findings show that gadolinium depositions in the brain are restricted to blood vessel walls, while the neuropil is spared and apparent cellular reactions are absent.

Purpose To determine the effect of at least five serial injections of the macrocyclic gadolinium-based contrast agent (GBCA) gadoterate meglumine on the signal intensity (SI) of the dentate nucleus (DN) of the pediatric brain on nonenhanced T1-weighted magnetic resonance (MR) images. Materials and Methods In this retrospective, institutional review board-approved study, 41 pediatric patients (age range, 3-17 years) who were imaged in at least five consecutive 1.5-T MR examinations with the exclusive use of gadoterate meglumine (plus a final additional nonenhanced MR imaging examination) were evaluated. SI ratio differences between the first and last MR examination were calculated for DN-to-pons and DN-to-middle cerebellar peduncle (MCP) ratios in a region-of-interest-based analysis, and one-sample t tests were used to examine if the SI ratio differences differed from 0. Bayes factors were calculated to quantify the strength of evidence for each test. Results Patients underwent a mean of 8.6 ± 3.9 GBCA administrations (mean accumulated dose, 32.07 mmol ± 17.62, with an average of 16.7 weeks ± 7.9 between every administration). Both ratio differences did not differ significantly from 0 (DN-to-pons ratio: -0.0012 ± 0.0101, P = .436; DN-to-MCP ratio: 0.0007 ± 0.0088, P = .604), and one-sided Bayes factors provided substantial evidence against an SI ratio increase (0.10 for DN-to-pons ratio; 0.27 for DN-to-MCP ratio). Conclusion No increase of the SI in the DN was found after a mean of 8.6 serial injections of the macrocyclic GBCA gadoterate meglumine in pediatric patients, confirming previous studies that did not find this effect after serial injections of macrocyclic GBCAs in adults. © RSNA, 2017.

Purpose To determine the effect of more than 20 serial injections of macrocyclic gadolinium-based contrast agents (GBCAs) on the signal intensity (SI) of the dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance (MR) images. Materials and Methods In this retrospective, institutional review board-approved study, 33 patients who underwent at least 20 consecutive MR imaging examinations (plus an additional MR imaging for reference) with the exclusive use of macrocyclic GBCAs gadoterate meglumine and gadobutrol were analyzed. SI ratio differences were calculated for DN-to-pons and DN-to-middle cerebellar peduncle (MCP) ratios by subtracting the SI ratio at the first MR imaging examination from the SI ratio at the last MR imaging examination. One-sample t tests were used to examine if the SI ratio differences differed from 0, and Bayes factors were calculated to quantify the strength of evidence for each test. Results Patients underwent a mean of 23.03 ± (standard deviation) 4.20 GBCA administrations (mean accumulated dose, 491.21 mL ± 87.04 of a 0.5 M GBCA solution) with an average of 12.09 weeks ± 2.16 between every administration. Both ratio differences did not differ significantly from 0 (DN-to-pons ratio: -0.0032 ± 0.0154, P = .248; DN-to-MCP ratio: -0.0011 ± 0.0093, P = .521), and one-sided Bayes factors provided substantial to strong evidence against an SI ratio increase (Bayes factor for DN-to-pons ratio = 0.09 and that for DN-to-MCP ratio = 0.12). Conclusion The study indicates that 20 or more serial injections of macrocyclic GBCAs administered with on average 3 months between each injection are not associated with an SI increase in the DN. © RSNA, 2016.

Common medical imaging techniques usually employ contrast agents that are chemically labeled, e.g. with radioisotopes in the case of PET, iodine in the case of CT or paramagnetic metals in the case of MRI to visualize the heterogeneity of the tumor microenvironment. Recently, it was shown that natural unlabeled D-glucose can be used as a nontoxic biodegradable contrast agent in Chemical Exchange sensitive Spin-Lock (CESL) magnetic resonance imaging (MRI) to detect the glucose uptake and potentially the metabolism of tumors. As an important step to fulfill the clinical needs for practicability, reproducibility and imaging speed we present here a robust and quantitative T 1ρ -weighted technique for dynamic glucose enhanced MRI (DGE-MRI) with a temporal resolution of less than 7 seconds. Applied to a brain tumor patient, the new technique provided a distinct DGE contrast between tumor and healthy brain tissue and showed the detailed dynamics of the glucose enhancement after intravenous injection. Development of this fast and quantitative DGE-MRI technique allows for a more detailed analysis of DGE correlations in the future and potentially enables non-invasive diagnosis, staging and monitoring of tumor response to therapy., Competing Interests: The authors declare no competing financial interests.

In December 2013, a groundbreaking study by Kanda et al. was published showing that the serial injection of gadolinium based contrast agents (GBCAs) is correlated with a signal intensity increase in the dentate nucleus and the globus pallidus on unenhanced T1 weighted MR images. Subsequent studies by Kanda et al. and McDonald et al. on brain tissue from deceased patients provided evidence that the reported signal intensity increase in the brain correlates with gadolinium deposits in the brain tissue. In the following, multiple retrospective patient studies and animal studies assessed the potential of the marketed GBCAs to cause hyperintensities or gadolinium deposits in the brain, respectively. This review summarizes the evidence provided by these studies and additionally takes into account data from in vitro studies on the stability of GBCAs. The author concludes that there is a body of evidence suggesting that the potential of a GBCA to cause hyperintensities or gadolinium deposition in the brain corresponds with its stability and is particularly depending on the group of the specific GBCA as either linear or macrocyclic., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: Recent studies reported an increase in the dentate nucleus (DN)-to-pons signal intensity (SI) ratio (DN-pons SI ratio) on unenhanced T1-weighted images in patients who received consecutive serial injections of linear gadolinium-based contrast agents (GBCAs). In contrast, most studies found no increase in the DN-pons SI ratio when patients were treated with consecutive serial injections of macrocyclic GBCAs. However, the potential difference between macrocyclic and linear GBCAs has never been assessed in individuals who received subsequent applications of both contrast agents. In this retrospective study, we assessed the evolution of the DN-pons SI ratio change in patients that were treated with a comparable number of serial consecutive injections of the linear GBCA gadopentetate dimeglumine and subsequent serial injections of the macrocyclic GBCAs gadobutrol and gadoterate meglumine., Materials and Methods: Data of 36 patients was analyzed. All patients underwent at least 5 consecutive administrations of the linear GBCA gadopentetate dimeglumine followed by an equal number of consecutive administrations of the macrocyclic GBCA gadobutrol. In 12 of the 36 patients, 5 or more final consecutive injections of the macrocyclic GBCA gadoterate meglumine were analyzed additionally. The difference of DN-pons SI ratios on unenhanced T1-weighted images was calculated by subtracting the ratio at the first examination from the ratio at the last examination in each of the 3 periods., Results: The mean DN-pons SI ratio difference in the gadopentetate dimeglumine period was significantly greater than 0 (mean ± SD, 0.0448 ± 0.0345; P < 0.001), whereas the mean DN-pons SI ratio difference in the subsequent gadobutrol and gadoterate meglumine period was significantly smaller than 0 (gadobutrol: -0.0178 ± 0.0459, P = 0.026; gadoterate meglumine: -0.0250 ± 0.0284, P = 0.011)., Conclusions: In this observational study, the application of the linear GBCA gadopentetate dimeglumine was associated with a DN-pons SI ratio increase, whereas subsequent applications of the macrocyclic GBCAs gadobutrol or gadoterate meglumine in the same patients were not. Rather, the current data tentatively suggest a decrease in preexisting hyperintensities over time when linear GBCAs are changed to macrocyclic GBCAs, potentially indicating a washout effect or precipitation of gadolinium. Future patient studies need to include control groups to replicate the present results, and additional animal studies should be conducted to clarify the underlying mechanism of the proposed SI decrease.

Objective: The aim of this study was to compare changes in the signal intensity (SI) ratio of the dentate nucleus (DN) to the pons, DN to cerebrospinal fluid (CSF), and globus pallidus (GP) to thalamus on unenhanced T1-weighted magnetic resonance imaging (MRI) scans after serial injections of the macrocyclic gadolinium-based contrast agent gadobutrol., Materials and Methods: Thirty patients who had received at least 5 MRI examinations (plus an additional last MRI for reference) with the exclusive use of gadobutrol, resulting in a total cumulative dose of 54.1 ± 30.4 mL gadobutrol, were analyzed retrospectively. Signal intensity ratio differences were calculated for DN-to-pons, DN-to-CSF, and GP-to-thalamus ratios by subtracting the SI ratio at the first MRI from the SI ratio at the last MRI scan. One-sample t tests were employed to examine if they differed from 0. Regression and correlational analyses were performed to examine whether the SI ratio differences were predicted by a number of control variables., Results: Signal intensity ratio differences did not differ significantly from 0, neither for the DN-to-pons ratio (-0.0035 ± 0.0476, P = 0.69), the DN-to-CSF ratio (-0.0539 ± 0.3217, P = 0.37), nor the GP-to-thalamus ratio (-0.0020 ± 0.0211, P = 0.60). None of the control variables predicted changes in SI ratios., Conclusions: In contrast to a recently published study, we did not find signal increases in the DN or in the GP after serial injections of gadobutrol, even though the total dose applied here was considerably larger than in the respective study. This finding adds further support to the hypothesis that the molecular structure of a gadolinium-based contrast agent as either macrocyclic or linear is a crucial factor for its potential to cause gadolinium deposition in the brain. Future studies should further assess this hypothesis by additional animal investigations as well as histopathological and clinical correlation studies.

Objectives: The aim of this study was to compare changes in signal intensity (SI) ratios of the dentate nucleus (DN) to pons and cerebrospinal fluid (CSF) on unenhanced T1-weighted magnetic resonance imaging (MRI) scans between the first and last MRI using the linear gadolinium-based contrast agent gadobenate dimeglumine., Materials and Methods: The study was approved by the ethical committee of the University of Heidelberg (S-324/2014), and written informed consent was waived due to the retrospective character of the study. Fifty patients who underwent at least 5 consecutive MRI examinations (plus an additional last MRI for reference) with the exclusive use of gadobenate dimeglumine were analyzed retrospectively. The difference of DN-to-pons and DN-to-CSF mean SI ratios was calculated on unenhanced T1-weighted images between the first and last examination. Results were compared with previously published data on gadopentetate dimeglumine and gadoterate meglumine., Results: Signal intensity ratio differences for DN-to-pons and DN-to-CSF were significantly greater than 0 (pons: 0.0399 ± 0.0307, P < 0.001; CSF: 0.1439 ± 0.1524, P < 0.001). No control variable consistently predicted the SI ratio difference for the DN-to-pons and the DN-to-CSF ratio. Compared with previously published data, the difference in SI increase between gadopentetate dimeglumine and gadobenate dimeglumine was not significant for the DN-to-pons ratio (P = 0.906). In contrast, the DN-to-CSF ratio difference was significantly lower (P < 0.001) for gadobenate dimeglumine. Dentate nucleus-to-pons (P < 0.001) and DN-to-CSF (P = 0.017) ratio differences were both significantly higher for gadobenate dimeglumine than for gadoterate meglumine., Conclusions: The present study found an increase in SI in the DN after serial injections of gadobenate dimeglumine. Further studies are needed to clarify the potential of different linear gadolinium-based contrast agents to cause SI increase in the DN.

Purpose: To compare changes in signal intensity (SI) ratios of the dentate nucleus (DN) and the globus pallidus (GP) to those of other structures on unenhanced T1-weighted magnetic resonance (MR) images between linear and macrocyclic gadolinium-based contrast agents (GBCAs)., Materials and Methods: The study was approved by the ethical committee of the University of Heidelberg (reference no. S-324/2014). Owing to the retrospective character of the study, the ethical committee did not require any written informed consent. Two groups of 50 patients who underwent at least six consecutive MR imaging examinations with the exclusive use of either a linear GBCA (gadopentetate dimeglumine) or a macrocyclic GBCA (gadoterate meglumine) were analyzed retrospectively. The difference in mean SI ratios of DN to pons and GP to thalamus on unenhanced T1-weighted images from the last and first examinations was calculated. One-sample and independent-sample t tests were used to assess the difference in SI ratios for both groups, and regression analysis was performed to account for potential confounders., Results: The SI ratio difference in the linear group was greater than 0 (mean DN difference ± standard deviation, 0.0407 ± 0.0398 [P < .001]; GP, 0.0287 ± 0.0275 [P < .001]) and significantly larger (DN, P < .001 and standardized difference of 1.16; GP, P < .001 and standardized difference of 0.81) than that in the macrocyclic group, which did not differ from 0 (DN, 0.0016 ± 0.0266 [P = .680]; GP, 0.0031 ± 0.0354 [P = .538]). The SI ratio difference between the last and first examinations for the DN remained significantly different between the two groups in the regression analysis (P < .001)., Conclusion: This study indicates that an SI increase in the DN and GP on T1-weighted images is caused by serial application of the linear GBCA gadopentetate dimeglumine but not by the macrocyclic GBCA gadoterate meglumine. Clinical implications of this observation remain unclear., (RSNA, 2015)

The Contrast Media Safety Committee of the European Society of Urogenital Radiology has, together with the Preanalytical Phase Working Group of the EFLM Science Committee, reviewed the literature and updated its recommendations to increase awareness and provide insight into these interferences. [ABSTRACT FROM AUTHOR]