Dose Of Gadolinium-based Contrast Agent Research Articles

Low-dose GBCA administration for brain tumour dynamic contrast enhanced MRI: a feasibility study

A key limitation of current dynamic contrast enhanced (DCE) MRI techniques is the requirement for full-dose gadolinium-based contrast agent (GBCA) administration. The purpose of this feasibility study was to develop and assess a new low GBCA dose protocol for deriving high-spatial resolution kinetic parameters from brain DCE-MRI. Nineteen patients with intracranial skull base tumours were prospectively imaged at 1.5 T using a single-injection, fixed-volume low GBCA dose, dual temporal resolution interleaved DCE-MRI acquisition. The accuracy of kinetic parameters (ve, Ktrans, vp) derived using this new low GBCA dose technique was evaluated through both Monte-Carlo simulations (mean percent deviation, PD, of measured from true values) and an in vivo study incorporating comparison with a conventional full-dose GBCA protocol and correlation with histopathological data. The mean PD of data from the interleaved high-temporal-high-spatial resolution approach outperformed use of high-spatial, low temporal resolution datasets alone (p < 0.0001, t-test). Kinetic parameters derived using the low-dose interleaved protocol correlated significantly with parameters derived from a full-dose acquisition (p < 0.001) and demonstrated a significant association with tissue markers of microvessel density (p < 0.05). Our results suggest accurate high-spatial resolution kinetic parameter mapping is feasible with significantly reduced GBCA dose.

Comprehensive Analysis of the Spatial Distribution of Gadolinium, Iron, Manganese, and Phosphorus in the Brain of Healthy Rats After High-Dose Administrations of Gadodiamide and Gadobutrol.

After the administration of gadolinium-based contrast agents (GBCAs), residual gadolinium (Gd) has been detected in a few distinct morphological structures of the central nervous system (CNS). However, a systematic, comprehensive, and quantitative analysis of the spatial Gd distribution in the entire brain is not yet available. The first aim of this study is to provide this analysis in healthy rats after administration of high GBCA doses. The second aim is to assess the spatial distributions and possible Gd colocalizations of endogenous iron (Fe), manganese (Mn), and phosphorus (P). In addition, the presence of Gd in proximity to blood vessels was assessed by immunohistochemistry. Male rats were randomly assigned to 3 groups (n = 3/group): saline (control), gadodiamide (linear GBCA), and gadobutrol (macrocyclic GBCA) with cumulative Gd doses of 14.4 mmol/kg of body mass. Five weeks after the last administration, the brains were collected and cryosectioned. The spatial distributions of Gd, Fe, Mn, and P were analyzed in a total of 130 sections, each covering the brain in 1 of the 3 perpendicular anatomical orientations, using laser ablation coupled with inductively coupled plasma mass spectrometry. Quantitative spatial element maps were generated, and the concentrations of Gd, Fe, and Mn were measured in 31 regions of interest covering various distinct CNS structures. Correlation analyses were performed to test for possible colocalization of Gd, Fe, and Mn. The spatial proximity of Gd and blood vessels was studied using metal-tagged antibodies against von Willebrand factor with laser ablation coupled with inductively coupled plasma mass spectrometry. After administration of linear gadodiamide, high Gd concentrations were measured in many distinct structures of the gray matter. This involved structures previously reported to retain Gd after linear GBCA, such as the deep cerebellar nuclei or the globus pallidus, but also structures that had not been reported so far including the dorsal subiculum, the retrosplenial cortex, the superior olivary complex, and the inferior colliculus. The analysis in all 3 orientations allowed the localization of Gd in specific subregions and layers of certain structures, such as the hippocampus and the primary somatosensory cortex. After macrocyclic gadobutrol, the Gd tissue concentration was significantly lower than after gadodiamide. Correlation analyses of region of interest concentrations of Gd, Fe, and Mn revealed no significant colocalization of Gd with endogenous Fe or Mn in rats exposed to either GBCA. Immunohistochemistry revealed a colocalization of Gd traces with vascular endothelium in the deep cerebellar nuclei after gadobutrol, whereas the majority of Gd was found outside the vasculature after gadodiamide. In rats exposed to gadodiamide but not in rats exposed to gadobutrol, high Gd concentrations were measured in various distinct CNS structures, and structures not previously reported were identified to contain Gd, including specific subregions and layers with different cytoarchitecture and function. Knowledge of these distinct spatial patterns may pave the way for tailored functional neurological testing. Signs for the localization of the remaining Gd in the vascular endothelium were prominent for gadobutrol but not gadodiamide. The results also indicate that local transmetalation with endogenous Fe or Mn is unlikely to explain the spatial patterns of Gd deposition in the brain, which argues against a general role of these metals in local transmetalation and release of Gd ions in the CNS.

Contrast Agent Dose Reduction in MRI Utilizing a Generative Adversarial Network in an Exploratory Animal Study.

The aim of this study is to use virtual contrast enhancement to reduce the amount of hepatobiliary gadolinium-based contrast agent in magnetic resonance imaging with generative adversarial networks (GANs) in a large animal model. With 20 healthy Göttingen minipigs, a total of 120 magnetic resonance imaging examinations were performed on 6 different occasions, 50% with reduced (low-dose; 0.005 mmol/kg, gadoxetate) and 50% standard dose (normal-dose; 0.025 mmol/kg). These included arterial, portal venous, venous, and hepatobiliary contrast phases (20 minutes, 30 minutes). Because of incomplete examinations, one animal had to be excluded. Randomly, 3 of 19 animals were selected and withheld for validation (18 examinations). Subsequently, a GAN was trained for image-to-image conversion from low-dose to normal-dose (virtual normal-dose) with the remaining 16 animals (96 examinations). For validation, vascular and parenchymal contrast-to-noise ratio (CNR) was calculated using region of interest measurements of the abdominal aorta, inferior vena cava, portal vein, hepatic parenchyma, and autochthonous back muscles. In parallel, a visual Turing test was performed by presenting the normal-dose and virtual normal-dose data to 3 consultant radiologists, blinded for the type of examination. They had to decide whether they would consider both data sets as consistent in findings and which images were from the normal-dose study. The pooled dynamic phase vascular and parenchymal CNR increased significantly from low-dose to virtual normal-dose (pooled vascular: P < 0.0001, pooled parenchymal: P = 0.0002) and was found to be not significantly different between virtual normal-dose and normal-dose examinations (vascular CNR [mean ± SD]: low-dose 17.6 ± 6.0, virtual normal-dose 41.8 ± 9.7, and normal-dose 48.4 ± 12.2; parenchymal CNR [mean ± SD]: low-dose 20.2 ± 5.9, virtual normal-dose 28.3 ± 6.9, and normal-dose 29.5 ± 7.2). The pooled parenchymal CNR of the hepatobiliary contrast phases revealed a significant increase from the low-dose (22.8 ± 6.2) to the virtual normal-dose (33.2 ± 6.1; P < 0.0001) and normal-dose sequence (37.0 ± 9.1; P < 0.0001). In addition, there was no significant difference between the virtual normal-dose and normal-dose sequence. In the visual Turing test, on the median, the consultant radiologist reported that the sequences of the normal-dose and virtual normal-dose are consistent in findings in 100% of the examinations. Moreover, the consultants were able to identify the normal-dose series as such in a median 54.5% of the cases. In this feasibility study in healthy Göttingen minipigs, it could be shown that GAN-based virtual contrast enhancement can be used to recreate the image impression of normal-dose imaging in terms of CNR and subjective image similarity in both dynamic and hepatobiliary contrast phases from low-dose data with an 80% reduction in gadolinium-based contrast agent dose. Before clinical implementation, further studies with pathologies are needed to validate whether pathologies are correctly represented by the network.

NIMG-12. DSC-MRI PERFUSION IMAGING IN UNTREATED BRAIN METASTASES USING THE CONSENSUS ACQUISITION PROTOCOL: A MULTI-SITE BENCHMARK STUDY

Abstract INTRODUCTION DSC-MRI perfusion methods are commonly used to evaluate both primary and metastatic brain cancer with the creation of maps of relative cerebral blood volume (rCBV). Recently, guidelines were established to ensure a standard DSC-MRI acquisition protocol that reduces inter-site variability. The purpose of this study was to initiate the determination of rCBV benchmark values using the DSC-MRI consensus protocol in treatment-naïve brain metastases. METHODS Patients from three sites with treatment-naïve, contrast-enhancing brain metastases on MRI were considered for inclusion in this retrospective study. The MRIs included pre- and post-contrast T1w(T1+C) images obtained after administration of gadolinium-based contrast agent (GBCA) (0.1 mmol/kg), which serves as the recommended preload for the DSC-MRI data collection. A 2nd GBCA dose (0.1 mmol/kg) was administered 40-60sec after the collection of baseline GRE-EPI images using recommended settings (FA=60o, TE/TR=30ms/1100-1250ms) for 120s. Calibrated pre/post T1w difference maps (dT1) were used for delineation of enhancing lesion, and standardized (calibrated) rCBV (sRCBV) created. Mean sRCBV for metastases were compared to normal appearing white matter (NAWM) and treatment-naive glioblastoma (GBM) from a previous study. Pairwise comparisons were performed using the Mann-Whitney nonparametric test. RESULTS N=52 patients with primary histology of lung (n=27); breast (n=6); skin (n=7); gastrointestinal (GI: n=3) and genitourinary (GU: n=9) cancers were included in comparison to GBM (n=31). The mean sRCBV for all metastases (1.77+/-1.05) is significantly lower (p=0.0003) than for GBM (2.67+/-1.34) but with both statistically greater (p&amp;lt; 0.0001) than NAWM (0.706+/-0.163). Individually, lung (1.47+/- 0.61), breast (2.275+/-0.87), skin (2.10+/-1.22), GI (1.91+/- 0.64) and GU (2.01+/-0.63) mean sRCBV are statistically greater than for NAWM. CONCLUSION Using the consensus DSC-MRI acquisition protocol confirms use of sRCBV to identify biologically active, treatment-naive brain metastases setting benchmark values for future applications.

Gadolinium-based contrast agent attenuation does not impact PET quantification in simultaneous dynamic contrast enhanced breast PET/MR.

Simultaneous PET/MR imaging involves injection of a radiopharmaceutical and often also includes administration of a gadolinium-based contrast agent (GBCA). Phantom model studies indicate that attenuation of annihilation photons by GBCAs does not bias quantification metrics of PET radiopharmaceutical uptake. However, a direct comparison of attenuation-corrected PET values before and after administration of GBCA has not been performed in patients imaged with simultaneous dynamic PET/MR. The purpose of this study was to investigate the attenuating effect of GBCAs on standardized uptake value (SUV) quantification of 18 F-fluorodeoxyglucose (FDG) uptake in invasive breast cancer and normal tissues using simultaneous PET/MR. The study included 13 women with newly diagnosed invasive breast cancer imaged using simultaneous dedicated prone breast PET/MR with FDG. PET data collection and two-point Dixon-based MR attenuation correction sequences began simultaneously before the administration of GBCA to avoid a potential impact of GBCA on the attenuation correction map. A standard clinical dose of GBCA was intravenously administered for the dynamic contrast enhanced MR sequences obtained during the simultaneous PET data acquisition. PET data were dynamically reconstructed into 60 frames of 30 s each. Three timing windows were chosen consisting of a single frame (30 s), two frames (60 s), or four frames (120 s) immediately before and after contrast administration. SUVmax and SUVmean of the biopsy-proven breast malignancy, fibroglandular tissue of the contralateral normal breast, descending aorta, and liver were calculated prior to and following GBCA administration. Percent change in the SUV metrics were calculated to test for a statistically significant, non-zero percent change using Wilcoxon signed-rank tests. No statistical change in SUVmax or SUVmean was found for the breast malignancies or normal anatomical regions during the timing windows before and after GBCA administration. GBCAs do not significantly impact the results of PET quantification by means of additional attenuation. However, GBCAs may still affect quantification by affecting MR acquisitions used for MR-based attenuation correction which this study did not address. Corrections to account for attenuation due to clinical concentrations of GBCAs are not necessary in simultaneous PET/MR examinations when MR-based attenuation correction sequences are performed prior to GBCA administration.

Surrogate vascular input function measurements from the superior sagittal sinus are repeatable and provide tissue-validated kinetic parameters in brain DCE-MRI

Accurate vascular input function (VIF) derivation is essential in brain dynamic contrast-enhanced (DCE) MRI. The optimum site for VIF estimation is, however, debated. This study sought to compare VIFs extracted from the internal carotid artery (ICA) and its branches with an arrival-corrected vascular output function (VOF) derived from the superior sagittal sinus (VOFSSS). DCE-MRI datasets from sixty-six patients with different brain tumours were retrospectively analysed and plasma gadolinium-based contrast agent (GBCA) concentration-time curves used to extract VOF/VIFs from the SSS, the ICA, and the middle cerebral artery. Semi-quantitative parameters across each first-pass VOF/VIF were compared and the relationship between these parameters and GBCA dose was evaluated. Through a test–retest study in 12 patients, the repeatability of each semiquantitative VOF/VIF parameter was evaluated; and through comparison with histopathological data the accuracy of kinetic parameter estimates derived using each VOF/VIF and the extended Tofts model was also assessed. VOFSSS provided a superior surrogate global input function compared to arteries, with greater contrast-to-noise (p < 0.001), higher peak (p < 0.001, repeated-measures ANOVA), and a greater sensitivity to interindividual plasma GBCA concentration. The repeatability of VOFSSS derived semi-quantitative parameters was good to excellent (ICC = 0.717–0.888) outperforming arterial based approaches. In contrast to arterial VIFs, kinetic parameters obtained using a SSS derived VOF permitted detection of intertumoural differences in both microvessel surface area and cell density within resected tissue specimens. These results support the usage of an arrival-corrected VOFSSS as a surrogate vascular input function for kinetic parameter mapping in brain DCE-MRI.

Effect of Contrast Agent Dose Reduction on Vascular Enhancement and Image Quality in Thoracoabdominal Dynamic 3-Dimensional Magnetic Resonance Angiography: A Systematic Intraindividual Analysis in Pigs.

High spatial and temporal resolution contrast-enhanced magnetic resonance angiography (MRA) with gadolinium-based contrast agents (GBCAs) at standard dose offers both detailed anatomic information on both arterial and venous vessels and hemodynamic characteristics. Several preclinical and clinical dynamic 3-dimensional (3D) MRA studies that focused on arterial vessels only proposed that high image quality may also be achieved with significantly reduced GBCA doses, calling into question the need to use standard doses. A systematic analysis of GBCA doses and resulting image quality for both arteries and veins has not yet been performed. The purpose of this study was therefore to systematically analyze dose-dependent vascular enhancements in dynamic 3D-MRA of the thoracoabdominal vasculature at 1.5 T in an animal model to determine the optimal contrast agent protocol for optimized vascular assessment. The vascular enhancement in thoracoabdominal dynamic 3D-MRA (time-resolved angiography with interleaved stochastic trajectories, TWIST at 1.5 T) was interindividually and intraindividually compared in 5 anesthetized Göttingen minipigs using gadobutrol at the standard dose (0.1 mmol/kg body weight, ie, 0.1 mL/kg) and at reduced doses (0.08, 0.06, 0.04, 0.02 mmol/kg) in a randomized order. All injections were performed at 2 mL/s followed by 20 mL saline. Images were quantitatively analyzed, measuring signal intensities in 5 regions that covered the passage of the GBCA through the body at different representative stages of circulation (pulmonary, arterial, and venous system). The evaluation of GBCA dose-dependent signal intensity changes in the different vascular regions was performed by linear regression analysis.The qualitative image analysis of dynamic 3D-MRA by 3 independent radiologists included the visibility of 25 arterial and venous vessel segments at different stages of GBCA passage. Possible quality losses were statistically tested by comparing image quality ratings at the reduced dose with that of the standard dose using Friedman test followed by Dunn post hoc test for multiple comparison. Significance was stated at P < 0.05. Quantitative analysis revealed shorter time-to-peak intervals and bolus durations in line with decreasing GBCA dose and volume in all vessels. Although the peak signal was almost independent of the administered GBCA dose at the level of the pulmonary trunk, a linear signal decrease in the abdominal aorta ( r2 = 0.96), the renal arteries ( r2 = 0.99), the inferior vena cava ( r2 = 0.99), and the portal vein ( r2 = 0.97) was observed. Cumulative analysis of arterial segments revealed significantly lower image quality at doses below 40% of the standard dose, whereas in venous segments, significantly lower image quality was observed at doses below 60% of the standard dose. In dynamic 3D-MRA at 1.5 T, dose reduction leads to a signal loss that is most pronounced in the venous system and results in significantly lower image quality according to the dose and vessels of interest. Careful dose reduction is thus required according to the specific diagnostic needs. For dynamic 3D-MRA of the arterial and venous system, GBCA doses of at least 60% of the standard dose up to the full dose are preferable, whereas 40% of the standard dose seems feasible if only the arterial system is to be imaged.

The effect of gadolinium-based contrast-agents on automated brain atrophy measurements by FreeSurfer in patients with multiple sclerosis

ObjectiveTo determine whether reliable brain atrophy measures can be obtained from post-contrast 3D T1-weighted images in patients with multiple sclerosis (MS) using FreeSurfer.MethodsTwenty-two patients with MS were included, in which 3D T1-weighted MR images were obtained during the same scanner visit, with the same acquisition protocol, before and after administration of gadolinium-based contrast agents (GBCAs). Two FreeSurfer versions (v.6.0.1 and v.7.1.1.) were applied to calculate grey matter (GM) and white matter (WM) volumes and global and regional cortical thickness. The consistency between measures obtained in pre- and post-contrast images was assessed by intra-class correlation coefficient (ICC), the difference was investigated by paired t-tests, and the mean percentage increase or decrease was calculated for total WM and GM matter volume, total deep GM and thalamus volume, and mean cortical thickness.ResultsGood to excellent reliability was found between all investigated measures, with ICC ranging from 0.926 to 0.996, all p values < 0.001. GM volumes and cortical thickness measurements were significantly higher in post-contrast images by 3.1 to 17.4%, while total WM volume decreased significantly by 1.7% (all p values < 0.001).ConclusionThe consistency between values obtained from pre- and post-contrast images was excellent, suggesting it may be possible to extract reliable brain atrophy measurements from T1-weighted images acquired after administration of GBCAs, using FreeSurfer. However, absolute values were systematically different between pre- and post-contrast images, meaning that such images should not be compared directly. Potential systematic effects, possibly dependent on GBCA dose or the delay time after contrast injection, should be investigated.Trial registrationClinical trials.gov. identifier: NCT00360906.Key Points• The influence of gadolinium-based contrast agents (GBCAs) on atrophy measurements is still largely unknown and challenges the use of a considerable source of historical and prospective real-world data.• In 22 patients with multiple sclerosis, the consistency between brain atrophy measurements obtained from pre- and post-contrast images was excellent, suggesting it may be possible to extract reliable atrophy measurements in T1-weighted images acquired after administration of GBCAs, using FreeSurfer.• Absolute values were systematically different between pre- and post-contrast images, meaning that such images should not be compared directly, and measurements extracted from certain regions (e.g., the temporal pole) should be interpreted with caution.

Neurologic Effects of Gadolinium Retention in the Brain after Gadolinium-based Contrast Agent Administration.

Background Concerns over the neurotoxic potential of retained gadolinium in brain tissues after intravenous gadolinium-based contrast agent (GBCA) administration have led to pronounced worldwide use changes, yet the clinical sequelae of gadolinium retention remain undefined. Purpose To assess clinical and neurologic effects and potential neurotoxicity of gadolinium retention in rats after administration of various GBCAs. Materials and Methods From March 2017 through July 2018, 183 male Wistar rats received 20 intravenous injections of 2.5 mmol per kilogram of body weight (80 human equivalent doses) of various GBCAs (gadodiamide, gadobenate, gadopentetate, gadoxetate, gadobutrol, gadoterate, and gadoteridol) or saline over 4 weeks. Rats were evaluated 6 and 34 weeks after injection with five behavioral tests, and inductively coupled plasma mass spectrometry, transmission electron microscopy, and histopathology were performed on urine, serum, cerebrospinal fluid (CSF), basal ganglia, dentate nucleus, and kidney samples. Dunnett post hoc test and Wilcoxon rank sum test were used to compare differences between treatment groups. Results No evidence of differences in any behavioral test was observed between GBCA-exposed rats and control animals at either 6 or 34 weeks (P = .08 to P = .99). Gadolinium concentrations in both neuroanatomic locations were higher in linear GBCA-exposed rats than macrocyclic GBCA-exposed rats at 6 and 34 weeks (P < .001). Gadolinium clearance over time varied among GBCAs, with gadobutrol having the largest clearance (median: 62% for basal ganglia, 70% for dentate) and gadodiamide having no substantial clearance. At 34 weeks, gadolinium was largely cleared from the CSF and serum of gadodiamide-, gadobenate-, gadoterate-, and gadobutrol-exposed rats, especially for the macrocyclic agents (range: 70%-98% removal for CSF, 34%-94% removal for serum), and was nearly completely removed from urine (range: 96%-99% removal). Transmission electron microscopy was used to detect gadolinium foci in linear GBCA-exposed brain tissue, but no histopathologic differences were observed for any GBCA. Conclusion In this rat model, no clinical evidence of neurotoxicity was observed after exposure to linear and macrocyclic gadolinium-based contrast agents at supradiagnostic doses. © RSNA, 2022 Online supplemental material is available for this article.

Screening Breast MRI and Gadolinium Deposition: Cause for Concern?

Gadolinium-based contrast agents (GBCAs) have been used worldwide for over 30 years and have enabled lifesaving diagnoses. Contrast-enhanced breast MRI is frequently used as supplemental screening for women with an elevated lifetime risk of breast cancer. Data have emerged that indicate a fractional amount of administered gadolinium is retained in the bone, skin, solid organs, and brain tissues of patients with normal renal function, although there are currently no reliable data regarding the clinical or biological significance of this retention. Linear GBCAs are associated with a higher risk of gadolinium retention than macrocyclic agents. Over the course of their lives, screened women may receive high cumulative doses of GBCA. Therefore, as breast MRI screening utilization increases, thoughtful use of GBCA is indicated in this patient population.

Editorial Comment: Toward Meeting ACR-ASNR Guidelines for Reducing Gadolinium-Based Contrast Agent Dose in Brain MRI Examinations

Editorial Comment: Toward Meeting ACR-ASNR Guidelines for Reducing Gadolinium-Based Contrast Agent Dose in Brain MRI Examinations

Gadolinium Tissue Distribution in a Large-Animal Model after a Single Dose of Gadolinium-based Contrast Agents.

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.

Effect of at Least 10 Serial Gadobutrol Administrations on Brain Signal Intensity Ratios on T1-Weighted MRI in Children: A Matched Case-Control Study.

BACKGROUND. An association is recognized between linear gadolinium-based contrast agents (GBCAs) and intracranial gadolinium retention in children. The relation between macrocyclic GBCAs and gadolinium retention remains incompletely understood. OBJECTIVE. The purpose of this study was to assess whether 10 or more administrations of the macrocyclic GBCA gadobutrol are associated with increased signal intensity (SI) in the dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted MRI of children and to explore clinical variables potentially associated with T1 hyperintensity. METHODS. The case group consisted of 25 children (13 boys, 12 girls; mean age, 7 ± 4 years; range, 2-18 years) who underwent at least 10 (mean, 15 ± 6; range, 10-34) contrast-enhanced MRI examinations exclusively with gadobutrol. The control group consisted of 25 age- and sex-matched patients undergoing MRI who had never been exposed to gadolinium. Two observers in consensus using a 3-point scale assessed visual T1 hyperintensity in the DN and GP. One observer placed ROIs on T1-weighted images to mark the DN, GP, middle cerebellar peduncle (MCP), and pulvinar of the thalamus bilaterally to compute mean DN-to-MCP and GP-to-thalamus SI ratios. SI ratios were compared between the macrocyclic GBCA and control groups. In the macrocyclic GBCA group, Pearson correlation analysis was conducted between SI ratios and clinical variables. ROI measurements were repeated by the original reader and an independent reader, and interobserver and intraobserver agreement were computed by means of Lin concordance correlation coefficient (ρc). RESULTS. No patient had visual T1 hyperintensity in the DN or GP. No significant difference between the macrocyclic GBCA and control groups was observed for DN-to-MCP SI ratio (0.95 ± 0.05 vs 0.95 ± 0.03; p = .67) or GP-to-thalamus SI ratio (1.05 ± 0.06 vs 1.04 ± 0.06; p = .65). In the macrocyclic GBCA group, no significant correlation was observed between DN-to-MCP SI ratio or GP-to-thalamus SI ratio and age (r = 0.355, p = .08; r = 0.167, p = .42), number of contrast-enhanced MRI examinations (r = 0.247, p = .23; r = 0.203, p = .33), mean time between examinations (r = 0.193, p = .36; r = 0.047, p = .82), or cumulative macrocyclic GBCA dose (r = 0.434, p = .07; r = 0.270, p = .19). Interobserver and intraobserver agreement was substantial for DN-to-MCP SI and GP-to-TH SI ratios (ρc = 0.931-0.974). CONCLUSION. Ten or more serial gadobutrol administrations were not associated with T1 hyperintensity in the DN or GP of children. CLINICAL IMPACT. Selection of gadobutrol as an MRI contrast agent may reduce risk of gadolinium retention in children. The findings may help guide practices for GBCA administration to children.

Influence of aging and gadolinium exposure on T1, T2, and T2*-relaxation in healthy women with an increased risk of breast cancer with and without prior exposure to gadoterate meglumine at 3.0-T brain MR imaging

ObjectivesWe examined the effects of aging and of gadolinium-based contrast agent (GBCA) exposure on MRI measurements in brain nuclei of healthy women.MethodsThis prospective, IRB-approved single-center case-control study enrolled 100 healthy participants of our high-risk screening center for hereditary breast cancer, who had received at least six doses of macrocyclic GBCA (exposed group) or were newly entering the program (GBCA-naïve group). The cutoff “at least six doses” was chosen to be able to include a sufficient number of highly exposed participants. All participants underwent unenhanced 3.0-T brain MRI including quantitative T1, T2, and R2* mapping and T1- and T2-weighted imaging. The relaxation times/signal intensities were derived from region of interest measurements in the brain nuclei performed by a radiologist and a neuroradiologist, both board certified. Statistical analysis was based on descriptive evaluations and uni-/multivariable analyses.ResultsThe participants (exposed group: 49, control group: 51) were aged 42 ± 9 years. In a multivariable model, age had a clear impact on R2* (p < 0.001–0.012), T2 (p = 0.003–0.048), and T1 relaxation times/signal intensities (p < 0.004–0.046) for the majority of deep brain nuclei, mostly affecting the substantia nigra, globus pallidus (GP), nucleus ruber, thalamus, and dentate nucleus (DN). The effect of prior GBCA administration on T1 relaxation times was statistically significant for the DN, GP, and pons (p = 0.019–0.037).ConclusionsIn a homogeneous group of young to middle-aged healthy females aging had an effect on T2 and R2* relaxation times and former GBCA applications influenced the measured T1 relaxation times.Key PointsThe quantitative T1, T2, and R2* relaxation times measured in women at high risk of developing breast cancer showed characteristic bandwidth for all brain nuclei examined at 3.0-T MRI.The effect of participant age had a comparatively strong impact on R2*, T2, and T1 relaxation times for the majority of brain nuclei examined.The effect of prior GBCA administrations on T1 relaxation times rates was comparatively less pronounced, yielding statistically significant results for the dentate nucleus, globus pallidus, and pons.Summary statementHealthy women with and without previous GBCA-enhanced breast MRI exhibited age-related T2* and T2 relaxation alterations at 3.0 T-brain MRI. T1 relaxation alterations due to prior GBCA administration were comparatively less pronounced.

MR Imaging of Endolymphatic Hydrops in Five Minutes.

In this study, we present images acquired by a fast-imaging method for the evaluation of endolymphatic hydrops after intravenous administration of a single dose of gadolinium-based contrast agent. We utilized the hybrid of reversed image of MR cisternography and a positive perilymph signal by heavily T2- weighted 3D-fluid attenuated inversion recovery-multiplied by T2 (HYDROPS2-Mi2) method combined with deep learning reconstruction denoising. The scan time for the fast protocol was approximately 5 mins, which is far shorter than previously reported scan times. The fast acquisition provides similar image quality and less motion artifacts compared to the longer method.

Susceptibility-Weighted Imaging of the Pediatric Brain after Repeat Doses of Gadolinium-Based Contrast Agent.

Gadolinium complexes have paramagnetic properties; thus, we aimed to determine the susceptibility changes in the globus pallidus and dentate nucleus following administration of linear or macrocyclic gadolinium-based contrast agents in children. Thirty-three patients with linear gadolinium-based contrast agent gadopentetate dimeglumine administration, 33 age- and sex-matched patients with macrocyclic gadolinium-based contrast agent gadobutrol administration, and 33 age- and sex-matched control subjects without gadolinium exposure were enrolled in this retrospective study. The signal intensity on SWI and T1WI was determined in the dentate nucleus, middle cerebellar peduncle, globus pallidus, and pulvinar of the thalamus in an ROI-based analysis to calculate dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios. A repeated measures ANOVA was performed to compare SWIminimum, SWImean, and T1WI signal intensity ratios between gadolinium-based contrast agent groups and control subjects. Pearson correlation analysis was performed to determine any correlation between signal intensity ratios and variables. Dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios for both SWImean and SWIminimum were lower for the linear gadolinium-based contrast agent group compared with macrocyclic gadolinium-based contrast agent and control groups (P < .05). No significant difference of the SWImean and SWIminimum ratios were noted between the macrocyclic gadolinium-based contrast agent group and the control group (P > .05). Both dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios on T1WI in the linear gadolinium-based contrast agent group were higher than in the control group and the macrocyclic gadolinium-based contrast agent group (P < .05). A negative correlation was identified between SWImean and SWIminimum ratios and the number of linear gadolinium-based contrast agent administrations (dentate nucleus-to-middle cerebellar peduncle ratio: SWImean, r = -0.43, P = .005; SWIminimum, r = -0.38, P = .011; globus pallidus-to-thalamus ratio: SWImean, r = -0.39, P = .009; SWIminimum, r = -0.33, P = .017). SWI analysis of the pediatric brain demonstrated a statistically significant decrease in SWIminimum and SWImean values for the dentate nucleus and globus pallidus after administration of linear gadolinium-based contrast agents but not macrocyclic gadolinium-based contrast agents.

Patterns of use, effectiveness and safety of gadolinium contrast agents: a European prospective cross-sectional multicentre observational study

BackgroundThe EU gadolinium-based contrast agents (GBCA) market has changed in recent years due to the European Medicines Agency decision to suspend the marketing authorisation of linear GBCA and the marketing authorisation of new generic macrocyclic GBCA. The study aims to understand the patterns of (GBCA) use, and to study the effectiveness and safety of GBCA in routine practice across Europe.MethodsProspective, cross-sectional, multicentre, observational study in patients undergoing contrast-enhanced magnetic resonance. Reported usage patterns included indication, referral and examination details. Assessment of effectiveness included changes in radiological diagnosis, diagnostic confidence and image quality. Safety data were collected by spontaneous patient adverse event (AE) reporting.Results2118 patients were included from 8 centres across 5 European countries between December 2018 and November 2019. Clariscan, Dotarem (gadoteric acid), Gadovist (gadobutrol) and ProHance (gadoteridol) were utilised in 1513 (71.4%), 356 (16.8%), 237 (11.2%) and 12 (0.6%) patients, respectively. Most were performed in CNS-related indications (46.2%). Mean GBCA doses were 0.10 mmol/kg body weight, except for Gadovist (mean 0.12 mmol/kg). GBCA use increased confidence in diagnosis in 96.2% of examinations and resulted in a change in radiological diagnosis in 73.9% of patients. Image quality was considered excellent or good in 96.1% of patients and across all GBCA. Four patients reported AEs (0.19%), with only 1 (0.05%) considered serious.ConclusionsThis European study confirmed that GBCAs are used appropriately in Europe for a wide range of indications. The study demonstrated a significant increase in diagnostic confidence after GBCA use and confirmed the good safety profile of GBCAs, with comparable results for all agents used.

Reducing Contrast Agent Dose in Cardiovascular MR Angiography with Deep Learning.

Contrast-enhanced magnetic resonance angiography (MRA) is used to assess various cardiovascular conditions. However, gadolinium-based contrast agents (GBCAs) carry a risk of dose-related adverse effects. To develop a deep learning method to reduce GBCA dose by 80%. Retrospective and prospective. A total of 1157 retrospective and 40 prospective congenital heart disease patients for training/validation and testing, respectively. A 1.5 T, T1-weighted three-dimensional (3D) gradient echo. A neural network was trained to enhance low-dose (LD) 3D MRA using retrospective synthetic data and tested with prospective LD data. Image quality for LD (LD-MRA), enhanced LD (ELD-MRA), and high-dose (HD-MRA) was assessed in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and a quantitative measure of edge sharpness and scored for perceptual sharpness and contrast on a 1-5 scale. Diagnostic confidence was assessed on a 1-3 scale. LD- and ELD-MRA were assessed against HD-MRA for sensitivity/specificity and agreement of vessel diameter measurements (aorta and pulmonary arteries). SNR, CNR, edge sharpness, and vessel diameters were compared between LD-, ELD-, and HD-MRA using one-way repeated measures analysis of variance with post-hoc t-tests. Perceptual quality and diagnostic confidence were compared using Friedman's test with post-hoc Wilcoxon signed-rank tests. Sensitivity/specificity was compared using McNemar's test. Agreement of vessel diameters was assessed using Bland-Altman analysis. SNR, CNR, edge sharpness, perceptual sharpness, and perceptual contrast were lower (P< 0.05) for LD-MRA compared to ELD-MRA and HD-MRA. SNR, CNR, edge sharpness, and perceptual contrast were comparable between ELD and HD-MRA, but perceptual sharpness was significantly lower. Sensitivity/specificity was 0.824/0.921 for LD-MRA and 0.882/0.960 for ELD-MRA. Diagnostic confidence was 2.72, 2.85, and 2.92 for LD, ELD, and HD-MRA, respectively (PLD-ELD , PLD-HD < 0.05). Vessel diameter measurements were comparable, with biases of 0.238 (LD-MRA) and 0.278 mm (ELD-MRA). Deep learning can improve contrast in LD cardiovascular MRA. 2 TECHNICAL EFFICACY: Stage 2.

Acute Chelation Therapy-Associated Changes in Urine Gadolinium, Self-reported Flare Severity, and Serum Cytokines in Gadolinium Deposition Disease.

The aim of this study was to determine the following in patients who have undergone magnetic resonance imaging with gadolinium-based contrast agents (GBCAs) and meet the proposed diagnostic criteria for gadolinium deposition disease (GDD): (1) the effectiveness of chelation therapy (CT) with intravenous Ca-diethylenetriaminepentaacetic acid in removing retained gadolinium (Gd) and factors affecting the amount removed; (2) the frequency of CT-induced Flare, that is, GDD diagnostic symptom worsening, and factors affecting Flare intensity; (3) whether, as reported in a separate cohort, GDD patients' serum cytokine levels differ significantly from those in healthy normal controls and change significantly in response to CT; and (4) whether urine Gd, Flare reaction, and serum cytokine findings in GDD patients are mimicked in non-ill patients described as having gadolinium storage condition (GSC). Twenty-one GDD subjects and 3 GSC subjects underwent CT. Patients provided pre-CT and post-CT 24-hour urine samples for Gd content determination along with pre-CT and 24-hour post-CT serum samples for cytokine analysis. Patients rated potential Flare 24 hours after CT. Pre-CT and post-CT 24-hour urine Gd analyses and Luminex serum cytokine assays were performed blind to patients' GDD and GSC status and all other data except age and sex. Serum cytokine levels in a healthy normal control group of age- and sex-matched subjects drawn from Stanford influenza vaccination studies were measured once, contemporaneously with those of GDD and GSC patients, using the same Luminex assay. Urine Gd amounts increased post-CT by 4 times or more after 87% of the 30 CT sessions. The most important factors appeared to be the time since the last GBCA dose and the cumulative dose received. Urine Gd amounts for GDD and GSC patients fell in the same ranges. All GDD patients, and no GSC patient, reported a Flare 24 hours post-CT. Linear regression found that Flare intensity was significantly predicted by a model including pre- and post-CT Gd amounts and the number of GBCA-enhanced magnetic resonance imaging. Post-CT, multiple cytokines showed strong positive relationships with GDD patients' Flare intensity in multivariable models. The pre-CT serum levels of 12 cytokines were significantly different in GDD patients compared with healthy flu vaccine controls. The small number of GSC patients precluded analogous statistical testing. Post-CT, GDD patients' serum levels of 20 cytokines were significantly decreased, and 2 cytokines significantly increased. These cytokines did not exhibit the same change pattern in the 3 GSC patients. The small number of GSC patients precluded statistical comparisons of GSC to GDD patients' results. In this preliminary study, 24-hour urine Gd content increased markedly and similarly in GDD and GSC patients after Ca-diethylenetriaminepentaacetic acid CT. Post-CT Flare reaction developed only in GDD patients. The current study is the second finding significantly different serum cytokine levels in GDD patients compared with healthy normal controls. These differences and the difference between GDD and GSC patients' Flare and cytokine responses to CT suggest some inflammatory, immunologic, or other physiological differences in patients with GDD. Further research into the treatment and physiological underpinnings of GDD is warranted.

Signal Intensity Changes in the Dentate Nucleus and Globus Pallidus of Multiple Sclerosis Patients Undergoing Multiple Brain Magnetic Resonance Imaging with Gadolinium-Based Contrast Agents

Objective: To investigate the correlation between cumulative doses of gadolinium-based contrast agents and increased signal intensity (SI) in the dentate nucleus (DN) and globus pallidus (GP). Methods: Our retrospective trial involved 21 multiple sclerosis patients (11 women, 10 men; mean age: 39.21±10.24, range: 20 to 57 years) who underwent a serial number of multiple cranial magnetic resonance imaging (MRI) examinations in the radiology department of our tertiary care center. Average signal intensities on the DN, pons, GP and thalamus on unenhanced T1-weighted magnetic resonance images were taken into account. The signal intensity in the DN was proportioned to the signal intensity in the pons, whereas the signal intensity in GP to the signal intensity in the thalamus. Any relationship between the DN-to-pons or GP-to-thalamus signal intensity ratios and previous gadolinium-based contrast administrations was sought by means of repeated measures ANOVA. Results: Increases in both DN-to-pons and GP-to-thalamus signal intensity ratios displayed a significant correlation with previous administrations of gadolinium-based contrast agents (p&lt;0.001 for both). A remarkable increase was detected in DN-to-pons and GP-to-thalamus signal intensity ratios between the first and last MRI examinations (p&lt;0.001 for both). Conclusion: Our results support the association between increase in the SI of the DN and GP to the number of gadolinium-enhanced MRI scans in MS patients. The increase in T1 SI seems to be linked with the number of enhanced MRI scans.