Macrocyclic Gadolinium-based Contrast Agents Research Articles

Gadolinium Contrast Agent Deposition in Children.

Over the past few years, a large number of studies have evidenced increased signal intensity in the deep brain nuclei on unenhanced T1-MRI images achieved by the application of gadolinium-based contrast agents (GBCAs). The deposition of gadolinium in the brain, bone, and other tissues following administration of GBCAs has also been confirmed in histological studies in rodents and in necropsy studies in adults and children. Given the distinct physiological characteristics of children, this review focuses on examining the current research on gadolinium deposition in children, particularly studies utilizing novel methods and technologies. Furthermore, the article compares safety research findings of linear GBCAs and macrocyclic GBCAs in children, with the aim of offering clinicians practical guidance based on the most recent research outcomes. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

[Gd(HB-DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP-DO3A)] (Prohance®).

[Gd(HP-DO3A)] (gadoteridol) as an active compound of ProHance® is a widely employed contrast agent in clinical MRI scans in the last 30 years. Recent concerns about the long-term retention of gadolinium-based contrast agents (GBCAs) led to a deeper investigation of the structural features underlying the integrity of the paramagnetic metal complex. Several human and nonclinical studies have noted marked differences among the macrocyclic GBCAs, with the least retention of Gd traces and most rapid elimination consistently being reported for [Gd(HP-DO3A)]. It was deemed of interest to assess how minor structural/electronic changes associated to the ligand structure may affect basic properties of the metal complex with several [Gd(HP-DO3A)] analogues synthesized and characterized in the last years. We recently reported that the closest homolog of [Gd(HP-DO3A)], i. e.: [Gd(HB-DO3A)], in which a (±)-2-hydroxy-1-propyl pendant arm is replaced by a (±)-2-hydroxy-1-butyl moiety, showed a significantly different retention behaviour in the model interaction with collagen, despite the apparently very minor structural difference. In this paper we report a comprehensive study of the structural, thermodynamic, kinetic and relaxation properties of [Gd(HB-DO3A)], compared to the parent [Gd(HP-DO3A)] and to other closely related macrocyclic GBCAs to assess whether very minor structural changes can modulate the physico-chemical properties of Gd3+ complexes.

Contrast Media-driven Anthropogenic Gadolinium: Knowns and Unknowns.

Gadolinium-based contrast agents (GBCAs) have augmented the capabilities of MRI, which has led to their widespread and increasing use in radiology practice. GBCAs are introduced into the environment through disposal of unused product and elimination after intravenous injection, both primarily via liquid dispersion into the environment. This human introduction of gadolinium into the environment, referred to as anthropogenic gadolinium, is associated with the detection of gadolinium in water systems, raising concerns for potential adverse impact and prompting certain mitigation actions. This article summarizes the existing knowledge and problem scope, conveys the relevant underlying chemical principles of chelate dissociation, and offers an inferred perspective that the magnitude of the problem is most unlikely to cause human harm. The merits and limitations regarding possible mitigation tactics, such as collecting urine after GBCA administration, use of lower-dose high-relaxivity macrocyclic GBCAs, and the option for virtual contrast-enhanced examinations, will be discussed. Finally, the potential for monitoring gadolinium uptake in bone will be presented, and recommendations for future research will be offered. © RSNA, 2024 See also the article by Ibrahim et al in this issue. See also the article by McKee et al in this issue.

Pharmacokinetics, safety, and tolerability of the novel tetrameric gadolinium-based MRI contrast agent gadoquatrane in healthy Chinese and Japanese men: Two randomized dose-escalation studies including concentration–QTc modeling

PurposeTo investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). Participants and methodsIn two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01–0.1 mmol gadolinium/kg body weight) or placebo. Study procedures included blood sampling and collection of urine for pharmacokinetic analyses and safety assessments. ResultsTwenty-five healthy Japanese men (mean age ± standard deviation: 26±5.9 years) and 23 healthy Chinese men (31±7.6 years old) were evaluated. In both studies, the pharmacokinetic profile of gadoquatrane was characterized by rapid distribution of the drug into the extracellular space and fast renal elimination. Postdose gadolinium concentrations rapidly declined with a geometric mean effective half-life of 1.3–1.4 h. The exposure increased approximately dose-proportionally with dose. The body weight-normalized volume of distribution was constant across dose levels (0.21–0.24 L/kg). Total recovery of gadolinium in urine amounted to 82–95 % (Study 1) and 96–99 % (Study 2) of the dose administered.Only a few mild, transient adverse events were reported, none of which gave rise to any safety concerns. Exploratory drug concentration–QTc modeling indicated no risk of a clinically relevant QT/QTc prolongation at the anticipated diagnostic dose. ConclusionGadoquatrane was safe and well tolerated at all doses tested. The pharmacokinetic profile was essentially the same as that of other extracellular macrocyclic gadolinium-based contrast agents and was consequentially also similar for Japanese and Chinese participants.

The effect of macrocyclic ionic and non-ionic gadolinium agents on neuronal injury and myelin loss in the spinal cords of rats with and without diabetes mellitus

BackgroundThe effect of gadolinium-based contrast agents (GBCA) on the spinal cord is not established, especially in patients with diabetes mellitus. PurposeTo investigate neuronal and myelin loss in the spinal cord when employing macrocyclic ionic Gadoterate Meglumine (Gd-DOTA) and non-ionic Gadobuterol (Gd-BT-DO3A) GBCA in rats with and without diabetes mellitus. Materials and methodsThis study was performed between November 2018 and February 2020. Sixty young Sprague Dawley white rats (n = 6/group) were given injections of two macrocyclic GBCA: 0.5 mmol/ml Gd-DOTA and 1 mmol/ml Gd-BT-DO3A, using volumes based of the recommended doses (0.1 ml and 0.2 ml) for 42 days in both healthy and diabetic rats. Control groups received saline injections. Morphological assessment of spinal cord tissues was performed on three spinal segments. Neuronal counts in the ventral horns and myelin sparing percentage in the white matter were determined and compared in each group employing one-way ANOVA and Dunnett test for each category followed by three-way factorial analysis. ResultsLow neuronal count and myelin percentage-area were obtained in groups receiving 0.2 ml Gd-DOTA (p = .001;p = .002;p < .001 neurons; and p < .001;p = .007;p = .001 myelin %) and Gd-BT-DO3A (p = .01;p = .048;p = .006 neurons; p < .001;p = .01;p = .001 myelin %). Similarly, neuronal loss was seen in diabetics receiving low volume-injection (0.1 ml) of Gd-DOTA (p = .04;p = .03;p = .42), Gd-BT-DO3A (p = .002;p = .007;p = .01); or high volume-injection (0.2 ml) of Gd-DOTA (p = .001;p = .003;p = .01) or Gd-BT-DO3A (p < .001,p = .002;p = .002), with associated decrease in myelin sparing for each category with low dose Gd-DOTA (p < .001, p = .001; p. = 09),Gd-BT-DO3A (p = .003;p = .003;p = .007); or the higher dose counterparts of Gd-DOTA (p < .001; p < .00; p = .001) and Gd-BT-DO3A (p < .001, p < .001, p < .001).Damage was observed using the standard dose (equivalent of 0.1 mmol/kg for rats) of Gd-DOTA (0.2 ml) but not that of Gd-BT-DO3A (0.1 ml) in healthy rats. ConclusionMultiple high-volume injections of gadoterate meglumine and gadobuterol are associated with neuronal and myelin injury in the spinal cord, more so in rats with diabetes mellitus.

Clinical Safety of Gadobutrol: Review of Over 25 Years of Use Exceeding 100 Million Administrations.

The macrocyclic gadolinium-based contrast agent gadobutrol was introduced to the market in February 1998. Over the last 25 years, gadobutrol has been administered more than 100 million times worldwide providing a wealth of data related to safety. The aim of this study was to perform a thorough review and status update on gadobutrol's safety. Safety data from the clinical phase II-IV program and postmarketing surveillance were descriptively analyzed from February 1998 until December 31, 2022. Literature on special at-risk populations and specific safety aspects was critically summarized. Forty-five clinical phase II-IV studies recruited 7856 patients receiving gadobutrol. Drug-related adverse events (AEs) were reported in 3.4% and serious AEs in <0.1% of patients. Nausea (0.7%) and dysgeusia (0.4%) were the most reported AEs. All other drug-related AEs occurred ≤0.3%. After more than 100 million gadobutrol administrations, overall adverse drug reactions (ADRs) from postmarketing surveillance (including clinical trials) were rare with an overall reporting rate of 0.0356%, hypersensitivity reactions (0.0147%), nausea (0.0032%), vomiting (0.0025%), and dyspnea (0.0010%). All other ADRs were <0.001%. No trend for higher rates of AEs was found in patients with reduced renal or liver function. Seven clinical studies reported safety findings in 7292 children ≤18 years, thereof 112 newborns/toddlers younger than 2 years. Overall, 61 ADRs (0.84%) were reported, including 3 serious ones. Adverse events in patients ≥65 years of age ("elderly") were significantly less frequent than in younger patients. A total of 4 reports diagnostic of or consistent with nephrogenic systemic fibrosis have been received. No causal relationship has been established between clinical signs and symptoms and the presence of small amounts of gadolinium in the body in patients with normal renal function after use of gadobutrol. More than 100 million administrations worldwide have shown gadobutrol's well-established benefit-risk profile in any approved indication and populations.

Gadolinium Presence in Rat Skin: Assessment of Histopathologic Changes Associated with Small Fiber Neuropathy.

Background The presence of gadolinium traces in the skin after administration of gadolinium-based contrast agents (GBCAs) raised safety concerns regarding a potential association with small fiber neuropathy (SFN). Purpose To investigate signs of SFN in rat foot pads by quantification of the intraepidermal nerve fiber density (IENFD) after multiple GBCA administrations and to evaluate gadolinium concentration, chemical species, and clearance. Materials and Methods Fifty rats received eight intravenous injections of either gadodiamide, gadobutrol, gadoterate, gadoteridol (8 × 0.6 mmol per kilogram of body weight), or saline (1.2 mL per kilogram of body weight), within 2 weeks and were sacrificed 5 days or 5 weeks after the last injection. IENFD was determined with protein gene product (PGP) 9.5 immunofluorescent staining and blinded and automated image analysis. The gadolinium and GBCA concentrations were measured with inductively coupled plasma mass spectrometry (ICP-MS), laser ablation ICP-MS, and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). P values were calculated using linear contrasts of model analysis. Results The IENFD (measured as geometric mean [SD] and in number of nerve fibers per millimeter of epidermis) was not significantly altered after 5 days (saline, 8.4 [1.1]; gadobutrol, 9.7 [1.2]; gadoterate, 9.2 [1.2]; gadoteridol, 9.9 [1.3]; gadodiamide, 10.5 [1.2]) or 5 weeks (saline, 19.7 [1.4]; gadobutrol, 16.4 [1.6]; gadoterate, 14.3 [1.6]; gadoteridol, 22.2 [1.8]; gadodiamide, 17.9 [1.4]). Gadolinium skin concentrations were highest for gadodiamide after 5 days (16.0 nmol/g [1.1]) and 5 weeks (10.6 nmol/g [1.2], -33%). Macrocyclic agents were lower at 5 days (gadoteridol, 2.6 nmol/g [1.2]; gadobutrol, 2.7 nmol/g [1.1]; and gadoterate, 2.3 nmol/g [1.2]) and efficiently cleared after 5 weeks (gadoteridol, -95%; gadobutrol and gadoterate, -96%). The distribution of gadolinium and IENF did not visually overlap. For macrocyclic agents, gadolinium was found in sweat glands and confirmed to be intact chelate. Conclusion There were no signs of SFN in rat foot pads using multiple dosing regimens at two time points after administration of GBCAs. Macrocyclic GBCAs exhibited lower levels of gadolinium in the skin and were effectively eliminated within 5 weeks compared with linear gadodiamide, and intact macrocyclic GBCA was detected in sweat glands. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Clement in this issue.

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.

Detection of Brain Metastases by Contrast-Enhanced MRI: Comparison of Gadopiclenol and Gadobenate in a Mouse Model.

The aim of this study was to evaluate the capacity of gadopiclenol, a high-relaxivity gadolinium-based contrast agent to detect brain metastases in mice as a function of dose (0.08 mmol/kg or 0.1 mmol/kg) compared with gadobenate at 0.1 mmol/kg. Brain metastases were induced by ultrasound-guided intracardiac implantation of 1.10 5 MDA-MB-231Br cells in the left ventricle of 18 anesthetized Balb/c Nude nu/nu female mice. At day 28 ± 3 after cell injection, each mouse received 2 crossover intravenous injections at 24-hour intervals, randomly selected from 2 doses of gadopiclenol (0.08 mmol/kg or 0.1 mmol/kg) and gadobenate (0.1 mmol/kg) with n = 6 mice/group (3 groups). Brain magnetic resonance imaging sessions were performed at 4 weeks on a 2.35 T magnet with a 3-dimensional T1-weighted high-resolution gradient echo sequence, before and after each injection. Images were blindly and randomly analyzed to detect enhancing lesions. Contrast-to-noise ratio between the metastases and the surrounding healthy parenchyma was calculated, based on region-of-interest signal measurements. In 2 animals per group, an early time point was added to the protocol (day 22 ± 3) to evaluate the sensitivity of detection as a function of time. After the last imaging session, the presence and location of whole-brain metastases were confirmed by histology in 4 mice. After gadopiclenol, approximately twice as many metastases were detected compared with gadobenate, regardless of the dose. Contrast-to-noise ratios of the detected metastases were 2.3 and 3.3 times higher with gadopiclenol at 0.08 mmol/kg and 0.1 mmol/kg, respectively, compared with gadobenate at 0.1 mmol/kg ( P < 0.0001). Gadopiclenol at the dose of 0.1 mmol/kg resulted in a 1.4-fold higher contrast compared with gadopiclenol at 0.08 mmol/kg ( P < 0.02). In a subset of mice that were imaged 1 week earlier, 2 metastases were detected with gadopiclenol and not with gadobenate. The high-relaxivity macrocyclic gadolinium-based contrast agent gadopiclenol allowed higher diagnostic performance for detecting brain enhancing metastases in terms of contrast-to-noise ratio and number of detected metastases compared with gadobenate, at both equal (0.1 mmol/kg) dose and 20% lower Gd dose (0.08 mmol/kg). Tumor detection was higher after gadopiclenol at the dose of 0.1 mmol/kg compared with 0.08 mmol/kg.

Preclinical Safety Assessment of Gadopiclenol: A High-Relaxivity Macrocyclic Gadolinium-Based MRI Contrast Agent.

Gadopiclenol is a new high-relaxivity macrocyclic gadolinium-based contrast agent for magnetic resonance imaging of the central nervous system and other body regions. The product has been approved by US Food and Drug Administration and is currently being evaluated by European Medicines Agency. For risk assessment of the single diagnostic use in humans, the safety profile of gadopiclenol was evaluated with a series of preclinical studies. With exception of dose-ranging studies, all safety pharmacology and toxicology studies were performed in compliance with Good Laboratory Practice principles. Safety pharmacology studies were conducted to assess potential effects on cardiovascular (in vitro and in dogs), respiratory (in rats and guinea pigs), neurological (in rats), and renal endpoints (in rats). Toxicology studies were also performed to investigate acute toxicity (in rats and mice), extended single-dose (in rats and dogs) and repeated-dose toxicity (in rats and dogs), reproductive (in rats), developmental (in rats and rabbits) and juvenile toxicity (in rats), as well as genotoxicity (in vitro and in rats), local tolerance (in rabbits), potential immediate hypersensitivity (in guinea pigs), and potential tissue retention of gadolinium (in rats). Safety pharmacology studies conducted at high intravenous (IV) doses showed a satisfactory tolerance of gadopiclenol in the main body systems. After either single or repeated IV dosing (14 and 28 days) in rats and dogs, gadopiclenol was well tolerated even at high doses. The no-observed-adverse-effect level values (ie, the highest experimental dose without adverse effects) representing between 8 times in rats and 44 times in dogs (based on the exposure), the exposure achieved in humans at the intended diagnostic dose, provide a high safety margin. No or only minor and reversible effects on body weight, food consumption, clinical signs, clinical pathology parameters, or histology were observed at the highest doses. The main histological finding consists in renal tubular vacuolations (exacerbated after repeated exposure), which supports a well-known finding for this class of compounds that has no physiological consequence on kidney function. Reproductive toxicity studies showed no evidence of effects on reproductive performance, fertility, perinatal and postnatal development in rats, or reproductive development in rats or rabbits. The safety profile of gadopiclenol in juvenile rats was satisfactory like in adults. Gadopiclenol was not genotoxic in vitro in the Ames test, a mouse lymphoma assay, and a rat in vivo micronucleus test. There were no signs of local intolerance at the injection site after IV and intra-arterial administration in rabbits. However, because of minor signs of intolerance after perivenous administration, misadministration must be avoided. Gadopiclenol exhibited no signs of potential to induce immediate hypersensitivity in guinea pigs. High safety margins were observed between the single diagnostic dose of 0.05 mmol/kg in humans and the doses showing effects in animal studies. Gadopiclenol is, therefore, well tolerated in various species (mice, rats, dogs, rabbits, and guinea pigs). All observed preclinical data support the clinical approval.

Reliability of signal intensity in the basal ganglia on non-contrast T1-weighted MR scans after repetitive application of a gadolinium-based contrast agent in pediatric neuro-oncology patients

PurposeTo evaluate the reliability of signal intensity (SI) changes in the basal ganglia as a supposed indicator of gadolinium deposition in the brain after repetitive application of gadolinium-based contrast agents (GBCAs) in a pediatric neuro-oncological collective. MethodsOne hundred and eight neuropediatric patients (54 male, 54 female, 0–17 years old), with repetitive GBCA-enhanced cranial MRIs between 2003 and 2017, were retrospectively analyzed. Two radiologists measured SI in the nucleus dentatus (ND), globus pallidus (GP), thalamus (T), and the pons (P). The NDP and GPT ratio were calculated. An intraclass correlation coefficient, and multiple linear regressions with subsequent stepwise backward variable selection were performed to evaluate the influence of gender, patient’s age at the first MRI, time interval between the first and last MRI, linear or macrocyclic GBCAs, residual pathology, treatments, and magnet field strengths. ResultsThe inter-reader agreement was good for GPT and NDP in the whole collective (ICC = 0.837 and ICC = 0.793) and for children >2 years of age (ICC = 0.874 and ICC = 0.790), but poor to moderate for children ≤2 years of age (ICC = 0.397 and ICC = 0.748). The intra-reader agreement was good (ICC = 0.910 and ICC = 0.882). An SI increase was only observed for both readers in GPT (p = 0.003, or p < 0.001). None of the considered cofactors showed a consistent effect on SI changes for either readers or regions. ConclusionMeasurements of SI changes in the basal ganglia are not a reliable parameter with which to evaluate or estimate gadolinium deposition in the brain or to identify suspicious influential factors after repeated GBCA applications.

Gadolinium-based Contrast Agent Biodistribution and Speciation in Rats.

Background Gadolinium retention has been observed in organs of patients with normal renal function; however, the biodistribution and speciation of residual gadolinium is not well understood. Purpose To compare the pharmacokinetics, distribution, and speciation of four gadolinium-based contrast agents (GBCAs) in healthy rats using MRI, mass spectrometry, elemental imaging, and electron paramagnetic resonance (EPR) spectroscopy. Materials and Methods In this prospective animal study performed between November 2021 and September 2022, 32 rats received a dose of gadoterate, gadoteridol, gadobutrol, or gadobenate (2.0 mmol/kg) for 10 consecutive days. GBCA-naive rats were used as controls. Three-dimensional T1-weighted ultrashort echo time images and R2* maps of the kidneys were acquired at 3, 17, 34, and 52 days after injection. At 17 and 52 days after injection, gadolinium concentrations in 23 organ, tissue, and fluid specimens were measured with mass spectrometry; gadolinium distribution in the kidneys was evaluated using elemental imaging; and gadolinium speciation in the kidney cortex was assessed using EPR spectroscopy. Data were assessed with analysis of variance, Kruskal-Wallis test, analysis of response profiles, and Pearson correlation analysis. Results For all GBCAs, the kidney cortex exhibited higher gadolinium retention at 17 days after injection than all other specimens tested (mean range, 350-1720 nmol/g vs 0.40-401 nmol/g; P value range, .001-.70), with gadoteridol showing the lowest level of retention. Renal cortex R2* values correlated with gadolinium concentrations measured ex vivo (r = 0.95; P < .001), whereas no associations were found between T1-weighted signal intensity and ex vivo gadolinium concentration (r = 0.38; P = .10). EPR spectroscopy analysis of rat kidney cortex samples showed that all GBCAs were primarily intact at 52 days after injection. Conclusion Compared with other macrocyclic GBCAs, gadoteridol administration led to the lowest level of retention. The highest concentration of gadolinium was retained in the kidney cortex, but T1-weighted MRI was not sensitive for detecting residual gadolinium in this tissue. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Tweedle in this issue.

Elemental Bioimaging of Sheep Bone and Articular Cartilage After Single Application of Gadolinium-Based Contrast Agents.

Gadolinium-based contrast agents (GBCAs) are applied to enhance magnetic resonance imaging. Gadolinium (Gd), a rare earth metal, is used in a chelated form when administered as GBCA to patients. There is an ongoing scientific debate about the clinical significance of Gd retention in tissues after administration of GBCAs. It is known that bone serves as Gd reservoir, but only sparse information on localization of Gd in bone is available. The aim of this study was to compare Gd tissue concentration and spatial distribution in femoral epiphysis and diaphysis 10 weeks after single-dose injection of linear and macrocyclic GBCAs in a large animal model. In this prospective animal study, Swiss-Alpine sheep (n = 36; age range, 4-10 years) received a single injection (0.1 mmol/kg) of macrocyclic (gadobutrol, gadoteridol, and gadoterate meglumine), linear (gadodiamide and gadobenate dimeglumine) GBCAs, or saline. Ten weeks after injection, sheep were killed, and femur heads and shafts were harvested. Gadolinium spatial distribution was determined in 1 sample of each treatment group by laser ablation-inductively coupled plasma-mass spectrometry. All bone specimens were analyzed histopathologically. Injection of GBCAs in female Swiss-Alpine sheep (n = 36) resulted in Gd localization at the endosteal and periosteal surface and in a subset of GBCAs additionally at the cement lines and the bone cartilage junction. No histopathological alterations were observed in the investigated tissue specimens. Ten weeks after single injection of a clinically relevant dose in adult sheep, both linear species of GBCA resulted in considerably higher accumulation than macrocyclic GBCAs. Gadolinium deposits were restricted to distinct bone and cartilage compartments, such as in bone linings, cement lines, and bone cartilage junctions. Tissue histology remained unaffected.

Evaluation of gadolinium deposition in cortical bone using three-dimensional ultrashort echo time quantitative susceptibility mapping: A preliminary study.

The aim of the current study was to investigate the feasibility of three-dimensional ultrashort echo time quantitative susceptibility mapping (3D UTE-QSM) for the assessment of gadolinium (Gd) deposition in cortical bone. To this end, 40 tibial bovine cortical bone specimens were divided into five groups then soaked in phosphate-buffered saline (PBS) solutions with five different Gd concentrations of 0, 0.4, 0.8, 1.2, and 1.6 mmol/L for 48 h. Additionally, eight rabbits were randomly allocated into three groups, consisting of a normal-dose macrocyclic gadolinium-based contrast agent (GBCA) group (n = 3), a high-dose macrocyclic GBCA group (n = 3), and a control group (n = 2). All bovine and rabbit tibial bone samples underwent magnetic resonance imaging (MRI) on a 3-T clinical MR system. A 3D UTE-Cones sequence was utilized to acquire images with five different echo times (i.e., 0.032, 0.2, 0.4, 0.8, and 1.2 ms). The UTE images were subsequently processed with the morphology-enabled dipole inversion algorithm to yield a susceptibility map. The average susceptibility was calculated in three regions of interest in the middle of each specimen, and the Pearson's correlation between the estimated susceptibility and Gd concentration was calculated. The bone samples soaked in PBS with higher Gd concentrations exhibited elevated susceptibility values. A mean susceptibility value of -2.47 ± 0.23 ppm was observed for bovine bone soaked in regular PBS, while the mean QSM value increased to -1.75 ± 0.24 ppm for bone soaked in PBS with the highest Gd concentration of 1.6 mmol/L. A strong positive correlation was observed between Gd concentrations and QSM values. The mean susceptibility values of rabbit tibial specimens in the control group, normal-dose GBCA group, and high-dose GBCA group were -4.11 ± 1.52, -3.85 ± 1.33, and -3.39 ± 1.35 ppm, respectively. In conclusion, a significant linear correlation between Gd in cortical bone and QSM values was observed. The preliminary results suggest that 3D UTE-QSM may provide sensitive noninvasive assessment of Gd deposition in cortical bone.

Species-dependent uptake of gadolinium in Chlamydomonas reinhardtii algae

Single cell-inductively coupled plasma-mass spectrometry (sc-ICP-MS) was used in this study as a valuable tool to assess the species-dependent uptake of metallopharmaceuticals into algal cells. Chlamydomonas reinhardtii algae were incubated for 24 h with four Gadolinium-based contrast agents (GBCAs) and GdCl3. A species dependency towards the uptake of the tested Gd species was observed. Using single cell-ICP-MS, a Gd signal corresponding to single cell events was detected for GdCl3 and the linear GBCAs Omniscan® (Gadodiamide, Gd-DTPA-BMA) and Magnevist® (Gadodiamide, Gd-DTPA). For the macrocyclic complexes Dotarem® (Gadoteric acid, Gd-DOTA) and Gadovist® (Gadobutrol, Gd-BT-DO3A), no such Gd signal was visible. Total Gd analysis via ICP-MS confirmed the presence of Gd in the cells only after incubation with GdCl3 and the linear GBCAs, while only small amounts of Gd were detected for the incubations with macrocyclic GBCAs. Furthermore, the results showed that more Gd is bound to cell structures or macromolecules, while smaller amounts are present in the lysate. Using hydrophilic interaction liquid chromatography (HILIC)-ICP-MS, the soluble Gd species in the lysate were analyzed to determine if the initial Gd complexes were still intact. Surprisingly, no intact GBCAs were detected in the lysates of any incubation solution, possibly due to a change in Gd speciation. Further research is needed to assess which Gd species are present in the lysate, while “free” Gd ions or adducts with cell constituents are the most likely explanation. This study highlights the need for species-dependent investigation of elements in aquatic organisms. Moreover, the uptake of linear GBCAs and their species alteration raises the question of a potential accumulation of Gd in the food chain.

Analysis of the elemental species-dependent uptake of lanthanide complexes in Arabidopsis thaliana plants by LA-ICP-MS

Gadolinium-based contrast agents (GBCAs) are found increasingly in different water bodies, making the investigation of their uptake and distribution behavior in plants a matter of high interest to assess their potential effects on the environment. Depending on the used complexing agent, they are classified into linear or macrocyclic GBCAs, with macrocyclic complexes being more stable. In this study, by using TbCl3, Gd-DTPA-BMA, and Eu-DOTA as model compounds for ionic, linear, and macrocyclic lanthanide species, the elemental species-dependent uptake into leaves of Arabidopsis thaliana under identical biological conditions was studied. After growing for 14 days on medium containing the lanthanide species, the uptake of all studied compounds was confirmed by means of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Furthermore, the uptake rate of TbCl3 and the linear Gd-DTPA-BMA was similar, with Tb and Gd hotspots colocated in the areas of hydathodes and the trichomes of the leaves. In contrast, in the case of the macrocyclic Eu-DOTA, Eu was mainly located in the leaf veins. Additionally, Eu was colocated with Tb and Gd in the hydathode at the tip of the leave. Removal of the lanthanide species from the medium led to a decrease in signal intensities, indicating their subsequent release to some extent. However, seven days after the removal, depositions of Eu, Gd, and Tb were still present in the same areas of the leaves as before, showing that complete elimination was not achieved after this period of time. Overall, more Eu was present in the leaves compared to Gd and Tb, which can be explained by the high stability of the Eu-DOTA complex, potentially leading to a higher transport rate into the leaves, whereas TbCl3 and Gd-DTPA-BMA could interact with the roots, reducing their mobility.

Elemental bioimaging and transcriptomics reveal unchanged gene expression in mouse cerebellum following a single injection of Gadolinium-based contrast agents

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.

Skin Toxicity After Exposure to Gadolinium-Based Contrast Agents in Normal Renal Function, Using Clinical Approved Doses: Current Status of Preclinical and Clinical Studies.

The aim of this study was to summarize the current preclinical and clinical evidence on the association between exposure to gadolinium (Gd) compounds and skin toxicity in a setting similar to clinical practice. A search of MEDLINE and PubMed references from January 2000 to December 2022 was performed using keywords related to gadolinium deposition and its effects on the skin, such as "gadolinium," "gadolinium-based contrast agents," "skin," "deposition," and "toxicity." In addition, cross-referencing was added when appropriate. For preclinical in vitro studies, we included all the studies that analyzed the response of human dermal fibroblasts to exposure to various gadolinium compounds. For preclinical animal studies and clinical studies, we included only those that analyzed animals or patients with preserved renal function (estimated glomerular filtration rate >30 mL/min/1.73 m2), using a dosage of gadolinium-based contrast agents (GBCAs) similar to that commonly applied (0.1 mmol/kg). Forty studies were selected. Preclinical findings suggest that Gd compounds can produce profibrotic responses in the skin in vitro, through the activation and proliferation of dermal fibroblasts and promoting their myofibroblast differentiation. Gadolinium influences the process of collagen production and the collagen content of skin, by increasing the levels of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1. Preclinical animal studies show that Gd can deposit in the skin with higher concentrations when linear GBCAs are applied. However, these deposits decrease over time and are not associated with obvious macroscopic or histological modifications. The clinical relevance of GBCAs in inducing small fiber neuropathy remains to be determined. Clinical studies show that Gd is detectable in the skin and hair of subjects with normal renal function in higher concentrations after intravenous administration of linear compared with macrocyclic GBCA. However, these deposits decrease over time and are not associated with cutaneous or histological modifications. Also, subclinical dermal involvement related to linear GBCA exposure may be detectable on brain MRI. There is no conclusive evidence to support a causal relationship between GBCA administration at the clinical dose and cutaneous manifestations in patients with normal renal function. Gadolinium can produce profibrotic responses in the skin, especially acting on fibroblasts, as shown by preclinical in vitro studies. Gadolinium deposits are detectable in the skin even in subjects with normal renal function with higher concentrations when linear GBCAs are used, as confirmed by both preclinical animal and human studies. There is no proof to date of a cause-effect relationship between GBCA administration at clinical doses and cutaneous consequences in patients with normal renal function. Multiple factors, yet to be determined, should be considered for sporadic patients with normal renal function who develop clinical skin manifestations temporally related to GBCA administration.

Gadolinium retention in a rat model of subtotal renal failure: are there differences among macrocyclic GBCAs?

BackgroundGd levels are higher in tissues of animals with compromised renal function, but studies to compare levels after exposure to different macrocyclic gadolinium-based contrast agents (GBCAs) are lacking. We compared Gd levels in tissues of subtotally nephrectomised (SN) rats after repeated exposure to macrocyclic GBCAs.MethodsSprague–Dawley SN male rats (19 per group) received 16 injections of gadoteridol, gadobutrol, or gadoterate meglumine at 0.6 mmol Gd/kg 4 times/weeks over 4 weeks. A control group of healthy male rats (n = 10) received gadoteridol at the same dosage. Plasma urea and creatinine levels were monitored. Blood, cerebrum, cerebellum, liver, femur, kidney(s), skin and peripheral nerves were harvested for Gd determination by inductively coupled plasma-mass spectrometry at 28 and 56 days after the end of treatment.ResultsPlasma urea and creatinine levels were roughly twofold higher in SN rats than in healthy rats at all timepoints. At day 28, Gd levels in the peripheral nerves of gadobutrol- or gadoterate-treated SN animals were 5.4 or 7.2 times higher than in gadoteridol-treated animals (p < 0.001). Higher Gd levels after administration of gadobutrol or gadoterate versus gadoteridol were also determined in kidneys (p ≤ 0.002), cerebrum (p ≤ 0.001), cerebellum (p ≤ 0.003), skin (p ≥ 0.244), liver (p ≥ 0.053), and femur (p ≥ 0.271). At day 56, lower Gd levels were determined both in SN and healthy rats for all GBCAs and tissues, except the femur.ConclusionsGd tissue levels were lower following gadoteridol exposure than following gadobutrol or gadoterate exposure.

Higher magnetic susceptibility of globus pallidus in patients after macrocyclic GBCAs: assessment using quantitative susceptibility mapping.

As previous studies reported, gadolinium deposits in globus pallidus (GP) and dentate nucleus (DN) after repeated administrations of gadolinium-based contrast agents (GBCAs) and a signal intensity (SI) increase on T1-weighted images were related to linear GBCAs, not macrocyclic GBCAs. To identify whether quantitative susceptibility mapping (QSM) could measure a subtle increase in magnetic susceptibility in DN and GP in patients after repeated administrations of gadoteric acid meglumine (Gd-DOTA). In this study, 50 patients with cerebral tumors who had received at least three injections of Gd-DOTA (GBCA group) and 50 individuals without a history of GBCA injections (non-GBCA group) were included. The image data for QSM and T1-weighted images were reviewed. Spearman rank correlation was used to estimate the associations between the values (magnetic susceptibility of QSM and SI ratios of T1-weighted images) and the number of Gd-DOTA injections. The mean magnetic susceptibility of GP in GBCA group was 0.136 ± 0.031 ppm, which was significantly higher than that in control group (0.114 ± 0.030 ppm) (P = 0.001). In the GBCA group (n = 50), we found a substantial positive correlation between magnetic susceptibility of GP and the number of Gd-DOTA injections according to Spearman rank correlation coefficient (ρ = 0.673, P = 0.0001). There was a modest but significant correlation between magnetic susceptibility of DN and the number of Gd-DOTA injections (ρ = 0.311, P = 0.028). In comparison to the control group, the magnetic susceptibility of GP in the GBCA group was significantly higher and had a substantial positive association with the number of Gd-DOTA injections.