Gadolinium Presence Research Articles

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.

Incidence of myocarditis among patients recovered from COVID-19 infection identified using cardiac magnetic resonance imaging

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Coronavirus disease 2019 (COVID-19) has caused significant morbidity and mortality worldwide and has been associated with several cardiac complications including myocarditis. COVID-19 patients with myocardial injury have worse clinical outcomes than those without cardiac involvement. Hence, early detection of myocardial involvement in those who have recovered would be helpful in risk stratification of these patients. Locally, there has been no literature regarding cardiac involvement detected by cardiac magnetic resonance (CMR) imaging among COVID-19 patients. This study aims to report the incidence of patients who developed myocarditis among those who recovered from COVID-19 infection and who underwent CMR imaging in our institution. Methodology A single-center retrospective cohort study was performed in our institution. Consecutive patients from January 1, 2020, to December 31, 2021, who were initially referred for cardiac CMR examination due to cardiac symptoms and who met the following inclusion criteria 1) 19 years old and above; 2) with a history of a previously confirmed diagnosis of COVID-19 using reverse transcription-polymerase chain reaction (RT-PCR) swab test; 3) patients were considered recovered by the discharging criteria and 4) underwent CMR imaging for evaluation to rule out myocarditis in our institution. The primary outcome was determining the number of patients with positive and negative conventional MRI findings based on late gadolinium enhancement and edema. Results Fifty-four percent (54%) of patients had positive conventional MRI findings indicative of myocarditis (myocardial edema or late gadolinium presence). The most common co-morbid condition remains to be Hypertension (55%), followed by Diabetes Mellitus (17%). Dyspnea, palpitations and chest discomfort were the most commonly reported symptoms in 29 (54%), 24 (44%) and 21 (39%) patients, respectively. Twenty-nine patients (54%) were observed with increased T2 signal or positive LGE. Myocardial edema was found in 9 (31%) patients. Among them, 8 (57%) patients were observed with positive LGE. There was no significant difference of LV and RV systolic function among patients with positive and negative conventional CMR findings. Conclusion Myocarditis is one of the cardiovascular complications among patients who recovered from COVID-19, as demonstrated by our cardiac MRI study. Evaluation of the cardiac status of recovered COVID-19 patients needs to be closely monitored, and cardiac MRI may be a sensitive imaging tool to investigate any cardiac involvement further. This study provided local data on those with potential structural changes and cardiac complications aligned with the clinical history, which may be unique in our population after recovering from the disease. Further research with a larger sample size, risk factors, and the intervention to prevent disease progression may need more attention.

The Effect of Gadolinium-Based Contrast Agents on Longitudinal Changes of Magnetic Resonance Imaging Signal Intensities and Relaxation Times in the Aging Rat Brain.

ObjectivesThe aim of the study was to investigate the possible influence of changes in the brain caused by age on relaxometric and relaxation time–weighted magnetic resonance imaging (MRI) parameters in the deep cerebellar nuclei (DCN) and the globus pallidus (GP) of Gd-exposed and control rats over the course of 1 year.Materials and MethodsTwenty-five Wistar-Han rats were equally subdivided into 5 groups and initially received 8 injections on 4 consecutive days per week of either 3.6 mL/kg body weight saline (group I–III) or 1.8 mmol Gd/kg body weight gadobutrol (group IV) or gadodiamide (group V). T1- and T2-weighted scans, as well as relaxation maps, were acquired at 1 week (all groups); 5, 12, 20, and 26 weeks (saline II, gadobutrol, gadodiamide); and at 35, 44, and 52 weeks (saline III, gadobutrol, gadodiamide) after the last administration. Saline I was euthanized after 1 week, saline II after 26 weeks, and the remaining groups after 52 weeks. Signal intensities (SIs) were evaluated for the DCN/pons (P) and the GP/piriform cortex (PC) ratios, and relaxation times for the DCN and the GP. Brain tissue was extracted, and the gadolinium, iron, and manganese contents were quantified with inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation–ICP-MS imaging.ResultsT1-weighted SI ratios did not show any significant trend with age in any region. The between-group analysis at 52 weeks resulted in a significant difference for the DCN/P and GP/PC region ratio between gadodiamide and its comparators. T1 relaxation times dropped with increasing age in the GP with a 10% to 20% difference between first and last measurement for all groups, and in the DCN <10% with a significant decrease for the gadodiamide group only (DCN: P = 0.0158). Group-related differences were observed at the last measurement time point for T1 values between gadodiamide and saline III in the DCN (P = 0.0153) and gadodiamide and gadobutrol in the GP (P = 0.0287). Analysis of the SI ratios of the T2-weighted images revealed a significant increase for the DCN/P and a decrease for the GP/PC with increasing age for all groups and no differences at 52 weeks after the last injection between groups. T2 values of the GP showed a significant linear decrease over time for all groups (saline I–III: P = 0.0101; gadobutrol: P = 0.0001; gadodiamide: P = 0.0142) in the aging rat brain. Quantitative imaging of manganese and iron by laser ablation–ICP-MS showed a linear increase for the saline groups in the GP for both metals (Fe: P < 0.0001; Mn: P = 0.0306) and in the DCN for manganese only (P = 0.0187), but no differences between groups at 52 weeks.ConclusionsExtensive MRI evaluation did not reveal an indication of SI or relaxation time changes associated with multiple exposure to the macrocyclic-chelated GBCA gadobutrol in the DCN and the GP. With increasing age, a T1 and T2 shortening in the GP and an increase in T2-weighted SI ratio in the DCN/P, as well as a decrease in the GP/PC, were observed for all groups. Such age-related changes can potentially bias MRI results as an indicator for gadolinium presence in the brain.

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.

Automated workflow for volumetric assessment of signal intensity ratio on T1-weighted MR images after multiple gadolinium administrations

Purpose: Repeated injections of linear gadolinium-based contrast agent (GBCA) have shown correlations with increased signal intensities (SI) on unenhanced T1-weighted (T1w) images. Assessment is usually performed manually on a single slice and the SI as an average of a freehand region-of-interest is reported. We aim to develop a fully automated software that segments and computes SI ratio of dentate nucleus (DN) to pons (DN/P) and globus pallidus (GP) to thalamus (GP/T) for the assessment of gadolinium presence in the brain after a serial GBCA administrations. Approach: All patients ( ) underwent at least eight GBCA enhanced scans. The modal SI in the DN, GP, pons, and thalamus were measured volumetrically on unenhanced T1w images and corrected based on the reference protocol (measurement 1) and compared to the SI-uncorrected-modal-volume (measurement 2), SI-corrected-mean-volume (measurement 3), as well as SI-corrected-modal-single slice (measurement 4) approaches. Results: Automatic processing worked on all 2119 studies (1150 at 1.5T and 969 at 3T). DN/P were (1.5T) and (3T). GP/T were (1.5T) and (3T). Modal DN/P ratios from volumetric assessment at 1.5T failed to show a statistical difference with or without SI corrections ( ). All other -tests demonstrated significant differences (measurement 2, 3, 4 compared to 1, ). Conclusion: The fully automatic method is an effective powerful tool to streamline the analysis of SI ratios in the deep brain tissues. Divergent SI ratios using different approaches reinforces the need to standardize the measurement for the research in this field.

The anterior eye chamber: entry of the natural excretion pathway of gadolinium contrast agents?

Previous studies provided evidence that gadolinium can be found in the aqueous chamber (AC) of the eye several hours post injection (p.i.) of gadolinium-based contrast agents (GBCAs). This study aimed to investigate whether gadolinium can be detected promptly after injection of a macrocyclic GBCA on contrast-enhanced T1-weighted MRI in the AC of children. This retrospective study encompassed MRI of 200 healthy eyes of children suffering from retinoblastoma of the contralateral eye. MRI was performed with an orbital coil with the children in a state of general anesthesia. Differences of signal intensity ratios (∆SIRs) of the AC to the lens were determined between pre and post contrast-enhanced T1-weighted images (Dotarem®, Guerbet, 0.1ml/kg body weight, mean (standard deviation) p.i. time = 12:24 (± 2:31) min). A highly significant signal intensity increase was found in the AC of healthy eyes 12min after GBCA injection (median ∆SIR (interquartile range) = + 0.08 (0.05-0.12), p < 0.0001). In addition, gadolinium enhancement showed a strong negative correlation with children's age in multivariate analysis with adjustment for p.i. time (p < 0.0001). GBCA leakage into the AC of healthy infantile eyes was found promptly after injection. The negative correlation between patient age and GBCA enhancement might be explained by a maturation process of the blood-aqueous barrier or Schlemm's canal. Future studies should assess the duration and potential diagnostic applications as well as possible safety concerns of gadolinium presence in the AC. • Leakage of gadolinium-based contrast agent into the aqueous chamber of infantile eyes was found promptly after intravenous injection (p < 0.0001). • Gadolinium enhancement of the anterior eye chamber was negatively correlated with the children's age (p < 0.0001).

Gadolinium Presence in the Brain After Administration of the Liver-Specific Gadolinium-Based Contrast Agent Gadoxetate: A Systematic Comparison to Multipurpose Agents in Rats.

Clinical studies have reported different results regarding the signal intensity (SI) increase in the dentate nucleus on unenhanced T1-weighted magnetic resonance imaging (MRI) after repeated administrations of gadolinium-based contrast agents (GBCAs). The aim of this study was to evaluate MRI SI changes and gadolinium (Gd) brain concentrations in an animal model after repeated administration of liver-specific linear gadoxetate in comparison to multipurpose linear and macrocyclic GBCAs. Recently, it was demonstrated that small amounts of GBCAs are able to cross the blood-cerebrospinal fluid (CSF) barrier. Therefore, a secondary aim was to test if the administration of these GBCAs directly into the CSF results in a similar MRI pattern and brain Gd concentration than after systemic intravenous injection. Forty-eight Han-Wistar rats were equally divided into the following 4 groups: gadoxetate (liver-specific linear), gadodiamide (multipurpose linear), gadobutrol (multipurpose macrocyclic), and control (saline, artificial CSF). For systemic application, 6 animals per group received 8 intravenous injections on 4 consecutive days per week over 2 weeks using a dose of 0.15 mmol/kg for gadoxetate and 0.6 mmol/kg for multipurpose GBCAs per injection, which corresponds to the recommended clinical dose in humans. For CSF application, 6 animals per group received one intracisternal administration of 0.31 μmol Gd (gadoxetate) and 1.25 μmol Gd (multipurpose GBCAs) or an equal volume of artificial CSF. Brain MRI was performed after a period of 5 weeks to evaluate the SI in deep cerebellar nuclei (DCN) and brain stem. Subsequently, animals were euthanized and their brains were dissected for Gd quantification by inductively coupled plasma-mass spectrometry. Visually evident increased SIs in the DCN were observed in blinded image review only after administration of gadodiamide. The respective SI ratios between DCN and brain stem were significantly higher compared with the control groups (P = 0.009 and P = 0.002 for intravenous and intracisternal application, respectively), whereas no difference was found for gadoxetate and gadobutrol (P ≥ 0.9). Inductively coupled plasma-mass spectrometry revealed the lowest Gd content in the brain tissue after administration for gadoxetate. The mean Gd concentrations in the cerebellum were 0.08 nmol/g (gadoxetate), 2.66 nmol/g (gadodiamide), and 0.26 nmol/g (gadobutrol) after intravenous administration, and 0.28 nmol/g (gadoxetate), 3.23 nmol/g (gadodiamide), and 0.69 nmol/g (gadobutrol) after intracisternal application. This rat study demonstrates distinct differences in the presence of gadolinium in the brain between the liver-specific linear gadoxetate and the multipurpose linear GBCA gadodiamide. No MRI signal alterations were observed after 8 dose-adapted intravenous or a single intracisternal administrations of gadoxetate and multipurpose macrocyclic gadobutrol. The Gd concentrations in the brain 5 weeks after intravenous administration of gadoxetate were an order of magnitude lower compared with gadodiamide and slightly lower than for gadobutrol. Likely reasons for these differences are the 4-fold lower dose, the dual excretion pathway, and the higher complex stability of gadoxetate compared with multipurpose linear GBCAs. The similar findings for both routes of GBCA administration underlines the assumption that the very small amount of GBCAs that cross the blood-CSF barrier is further transported into the brain tissue.

Increased signal intensities and gadolinium levels in the brain after administration of gadolinium-based MR contrast agents : Clinical observations and results from preclinical research

Numerous clinical MRI studies have been published that describe an association between the repeated administration of (linear) gadolinium-based contrast agents and increased signal intensity in certain brain areas. In November 2017, the European Commission suspended the use of some of these contrast agents. The background for this decision, both regulatory and scientific, are presented and discussed. The regulatory decisions are evaluated and the clinical and preclinical literature is discussed. Differences in the structure and stability of gadolinium-based contrast agent molecules explain the observed increased signal intensities in individual brain regions (e. g. dentate nucleus) after administration of multiple doses of linear contrast agents. This phenomenon was not observed after administration of multiple doses of macrocyclic contrast agents. Preclinical studies have confirmed these results. To date, no clinical symptoms have been confirmed to be associated with the increased signal intensity or gadolinium presence in the brain.

Gadolinium presence, MRI hyperintensities, and glucose uptake in the hypoperfused rat brain after repeated administrations of gadodiamide

The discussed topic about gadolinium-based contrast agents (GBCA) safety has recently been revived due to the evidence of hyperintensities observed in the dentate nucleus (DN) and globus pallidus (GP) in the brain of patients with normal kidney function. Several preclinical studies have been conducted to understanding how the use of GBCAs can promote the gadolinium deposition in the brain. Here, we evaluate the impact of chronic cerebral hypoperfusion on gadolinium presence. T1 hyperintensities and BBB integrity were evaluated by MRI in chronically hypoperfused and healthy rats injected with either gadodiamide or hypertonic saline. Additionally, the assessment of glucose metabolism by PET imaging and the gadolinium content by ICP-MS was performed after the last MR scan. Chronically hypoperfused rats displayed a greater MRI T1w signal in the DCN and hippocampus compared to Sham-operated animals, suggesting gadolinium accumulation. Dynamic contrast-enhanced (DCE) MRI assessment of BBB permeability revealed loss of integrity (high Ktrans) after rat injury in the dentate nuclei and hippocampus. Ex vivo tissue analysis showed greater gadolinium retention in the cerebellum and subcortical regions, supporting the imaging finding. FDG-PET imaging of the cerebellum did not reveal abnormal uptake in the DCN after chronic cerebral hypoperfusion. Higher signal intensity followed by higher Gd concentration observed in DCN and hippocampus of animals subjected to cerebral injury can be associated with an increase in BBB permeability due to the applied vascular dementia animal model. Nonetheless, no glucose metabolism abnormalities were detected in chronically hypoperfused cerebellum.

Methodological Aspects for Preclinical Evaluation of Gadolinium Presence in Brain Tissue: Critical Appraisal and Suggestions for Harmonization-A Joint Initiative.

Gadolinium (Gd)-based contrast agents (GBCAs) are pharmaceuticals that have been approved for 30 years and used daily in millions of patients worldwide. Their clinical benefits are indisputable. Recently, unexpected long-term presence of Gd in the brain has been reported by numerous retrospective clinical studies and confirmed in preclinical models particularly after linear GBCA (L-GBCA) compared with macrocyclic GBCA (M-GBCA). Even if no clinical consequences of Gd presence in brain tissue has been demonstrated so far, in-depth investigations on potential toxicological consequences and the fate of Gd in the body remain crucial to potentially adapt the clinical use of GBCAs, as done during the nephrogenic systemic fibrosis crisis. Preclinical models are instrumental in the understanding of the mechanism of action as well as the potential safety consequences. However, such models may be associated with risks of biases, often related to the protocol design. Selection of adequate terminology is also crucial. This review of the literature intends to summarize and critically discuss the main methodological aspects for accurate design and translational character of preclinical studies.

Non-clinical assessment of safety and gadolinium deposition after cumulative administration of gadobenate dimeglumine (MultiHance®) to neonatal and juvenile rats

To determine the impact of single and cumulative doses of MultiHance on toxicity, pharmacokinetics, tissue gadolinium presence, behavior and neurological function in juvenile rats. Juvenile male and female rats received either physiological saline or MultiHance at 0.6, 1.25 or 2.5 mmol/kg bodyweight. Animals received either single or six consecutive MultiHance administrations and were sacrificed the day after the last administration or after a 60-day treatment-free period. Animals were assessed for behavior, cognitive function, grip strength, gait, pupillary reflex, and auditory reflex, as well as for physical development, sexual maturation and histopathology. Gadolinium presence in brain, femur, kidneys, liver and skin was determined using inductively coupled plasma-mass spectrometry (ICP-MS). No effects of MultiHance on behavior, cognitive function or any other parameter were noted, even for the highest administered cumulative dose (15 mmol/kg). Gadolinium presence was variable across tissues and decreased during the 60-day treatment-free period. The highest levels were noted in the femur and the lowest levels in the brain. Gadolinium presence in juvenile rat brain following single or repeated MultiHance administrations was minimal and non-impactful.

Neutron ESR dosimetry through ammonium tartrate with low Gd content.

This paper continues analyses on organic compounds for application in neutron dosimetry performed through electron spin resonance (ESR). Here, the authors present the results obtained by ESR measurements of a blend of ammonium tartrate dosemeters and gadolinium oxide (5 % by weight). The choice of low amount of Gd is due to the need of improving neutron sensitivity while not significantly influencing tissue equivalence. A study of the effect of gadolinium presence on tissue equivalence was carried out. The experiments show that the neutron sensitivity is enhanced by more than an order of magnitude even with this small additive content. Monte Carlo simulations on the increment of energy release due to gadolinium presence were carried, and the results were in good agreement with the experimental data.