Gadolinium Retention Research Articles

Increased Retention of Gadolinium in the Inflamed Brain After Repeated Administration of Gadopentetate Dimeglumine: A Proof-of-Concept Study in Mice Combining ICP-MS and Micro- and Nano-SR-XRF.

The aim of this study was to determine in vivo if brain inflammation leads to increased gadolinium (Gd) retention in brain tissue after repeated applications of Gd-based contrast agents (GBCAs). Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice (n = 6). Experimental autoimmune encephalomyelitis and healthy control mice (n = 4) received 2.5 mmol/kg Gd-DTPA over 10 days (8 injections, cumulated dose of 20 mmol/kg), starting at day 14 post immunization when EAE mice reached the maximal clinical disability. In a group of mice, T1-weighted 2-dimensional RARE images were acquired before the first GBCA injection and 1 day after the last injection. Mice were killed either 1 day or 10 days after the last Gd application. From each single animal, a brain hemisphere was used for Gd detection using inductively coupled plasma mass spectrometry, whereas the other hemisphere was processed for histology and synchrotron x-ray fluorescence spectroscopy (SR-XRF) analysis. Gadolinium deposition in inflamed brains was mapped by SR-XRF 1 day after the last Gd-DTPA injections, although only mild signal hyperintensity was found on unenhanced T1-weighted images. In addition, using inductively coupled plasma mass spectrometry, we detected and quantified Gd in both healthy and EAE brains up to 10 days after the last injections. However, EAE mouse brains showed higher levels of Gd (mean ± SD, 5.3 ± 1.8 μg/g; range, 4.45-8.03 μg/g) with respect to healthy controls (mean ± SD, 2.4 ± 0.6 μg/g; range, 1.8-3.2 μg/g). By means of micro-SR-XRF, we identified submicrometric Gd hotspots in all investigated samples containing up to 5893 μg Gd/g tissue. Nano-SR-XRF further indicated that Gd small hotspots had an average size of ~160 nm diameter and were located in areas of high inflammatory activity. After repeated administrations of Gd-DTPA, ongoing inflammation may facilitate the retention of Gd in the brain tissue. Thus, neuroinflammation should be considered as a risk factor in the recommendation on use of linear GBCA-enhanced MRI.

Update on Gadolinium-Based Contrast Agent-Enhanced Imaging in the Genitourinary System.

OBJECTIVE. The purpose of this article is to review gadolinium-based contrast agent (GBCA)-enhanced MRI applications in the genitourinary system. CONCLUSION. Nephrogenic systemic fibrosis is rare or nonexistent with standard dosing of group II GBCAs. Gadolinium retention, cost, and examination times are emerging considerations affecting GBCA use. GBCA is unnecessary to diagnose adrenal adenomas, simple cysts, and some Bosniak category II cysts; however, it is required to determine solid or septal renal mass enhancement. Biparametric prostate MRI requires high-quality and reproducible DWI; therefore, dynamic contrast-enhanced MRI remains valuable in selected prostate MRI examinations.

Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents

PurposeTo quantitate gadolinium deposits in gliomas and adjacent normal brain specimens, and to evaluate their association with tumor contrast enhancement and the type of gadolinium-based contrast agent (GBCA) used.MethodsA total of 69 patients with primary glioma who underwent contrast-enhanced magnetic resonance imaging (MRI) prior to surgery were included in this retrospective study. Gadolinium was measured from histologically viable tumor, normal brain, and necrosis within the sample, when available, using inductively coupled plasma mass spectrometry (ICP-MS). Tumor contrast enhancement was categorized as none, minimal, or noticeable. Differences in gadolinium deposits by contrast enhancement and GBCA type were assessed.ResultsSeven patients received linear GBCA and 62 macrocyclic, respectively. At the time of surgery, gadolinium deposits were detected in 39 out of 69 (57%) tumor samples, 8 out of 13 (62%) normal brain, and 12 out of 14 (86%) necrotic specimens. Gadolinium was detected in both enhancing and non-enhancing tumors, but was greatest in gliomas with noticeable enhancement (p = 0.02). Administration of linear agents gadodiamide and gadopentetate dimeglumine resulted in significantly higher tumor gadolinium relative to macrocyclic gadoterate meglumine (p < 0.01 and p < 0.05, respectively). Normal brain and necrosis also showed higher gadolinium after exposure to linear gadodiamide (both p < 0.05). In multivariate regression, GBCA type (linear/macrocyclic) was the most powerful predictor of tumor gadolinium retention (p < 0.001).ConclusionGadolinium can be detected in both enhancing and non-enhancing gliomas, neighboring normal brain, and necrosis. Gadolinium retention is higher after exposure to linear GBCAs compared with the macrocyclic gadoterate meglumine.

The use of a binary chelate formulation: Could gadolinium based linear contrast agents be rescued by the addition of zinc selective chelates?

Tissue and bone retention of gadolinium based contrast agents (GBCAs) has become a clinical concern because of the potential short and long term toxic effects of free gadolinium. This is a critical problem for most open-chain agents that more readily transmetallate in vivo, in comparison to macrocyclic compounds. Gadolinium diethylene tri-aminepentaacetic acid bis-glucosamide (Gd-DTPA-BIGA) is an experimental, open-chain contrast agent which has a significantly increased relaxivity coefficient in comparison to other GBCAs. This results in greater signal intensity and improved contrast enhancement. These superior imaging qualities initiated a search for a solution to the transmetallation of this agent. Plasma zinc is a well-known GBCA transmettalation agent. Since the base chelate of Gadodiamide (Gd-DPTA-Bis-Methylamide or Omniscan), DTPA-Bis-Methylamide (DTPA-BMA), readily transmettalates with and binds serum zinc, we hypothesized that a plasma “zinc sink,” may significantly reduce transmetallation of linear agents. 5% DTPA-BMA was added to a formulation of Gd-DTPA-BIGA, which was tested against the original formulation of Gd-DTPA-BIGA with 0.2% of the base chelate DTPA-BIGA. These formulations, including gadodiamide, were labeled with 153GdCl3 followed by infusion into cohorts of Sprague Dawley rats which were sacrificed at 1, 30 and 60 days. Internal organs were harvested, along with blood, skin and femur, and analyzed for residual gadolinium. A subset of tissues were also interrogated with ICP-MS. Labeled Gadodiamide and saline where used as controls.Conclusion: The addition of 5% DTPA-BMA, as a zinc binding agent, reduced the transmetallation of the linear agent Gd-DTPA-BIGA, in comparison to its original formulation supplemented with 0.2% BIGA. This result indicates that supplementing linear GBCAs with ancillary chelates may hold promise for reducing, or eliminating the biological archiving of gadolinium in tissues. In addition, this paper provides valuable animal data on the long term retention of gadolinium from linear based contrast agents.

MRI features suggestive of gadolinium retention do not correlate with Expanded Disability Status Scale worsening in Multiple Sclerosis.

Different studies showed correlations between gadolinium-based contrast agent (GBCA) administrations and dentate nucleus (DN) T1-weighted hyperintensity. The clinical impact of gadolinium retention, however, is still largely unknown. The aim of this study was to investigate relations between MRI and clinical disability in relapsing-remitting multiple sclerosis (RR-MS) patients. In this retrospective study, clinical data were obtained from 74 RR-MS patients at baseline and after a mean follow-up time of 3.6years, including the expanded disability status scale (EDSS) score and its change (ΔEDSS). Patients were considered showing clinical worsening if they score a ΔEDSS ≥ 1 (for baseline EDSS ≤ 5.5) or ΔEDSS ≥ 0.5 (for baseline EDSS > 5.5). From the MRI data, the presence of bilateral DN hyperintensity was recorded along with the calculation of longitudinal relaxation rate (R1) maps. Patients with DN hyperintensity showed similar ΔEDSS change compared to those without visible changes on T1-weighted images (p = 0.32). Similarly, no DN-R1 difference was found comparing stable patients with those showing a significant clinical worsening (p = 0.54). Finally, no significant effect of DN-R1 values explained the variance in ΔEDSS (p = 0.76), thus suggesting their independence from the clinical outcome. MS patients with DN hyperintensity show similar EDSS changes compared to subjects without DN high-signal intensity. Furthermore, mean DN-R1 values of patients with significant clinical worsening were comparable to those of stable subjects and were unrelated to clinical disability. Taken together, these findings suggest that gadolinium retention in the brain of MS patients does not affect their clinical worsening, expressed by the EDSS change.

The Rise of Off-Label Iron-Based Agents in Magnetic Resonance Imaging

Gadolinium-based contrast agents (GBCAs) used in MRI have come under fire due to concerns about nephrogenic systemic fibrosis (NSF) and gadolinium retention. These concerns have prompted a search for alternatives to GBCAs. One attractive candidate is superparamagnetic iron oxide (SPIO). Over the past 20 years, several SPIO agents have been developed and approved for niche clinical applications in MRI. One interesting SPIO agent is ferumoxytol (Feraheme®), an FDA-approved intravenous medication used to treat iron-deficiency anemia in patients with chronic kidney disease. In preliminary studies examining its off-label use as an intravenous contrast agent, ferumoxytol appeared promising for MRI and MR angiography. However, experience with this agent remains limited. One key benefit of ferumoxytol is that it carries no risk of NSF in patients with impaired renal function. On the other hand, ferumoxytol has been reported to cause severe adverse events, including hypotension, hypersensitivity reactions, anaphylaxis, and death. Moreover, the rate of such events has been substantially greater than those observed with GBCAs or nonionic iodinated contrast media. In response to these data, the FDA issued a black box warning for ferumoxytol in 2015. To ensure patient safety, hospitals and imaging facilities must develop a plan to train MRI personnel to recognize and manage adverse reactions to ferumoxytol. Another challenge of using ferumoxytol concerns its pharmacokinetics and biodistribution, which differ from those of GBCAs. These differences can lead to unexpected patterns or persistence of tissue enhancement on MRI. In particular, ferumoxytol can remain in the body for days, weeks, or months after intravenous administration, potentially causing an unsuspecting radiologist to misinterpret an MRI. The decision to use ferumoxytol for a specific patient and clinical indication requires the radiologists to carefully weigh risk-benefit tradeoffs and consider alternative diagnostic tests.

MRI Brain Signal Intensity and Relaxation Times in Individuals with Prior Exposure to Gadobutrol.

Purpose To perform follow-up brain MRI in volunteer participants who had previously received multiple doses of gadobutrol and to assess for changes in signal intensities and relaxation times. Materials and Methods This prospective study included 160 participants who received gadobutrol only between 2007 and 2017. The participants were separated into two groups, including participants with at least five contrast agent-enhanced examinations and normal kidney function (group 1) or at least one examination and impaired renal function (group 2). Control groups with normal and impaired renal function (groups 3 and 4) without history of contrast agent exposure were included for comparison. Unenhanced brain MRI was performed in 220 participants (76, 84, 25, and 35 participants in groups 1-4, respectively) with T1-weighted spin-echo and T1 and T2 mapping to determine visual signal intensity changes, signal intensity ratios (globus pallidus-to-thalamus and dentate nucleus-to-pons ratios), and T1 and T2 relaxation times. Results In groups 1 and 2, neither visual signal alterations nor differences in signal intensity ratio or T2 mapping were found. T1 mapping showed no changes for dentate nucleus, pons, and thalamus. However, shorter T1 relaxation times in the globus pallidus were found in group 1 compared with group 3 (difference of -26.2 msec; P = .002), which correlated with the number of previous gadobutrol doses in this group (P = .001). Conclusion In study participants who had previously received gadobutrol, brain MRI showed no differences relative to healthy control participants without gadobutrol exposure. However, quantitative T1 measurements might indicate gadolinium retention in the globus pallidus. © RSNA, 2018 Online supplemental material is available for this article.

The biological fate of gadolinium-based MRI contrast agents: a call to action for bioinorganic chemists.

Gadolinium-based contrast agents (GBCAs) are widely used with clinical magnetic resonance imaging (MRI), and 10 s of millions of doses of GBCAs are administered annually worldwide. GBCAs are hydrophilic, thermodynamically stable and kinetically inert gadolinium chelates. In clinical MRI, 5-10 millimoles of Gd ion is administered intravenously and the GBCA is rapidly eliminated intact primarily through the kidneys into the urine. It is now well-established that the Gd3+ ion, in some form(s), is partially retained in vivo. In patients with advanced kidney disease, there is an association of Gd retention with nephrogenic systemic fibrosis (NSF) disease. However Gd is also retained in the brain, bone, skin, and other tissues in patients with normal renal function, and the presence of Gd can persist months to years after the last administration of a GBCA. Regulatory agencies are restricting the use of specific GBCAs and inviting health care professionals to evaluate the risk/benefit ratio prior to using GBCAs. Despite the growing number of studies investigating this issue both in animals and humans, the biological distribution and the chemical speciation of the residual gadolinium are not fully understood. Is the GBCA retained in its intact form? Is the Gd3+ ion dissociated from its chelator, and if so, what is its chemical form? Here we discuss the current state of knowledge regarding the issue of Gd retention and describe the analytical and spectroscopic methods that can be used to investigate the Gd speciation. Many of the physical methods that could be brought to bear on this problem are in the domain of bioinorganic chemistry and we hope that this review will serve to inspire this community to take up this important problem.

Reductive microenvironment responsive gadolinium-based polymers as potential safe MRI contrast agents.

Accumulation of nano-scale contrast agents in body tissues potentially induces adverse effects associated with free Gd(iii) ion release from the nano-scale system, such as nephrogenic systemic fibrosis and gadolinium deposition in the brain tissue. A novel formulation strategy was proposed herein for Gd-based macromolecular MRI contrast agents (Gd-mCAs), which may significantly reduce Gd(iii) retention but maintain sufficient imaging contrast. Biodegradable poly[N-(1,3-dihydroxypropyl)methacrylamide] copolymers (pDHPMA) were synthesized from N-(1,3-dihydroxypropyl)methacrylamide (DHPMA) as a monomer and enzyme-responsive short peptide (GFLG) as a chain transfer agent. Small molecular Gd-chelate (Gd-DOTA) was conjugated onto the copolymer backbone through a sulfide bond or a GSH-sensitive cleavable disulfide bond to produce two novel Gd-mCAs (pDHPMA-Cy5.5-DOTA-Gd or pDHPMA-Cy5.5-SS-DOTA-Gd) for tumor diagnosis. Their relaxivities were 10.49 and 10.24 mM-1 s-1 respectively, which were significantly higher than that of DTPA-Gd (3.97 mM-1 s-1). Compared with pDHPMA-Cy5.5-DOTA-Gd, pDHPMA-Cy5.5-SS-DOTA-Gd had a shorter Gd(iii) retention time but maintained a sufficient contrast efficacy. We have demonstrated that the conjugation of small molecular Gd-chelate to biodegradable macromolecular carriers through a ROX-sensitive biocleavable disulfide bond may be an efficient strategy for formulating safe biodegradable Gd-based pDHPMA copolymers as MRI contrast agents.

Measurements of signal intensity of globus pallidus and dentate nucleus suggest different deposition characteristics of macrocyclic GBCAs in children.

IntroductionThe safety of using GBCAs to enhance the visibility of body structures is currently discussed due to possible gadolinium retention in brain structures. The aim of the study was to evaluate the effect of multiple exposures to macrocyclic GBCAs in children.Materials and methodsThis retrospective, single-center study included data from 43 patients who had received ≥4 injections of macrocyclic GBCAs during MRI examinations over performed over 8 to 84 months. Signal intensity was measured on unenhanced T1-weighted MRI, and globus pallidus to thalamus (GP/Th) and dentate nucleus to pons (DN/P) ratios were calculated. The differences in ratios were tested with the Student’s t-test or the Wilcoxon rank sum test. For categorical data, Pearson's chi-squared test was used. Relationships were analyzed with the Spearman's rank correlation coefficient.ResultsPatients with the mean age of 7.5 years (SD = 4.2) received 8.19 (SD = 3.63) injections of GBCAs on average. Differences in GP/Th and DN/P ratios between the first and the last measurement were insignificant. Children before the end of myelination process (≤2 years of age) had the first GP/Th ratio values significantly lower than those >2 years of age (p = 0.0284), which than increased at the final scan and reached the level similar to values obtained in the group of >2 years of age.ConclusionsMaturation of the brain may affect both signal intensity of brain structures and susceptibility to GBCAs; thus, assessment of signal intensity of the brain structures should be conducted taking into account the age of a child.

Development of an Aptamer-Conjugated Polyrotaxane-Based Biodegradable Magnetic Resonance Contrast Agent for Tumor-Targeted Imaging.

Gadolinium-based magnetic resonance imaging (MRI) contrast agents with biodegradability, biosafety, and high efficiency are highly desirable for tumor diagnosis. Herein, a biodegradable, AS1411-conjugated, α-cyclodextrin polyrotaxane-based MRI contrast agent (AS1411-G2(DTPA-Gd)-SS-PR) was developed for targeted imaging of cancer. The polyrotaxane-based contrast agent was achieved by the complexation of α-cyclodextrin (α-CD) and a linear poly(ethylene glycol) (PEG) chain containing disulfide linkages at two terminals. The disulfides enable the dethreading of the polyrotaxane into excretable small units due to cleavage of the disulfide linkages by reducing agents such as intracellular glutathione (GSH). Furthermore, the second-generation lysine dendron conjugated with gadolinium chelates and AS1411, a G-quadruplex oligonucleotide that has high binding affinity to nucleolin generally presenting a high level on the surface of tumor cells, coupled to the α-CD via click chemistry. The longitudinal relaxivity of AS1411-G2(DTPA-Gd)-SS-PR (11.7 mM-1 s-1) was two times higher than the clinically used Gd-DTPA (4.16 mM-1 s-1) at 0.5 T. The in vitro degradability was confirmed by incubating with 10 mM 1,4-dithiothreitol (DTT). Additionally, the cytotoxicity, histological assessment, and gadolinium retention studies showed that the prepared polyrotaxane-based contrast agent had a superior biocompatibility and was predominantly cleared renally without long-term accumulation toxicity. Importantly, AS1411-G2(DTPA-Gd)-SS-PR displayed the enhanced performance in MRI of breast cancer cells in vitro as well as a subcutaneous breast tumor in vivo due to the targeting ability of the AS1411 aptamer. The enhanced performance was due to efficient multivalent interactions with tumor cells, producing faster accumulation and longer contrast imaging time at the tumor site. This work clearly confirms that the specially designed and fabricated α-CD-based polyrotaxane is a promising contrast agent with an excellent contrast imaging performance and biosafety for tumor MR imaging.

Exposure of Macrophages to Low-Dose Gadolinium-Based Contrast Medium: Impact on Oxidative Stress and Cytokines Production.

The toxicity of gadolinium-based contrast agents (GBCAs) has drawn a lot of attention. Nephrogenic systemic fibrosis (NSF), a lethal disease related to the use of GBCAs, is still not understood. Recently, gadolinium retention is found in brain tissues after repeated use of GBCAs in magnetic resonance imaging (MRI). However, most of the works investigating the toxicity of GBCAs are focusing on its high-concentration (0.5–10 mM) part, which is not reflective of the physiological conditions in human beings. Macrophages play a regulatory role in immune responses and are responsible for the fibrosis process. Their role in gadolinium retention and the pathogenesis of NSF, however, has seldom been investigated. This study aimed to evaluate the immune response generated by macrophages (RAW 264.7) exposing to low levels of GBCAs. The incubation concentration of GBCAs, including Omniscan®, Primovist®, Magnevist®, and Gadovist®, is proportional to the level of gadolinium uptake when detected via inductively coupled plasma mass spectrometry (ICP-MS) and imaged by MRI, whereas Primovist® treatment groups have highest gadolinium uptake among all of the tested concentrations. Low-concentration (2.5 μmol/L) Gd chloride or GBCAs exposure promoted the reactive production of oxygen species (ROS), nitrate/nitrite, prostaglandin E2 (PGE2), and suppressed the potential of mitochondrial membrane. There was higher ROS, nitrate/nitrite, and PGE2 production in the Primovist®, Omniscan®, and Magnevist® groups compared to the Gadovist® group. In face of lipopolysaccharide (LPS) stimulation, Primovist®, Omniscan®, and Magnevist® groups exhibited elevated nitrite/nitrate and suppressed IL-1β secretion and IL-6 and IL-10 secretion. Moreover, upon LPS stimulation, there is decreased TNF-α secretion 4 hours after Primovist® or Omiscan® exposure but the TNF-α secretion increased at 24 hours. Our data suggest that there is upregulated inflammation even in the presence of low levels of GBCAs, even similar to the physiological condition in murine macrophage. Further investigation of GBCAs on the human macrophage or in vivo animal study may clarify the role of macrophage on the pathogenesis of NSF and other GBCAs-related disease.

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Physicians' awareness of gadolinium retention and MRI timing practices in the longitudinal management of pituitary tumors: a "Pituitary Society" survey.

In view of mounting attention related to possible brain retention of gadolinium-based contrast agents (GBCAs) in patients with normal renal function, our purpose was to detail results from a survey of pituitary experts to assess: 1) the timing interval and frequency of pituitary magnetic resonance imaging (MRI) following surgical and/or medical and/or radiation therapy of pituitary tumors, 2) awareness of the types of GBCAs used and their possible safety issues. The Pituitary Society Education Committee composed a survey with 12 multiple choice questions, 8 of which specifically addressed the time interval and frequency of MRI in the longitudinal management of pituitary tumors. The survey was distributed at two meetings; the International Pituitary Neurosurgeons Society conference in San Diego, CA, on February 18th, 2018, and the Pituitary Society Membership and Career Development Forum, Chicago, IL on March 18th, 2018. There is consensus among pituitary endocrinologists and neurosurgeons that long-term repeated imaging is recommended in most pituitary tumors, although the precise strategy of timing varied depending on the specialist group and the specific clinical context of the adenoma. The data also suggest that International Pituitary Neurosurgeons Society neurosurgeons, as well as Pituitary Society neuroendocrinologists, are sometimes unaware of which contrast agents are used by their institution, and many are also unaware that evidence of long-term brain retention has been reported with the use of GBCAs in patients with normal function. International pituitary endocrinologists and pituitary neurosurgeons experts suggest ongoing MRIs for the management of pituitary tumors; strategies vary based on clinical context, but also on individual experience and practice.

Standardized assessment of the signal intensity increase on unenhanced T1-weighted images in the brain: the European Gadolinium Retention Evaluation Consortium (GREC) Task Force position statement.

After the initial report in 2014 on T1-weighted (T1w) hyperintensity of deep brain nuclei following serial injections of linear gadolinium-based contrast agents (GBCAs), a multitude of studies on the potential of the marketed GBCAs to cause T1w hyperintensity in the brain have been published. The vast majority of these studies found a signal intensity (SI) increase for linear GBCAs in the brain-first and foremost in the dentate nucleus-while no SI increase was found for macrocyclic GBCAs. However, the scientific debate about this finding is kept alive by the fact that SI differences do not unequivocally represent the amount of gadolinium retained. Since the study design of the SI measurement in various brain structures is relatively simple, MRI studies investigating gadolinium-dependent T1w hyperintensity are currently conducted at multiple institutions worldwide. However, methodological mistakes may result in flawed conclusions. In this position statement, we assess the methodological basis of the published retrospective studies and define quality standards for future studies to give guidance to the scientific community and to help identify studies with potentially flawed methodology and misleading results. KEY POINTS: • A multitude of studies has been published on the potential of the marketed GBCAs to cause T1w hyperintensity in the brain. • The gadolinium-dependent T1w hyperintensity in the brain depends on patient's history, types of GBCAs used (i.e., linear vs. macrocyclic GBCAs) and MR imaging setup and protocols. • Quality standards for the design of future studies are needed to standardize methodology and avoid potentially misleading results from retrospective studies.

Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?

The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods. A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals. Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect. No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate.

Self-identified gadolinium toxicity: comparison of gadolinium in bone and urine to healthy gadolinium-based contrast agent exposed volunteers

Objective: To report additional gadolinium bone and urine data that can contribute to gaps in knowledge with respect to gadolinium uptake and retention in the body. Approach: In vivo measurements of gadolinium retention in the tibia bone were performed on individuals self-identified as exhibiting symptoms of gadolinium toxicity as a result of receiving GBCA, as well as on control individuals. Gadolinium urine measurements for controls, symptomatic exposed, and non-symptomatic exposed were conducted through Mayo Medical Laboratories. Main results: Gadolinium bone concentration in the exposed group is significantly higher than the control group (p < 0.01), with a significant difference between symptomatic and non-symptomatic (p < 0.01), using a one-tailed t test on variance-weighted means. Gadolinium urine levels in both control subjects and non-symptomatic exposed subjects are significantly lower than symptomatic exposed subjects (p ≤ 0.05). A linear regression analysis for gadolinium urine levels and GBCA dose resulted in a positive linear relationship (R2 = 0.91, p < 0.01). Gadolinium levels in urine and gadolinium concentration in bone were found to have a non-significant relationship (R2 = 0.11, p = 0.3). Significance: Significant differences in gadolinium levels in bone and urine are observed between individuals experiencing symptoms of gadolinium toxicity and for those who are not exhibiting symptoms. No correlation was observed between gadolinium in bone and gadolinium excreted in urine, suggesting that the retention of gadolinium in the body is complicated, involving multiple long-term storage sites.

LA-ICP-MS/MS improves limits of detection in elemental bioimaging of gadolinium deposition originating from MRI contrast agents in skin and brain tissues

A novel analytical method to detect the retention of gadolinium from contrast agents for magnetic resonance imaging (MRI) in tissue samples of patients is presented. It is based on laser ablation - inductively coupled plasma - triple quadrupole - mass spectrometry (LA-ICP-MS/MS). Both Gd and P were monitored with a mass shift of +16, corresponding to mono-oxygenated species, as well as Zn, Ca, and Fe on-mass. This method resulted in a significantly reduced background and improved limits of detection not only for phosphorus, but also for gadolinium. These improvements were essential to perform elemental bioimaging with improved resolution of 5 μm x 5 μm, allowing the detection of small Gd deposits in fibrotic skin and brain tumour tissue with diameters of approximately 50 μm. Detailed analyses of these regions revealed that most Gd was accompanied with P and Ca, indicating co-precipitation.

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.

Gadolinium Retention After Contrast-Enhanced MRI

This Viewpoint discusses the retention of gadolinium, used in contrast-enhanced MRI, in skin and kidney tissue and the efforts of experts from radiological societies, the NIH, and the FDA to study the safety of this element in clinical use.