Gadolinium Deposition In Brain Research Articles

Gadolinium Brain Deposition in the globus pallidus and dentate nucleus after serial administrations of a macrocyclic gadolinium-based contrast agent in oncologic pediatric patients

Introduction: Gadolinium deposition in the human brain, especially in the Globus Pallidus (GP) and the Dentate Nucleus (DN) has been reported after the administration of linear Gadolinium-Based Contrast Agents (GBCAs). This study aims to determine whether repeated injections of macrocyclic GBCA are associated with an increased Signal Intensity (SI) on T1-weighted sequences in the Globus Pallidus (GP) and Dentate Nucleus (DN) in oncologic pediatric patients. Materials and methods: This retrospective monocentric cohort study included consecutive children with at least two MRIs performed after administration of macrocyclic GBCAs. The SI measurements were determined on unenhanced T1-weighted images by drawing a circular region of interest (ROI) within GP and Thalamus (TH) and DN, Pons (P), at baseline, and at last MRI. SI ratios and the differences in ratios (GP/TH) and (DN/P) between the first and last MRI calculated. Results: Out of 413 consecutive children attending Leon Berard cancer center, 50 patients were included, and data analysis showed significantly increased GP/TH SI ratios between the first and the last MRI (p =0.0305). The DN/P SI ratios did not significantly differ between the first and the last MRI (p=0.2668). Conclusion: This study showed an increased SI in GP after several intravenous administrations of macrocyclic GBCAs but no increased SI was identified in the DN. Although no clinical adverse effects have been reported so far, the gadolinium deposits in the brain should be carefully monitored, especially in children who still undergo neurodevelopment.

Effects of Gadolinium Deposition in the Brain on Motor or Behavioral Function: A Mouse Model.

Background Recent studies showing gadolinium deposition in multiple organs have raised concerns about the safety of gadolinium-based contrast agents (GBCAs). Purpose To explore whether gadolinium deposition in brain structures will cause any motor or behavioral alterations. Materials and Methods This study was performed from July 2019 to December 2020. Groups of 17 female BALB/c mice were each repeatedly injected with phosphate-buffered saline (control group, group A), a macrocyclic GBCA (group B), or a linear GBCA (group C) for 8 weeks (5 mmol per kilogram of bodyweight per week for GBCAs). Brain MRI studies were performed every other week to observe the signal intensity change caused by the gadolinium deposition. After the injection period, rotarod performance test, open field test, elevated plus-maze test, light-dark anxiety test, locomotor activity assessment test, passive avoidance memory test, Y-maze test, and forced swimming test were performed to assess the locomotor abilities, anxiety level, and memory. Among-group differences were compared by using one-way or two-way factorial analysis of variance with Tukey post hoc testing or Dunnett post hoc testing. Results Gadolinium deposition in the bilateral deep cerebellar nuclei was confirmed with MRI only in mice injected with a linear GBCA. At 8 weeks, contrast ratio of group C (0.11; 95% CI: 0.10, 0.12) was higher than that of group A (-2.1 × 10-3; 95% CI: -0.011, 7.5 × 10-3; P < .001) and group B (2.7 × 10-4; 95% CI: -8.2 × 10-3, 8.7 × 10-3; P < .001). Behavioral analyses showed that locomotor abilities, anxiety level, and long-term or short-term memory were not different in mice injected with linear or macrocyclic GBCAs. Conclusion No motor or behavioral alterations were observed in mice with brain gadolinium deposition. Also, the findings support the safety of macrocyclic gadolinium-based contrast agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Chen in this issue.

Gadolinium Deposition in Brain after Intravenous Injection of Gadolinium-based Contrast Agents

Background: Gadolinium-based contrast agents (GBCA) are commonly used in MRI. GBCA have been linked to signal changes in dentate nucleus and globus pallidus. Purpose: To assess the degree of gadolinium accumulation in brain structures among patients with GBCA administrations. Materials and methods: Retrospective study included 224 patients: 197 patients who underwent more than two MRI with linear-type GBCA and 27 patients from control group who underwent at least two MRI without GBCA. Results: Statistical analysis of the main group revealed positive correlation between difference in signal intensity of GP/thalamus ratio to the number of previous MRI with GBCA (r=0.145, p=0.042), with a time interval between first and last MRI (r=0,221, p=0,002), as well as to patients age (r=0.145, p=0.042). For difference in ND/ pons ratio positive correlation was found only with the number of previous studies with GBCA (r=0.172, p=0.016). Statistical analysis of patients who received GBCA of the same type (gadodiamide or gadopentetic acid) revealed the following correlations: in patients who were administered gadodiamide, a positive correlation was found between ND/pons ratio and the number of previous studies with GBCA (r=0,280, p&lt;0,5). In patients who were administered gadopentetic acid, no correlation was found between the difference in GP/thalamus ratio, in ND/pons ratio and the number of studies with GBCA. Conclusions: Increased signal intensity at the pale globes and the dentate nuclei on pre-contrast images may be related to the number of studies performed with linear-type GBCA.

Gadolinium-Based Contrast Agent Use, Their Safety, and Practice Evolution.

Gadolinium-based contrast agents (GBCAs) have provided much needed image enhancement in magnetic resonance imaging (MRI) important in the advancement of disease diagnosis and treatment. The paramagnetic properties of ionized gadolinium have facilitated these advancements, but ionized gadolinium carries toxicity risk. GBCAs were formulated with organic chelates designed to reduce these toxicity risks from unbound gadolinium ions. They were preferred over iodinated contrast used in computed tomography and considered safe for use. As their use expanded, the development of new diseases associated with their use (including nephrogenic systemic fibrosis) has drawn more attention and ultimately caution with their clinical administration in those with impaired renal function. Use of GBCAs in those with preserved renal function was considered to be safe. However, in this new era with emerging clinical and experimental evidence of brain gadolinium deposition in those with repeated exposure, these safety assumptions are once again brought into question. This review article aims to add new perspectives in thinking about the role of GBCA in current clinical use. The new information begs for further discussion and consideration of the risk-benefit ratio of use of GBCAs.

Intravenous gadolinium-based hepatocyte-specific contrast agents (HSCAs) for contrast-enhanced liver magnetic resonance imaging in pediatric patients: what the radiologist should know.

Hepatocyte-specific contrast agents (HSCAs) are a group of intravenous gadolinium-based MRI contrast agents that can be used to characterize hepatobiliary pathology. The mechanism by which these agents are taken up by hepatocytes and partially excreted into the biliary tree improves characterization of hepatic lesions and biliary abnormalities relative to conventional extracellular gadolinium-based contrast agents (GBCAs). This manuscript presents an overview of HSCA use in pediatric patients with the intent to provide radiologists a guide for clinical use. We review available HSCAs and discuss dosing and age specifications for use in children. We also review various hepatic and biliary indications for HSCA use in children, with emphasis on the imaging characteristics distinct to HSCAs, as well as discussion of pitfalls one can encounter when imaging with HSCAs. Given the growing concern regarding gadolinium deposition in soft tissues and brain, we also discuss safety of HSCA use in children.

Cumulative gadodiamide administration leads to brain gadolinium deposition in early MS.

Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS. A total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration <2 years at baseline and received exclusively gadodiamide at all MRI time points. SI ratio (SIR) to pons and CSF of lateral ventricle volume (CSF-LVV) were assessed. Analysis of covariance and correlation analyses, adjusted for age, sex, and region of interest volume, were used. The mean follow-up time was 55.4 months, and the mean number of gadolinium-based contrast agents administrations was 9.2. At follow-up, 49.3% of patients with MS and no controls showed DN T1 hyperintensity (p < 0.001). The mean SIR of DN (p < 0.001) and of GP (p = 0.005) to pons and the mean SIR of DN, GP, and thalamus to CSF-LVV were higher in patients with MS compared to controls (p < 0.001). SIR of DN to pons was associated with number of gadodiamide doses (p < 0.001). No associations between SIR of DN, GP, and thalamus and clinical and MRI outcomes of disease severity were detected over the follow-up. DN, GP, and thalamus gadolinium deposition in early MS is associated with lifetime cumulative gadodiamide administration without clinical or radiologic correlates of more aggressive disease.

Gadolinium-based contrast agents - review of recent literature on magnetic resonance imaging signal intensity changes and tissue deposits, with emphasis on pediatric patients.

Gadolinium has been used as a base for contrast agents in MRI for the last three decades. Numerous studies over the last 4years have reported increased signal intensity in deep brain nuclei in non-contrast MRI images following gadolinium-based contrast agent (GBCA) administration. Pathology studies performed on adults and children, and rodent necropsy studies have also shown gadolinium deposition in brain and other tissues after GBCA administration. The purpose of this review was to summarize and discuss the knowledge gained from these reports and the relevance for imaging pediatric patients.

Gadolinium Deposition in Neurology Clinical Practice.

Background: Magnetic resonance imaging (MRI) enhanced with gadolinium-based contrast agents (GBCAs) is an essential tool in the diagnosis and management of many neurologic diseases, including multiple sclerosis, brain tumors, and infections. The clinical utility of GBCAs is evidenced by their widespread use. GBCAs are produced in macrocyclic and linear forms. Since 2014, evidence has suggested that repeated administration of GBCAs can lead to gadolinium deposition in the brain. Methods: We review the literature on gadolinium deposition, including both animal and human studies, as well as the literature on GBCA-associated health outcomes. Additionally, we summarize and discuss the updated medical society recommendations and perspectives on GBCA use in clinical practice. Results: The first publication reporting gadolinium deposition in the human brain was published in 2014. Since that seminal report, multiple studies have demonstrated that exposure to linear GBCAs is associated with gadolinium deposition in the dentate nucleus and globus pallidus as seen on brain MRI. Macrocyclic GBCA exposure has not convincingly been associated with gadolinium deposition evident on brain MRI. Conclusion: Clear evidence demonstrates that GBCAs lead to gadolinium deposition in the brain in a dose-dependent manner; however, only linear GBCAs have been associated with gadolinium deposition visualized on MRI. To date, no evidence links gadolinium deposition with any adverse health outcome. Updated medical society guidelines emphasize the importance of an individualized risk-benefit analysis with each administration of GBCAs.

Can unenhanced brain magnetic resonance imaging be used in routine follow up of meningiomas to avoid gadolinium deposition in brain?

PurposeWe hypothesized that unenhanced brain MRI can be used in follow up of patients with intracranial meningioma to avoid gadolinium deposition in the brain and allow measurement of meningioma dimensions from pre-contrast T2-weighted images. MethodsDimensions of meningiomas were measured on pre-contrast T2, post-contrast T1 weighted images. ResultsThe sizes of meningiomas in post-contrast axial T1-weighted images were similar with that in pre-contrast axial T2-weighted images. Signal intensity increase was detected in dentate nucleus and globus pallidus (P < 0.05). ConclusionGadolinium deposition could be avoided in patients with meningioma by using unenhanced brain MRI for follow up scans.

Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives.

In the past 4 years, many publications described a concentration-dependent deposition of gadolinium in the brain both in adults and children, seen as high signal intensities in the globus pallidus and dentate nucleus on unenhanced T1-weighted images. Postmortem human or animal studies have validated gadolinium deposition in these T1-hyperintensity areas, raising new concerns on the safety of gadolinium-based contrast agents (GBCAs). Residual gadolinium is deposited not only in brain, but also in extracranial tissues such as liver, skin, and bone. This review summarizes the current evidence on gadolinium deposition in the human and animal bodies, evaluates the effects of different types of GBCAs on the gadolinium deposition, introduces the possible entrance or clearance mechanism of the gadolinium and potential side effects that may be related to the gadolinium deposition on human or animals, and puts forward some suggestions for further research.

Signal Changes in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted Magnetic Resonance Images After Intrathecal Administration of Macrocyclic Gadolinium Contrast Agent.

The aim of this study was to evaluate signal changes in the dentate nucleus and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance (MR) images (T1 WI) in a cohort of patients who have received intrathecal macrocyclic ionic gadolinium-based contrast agent (GBCA) gadoterate meglumine. A group of 20 patients (male/female ratio, 8:12; mean age, 39.5 ± 15.5 years) who had not received intravenous GBCA but had received an intrathecal macrocyclic ionic GBCA (plus baseline and an additional final magnetic resonance imaging [MRI] for reference) from 2012 to 2017 were retrospectively included in this institutional review board-approved study. Two radiologists inspected T1-weighted 2-dimensional spin echo (n = 7) and 3-dimensional isotropic turbo field echo (n = 13) images on a 3 T MRI system to conduct visual evaluation and quantitative analysis. Baseline and final examination signal intensity (SI) ratios were assessed across time by using the same pulse sequences. For visual analysis, SI changes on the GP, thalamus (Th), cerebellar peduncle (CP), and dentate nucleus (DN) were graded as a 3-point scale. For quantitative analysis, SI ratio differences between the baseline and final MR examinations were estimated for the DN-to-CP and GP-to-Th ratios. One-sample t tests were used to investigate whether they differed from 0. In addition, to investigate significant differences between the SI ratios for various pulse sequences, t tests were performed. The regression analysis was additionally used to find any correlation between SI ratio differences and various confounding variables including age, sex, or the mean interval between the baseline and final MR examinations. The SI ratio differences did not deviate significantly from 0, neither for the DN/CP ratio (0.013 ± 0.0584, P = 0.287) nor the GP/Th ratio (-0.0113 ± 0.0546, P = 0.366). The DN-to-CP and GP-to-Th SI ratio differences did not significantly deviate from 0 in the patient groups in either of the imaging sequences (P > 0.05) as well. Age, sex, and the mean interval between examinations did not influence SI ratio differences between examinations (P > 0.05). Intrathecal macrocyclic GBCA administration was not associated with measurable T1 SI changes in the GP and DN as an indicator of brain gadolinium deposition detectable by MRI.

The Impact of Gadolinium Deposition on Radiology Practice: An International Survey of Radiologists

Brain deposition of gadolinium following the administration of gadolinium-based contrast agents (GBCAs) was initially reported in 2014. Gadolinium deposition is now recognized as a dose-dependent consequence of exposure. The potential clinical implications are not yet understood. The purpose of this study was to determine radiologists' reporting practices in response to gadolinium deposition. An electronic survey querying radiologists' practices regarding gadolinium deposition was distributed by Radiopaedia.org from November-December 2015. Our study sample included 94 total respondents (50% academic; 27% private practice; 23% hybrid) from 30 different countries (USA 18%). Fifty-seven (62%) radiologists had observed brain gadolinium deposition on MRI brain studies howerver more than half of these (30 of 57) reported detecting dentate T1 shortening only rarely (<1/month). Among respondents, 58% (52 of 89) do not or would not include the finding in the radiology report; only 12 (13%) report the finding in the impression of their reports. The most common reason for not reporting gadolinium deposition was the risk of provoking unnecessary patient anxiety (29%, 20 of 70). Recent data on gadolinium deposition has led to a reported practice change in 24 of 87 (28%) of respondents. Recognition of, and attitudes toward, brain gadolinium deposition were inconsistent in this worldwide sample. Most surveyed radiologists do not routinely report dentate T1shortening as a marker of gadolinium deposition. Fear of provoking patient/clinician anxiety and an incomplete understanding of the implications of gadolinium deposition contribute to inconsistencies in reporting.

Gadolinium Brain Deposition after Macrocyclic Gadolinium Administration: A Pediatric Case-Control Study.

Purpose To determine whether signal intensity (SI) in T1 sequences as a potential indicator of gadolinium deposition increases after repeated administration of the macrocyclic gadolinium-based contrast agents (GBCAs) gadoteridol and gadoterate meglumine in a pediatric cohort. Materials and Methods This retrospective case-control study of children with brain tumors who underwent nine or more contrast material-enhanced brain magnetic resonance (MR) imaging studies from 2008 to 2015 was approved by the local ethics board. Informed consent was obtained for MR imaging. Twenty-four case patients aged 5-18 years and appropriate control patients with nonpathologic MR neuroimaging findings (and no GBCA administration), matched for age and sex, were inculded. SI was measured on unenhanced T1-weighted MR images for the following five regions of interest (ROIs): the dentate nucleus (DN), pons, substantia nigra (SN), pulvinar thalami, and globus pallidus (GP). Paired t tests were used to compare SI and SI ratios (DN to pons, GP to thalamus) between case patients and control patients. Pearson correlations between relative signal changes and the number of GBCA administrations and total GBCA dose were calculated. Results The mean number of GBCA administrations was 14.2. No significant differences in mean SI for any ROI and no group differences were found when DN-to-pons and GP-to-pulvinar ratios were compared (DN-to-pons ratio in case patients: mean, 1.0083 ± 0.0373 [standard deviation]; DN-to-pons ratio in control patients: mean, 1.0183 ± 0.01917; P = .37; GP-to-pulvinar ratio in case patients: mean, 1.1335 ± 0.04528; and GP-to-pulvinar ratio in control patients: mean, 1.1141 ± 0.07058; P = .29). No correlation was found between the number of GBCA administrations or the total amount of GBCA administered and signal change for any ROI. (Number of GBCA applications: DN: r = -0.254, P = .31; pons: r = -0.097, P = .65; SN: r = -0.194, P = .38; GP: r = -0.175, P = .41; pulvinar: r = -0.067, P = .75; total amount of administered GBCA: DN: r = 0.091, P = .72; pons: r = 0.106, P = .62; SN: r = -0.165, P = .45; GP: r = 0.111, P = .61; pulvinar: r = 0.173, P = .42.) Conclusion Multiple intravenous administrations of these macrocyclic GBCAs in children were not associated with a measurable increase in SI in T1 sequences as an indicator of brain gadolinium deposition detectable by using MR imaging. Additional imaging and pathologic studies are needed to confirm these findings. © RSNA, 2017 Online supplemental material is available for this article.

Use of gadolinium-based magnetic resonance imaging contrast agents and awareness of brain gadolinium deposition among pediatric providers in North America.

Numerous recent articles have reported brain gadolinium deposition when using linear but not macrocyclic gadolinium-based contrast agents (GBCAs). To determine the current landscape of gadolinium use among pediatric institutions and the knowledge base of radiologists and referring providers with regard to GBCAs and brain gadolinium deposition. We e-mailed voluntary closed surveys to 5,390 physicians in various pediatric professional societies between January 2016 and March 2016. We used chi-square and Fisher exact tests to compare response distributions among specialties. We found that 80% of surveyed pediatric hospitals use macrocyclic contrast agents. In the last year, 58% switched their agent, most commonly to gadoterate meglumine, with the most common reason being brain gadolinium deposition. Furthermore, surveys indicated that 23% of hospitals are considering switching, and, of these, 83% would switch to gadoterate meglumine; the most common reasons were brain gadolinium deposition and safety. Radiologists were more aware of brain gadolinium deposition than non-radiologist physicians (87% vs. 26%; P<0.0001). Radiologists and referring providers expressed similar levels of concern (95% and 89%). Twelve percent of radiologists and 2% of referring providers reported patients asking about brain gadolinium deposition. Radiologists were significantly more comfortable addressing patient inquiries than referring pediatric physicians (48% vs. 6%; P<0.0001). The number of MRIs requested by referring pediatric physicians correlated with their knowledge of brain gadolinium deposition, contrast agent used by their hospital, and comfort discussing brain gadolinium deposition with patients (P<0.0001). Since the discovery of brain gadolinium deposition, many pediatric hospitals have switched to or plan to switch to a more stable macrocyclic MR contrast agent, most commonly gadoterate meglumine. Despite this, there is need for substantial further education of radiologists and referring pediatric providers regarding GBCAs and brain gadolinium deposition.

Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function.

The purpose of this study was to determine whether gadolinium (Gd) is deposited in brain and bone tissues in patients receiving only non-Group 1 agents, either macrocyclic or linear protein interacting Gd-based contrast agents, with normal renal function. Group 1 agents are linear agents most associated with nephrogenic systemic fibrosis that the US Federal Drug Administration has defined as contraindicated in patients at risk for this disease. This study was institutional review board approved and Health Insurance Portability and Accountability Act compliant for retrospective review of records and also had signed autopsy consent authorizing use of decedent's tissue in research studies. Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non-Group 1 Gd-based contrast agent. Decedents with only noncontrast MRI or no MRI served as controls. Multiple brain areas, including globus pallidus and dentate nucleus, as well as bone and skin, were sampled and analyzed for Gd using inductively coupled plasma mass spectrometry. Gadolinium levels were compared between groups of decedents using the Mann-Whitney test and between brain and bone tissues of the same cases using the Wilcoxon signed-rank test. Of the 9 decedents, 5 received gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ), 2 received gadobutrol (Gadovist; Bayer Healthcare, Whippany, NJ), and 1 each had gadobenate (MultiHance; Bracco Diagnostics) and gadoxetate (Eovist; Bayer Healthcare). Gadolinium was found with all agents in all brain areas sampled with highest levels in globus pallidus and dentate. Bone levels measured 23 times higher (median) than brain levels (P = 0.008 for bone vs globus pallidus) and showed a significant correlation (r = 0.81, P = 0.022). In controls, Gd levels in the brain were at or below limits of measurement and were significantly lower compared with study cases (P = 0.005 for globus pallidus). Gadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function. Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two. Thus, the bone may serve as a surrogate to estimate brain deposition if brain Gd were to become a useful clinical or research marker.

Brain gadolinium deposition after administration of gadolinium-based contrast agents.

Gadolinium-based contrast agents (GBCAs) consist of gadolinium ions and a chelating agent that binds the gadolinium ion tightly so that its toxicity is not manifested. However, in 2013, an association between brain MRI abnormalities and a history of GBCA administration was first reported. Even in patients with normal renal function, increased signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images showed a positive correlation with previous exposure to linear chelate type GBCAs, but not to macrocyclic chelate type ones. This difference of GBCAs is speculated to reflect the stability of GBCAs, and de-chelated gadolinium deposition has been strongly suspected. Using inductively coupled plasma mass spectroscopy, gadolinium was detected from patients' brains with a history of repeated GBCA administration. In some cases, the gadolinium concentration of a patient's brain with normal renal function exceeded the gadolinium concentration of the skin in nephrogenic systemic fibrosis patients, but without any histological change. The actual risk has not been documented yet, but it seems important to consider the potential unknown risks of residual gadolinium in our decisions regarding GBCA administration, and to make efforts to minimize any residual gadolinium in the patient's body.