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Gadolinium Deposition in Deep Brain Structures: Relationship with Dose and Ionization of Linear Gadolinium-Based Contrast Agents.

ABSTRACT: BACKGROUND AND PURPOSE:Dose-dependent association between hyperintensity in deep brain structures on unenhanced T1WIs and gadolinium-based contrast agent administrations has been demonstrated with subsequent histopathological confirmation of gadolinium deposition. Our aim was to determine whether greater exposure to linear gadolinium-based contrast agent administration is associated with higher signal intensity in deep brain structures on unenhanced T1-weighted MR imaging. Secondary objective was to compare signal intensity differences between ionic and nonionic linear gadolinium-based contrast agents. MATERIALS AND METHODS:Subjects with secondary-progressive MS originally enrolled in a multicenter clinical trial were studied retrospectively. Eighty subjects (high-exposure cohort) received 9 linear gadolinium-based contrast agent administrations (30 nonionic/50 ionic) between week -4 and year 1 and a tenth administration by year 2. One hundred fifteen subjects (low-exposure cohort) received 2 administrations (40 nonionic/75 ionic) between week -4 and year 1 and a third administration by year 2. Signal intensities were measured on unenhanced T1WIs by placing sample-points on the dentate nucleus, globus pallidus, caudate, thalamus, pons, and white matter, and they were normalized using the following ratios: dentate/pons, globus pallidus/white matter, caudate/white matter, and thalamus/white matter. RESULTS:Between week -4 and year 1, subjects in the high-exposure cohort showed increased signal intensity ratios in all regions (P < .01), while the low-exposure cohort showed only an increase in the dentate nucleus (P = .003). Between years 1 and 2, when both cohorts received only 1 additional gadolinium-based contrast agent, no significant changes were observed. In the high-exposure cohort, significantly higher changes in signal intensity ratios were observed in subjects receiving linear nonionic than in those receiving linear ionic gadolinium-based contrast agents. CONCLUSIONS:Hyperintensity in deep brain structures from gadolinium deposition is related to the number of doses and the type of linear gadolinium-based contrast agent (nonionic greater than ionic) administration.

SUBMITTER: Kang H

PROVIDER: S-EPMC7655291 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Gadolinium Deposition in Deep Brain Structures: Relationship with Dose and Ionization of Linear Gadolinium-Based Contrast Agents.

Kang H H Hii M M Le M M Tam R R Riddehough A A Traboulsee A A Kolind S S Freedman M S MS Li D K B DKB

AJNR. American journal of neuroradiology 20180823 9

<h4>Background and purpose</h4>Dose-dependent association between hyperintensity in deep brain structures on unenhanced T1WIs and gadolinium-based contrast agent administrations has been demonstrated with subsequent histopathological confirmation of gadolinium deposition. Our aim was to determine whether greater exposure to linear gadolinium-based contrast agent administration is associated with higher signal intensity in deep brain structures on unenhanced T1-weighted MR imaging. Secondary obje ...[more]

PMID: 30139752

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Project description:OBJECTIVES: The purposes of this study were to evaluate the risk for analytical interference with gadolinium-based contrast agents (GBCAs) for the colorimetric measurement of serum iron (Fe³?) and to investigate the mechanisms involved. MATERIALS AND METHODS: Rat serum was spiked with several concentrations of all molecular categories of GBCAs, ligands, or "free" soluble gadolinium (Gd³?). Serum iron concentration was determined by 2 different colorimetric methods at pH 4.0 (with a Vitros DT60 analyzer or a Cobas Integra 400 analyzer). Secondly, the cause of interference was investigated by (a) adding free soluble Gd³? or Mn²? to serum in the presence of gadobenic acid or gadodiamide and (b) electrospray ionization mass spectrometry. RESULTS: Spurious decrease in serum Fe³? concentration was observed with all linear GBCAs (only with the Vitros DT60 technique occurring at pH 4.0) but not with macrocyclic GBCAs or with free soluble Gd³?. Spurious hyposideremia was also observed with the free ligands present in the pharmaceutical solutions of the linear GBCAs gadopentetic acid and gadodiamide (ie, diethylene triamine pentaacetic acid and calcium-diethylene triamine pentaacetic acid bismethylamide, respectively), suggesting the formation of Fe-ligand chelate.Gadobenic acid-induced interference was blocked in a concentration-dependent fashion by adding a free soluble Gd³? salt. Conversely, Mn²?, which has a lower affinity than Gd³? and Fe³? for the ligand of gadobenic acid (ie, benzyloxypropionic diethylenetriamine tetraacetic acid), was less effective (interference was only partially blocked), suggesting an Fe³? versus Gd³? transmetallation phenomenon at pH 4.0. Similar results were observed with gadodiamide. Mass spectrometry detected the formation of Fe-ligand with all linear GBCAs tested in the presence of Fe and the disappearance of Fe-ligand after the addition of free soluble Gd³?. No Fe-ligand chelate was found in the case of the macrocyclic GBCA gadoteric acid. CONCLUSIONS: Macrocyclic GBCAs induced no interference with colorimetric methods for iron determination, whereas negative interference was observed with linear GBCAs using a Vitros DT60 analyzer. This interference of linear GBCAs seems to be caused by the excess of ligand and/or an Fe³? versus Gd³? transmetallation phenomenon.

Project description:ObjectivesRetrospective studies in patients with primary brain tumors or other central nervous system pathologies as well as postmortem studies have suggested that gadolinium (Gd) deposition occurs in the dentate nucleus (DN) and globus pallidus (GP) after multiple administrations of primarily linear Gd-based contrast agents (GBCAs). However, this deposition has not been associated with any adverse effects or histopathological alterations. The aim of this preclinical study was to systematically examine differences between linear and macrocyclic GBCAs in their potential to induce changes in brain and skin histology including Gd distribution in high spatial resolution.Materials and methodsFifty male Wistar-Han rats were randomly allocated into control (saline, n = 10 rats) and 4 GBCA groups (linear GBCAs: gadodiamide and gadopentetate dimeglumine, macrocyclic GBCAs: gadobutrol and gadoteridol; n = 10 rats per group). The animals received 20 daily intravenous injections at a dose of 2.5 mmol Gd/kg body weight. Eight weeks after the last GBCA administration, the animals were killed, and the brain and skin samples were histopathologically assessed (hematoxylin and eosin; cresyl violet [Nissl]) and by immunohistochemistry. The Gd concentration in the skin, bone, brain, and skeletal muscle samples were analyzed using inductively coupled plasma mass spectroscopy (ICP-MS, n = 4). The spatial Gd distribution in the brain and skin samples was analyzed in cryosections using laser ablation coupled with ICP-MS (LA-ICP-MS, n = 3). For the ultra-high resolution of Gd distribution, brain sections of rats injected with gadodiamide or saline (n = 1) were assessed by scanning electron microscopy coupled to energy dispersive x-ray spectroscopy and transmission electron microscopy, respectively.ResultsNo histological changes were observed in the brain. In contrast, 4 of 10 animals in the gadodiamide group but none of the animals in other groups showed macroscopic and histological nephrogenic systemic fibrosis-like skin lesions. The Gd concentrations observed in the skin/brain samples (in nanomole Gd per gram of tissue) for each agent were as follows: gadodiamide: 1472 ± 115/11.1 ± 5.1, gadopentetate dimeglumine: 80.8 ± 6.2/13.1 ± 7.3, gadobutrol: 1.1 ± 0.5/0.7 ± 0.4, and gadoteridol: 1.7 ± 0.8/0.5 ± 0.2. The average detected residual Gd concentration in the brain was approximately 15-fold higher for linear than for macrocyclic GBCAs. The highest amounts of Gd found in brain corresponded to less than 0.0002% of the injected dose per gram of tissue. Using LA-ICP-MS, high Gd concentrations in the deep cerebellar nuclei and in the granular layer of the cerebellar cortex were detected only for linear gadodiamide and gadopentetate dimeglumine but not for gadoteridol or gadobutrol. The energy dispersive x-ray spectroscopy analysis revealed Gd-containing spots in the skin of animals administered gadodiamide and gadopentetate dimeglumine. Transmission electron microscopy revealed several Gd-containing spots in the region of the dentate nuclei in the brain of 1 animal injected with gadodiamide.ConclusionsAfter repeated high dosing, nephrogenic systemic fibrosis-like macroscopic and histopathological lesions of the skin were observed only in some of the gadodiamide-treated animals. No histopathological findings were detected in the rodent brain. The administration of linear GBCAs was associated with significantly higher Gd concentrations in the brain and skin compared with macrocyclic GBCA administration. The results of LA-ICP-MS demonstrated local accumulation of Gd within the deep cerebellar nuclei and the granular layer only after the administration of linear agents. In summary, the detected low Gd concentrations in the skin and brain were well correlated with the higher kinetic stability of macrocyclic GBCA.

Project description:BackgroundHypersensitivity reactions (HSRs) can occur unexpectedly and be life-threatening when gadolinium-based contrast agents (GBCAs) are used. Gadolinium deposition disease (GDD) and symptoms associated with gadolinium exposure (SAGE) have been controversial for a long time. However, similar studies are currently incomplete or outdated. Therefore, comparing the safety of different GBCAs in terms of HSRs and GDD/SAGE using the latest post-marketing safety data should yield further insights into safely using GBCAs.MethodsThe safety differences between all GBCAs to GDD and the spectrum of GBCA-related HSRs were all compared and analyzed by using the World Health Organization database VigiBase and the FDA Adverse Event Reporting System (FAERS) database in this study. A further analysis of SAGE was also conducted using FAERS data. The lower limit of the reporting odds ratio (ROR) 95% confidence interval was used for signal detection. Moreover, the frequency of HSRs was calculated by dividing the number of reports in VigiBase by the total sales volume (measured in millions) from 2008 to 2022 in the IQVIA Multinational Integrated Data Analysis System. All adverse events were standardized using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 26.0.ResultsThis study shows that all GBCAs have the potential to induce HSRs, with nonionic linear GBCAs exhibiting a comparatively lower signal. According to standardized MedDRA query stratification analysis, gadobutrol had a greater ROR025 for angioedema. The ROR025 of gadobenate dimeglumine and gadoteridol is larger for anaphylactic/anaphylactoid shock conditions. Regarding severe cutaneous adverse reactions, only gadoversetamide and gadodiamide showed signals in FAERS and VigiBase. There were also differences in the frequency of HSRs between regions. Regarding GDD, gadoterate meglumine, and gadoteridol had a lower ROR025. An analysis of the 29 preferred terms linked to SAGE indicated that special consideration should be given to the risk of skin induration associated with gadoversetamide, gadopentetate dimeglumine, gadobenate dimeglumine, gadodiamide, and gadoteridol. Additionally, gadodiamide and gadoteridol pose a greater risk of skin tightness compared to other GBCAs.ConclusionsThe risk differences among GBCAs using data from several sources were compared in this study. However, as a hypothesis-generating method, a clear causal relationship would require further research and validation.

Dataset Information

Gadolinium Deposition in Deep Brain Structures: Relationship with Dose and Ionization of Linear Gadolinium-Based Contrast Agents.

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Gadolinium Deposition in Deep Brain Structures: Relationship with Dose and Ionization of Linear Gadolinium-Based Contrast Agents.

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