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Conspicuous hyperintense dentate nucleus (A: 2003, B: 2005, C: 2010) and globus pallidus (D: 2003, E: 2005, F: 2010) on T1-weighted MRI of Patient 3.
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Gadolinium-based contrast agents (primarily those with linear chelates) are associated with a dose-dependent signal hyperintensity in the dentate nucleus and the globus pallidus on unenhanced T1-weighted MRI following administration to selected patients with normal renal function. The accumulation of gadolinium has also been reported in the skin, h...
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Significance
Gadolinium (Gd)-based contrast agents (GBCAs) are currently the mainstream clinical MRI contrast agents. Some GBCAs have shown a long-term toxicity—nephrogenic systemic fibrosis (NSF)—and Gd depositions in the brain. The NSF has triggered a Food and Drug Administration (FDA) black-box warning and a contraindication of some GBCAs. The f...
Citations
... To give some examples, intravenous GBCA application is associated with nephrogenic systemic fibrosis (NSF) in patients with reduced kidney function. In addition, gadolinium residues can be found in the brain, kidneys and bones of healthy patients, especially after repeated doses [2][3][4][5][6]. As a result, the European Medicines Agency recommended the suspension of the marketing authorities for some linear gadolinium-based contrast agent in 2017 [7], underlining the urgent need for alternatives. ...
Dextran-coated superparamagnetic iron oxide nanoparticles (SPIONDex) of various sizes can be used as contrast agents in magnetic resonance imaging (MRI) of different tissues, e.g., liver or atherosclerotic plaques, after intravenous injection. In previous studies, the blood compatibility and the absence of immunogenicity of SPIONDex was demonstrated. The investigation of the interference of SPIONDex with stimulated immune cell activation is the aim of this study. For this purpose, sterile and endotoxin-free SPIONDex with different hydrodynamic sizes (30 and 80 nm) were investigated for their effect on monocytes, dendritic cells (DC) and lymphocytes in concentrations up to 200 µg/mL, which would be administered for use as an imaging agent. The cells were analyzed using flow cytometry and brightfield microscopy. We found that SPIONDex were hardly taken up by THP-1 monocytes and did not reduce cell viability. In the presence of SPIONDex, the phagocytosis of zymosan and E. coli by THP-1 was dose-dependently reduced. SPIONDex neither induced the maturation of DCs nor interfered with their stimulated maturation. The particles did not induce lymphocyte proliferation or interfere with lymphocyte proliferation after stimulation. Since SPIONDex rapidly distribute via the blood circulation in vivo, high concentrations were only reached locally at the injection site immediately after application and only for a very limited time. Thus, SPIONDex can be considered immune compatible in doses required for use as an MRI contrast agent.
... However, ethical considerations did not allow us to include healthy volunteers without a medical indication for an iMRI with contrast agent. The decision to avoid unnecessary contrast agent application was based on prior findings of signal intensity increases in the dentate nucleus and globus pallidus on T1-weighted MR images after applying MR contrast agents that are still under investigation [66][67][68]. Third, the study lacks histological confirmation of endolymphatic hydrops since the in-vivo acquisition of histological specimens is currently not possible. ...
Knowledge of the physiological endolymphatic space (ELS) is necessary to estimate endolymphatic hydrops (ELH) in patients with vestibulocochlear syndromes. Therefore, the current study investigated age-dependent changes in the ELS of participants with normal vestibulocochlear testing. Sixty-four ears of 32 participants with normal vestibulocochlear testing aged between 21 and 75 years (45.8 ± 17.2 years, 20 females, 30 right-handed, two left-handed) were examined by intravenous delayed gadolinium-enhanced magnetic resonance imaging of the inner ear ( i MRI). Clinical diagnostics included neuro-otological assessment, video-oculography during caloric stimulation, and head-impulse test. i MRI data analysis provided semi-quantitative visual grading and automatic algorithmic quantitative segmentation of ELS volume (3D, mm ³ ) using a deep learning-based segmentation of the inner ear’s total fluid space (TFS) and volumetric local thresholding, as described earlier. As a result, following a 4-point ordinal scale, a mild ELH (grade 1) was found in 21/64 (32.8%) ears uni- or bilaterally in either cochlear, vestibulum, or both. Age and ELS were found to be positively correlated for the inner ear ( r (64) = 0.33, p < 0.01), and vestibulum ( r (64) = 0.25, p < 0.05). For the cochlea, the values correlated positively without reaching significance ( r (64) = 0.21). In conclusion, age-dependent increases of the ELS should be considered when evaluating potential ELH in single subjects and statistical group comparisons.
... Fourth, the size of the control group (n = 33) was small in comparison to the MD group (n = 105). However, due to findings of signal intensity in the dendate nucleus and globus pallidus on unenhanced T1-weighted MR images (97)(98)(99) that are still under investigation, measurements were restricted to inpatients of the Department of Neurology that underwent MRI with a contrast agent as part of their diagnostic workup and agreed to undergo iMRI sequences after 4 h. ...
Introduction: Verification of endolymphatic hydrops (ELH) via intravenous delayed Gadolinium (Gd) enhanced magnetic resonance imaging of the inner ear (iMRI) is developing into a standard clinical tool to investigate vestibulo-cochlear syndromes [1,2].
Methods: 108 participants, 75 patients with Meniere’s disease (MD; 55.2±14.9 years) and 33 vestibular healthy controls (HC; 46.4±15.6 years) were included to examine how (i) MR acquisition protocols influence the signal within endolymphatic space (ELS), (ii) ELS quantification methods correlate to each other [3,4] and clinical data, and finally, (iii) ELS extent influences MR-signals.
Results: Semi-quantitative (SQ) and 2D- or 3D-quantifications of the ELS were independent of signal intensity (SI) and signal-to-noise ratio (SNR) within 0.1 to 0.2 mmol/kg Gd dosage and 4h±30 min time delay (FWE corrected, p<0.05, Figure 1). Used methods correlated strongly (0.3-0.8) and were highly reproducible across raters, thresholds. 3D-quantifications showed least variability. Asymmetry indices and normalized ELH were most useful for predicting quantitative clinical data. ELH size influenced SI, but not SNR. SI could not predict the presence of ELH.
Conclusion: 1) Gd dosage of 0.1-0.2 mmol/kg after 4h30 min time delay suffices for ELS quantification. 2) A clinical SQ grading classification including a standardized level of evaluation reconstructed to anatomical fixpoints is needed. 3) ELS 3D-quantification methods are best suited for correlations with clinical variables, should include both ears and ELS values reported relative or normalized to size. 4) ELH leads to mild SI increases. However, these signal changes cannot be used to predict the presence of ELH.
References:
[1] Strupp M, Brandt T, Dieterich M. Vertigo - Leitsymptom Schwindel. 3rd ed. Berlin Heidelberg: Springer-Verlag (2021). doi: 10.1007/978-3-662-61397-9.
[2] Pyykkö I, Zou J, Gürkov R, Naganawa S, Nakashima T. “Imaging of Temporal Bone,” in Advances in Oto-Rhino-Laryngology, eds. J. Lea, D. Pothier (S. Karger AG), 12–31. doi:10.1159/000490268.
[2] Nakashima T, Naganawa S, Pyykko I, Gibson WPR, Sone M, Nakata S, Teranishi M. Grading of endolymphatic hydrops using magnetic resonance imaging. Acta Otolaryngol Suppl (2009)5–8. doi:10.1080/00016480902729827.
[3] Gerb J, Ahmadi SA, Kierig E, Ertl-Wagner B, Dieterich M, Kirsch V. VOLT: a novel open-source pipeline for automatic segmentation of endolymphatic space in inner ear MRI. J Neurol (2020) 267:185–196. doi:10.1007/s00415-020-10062-8.
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... High signal intensity in the DN and GP on unenhanced T1-weighted MR images was reported also in patients with impaired renal function by Barbieri et al. [117]. And of note, the authors reported that all three patients object of the study suffered from "transient sign of neurological disorders of undetermined cause'' [117]. ...
... High signal intensity in the DN and GP on unenhanced T1-weighted MR images was reported also in patients with impaired renal function by Barbieri et al. [117]. And of note, the authors reported that all three patients object of the study suffered from "transient sign of neurological disorders of undetermined cause'' [117]. Similar unexplained clinical observations have been reported by Swaminathan [118], who referred to "several patients with normal renal function and significant residual gadolinium who manifest new-onset unexplained extremity pain (neuralgic type) and stiffness without any definite evidence of NSF after exposure to GBCAs''. ...
This article reports known and emerging adverse health effects associated with the administration of gadolinium-based contrast agents. It focuses on the issue of the incomplete excretion of these drugs leading to the deposition of gadolinium in the tissues of the patients. The evidence of deposition is reviewed. The analysis presents gaps in our knowledge but also suggests neglected or still poorly considered parameters to possibly explain discrepancies among studies (e.g. off-label use; rate of administration; gadolinium concentration in the pharmaceutical formulation, cumulative metal toxicity). The article also presents a critical assessment of some aspects reported in the literature as well as future needs. Potential biases in the investigation and evaluation of the health/clinical implications associated with gadolinium deposition are pointed out. The analysis emphasizes that the vast majority of the clinical studies conducted up to date on gadolinium-based contrast agents were designed to assess acute toxicity and diagnostic efficacy of the agents, not to identify long-term health effects.
... Fourth, the size of the control group (n = 33) was small in comparison to the MD group (n = 105). However, due to findings of signal intensity in the dendate nucleus and globus pallidus on unenhanced T1-weighted MR images (97)(98)(99) that are still under investigation, measurements were restricted to inpatients of the Department of Neurology that underwent MRI with a contrast agent as part of their diagnostic workup and agreed to undergo iMRI sequences after 4 h. ...
In-vivo non-invasive verification of endolymphatic hydrops (ELH) by means of intravenous delayed gadolinium (Gd) enhanced magnetic resonance imaging of the inner ear (iMRI) is rapidly developing into a standard clinical tool to investigate peripheral vestibulo-cochlear syndromes. In this context, methodological comparative studies providing standardization and comparability between labs seem even more important, but so far very few are available. One hundred eight participants [75 patients with Meniere's disease (MD; 55.2 ± 14.9 years) and 33 vestibular healthy controls (HC; 46.4 ± 15.6 years)] were examined. The aim was to understand (i) how variations in acquisition protocols influence endolymphatic space (ELS) MR-signals; (ii) how ELS quantification methods correlate to each other or clinical data; and finally, (iii) how ELS extent influences MR-signals. Diagnostics included neuro-otological assessment, video-oculography during caloric stimulation, head-impulse test, audiometry, and iMRI. Data analysis provided semi-quantitative (SQ) visual grading and automatic algorithmic quantitative segmentation of ELS area [2D, mm²] and volume [3D, mm³] using deep learning-based segmentation and volumetric local thresholding. Within the range of 0.1–0.2 mmol/kg Gd dosage and a 4 h ± 30 min time delay, SQ grading and 2D- or 3D-quantifications were independent of signal intensity (SI) and signal-to-noise ratio (SNR; FWE corrected, p < 0.05). The ELS quantification methods used were highly reproducible across raters or thresholds and correlated strongly (0.3–0.8). However, 3D-quantifications showed the least variability. Asymmetry indices and normalized ELH proved the most useful for predicting quantitative clinical data. ELH size influenced SI (cochlear basal turn p < 0.001), but not SNR. SI could not predict the presence of ELH. In conclusion, (1) Gd dosage of 0.1–0.2 mmol/kg after 4 h ± 30 min time delay suffices for ELS quantification. (2) A consensus is needed on a clinical SQ grading classification including a standardized level of evaluation reconstructed to anatomical fixpoints. (3) 3D-quantification methods of the ELS are best suited for correlations with clinical variables and should include both ears and ELS values reported relative or normalized to size. (4) The presence of ELH increases signal intensity in the basal cochlear turn weakly, but cannot predict the presence of ELH.
... Gd 3+ cytotoxicity in neurons is another area of interest, as they contain many ion channels and calcium-dependent receptors that are known Gd 3+ targets. Gd 3+ deposition in the brain has also been reported and its accumulation may lead to debilitating outcomes [160,161]. A study by Huettner et al. examined the antagonistic effects of Gd 3+ on the GluR6 kainate receptor in dorsal root ganglion cells and hippocampal cells [162]. ...
Gadolinium (Gd)-containing chelates have been established as diagnostics tools. However, extensive use in magnetic resonance imaging has led to increased Gd levels in industrialized parts of the world, adding to natural occurrence and causing environmental and health concerns. A vast amount of data shows that metal may accumulate in the human body and its deposition has been detected in organs such as brain and liver. Moreover, the disease nephrogenic systemic fibrosis has been linked to increased Gd3+ levels. Investigation of Gd3+ effects at the cellular and molecular levels mostly revolves around calcium-dependent proteins, since Gd3+ competes with calcium due to their similar size; other reports focus on interaction of Gd3+ with nucleic acids and carbohydrates. However, little is known about Gd3+ effects on membranes; yet some results suggest that Gd3+ interacts strongly with biologically-relevant lipids (e.g., brain membrane constituents) and causes serious structural changes including enhanced membrane rigidity and propensity for lipid fusion and aggregation at much lower concentrations than other ions, both toxic and essential. This review surveys the impact of the anthropogenic use of Gd emphasizing health risks and discussing debilitating effects of Gd3+ on cell membrane organization that may lead to deleterious health consequences.
... It has been observed in patients with previous gadolinium administration a high signal intensity in the dentate nucleus and globus pallidus in the brain, with no association with renal function [78]. However, the association between gadolinium use for diagnostic techniques and these findings remains unclear [79]. Another condition associated with the use of gadolinium was described for the first time in 1997 as a nephrogenic fibrosing dermopathy; later in 2000, on a report about a scleromyxoedema like disease in patients with renal dialysis [80]. ...
Background:
Across the globe, diseases secondary to environmental exposures have been described, and it was also found that existing diseases have been modified by exposure to environmental chemicals or an environmental factor that has been found in their pathogenesis. The Institute of Medicine has shared a permanent concern related to the nations environmental health capacity since 1988.
Main body:
Contemporary imaging methods in the last 15 years started reporting alterations in different human systems such as the central nervous system, cardiovascular system and pulmonary system among others; evidence suggests the existence of a human environmental disease network. The primary anatomic regions, affected by environmental diseases, recently assessed with imaging methods include Brain (lead exposure, cerebral stroke, pesticide neurotoxicity), uses MRI, DTI, carotid ultrasonography and MRS; Lungs (smoke inhalation, organophosphates poisoning) are mainly assessed with radiography; Gastrointestinal system (chronic inflammatory bowel disease), recent studies have reported the use of aortic ultrasound; Heart (myocardial infarction), its link to environmental diseased has been proved with carotid ultrasound; and Arteries (artery hypertension), the impairment of aortic mechanical properties has been revealed with the use of aortic and brachial ultrasound.
Conclusions:
Environmental epidemiology has revealed that several organs and systems in the human body are targets of air pollutants. Current imaging methods that can assess the deleterious effects of pollutants includes a whole spectrum: radiography, US, CT and MRI. Future studies will help to reveal additional links among environmental disease networks.
... The presence of ELH was observed on the 3D-FLAIR images as enlarged negative-signal spaces inside the labyrinth, according to a previously reported method [32,33]. The decision to apply a single-dose contrast agent was made because of the ongoing discussion about gadolinium deposition within the dentate nucleus and globus pallidus after repeated administration of gadolinium-based contrast agents [34][35][36][37]. It was not considered ethical to apply higher doses of contrast agent if not necessary. ...
Background
Objective and volumetric quantification is a necessary step in the assessment and comparison of endolymphatic hydrops (ELH) results. Here, we introduce a novel tool for automatic volumetric segmentation of the endolymphatic space (ELS) for ELH detection in delayed intravenous gadolinium-enhanced magnetic resonance imaging of inner ear (iMRI) data.Methods
The core component is a novel algorithm based on Volumetric Local Thresholding (VOLT). The study included three different data sets: a real-world data set (D1) to develop the novel ELH detection algorithm and two validating data sets, one artificial (D2) and one entirely unseen prospective real-world data set (D3). D1 included 210 inner ears of 105 patients (50 male; mean age 50.4 ± 17.1 years), and D3 included 20 inner ears of 10 patients (5 male; mean age 46.8 ± 14.4 years) with episodic vertigo attacks of different etiology. D1 and D3 did not differ significantly concerning age, gender, the grade of ELH, or data quality. As an artificial data set, D2 provided a known ground truth and consisted of an 8-bit cuboid volume using the same voxel-size and grid as real-world data with different sized cylindrical and cuboid-shaped cutouts (signal) whose grayscale values matched the real-world data set D1 (mean 68.7 ± 7.8; range 48.9–92.8). The evaluation included segmentation accuracy using the Sørensen-Dice overlap coefficient and segmentation precision by comparing the volume of the ELS.ResultsVOLT resulted in a high level of performance and accuracy in comparison with the respective gold standard. In the case of the artificial data set, VOLT outperformed the gold standard in higher noise levels. Data processing steps are fully automated and run without further user input in less than 60 s. ELS volume measured by automatic segmentation correlated significantly with the clinical grading of the ELS (p < 0.01).ConclusionVOLT enables an open-source reproducible, reliable, and automatic volumetric quantification of the inner ears’ fluid space using MR volumetric assessment of endolymphatic hydrops. This tool constitutes an important step towards comparable and systematic big data analyses of the ELS in patients with the frequent syndrome of episodic vertigo attacks. A generic version of our three-dimensional thresholding algorithm has been made available to the scientific community via GitHub as an ImageJ-plugin.
... Gd-CAs are widely used in clinical practice but, in the last years, a focus on their associated risks has pointed out a triggering role in the development of particular nephrogenic system fibrosis (NSF) [11,12]. In fact, it was observed that patients with renal disease, after some MR angiographies, had to undergo dialysis for renal failure. ...
Nowadays, magnetic resonance imaging (MRI) is the first diagnostic imaging modality for numerous indications able to provide anatomical information with high spatial resolution through the use of magnetic fields and gradients. Indeed, thanks to the characteristic relaxation time of each tissue, it is possible to distinguish between healthy and pathological ones. However, the need to have brighter images to increase differences and catch important diagnostic details has led to the use of contrast agents (CAs). Among them, Gadolinium-based CAs (Gd-CAs) are routinely used in clinical MRI practice. During these last years, FDA highlighted many risks related to the use of Gd-CAs such as nephrotoxicity, heavy allergic effects, and, recently, about the deposition within the brain. These alerts opened a debate about the opportunity to formulate Gd-CAs in a different way but also to the use of alternative and safer compounds to be administered, such as manganese- (Mn-) based agents. In this review, the physical principle behind the role of relaxivity and the T1 boosting will be described in terms of characteristic correlation times and inner and outer spheres. Then, the recent advances in the entrapment of Gd-CAs within nanostructures will be analyzed in terms of relaxivity boosting obtained without the chemical modification of CAs as approved in the chemical practice. Finally, a critical evaluation of the use of manganese-based CAs will be illustrated as an alternative ion to Gd due to its excellent properties and endogenous elimination pathway.
... The characteristic of free gadolinium is extremely toxic and can cause central lobular necrosis of the liver, enzyme inhibition, a variety of hematologi-cal abnormalities [3], nephrogenic systemic fibrosis (NSF) [4,5] and many of the voltage calcium channel blocking [3,6,7]. Recently, Kanda, T. et al. and Barbieri, S. et al. found that gadolinium accumulates in the brain especially in dentate nuclei and globus pallidus and makes high signal intensity have an effect on unenhanced T1-weighted MR images after multiple injections of gadolinium [8][9][10]. ...
Background:
Gadolinium (Gd3+) is a chemical element belonging to the lanthanide group and commonly used in magnetic resonance imaging (MRI) as a contrast agent. However, recently, gadolinium has been reported deposition in the body after a patient receives multiple injections. Gadolinium is a potent block and competes with calcium diffusion into the presynaptic. There has not been a precise mechanism of gadolinium blocking calcium channel as a channel of calcium diffusion to presynaptic until now.
Objective:
This study aims to investigate the mechanism of calcium influx model and the effect of neurotransmitter release to the synaptic cleft influenced by the presence of Gd3+.
Material and methods:
Monte Carlo Cell simulation was used to analyze simulation and also Blender was used to create and visualize the model for synapse. The synapse modeled by a form resembling the actual synapse base on a spherical shape.
Results:
The presence of gadolinium around the presynaptic has been disturbing diffusion of calcium influx presynaptic. The result shows that the presence of gadolinium around the presynaptic has caused a decrease in the amount of calcium influx presynaptic. These factors contribute to reducing the establishment of the active membrane, then the amount of synaptic vesicle docking and finally the amount of released neurotransmitter.
Conclusion:
Gadolinium and calcium compete with each other across of calcium channel. The presence of gadolinium has caused a chain effect for signal transmission at the chemical synapse, reducing the amount of active membrane, synaptic vesicle docking, and releasing neurotransmitter.
