Gadolinium contrast agents: dermal deposits and potential effects on epidermal small nerve fibers.

Small fiber neuropathy (SFN) affects unmyelinated and thinly myelinated nerve fibers causing neuropathic pain with distal distribution and autonomic symptoms. In idiopathic SFN (iSFN), 30% of the cases, the underlying aetiology remains unknown. Gadolinium (Gd)-based contrast agents (GBCA) are widely used in magnetic resonance imaging (MRI). However, side-effects including musculoskeletal disorders and burning skin sensations were reported. We investigated if dermal Gd deposits are more prevalent in iSFN patients exposed to GBCAs, and if dermal nerve fiber density and clinical parameters are likewise affected. 28 patients (19 females) with confirmed or no GBCA exposure were recruited in three German neuromuscular centers. ISFN was confirmed by clinical, neurophysiological, laboratory and genetic investigations. Six volunteers (two females) served as controls. Distal leg skin biopsies were obtained according to European recommendations. In these samples Gd was quantified by elemental bioimaging and intraepidermal nerve fibers (IENF) density via immunofluorescence analysis. Pain phenotyping was performed in all patients, quantitative sensory testing (QST) only in a subset (15 patients; 54%). All patients reported neuropathic pain, described as burning (n = 17), jabbing (n = 16) and hot (n = 11) and five QST scores were significantly altered. Compared to an equal distribution significantly more patients reported GBCA exposures (82%), while 18% confirmed no exposures. Compared to unexposed patients/controls significantly increased Gd deposits and lower z-scores of the IENF density were confirmed in exposed patients. QST scores and pain characteristics were not affected. This study suggests that GBCA exposure might alter IENF density in iSFN patients. Our results pave the road for further studies investigating the possible role of GBCA in small fiber damage, but more investigations and larger samples are needed to draw firm conclusions.

Elemental bioimaging and transcriptomics reveal unchanged gene expression in mouse cerebellum following a single injection of Gadolinium-based contrast agents.

Gadolinium (Gd) deposition in the brain, first and foremost in the dentate nucleus in the cerebellum, following contrast enhanced MRI, rose awareness of potential adverse effects of gadolinium-based contrast agent (GBCA) administration. According to previous in vitro experiments, a conceivable side-effect of Gd deposition could be an alteration of gene expression. In the current study, we aimed to investigate the influence of GBCA administration on gene expression in the cerebellum of mice using a combination of elemental bioimaging and transcriptomics. In this prospective animal study, three groups of eight mice each were intravenously injected with either linear GBCA gadodiamide, macrocyclic GBCA gadoterate (1 mmol GBCA/kg body weight) or saline (NaCl 0.9%). Animals were euthanized four weeks after injection. Subsequently, Gd quantification via laser ablation-ICP-MS and whole genome gene expression analysis of the cerebellum were performed. Four weeks after single application of GBCAs to 24-31 days old female mice, traces of Gd were detectable in the cerebellum for both, the linear and macrocyclic group. Subsequent transcriptome analysis by RNA sequencing using principal component analysis did not reveal treatment-related clustering. Also differential expression analysis did not reveal any significantly differentially expressed genes between treatments.

A model to visualize the fate of iron after intracranial hemorrhage using isotopic tracers and elemental bioimaging.

Hemoglobin-iron is a red blood cell toxin contributing to secondary brain injury after intracranial bleeding. We present a model to visualize an intracerebral hematoma and secondary hemoglobin-iron distribution by detecting 58Fe-labeled hemoglobin (Hb) with laser ablation-inductively coupled plasma-mass spectrometry on mouse brain cryosections after stereotactic whole blood injection for different time periods. The generation of 58Fe-enriched blood and decisive steps in the acute hemorrhage formation and evolution were evaluated. The model allows visualization and quantification of 58Fe with high spatial resolution and striking signal-to-noise ratio. Script-based evaluation of the delocalization depth revealed ongoing 58Fe delocalization in the brain even 6 days after hematoma induction. Collectively, the model can quantify the distribution of Hb-derived iron post-bleeding, providing a methodological framework to study the pathophysiological basis of cell-free Hb toxicity in hemorrhagic stroke.

Gadolinium retention in the tunica media of arterial walls-a complementary study using elemental bioimaging and immunogold staining.

Gadolinium (Gd) deposition has been found in both animal and human tissues after injections of Gd-based contrast agents (GBCAs). Without the knowledge of which tissues are most affected, it is difficult to determine whether Gd accumulation could lead to any pathological changes. The current study aims at investigating histological sections of three patients who were exposed to GBCAs during their lifetime, and identify areas of Gd accumulation. Tissue sections of three autopsy cases were investigated by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to assess the distribution of Gd, and the deposition within tissue sections was quantified. Additional application of laser ablation-inductively coupled plasma-optical emission spectroscopy (LA-ICP-OES) enabled a sensitive detection of calcium (Ca) in the vessel walls, which is usually impeded in LA-ICP-MS due to the isobaric interference with argon. Complementary LA-ICP-MS and LA-ICP-OES analysis revealed that Gd was co-localized with zinc and Ca, in the area where smooth muscle actin was present. Notably, high levels of Gd were found in the tunica media of arterial walls, which requires further research into potential Gd-related toxicity in this specific location.

Combined speciation analysis and elemental bioimaging provide new insight into gadolinium retention in kidney.

This study uses a leaching approach in combination with elemental bioimaging and speciation analysis to obtain insight into the gadolinium species present in the kidney of rats that were treated with either a linear or a macrocyclic gadolinium-based contrast agent. Fresh frozen thin sections of the harvested kidneys were immersed halfway into water to wash out hydrophilic species and subsequently analyzed by laser ablation-inductively coupled plasma-mass spectrometry. The water-extracted gadolinium species were analyzed by means of hydrophilic interaction liquid chromatography-inductively coupled plasma-mass spectrometry. Information on the water-soluble species could not only be obtained from the full kidney, but also be traced back to its localization in the tissue. On longitudinal kidney sections treated with gadobutrol, it was found that water-insoluble, permanent Gd depositions were mainly located in the renal cortex, while water-soluble species were found in the medulla, which contains the intact contrast agent up to 1 year after injection. Moreover, kidney samples from gadodiamide-treated rats showed more water-insoluble Gd deposition in both the cortex and medulla, while the concentration of intact contrast agent in the water-soluble fraction was below the limit of detection after 12 months. In conclusion, this rapid approach allowed the spatially resolved differentiation between water-soluble and insoluble gadolinium deposition and is therefore capable of generating new insight into the retention and transportation behavior of gadolinium.

Gadolinium Tissue Distribution in a Large-Animal Model after a Single Dose of Gadolinium-based Contrast Agents.

Background There is an ongoing scientific debate about the degree and clinical importance of gadolinium deposition in the brain and other organs after administration of gadolinium-based contrast agents (GBCAs). While most published data focus on gadolinium deposition in the brain, other organs are rarely investigated. Purpose To compare gadolinium tissue concentrations in various organs 10 weeks after one injection (comparable to a clinically applied dose) of linear and macrocyclic GBCAs in a large-animal model. Materials and Methods In this prospective animal study conducted from March to May 2018, 36 female Swiss-Alpine sheep (age range, 4-10 years) received one injection (0.1 mmol/kg) of macrocyclic GBCAs (gadobutrol, gadoteridol, and gadoterate meglumine), linear GBCAs (gadodiamide and gadobenate dimeglumine), or saline. Ten weeks after injection, sheep were sacrificed and tissues were harvested. Gadolinium concentrations were quantified with inductively coupled plasma mass spectrometry (ICP-MS). Histologic staining was performed. Data were analyzed with nonparametric tests. Results At 10 weeks after injection, linear GBCAs resulted in highest mean gadolinium concentrations in the kidney (502 ng/g [95% CI: 270, 734]) and liver (445 ng/g [95% CI: 202, 687]), while low concentrations were found in the deep cerebellar nuclei (DCN) (30 ng/g [95% CI: 20, 41]). Tissue concentrations of linear GBCAs were three to 21 times higher compared with those of macrocyclic GBCAs. Administered macrocyclic GBCAs resulted in mean gadolinium concentrations of 86 ng/g (95% CI: 31, 141) (P = .08) in the kidney, 21 ng/g (95% CI: 4, 39) (P = .15) in liver tissue, and 10 ng/g (95% CI: 9, 12) (P > .99) in the DCN, which were not significantly elevated when compared with concentrations in control animals. No histopathologic alterations were observed irrespective of tissue concentrations within any examined organ. Conclusion Ten weeks after one injection of a clinically relevant dose of gadolinium-based contrast agents, the liver and kidney appeared to be reservoirs of gadolinium; however, despite gadolinium presence, no tissue injury was detected. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Clément in this issue.

Deposition patterns of iatrogenic lanthanum and gadolinium in the human body depend on delivered chemical binding forms.

BACKGROUND: Recently, gadolinium from linear GBCAs has been reported to deposit in various regions of the body. Besides gadolinium, other lanthanides are used in medical care. In the current study, we investigated deposition of lanthanum in two patients who received lanthanum carbonate as a phosphate binder due to chronic kidney injury and compared it to additionally found Gd deposition. METHODS: Tissue specimens of two patients with long-term application of lanthanum carbonate as well as possible GBCA application were investigated. Spatial distribution of gadolinium and lanthanum was determined by quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging of tissue sections. The deposition of gadolinium and lanthanum in different organs was compared, and the ratio of Gd concentration to La concentration (Gd-to-La-ratio) was investigated on an individual pixel base within the images. RESULTS: Deposition of Gd and La was found in all investigated tissues of both patients. Gd and La exhibited high spatial correlation for all samples, with the main deposition being located in the middle coat (tunica media) of blood vessels. The Gd-to-La-ratio was similar in the tissues investigated (between 8 ±â€¯4 (mean ±â€¯standard deviation) and 10 ±â€¯2), except for the thyroid vasculature and surrounding tissue (90 ±â€¯17) as well as the cerebellum (270 ±â€¯18). Here, the ratio was significantly increased towards higher Gd concentration. CONCLUSION: The results of this study demonstrate long-term deposition of La and comparable localization of additionally found Gd in various tissues of the body. La deposition was relatively low, considering the total administered amount of lanthanum carbonate of up to 11.5 kg, indicating a low absorption and/or high excretion of lanthanum. However, the total amount of deposited La is significant and raises questions about possible adverse side effects. The ratio-approach allows for the usage of the additionally generated Gd data, without detailed knowledge about possible GBCA applications. The significantly decreased Gd-to-La-ratio in the brain might be explained by the lanthanum being released and taken up as free La3+ ion in the stomach that impedes a crossing of the blood-brain-barrier while the intravenously injected GBCAs might dechelate first when they have already crossed the blood-brain-barrier.

Is Small Fiber Neuropathy Induced by Gadolinium-Based Contrast Agents?

OBJECTIVES: In recent years, complaints of patients about burning pain in arms and legs after the injection of gadolinium-based contrast agents (GBCAs) have been reported. In the current study, we investigated changes of small fibers in the epidermis as a potential cause of the patient complaints in a mouse model. METHODS: Six groups of 8 mice were intravenously injected with either a macrocyclic GBCA (gadoteridol, gadoterate meglumine, gadobutrol), a linear GBCA (gadodiamide or gadobenate dimeglumine) (1 mmol/kg body weight), or saline (NaCl 0.9%). Four weeks after injection, animals were euthanized, and footpads were assessed using immunofluorescence staining. Intraepidermal nerve fiber density (IENFD) was calculated, and the median number of terminal axonal swellings (TASs) per IENFD was determined. RESULTS: Nonparametric Wilcoxon signed-rank test revealed significantly lower IENFDs for all GBCAs compared with the control group (P < 0.0001) with the linear GBCAs showing significantly lower IENFDs than the macrocyclic GBCAs (P < 0.0001). The linear GBCAs presented significantly more TAS per IENFD than the control group (P < 0.0001), whereas no significant increase of TAS per IENFD compared with the control group was found for macrocyclic GBCAs (P < 0.237). INTERPRETATION: It is unclear whether or at what dosage the decrease of IENFDs and the increase of TAS per IENFD found in the current animal model will appear in humans and if it translates into clinical symptoms. However, given the highly significant findings of the current study, more research in this field is required.

Gadolinium deposition in the brain of dogs after multiple intravenous administrations of linear gadolinium based contrast agents.

OBJECTIVE: To determine the effect of a linear gadolinium-based contrast agent (GBCA) on the signal intensity (SI) of the deep cerebellar nuclei (DCN) in a retrospective clinical study on dogs after multiple magnetic resonance (MR) examinations with intravenous injections of gadodiamide and LA-ICP-MS analysis of a canine cerebellum after gadodiamide administration. ANIMALS: 15 client-owned dogs of different breeds and additionally 1 research beagle dog cadaver. PROCEDURES: In the retrospective study part, 15 dogs who underwent multiple consecutive MR imaging examinations with intravenous injection of linear GBCA gadodiamide were analyzed. SI ratio differences on unenhanced T1-weighted MR images before and after gadodiamide injections was calculated by subtracting SI ratios between DCN and pons of the first examination from the ratio of the last examination. Additionally, 1 research beagle dog cadaver was used for LA-ICP-MS (Laser ablation inductively coupled plasma mass spectrometry) analysis of gadolinium in the cerebellum as an add-on to another animal study. Descriptive and non-parametrical statistical analysis was performed and a p-value of < 0.05 was considered significant. RESULTS: No statistically significant differences of SI ratios, between DCN and pons, were detectable based on unenhanced T1-weighted MR images. LA-ICP-MS analyses showed between 1.5 to 2.5 µg gadolinium/g tissue in the cerebellum of the examined dog, 35 months after the last of 3 MRI examination with gadodiamide (two examinations at a dose of 1 x 0.1mmol/kg, last examination at a dose of 3 x 0.05mmol/kg). CONCLUSION AND CLINICAL RELEVANCE: Although the retrospective MRI study did not indicate any visible effect of SI increase after multiple gadodiamide exposures, further studies based on LA-ICP-MS showed that the optical threshold was not reached for a potential visible effect. Gadolinium was detectable at a level of 1.5 to 2.5 µg gadolinium/g tissue by using LA-ICP-MS in the cerebellum 35 months after last MRI examination. The general importance of gadolinium retention of subvisible contents requires further investigation.

Tracing the natural and anthropogenic influence on the trace elemental chemistry of estuarine macroalgae and the implications for human consumption.

Macroalgae (seaweed) has been shown to be an effective environmental indicator. We investigate the trace element chemistry of macroalgae samples from locations along the Firth of Forth and Forth Estuary in Scotland. The overall trend in elemental abundance (Os ≪ Re < Ag < U < Cd < Co < Ni < Pb < Cu < As < Zn ≪ I), and changes along the estuary (seawards: increase As, I, Cd, U, Re, Os; decrease Pb, Cu; mid-estuary peak Zn; based on certain species), are controlled by a number of factors, including: salinity, mixing and macroalgal species differences. Within the same macroalgal species, some elemental abundances (As, I, Pb, Cu, Cd and U) are affected by mixing between freshwater riverine and North Sea marine saltwater. Additional mixing of natural and anthropogenic inputs from the surrounding geology and industry are also observed, affecting Zn, Ni, Co, Re and Os. Macroalgae is also an increasingly popular food, with some species harvested in the Firth of Forth. Iodine (67-5061 ppm), lead (0.047-4.1 ppm) and cadmium (0.006-0.93 ppm) macroalgal abundances are at safe levels for human consumption (WHO limits). However, many samples exceed the American (3 ppm) and Australian (1 ppm) limits for inorganic arsenic in macroalgae, with values ranging 0-67 ppm. In most of the samples, soaking and cooking the macroalgae reduced the inorganic arsenic content to within the American and Australian limits. However, this has further implications if the macroalgae is used to cook soups (e.g., Dashi), as the leached elements become a significant component of the soup.

Validation and inter-laboratory study of selective hydride generation for fast screening of inorganic arsenic in seafood.

It is advisable to monitor and regulate inorganic arsenic (iAs) in food and feedstuff. This work describes an update and validation of a method of selective hydride generation (HG) with inductively coupled plasma mass spectrometry (ICP-MS) for high-throughput screening of iAs content in seafood samples after microwave-assisted extraction with diluted nitric acid and hydrogen peroxide. High concentration of HCl (8 M) for HG along with hydrogen peroxide in samples of a same concentration as used for extraction leads to a selective conversion of iAs to volatile arsine that is released and transported to the detector. A minor contribution from methylarsonate (≈20% to iAs) was found, while HG from dimethylarsinate, trimethylarsine oxide is substantially suppressed (less than 1% to iAs). Methodology was applied to Certified Reference Materials (CRMs) TORT-3, DORM-3, DORM-4, DOLT-4, DOLT-5, PRON-1, SQID-1 and ERM-CE278k, in some of them iAs has been determined for the first time, and to various seaweed samples from a local store. The results were always compared with a reference method and selectivity of iAs determination was evaluated. An inter-laboratory reproducibility was tested by comparative analyses of six fish and four seaweed samples in three European laboratories, with good agreement of the results. The method of HG-ICP-MS is sensitive (limit of detection 2 µg kg-1 iAs), well suited for screening of large number of samples and selective at iAs concentration levels at which maximum limits are expected to be set into EU legislation for marine samples.