Gd Deposition Research Articles

Assessment of gadolinium deposition in the brain tissue of pediatric and adult congenital heart disease patients after contrast enhanced cardiovascular magnetic resonance

BackgroundContrast enhanced magnetic resonance imaging (MRI) is an important tool for the assessment of extracardiac vasculature and myocardial viability. Gadolinium (Gd) brain deposition after contrast enhanced MRI has recently been described and resulted in a warning issued by the United States Food and Drug Administration. However, the prevalence of brain deposition in children and adults with congenital heart disease (CHD) undergoing cardiovascular magnetic resonance (CMR) is unclear. We hypothesized that Gd exposure as part of one or more CMRs would lead to a low rate of brain deposition in pediatric and adult CHD patients.MethodsWe queried our institutional electronic health record for all pediatric and adult CHD patients who underwent contrast enhanced CMR from 2005 to 2018 and had a subsequent brain MRI. Cases were age- and gender-matched to controls who were never exposed to Gd and underwent brain MRIs. The total number of contrast enhanced MRIs, type of Gd, and total Gd dose were determined. Brain MRIs were reviewed by a neuroradiologist for evidence of Gd deposition using qualitative and quantitative assessment. Quantitative assessment was performed using the dentate nucleus to pons signal intensity ratio (dp-SIR) on T1 weighted imaging. Continuous variables were analyzed using Mann–Whitney U and Spearman rank correlation tests. Normal SIR was defined as the 95% CI of the control population dp-SIR.ResultsSixty-two cases and 62 controls were identified. The most contrast enhanced MRIs in a single patient was five and the largest lifetime dose of Gd that any patient received was 0.75 mmol/kg. There was no significant difference in the mean dp-SIR of cases and controls (p = 0.11). The dp-SIR was not correlated with either the lifetime dose of Gd (rs = 0.21, p = 0.11) or the lifetime number of contrast enhanced studies (rs = 0.21, p = 0.11). Two cases and 2 controls had dp-SIRs above the upper bound of the 95% confidence interval for the control group. One case had qualitative imaging-based evidence of Gd deposition in the brain but had a dp-SIR within the normal range.ConclusionIn our cohort of pediatric and adult CHD patients undergoing contrast enhanced CMR, there was a low incidence of qualitative and no significant quantitative imaging-based evidence of Gd brain deposition.

Integration of gadolinium in nanostructure for contrast enhanced-magnetic resonance imaging.

Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics, which is further enhanced with the use of contrast agents (CAs). The most commonly used CAs are gadolinium-based contrast agents (GBCAs), in which gadolinium (Gd) is chelated with organic chelating agents (linear or cyclic). However, the use of GBCA is related to toxic side effect due to the release of free Gd3+ ions from the chelating agents. The repeated use of GBCAs has led to Gd deposition in various major organs including bone, brain, and kidneys. As a result, the use of GBCA has been linked to the development of nephrogenic systemic fibrosis (NSF). Due to the GBCA associated toxicities, some clinically approved GBCAs have been limited or revoked recently. Therefore, there is an urgent need for the development of new strategies to chelate and stabilize Gd3+ ions for contrast enhancement, safety profile, and selective imaging of a pathological site. Toward this endeavor, GBCAs have been engineered using different nanoparticulate systems to improve their stability, biocompatibility, and pharmacokinetics. Throughout this review, some of the important strategies for engineering small molecular Gd3+ chelates into a nanoconstruct is discussed. We focus on the development of GBCAs as liposomes, mesoporous silica nanoparticles (MSNs), polymeric nanocarriers, and plasmonic nanoparticles-based design strategies to improve safety and contrast enhancement for contrast enhanced-magnetic resonance imaging (Ce-MRI). We also discuss the in-vitro/in-vivo properties of strategically designed nanoscale MRI CAs, its potentials, and limitations. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Diagnostic Tools > Diagnostic Nanodevices Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Gadolinium deposition-"gadolinium deposition disease"

Gadolinium (Gd)-based contrast agents have been routinely used worldwide in diagnostic MRI since 1988. All routinely applied contrast agents for clinical use were considered extremely safe with regard to tolerance, adverse effects and diagnostic efficacy and when used at Food and Drug Administration-approved doses. With the identification of Gd-associated disorders, namely nephrogenic systemic fibrosis and adverse reactions, and in the longer term Gd-retention in the brain, this view changed and led to the withdrawal or restriction of approval of linear Gd chelates in Europe. Even though Gd deposition in different human body areas was described very early, recently published literature of intracerebral accumulation of contrast agents as well as deposition in bone have created surprising attention. Not only was the fact of Gd deposition in the body well known for many years, but there is currently no clinical evidence of patient symptoms and no resulting health issues of patients have been observed yet. The expression "gadolinium deposition disease" has been termed by active patient advocacy groups with an online presence with reports of individual members stating abroad spectrum of disorders yielding alarge symptom complex after administration of Gd-based contrast agents without evidence of any pre-existing or otherwise underlying disease process which could explain the mentioned disorder.

Impact of chelation timing on gadolinium deposition in rats after contrast administration

ObjectiveTo determine if gadolinium (Gd) can be rechelated once released from Gd-based contrast agents (GBCAs) and deposited in vivo. Despite extensive research comparing GBCAs and GBCA formulations as well as the ongoing debate about their risks of deposition and the role of Gd release, it remains unknown if retained Gd can be eliminated by administering chelating agents. Materials and methodsRats were injected intravenously with 10 doses of 1 mmol/kg gadodiamide and treated with intravenous Zn-DTPA (30 μmol/kg) concomitantly or 1, 4 or 8 h after GBCA administration (N = 3 rats per group). After euthanization, tissues were harvested three days after the last dose of gadodiamide and tissue Gd concentrations were assessed by ICP-MS. Additionally, a simulation of a single 0.1 mmol/kg gadopentetate dose with 30 μmol/kg DTPA given either concomitantly or within the first 24 h after GBCA was run; simulated tissue Gd concentrations were compared with those observed in rats to determine if simulated trends were accurate. ResultsConcomitant DTPA did not produce a significant reduction in Gd concentration in any organ for rats. There was a time-dependent trend in liver Gd reduction. The 1 h timepoint was associated with a non-significant increase in kidney, brain and femur Gd relative to untreated controls. There were no significant deviations from the model-predicted Gd changes. DiscussionBoth the simulation and rat study did not identify major benefits for chelation at the doses given, despite the simulation assuming all Gd deposited in tissues is unchelated. The potential redistribution in the rat study provide a compelling result that may impact the clinical relevance of further work investigating rechelation of Gd. Future work should further describe the three-dimensional dose-time-response relationship for preventing Gd deposition, and how that relates to long-term Gd toxicities.

Fabrication of gadolinium particle-based absorption gratings for neutron grating interferometry.

The imaging performance of a neutron-based Talbot-Lau interferometer depends to a great extent on the absorption characteristics of the source and analyzer gratings. Due to its high neutron attenuation, gadolinium (Gd) is the preferred material for grating fabrication, but suffers from difficulties with deposition time, stability, uniformity, and selectivity into high aspect ratio structures. Here we present a simple alternative method of Gd deposition into grating structures based on metallic particle suspension casting and subsequent doctor-blading. Surface analysis by confocal and electron scanning microscopy shows that a nearly clear, particle free silicon interface of the grating structure over a large area could be reached. Additionally, characterization by neutron radiography confirms a high effective Gd height and homogeneity over the whole grating area. In particular, grating trenches well below 10 μm width could be successfully filled with Gd and deliver excellent absorbing performance down to the sub-2 Å wavelength range. The findings confirm that we obtained an effective binary absorption profile for the fabricated gratings which is of great benefit for grating-based neutron imaging.

Cu–Ni–Gd coating with improved corrosion resistance on linen fabric by electroless plating for electromagnetic interference shielding

The main objective of this research is to fabricate conductive fabrics with good electromagnetic interference (EMI) shielding effectiveness (SE) and improved corrosion resistance. Such conductive fabrics can be prepared by a cost-effective electroless plating method with combination of eco-friendly dopamine (DoPA) self-polymerization technology, which involves successive steps of alkali treatment, 3-aminopropyltrimethoxysilane modification, Cobalt (Co) nanoparticles activation, Copper–Nickel–Gadolinium (Cu–Ni–Gd) deposition and Dopamine (DoPA) self-assembly. The functional groups introduced in modification and activation procedures are verified by FT-IR and XPS measurements. Refined effects of Gd on the structures and morphologies of resulting Cu–Ni–Gd coatings are illustrated by X-ray diffraction and field emission-scanning electron microscopy (FE-SEM) measurements. EMI SE values of Cu–Ni–Gd shielding fabrics are enhanced with increment of 5–7 decibels (dB) ranging from 30 to 4500 MHz compared with that of Gd-free Cu–Ni shielding fabrics. Furthermore, DoPA membrane polymerized on the top of metallic coatings acting as a barrier for corrosion media is demonstrated by measuring the corrosion resistance of DoPA coated shielding fabrics in 3.5wt.% NaCl solution. Overall, Cu–Ni–Gd shielding fabric with excellent EMI SE and durability endow them great potential in EMI shielding application.

Gadolinium Accumulation in the Deep Cerebellar Nuclei and Globus Pallidus After Exposure to Linear but Not Macrocyclic Gadolinium-Based Contrast Agents in a Retrospective Pig Study With High Similarity to Clinical Conditions.

ObjectiveThe aim of this retrospective study was to determine the gadolinium (Gd) concentration in different brain areas in a pig cohort that received repeated administration of Gd-based contrast agents (GBCAs) at standard doses over several years, comparable with a clinical setting.Material and MethodsBrain tissue was collected from 13 Göttingen mini pigs that had received repeated intravenous injections of gadopentetate dimeglumine (Gd-DTPA; Magnevist) and/or gadobutrol (Gadovist). The animals have been included in several preclinical imaging studies since 2008 and received cumulative Gd doses ranging from 7 to 129 mmol per animal over an extended period. Two animals with no history of administration of GBCA were included as controls. Brain autopsies were performed not earlier than 8 and not later than 38 months after the last GBCA application. Tissues from multiple brain areas including cerebellar and cerebral deep nuclei, cerebellar and cerebral cortex, and pons were analyzed for Gd using inductively coupled plasma mass spectrometry.ResultsOf the 13 animals, 8 received up to 48 injections of gadobutrol and Gd-DTPA and 5 received up to 29 injections of gadobutrol only. In animals that had received both Gd-DTPA and gadobutrol, a median (interquartile range) Gd concentration of 1.0 nmol/g tissue (0.44-1.42) was measured in the cerebellar nuclei and 0.53 nmol/g (0.29-0.62) in the globus pallidus. The Gd concentration in these areas in gadobutrol-only animals was 50-fold lower with median concentrations of 0.02 nmol/g (0.01-0.02) for cerebellar nuclei and 0.01 nmol/g (0.01-0.01) for globus pallidus and was comparable with control animals with no GBCA history. Accordingly, in animals that received both GBCAs, the amount of residual Gd correlated with the administered dose of Gd-DTPA (P ≤ 0.002) but not with the total Gd dose, consisting of Gd-DTPA and gadobutrol. The Gd concentration in cortical tissue and in the pons was very low (≤0.07 nmol/g tissue) in all animals analyzed.ConclusionMultiple exposure to macrocyclic gadobutrol is not associated with Gd deposition in brain tissue of healthy pigs. A single additional administration of linear Gd-DTPA is sufficient for Gd accumulation in the nucleus dentatus and globus pallidus, underlining the importance of obtaining a complete GBCA history in clinical studies.

Gadolinium-based Contrast Media, Cerebrospinal Fluid and the Glymphatic System: Possible Mechanisms for the Deposition of Gadolinium in the Brain.

After Kanda’s first report in 2014 on gadolinium (Gd) deposition in brain tissue, a considerable number of studies have investigated the explanation for the observation. Gd deposition in brain tissue after repeated administration of gadolinium-based contrast medium (GBCM) has been histologically proven, and chelate stability has been shown to affect the deposition. However, the mechanism for this deposition has not been fully elucidated. Recently, a hypothesis was introduced that involves the ‘glymphatic system’, which is a coined word that combines ‘gl’ for glia cell and ‘lymphatic’ system. According to this hypothesis, the perivascular space functions as a conduit for cerebrospinal fluid to flow into the brain parenchyma. The perivascular space around the arteries allows cerebrospinal fluid to enter the interstitial space of the brain tissue through water channels controlled by aquaporin 4. The cerebrospinal fluid entering the interstitial space clears waste proteins from the tissue. It then flows into the perivascular space around the vein and is discharged outside the brain. In addition to the hypothesis regarding the glymphatic system, some reports have described that after GBCM administration, some of the GBCM distributes through systemic blood circulation and remains in other compartments including the cerebrospinal fluid. It is thought that the GBCM distributed into the cerebrospinal fluid cavity via the glymphatic system may remain in brain tissue for a longer duration compared to the GBCM in systemic circulation. Glymphatic system may of course act as a clearance system for GBCM from brain tissue. Based on these findings, the mechanism for Gd deposition in the brain will be discussed in this review. The authors speculate that the glymphatic system may be the major contributory factor to the deposition and clearance of gadolinium in brain tissue.

Coherent normalization for in vivo measurements of gadolinium in bone

Objective: Recent evidence of gadolinium (Gd) deposition in bones of healthy individuals who have previously received Gd-based contrast agents (GBCAs) for MRI has led to a demand for in vivo measurement techniques. The technique of x-ray fluorescence provides a low risk and painless method to assess Gd deposition in bone, and has the potential to be a useful clinical tool. However, interpatient variability creates a challenge while performing in vivo measurements. Approach: We explored the use of coherent normalization, which involves normalizing the Gd K x-rays to the coherent scattered γ-ray from the excitation source, for bone Gd measurements through a series of phantom-based experiments and Monte Carlo simulations. Main results: We found coherent normalization is able to correct for variation in overlying tissue thickness over a wide range (0–12.2 mm). The Gd signal to coherent signal ratio is independent of tissue thickness for both experiments and Monte Carlo simulations. Significance: Coherent normalization has been demonstrated to be used in practice with normal healthy adults to improve in vivo bone Gd measurements.

Up to 52 administrations of macrocyclic ionic MR contrast agent are not associated with intracranial gadolinium deposition: Multifactorial analysis in 385 patients.

PurposeTo determine whether multiple repeated administrations of gadolinium-based macrocyclic ionic MR contrast agent (MICA) are associated with intracranial gadolinium deposition and identify the predisposing factors for deposition in various clinical situations.Materials and methodsIn this institutional review board-approved retrospective study, 385 consecutive patients who underwent MICA-enhanced MR imaging were enrolled. The dentate nucleus-to-pons (DN/P) and globus pallidus-to-thalamus (GP/Th) signal intensity (SI) ratios on unenhanced T1-weighted images were recorded by 2 independent readers and averaged. The mean DN/P and GP/Th SI ratio difference between the last and the first examinations were tested using the one-sample t-test. Student’s t-test and stepwise regression analysis were used to identify the predisposing factors for deposition based on the number of administrations, time interval, hepatic and renal function, magnetic field strength, and chemo- or radiation therapy.ResultsThe mean DN/P SI ratio difference was not different from zero (P = .697), even in patients with ≥20 administrations (n = 33). Only patients with abnormal renal function showed an increase in the mean DN/P SI ratio difference (P = .019). The mean DN/P SI ratio difference was not associated with any predisposing factors. However, the mean GP/Th SI ratio difference showed decrease (P < .001), which was associated with age (P = .007), number of administrations (P = .01) and number of radiation therapy sessions (P = .022) on multivariate analysis.ConclusionMultiple repeated administrations of MICA were not associated with increased T1 signal intensity in deep brain nuclei suggestive of Gd deposition in patients with normal renal function.

Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents

Retrospective 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. Fifty 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. No 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. After 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.

Gadolinium tissue deposition in brain and bone

Until recognition of the association of nephrogenic systemic fibrosis (NSF) and gadolinium based contrast agents (GBCA) in 2006, these agents were considered extremely safe and without major adverse effects. Even after the recognition of NSF, most physicians considered all GBCAs to be safe when used in patients with normal renal function. This belief has been called into question with the discovery by Kanda in 2014 that gadolinium (Gd) is deposited in brain tissue in patients with normal kidney function. Since that initial report, there have been a number of important studies analyzing the effects of various GBCAs in brain using MR T1 signal intensity measurements and postmortem tissue analyses with inductively coupled plasma mass spectrometry. From these our knowledge and understanding of some key issues surrounding these observations has rapidly evolved. This report reviews and summarizes many recent human and animal studies in combination with past studies to better understand Gd tissue deposition not only in brain but also in bone and skin. Brain tissue deposition was initially demonstrated to occur with less stable group 1 linear agents but recent postmortem studies now confirm that Gd deposition also occurs with more stable linear agents as well as with macrocyclic agents although at much lower levels. Although no adverse health effects have been documented to date, even for the group 1 agents that deposit Gd in higher amounts, the implications for possible unrecognized toxicity is discussed. Future studies are being pursued that may provide better understanding of the various chemical forms of Gd that are deposited in tissues. This may help elucidate relative risks of different types of agents, mechanisms involved and even recognition of potential downstream toxic effects.

Gadolinium deposition in the brain: Lessons learned from other metals known to cross the blood–brain barrier

The recent discovery of gadolinium (Gd) deposition in the brains of patients receiving Gd-based contrast agents (GBCAs) raises several important questions including by what mechanism Gd or GBCAs pass through the blood–brain barrier. Decades of research focused on the safety and stability of GBCAs have not identified any mechanism of uptake. Here we review findings of Gd deposition from human and animal data, and how distribution mechanisms elucidated for endogenous and toxic metals may explain entrance of Gd into the central nervous system. Three general uptake mechanisms are considered along with examples of metals known to enter the central nervous system by these routes: (1) carrier-mediated, (2) transporter-mediated and (3) passive. The potential for chelation therapy to reduce deposition is also discussed. The work reported for other metals provides guidance for how the mechanism of Gd deposition in the brain can be determined which is essential information for rational prevention or treatment.

Can gadolinium be re-chelated in vivo? Considerations from decorporation therapy

Gadolinium (Gd) and Gd-based contrast agents (GBCAs) have been observed to deposit in tissues of patients following contrast enhanced MR imaging procedures. A conservative approach for chelation therapy of this toxic metal dictates the assumption that minimal intact GBCAs are present. Currently the extent to which these deposits are primarily de-chelated Gd remains uncertain, prevailing knowledge suggests that for linear agents much of the Gd is de-chelated, while for the macrocyclic agents, the Gd may be still largely chelated. To extract Gd from tissues and facilitate its release, chelation therapy should be both safe and effective. Here we discuss chelation therapy as it relates to Gd deposition. The principles of chelation are reviewed, initially with reference to ligand stability in complex biological fluids. A model of decorporation and how it relates to elimination of Gd deposits is also reviewed. When more is learned about Gd deposition, optimal removal strategies must be developed using basic thermodynamic and kinetic principles.

Total gadolinium tissue deposition and skin structural findings following the administration of structurally different gadolinium chelates in healthy and ovariectomized female rats.

To assess the retention of gadolinium (Gd) in skin, liver, and bone following gadodiamide or gadoteric acid administration. Gd was measured in skin, liver and femur bone in female rats 10 weeks after administration of 17.5 mmol Gd/kg over 5 days of Gd agents. Rat skin microscopy, energy filtering transmission electron microscopy and elemental analysis were performed, and repeated after receiving the same dosage of gadodiamide in rats with osteoporosis induced with bilateral ovariectomy (OVX). The OVX was performed 60 days after the last injection of gadodiamide and animals sacrificed 3 weeks later. Gd concentration was 180-fold higher in the skin, 25-fold higher in the femur, and 30-fold higher in the liver in rats received gadodiamide than rats received gadoteric acid. The retention of Gd in the skin with gadodiamide was associated with an increase in dermal cellularity, and Gd encrustation of collagen fibers and deposition inside the fibroblasts and other cells. No differences in Gd concentration in liver, skin, and femur were observed between rats receiving gadodiamide with or without OVX. Gd tissue retention with gadodiamide was higher than gadoteric acid. Tissues Gd deposition did not alter following gadodiamide administration to ovariectomized rats.

T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats: Difference Between Linear and Macrocyclic Agents.

ObjectivesTo prospectively compare in healthy rats the effect of multiple injections of macrocyclic (gadoterate meglumine) and linear (gadodiamide) gadolinium-based contrast agents (GBCAs) on T1-weighted signal intensity in the deep cerebellar nuclei (DCN), including the dentate nucleus.Materials and MethodsHealthy rats (n = 7/group) received 20 intravenous injections of 0.6 mmol of gadolinium (Gd) per kilogram (4 injections per week during 5 weeks) of gadodiamide, gadoterate meglumine, or hyperosmolar saline (control group). Brain T1-weighted magnetic resonance imaging was performed before and once a week during the 5 weeks of injections and during 5 additional weeks (treatment-free period). Gadolinium concentrations were measured with inductively coupled plasma mass spectrometry in plasma and brain. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data.ResultsA significant and persistent T1 signal hyperintensity in DCN was observed only in gadodiamide-treated rats. The DCN-to-cerebellar cortex signal ratio was significantly increased from the 12th injection of gadodiamide (1.070 ± 0.024) compared to the gadoterate meglumine group (1.000 ± 0.033; P < 0.001) and control group (1.019 ± 0.022; P < 0.001) and did not significantly decrease during the treatment-free period. Total Gd concentrations in the gadodiamide group were significantly higher in the cerebellum (3.66 ± 0.91 nmol/g) compared with the gadoterate meglumine (0.26 ± 0.12 nmol/g; P < 0.05) and control (0.06 ± 0.10 nmol/g; P < 0.05) groups.ConclusionsRepeated administrations of the linear GBCA gadodiamide to healthy rats are associated with progressive and persistent T1 signal hyperintensity in the DCN, with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

Fabrication and characterization of the source grating for visibility improvement of neutron phase imaging with gratings

The fabrication of gratings including metal deposition processes for highly neutron absorbing lines is a critical issue to achieve a good visibility of the grating-based phase imaging system. The source grating for a neutron Talbot-Lau interferometer is an array of Gadolinium (Gd) structures that are generally made by sputtering, photo-lithography, and chemical wet etching. However, it is very challenging to fabricate a Gd structure with sufficient neutron attenuation of approximately more than 20 μm using a conventional metal deposition method because of the slow Gd deposition rate, film stress, high material cost, and so on. In this article, we fabricated the source gratings for neutron Talbot-Lau interferometers by filling the silicon structure with Gadox particles. The new fabrication method allowed us a very stable and efficient way to achieve a much higher Gadox filled structure than a Gd film structure, and is even more suitable for thermal polychromatic neutrons, which are more difficult to stop than cold neutrons. The newly fabricated source gratings were tested at the polychromatic thermal neutron grating interferometer system of HANARO at the Korea Atomic Energy Research Institute, and the visibilities and images from the neutron phase imaging system with the new source gratings were compared with those fabricated by a Gd deposition method.

Tissue gadolinium deposition in renally impaired rats exposed to different gadolinium-based MRI contrast agents: Evaluation with inductively coupled plasma mass spectrometry (ICP-MS)

ObjectivesTo quantify tissue gadolinium (Gd) deposition in renally impaired rats exposed to Gd-EOB-DTPA and other Gd-based MRI contrast agents by means of inductively coupled plasma mass spectrometry (ICP-MS), and to compare the differences in distribution among major organs as possible triggers for nephrogenic systemic fibrosis (NSF). MethodsA total of 15 renally impaired rats were injected with Gd-EOB-DTPA, Gd-DTPA-BMA and Gd-HP-DO3A. Gd contents of skin, liver, kidney, lung, heart, spleen, diaphragm and femoral muscle were measured by inductively coupled plasma mass spectrometry (ICP-MS). Histological assessment was also conducted. ResultsTissue Gd deposition in all organs was significantly higher (P=0.005~0.009) in the Gd-DTPA-BMA group than in the Gd-HP-DO3A and Gd-EOB-DTPA groups. In the Gd-DTPA-BMA group, Gd was predominantly deposited in kidney (1306±605.7μg/g), followed by skin, liver, lung, spleen, femoral muscle, diaphragm and heart. Comparing Gd-HP-DO3A and Gd-EOB-DTPA groups, Gd depositions in the kidney, liver and lung were significantly lower (P=0.009~0.011) in the Gd-EOB-DTPA group than in the Gd-HP-DO3A group although no significant differences were seen for any other organs. ConclusionsGd-EOB-DTPA is a stable and safe Gd-based contrast agent (GBCA) showing lower Gd deposition in major organs in renally impaired rats, compared with other GBCAs. This fact suggests that the risk of NSF onset would be low in the use of Gd-EOB-DTPA.

Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis--an autopsy-based review

Nephrogenic systemic fibrosis (NSF) is a systemic disorder of patients with severe renal insufficiency who have received gadolinium (Gd)-based magnetic resonance contrast agents (GBCAs). The causative association with Gd exposure was strengthened by the demonstration of Gd in various tissues of NSF patients, predominantly at the bulk chemical level. The distribution of Gd at the histologic level of organs other than skin has not been reported previously. We analysed tissues from an autopsy case with verified advanced NSF by light microscopy and scanning electron microscopy/energy-dispersive X-ray spectroscopy. Furthermore, we reviewed published literature to compare the histological and histochemical findings in NSF patients and chronic renal failure (CRF) patients without NSF. Insoluble Gd-phosphate deposits were detected in the skin, liver, lungs, intestinal wall (ileum), kidney, lymph node, skeletal muscle, dura mater and cerebellum of the NSF autopsy case, primarily in vascular walls. Some, but not all, Gd deposits were seen in fibrotic areas. Literature review highlighted that non-specific tissue fibrosis and calcification are frequent findings in tissues of patients with CRF with and without NSF. Vascular and extracellular Gd deposits are found in multiple organs of NSF patients, associated with calcification, and often in fibrotic areas. Gd deposits are not seen in patients with CRF unexposed to GBCAs but rarely may be seen in GBCA-exposed patients without clinical signs of NSF. Apart from diagnostic findings in skin, fibrosis of muscle and dura may be more prominent in NSF patients. Our findings should stimulate further investigation of mechanisms of fibrosis and pathologic calcification.

Quantification of gadolinium in fresh skin and serum samples from patients with nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) is a rare, potentially fatal fibrosing disorder associated with renal insufficiency and gadolinium (Gd)-based contrast exposure. The cause remains unknown. To date, all efforts to investigate skin Gd concentrations in patients with NSF have been performed on paraffin-embedded samples, and Gd deposition has not been correlated with disease activity by a statistically significant analysis. We sought to: (1) quantify Gd concentration in fresh tissue skin biopsy specimens; (2) quantify and compare synchronous Gd concentration of affected skin and unaffected skin in patients with NSF (n = 13) with a control group (n = 13); and (3) quantify serum Gd. We used inductively coupled plasma mass spectrometry. In patients with NSF, the mean ratio of paired Gd concentrations of affected skin to unaffected skin was 23.1, ranging from 1.2 to 88.9. Mean serum Gd concentrations in patients with NSF were 4.8 ng/mL, which is more than 10 times the level in control patients. A statistically significant correlation existed between serum and affected skin Gd concentrations (r(2) = .74, P < .0001). Because of the feasibility of this study, the main limitation was the small sample size (n = 13 affected and 13 control). Determination of Gd concentrations in fresh skin samples and serum using inductively coupled plasma mass spectrometry demonstrates significant differences in the amounts of Gd in involved versus nonlesional skin of patients with NSF. This supports the role of differential free Gd deposition from Gd-based contrast in the pathogenesis of NSF.