Elemental Imaging of Long-term Gadolinium Retention in Rodent Femur.

Background The use of gadolinium-based contrast agents (GBCAs) is linked to gadolinium retention in the skeleton of healthy individuals. The mechanism of gadolinium incorporation into bone tissue is not fully understood and requires spatially resolved analysis to locate the gadolinium. Purpose To compare the quantitative distribution of gadolinium retained over time in rodent femur following the administration of gadodiamide and gadobutrol at three different time points. Materials and Methods In this animal study conducted between May 2018 and April 2020, 108 9-week-old healthy rats were repeatedly injected with either gadodiamide, gadobutrol, or saline solution and were killed 1, 3, or 12 months after the last injection. The femurs of six female and six male rats per each group and time point were collected. Quantitative elemental imaging of gadolinium in longitudinal thin sections was performed on one sample per sex with use of laser ablation inductively coupled plasma mass spectrometry (ICP-MS). Gadolinium concentration was determined with use of ICP-MS on the samples of all animals (six per group). Mann-Whitney U tests were applied on pairwise comparisons to determine potential sex effect and GBCA effect on gadolinium concentrations. Results The highest gadolinium retention was observed in the gadodiamide group (concentration, 97-200 nmol · g-1), exceeding the mean concentration in the gadobutrol group (6.5-17 nmol · g-1). However, the gadolinium distribution pattern was similar for both contrast agents, showing prominent gadolinium retention at endosteal surfaces, in the bone marrow, and in small tissue pores. Gadolinium distribution in cortical bone changed over time, initially showing a thin rim of higher concentration close to the periosteum, which appeared to grow wider and move toward the interior of the femur over 1 year. Conclusion For both gadolinium-based contrast agents, gadolinium retention in rat bone was initially located close to the periosteum and bone cavities and changed with bone remodeling processes. The relevance to long-term storage of gadolinium in humans remains to be determined. © RSNA, 2022 Online supplemental material is available for this article.

Long-term Gadolinium Retention in the Healthy Rat Brain: Comparison between Gadopiclenol, Gadobutrol, and Gadodiamide.

Background Safety concerns caused by gadolinium retention call for the development of high-relaxivity gadolinium-based contrast agents (GBCAs) allowing minimal dosing. Purpose To investigate brain gadolinium retention in healthy rats after exposure to gadopiclenol (Elucirem, Guerbet; macrocyclic GBCA) compared with gadobutrol (Gadovist or Gadavist, Bayer; macrocyclic GBCA) and gadodiamide (Omniscan, GE Healthcare; linear GBCA) over 1 year. Materials and Methods In this study conducted between May 2018 and April 2020, 9-week-old healthy Sprague Dawley rats received five injections of either gadopiclenol, gadobutrol, or gadodiamide (2.4 mmol of gadolinium per kilogram of body weight for each), or saline (control animals) over a period of 5 weeks. Rats were randomly assigned to different groups (six female and six male rats per group). MRI examinations were performed before euthanasia at 1, 3, 5, or 12 months after the last injection. Brains were sampled to determine the total gadolinium content via inductively coupled plasma mass spectrometry (ICP-MS), to characterize gadolinium species with size exclusion chromatography (SEC)-ICP-MS, and to perform elemental mapping with laser ablation (LA)-ICP-MS. Mann-Whitney tests were performed on pairwise comparisons of the same time points. Results For both macrocyclic agents, no T1 signal hyperintensities were observed in the cerebellum, and approximately 80% of gadolinium washout was found between 1 month (gadobutrol, 0.30 nmol/g; gadopiclenol, 0.37 nmol/g) and 12 months (gadobutrol, 0.062 nmol/g; gadopiclenol, 0.078 nmol/g). After 12 months, only low-molecular-weight gadolinium species were detected in the soluble fraction. Gadodiamide led to significantly higher gadolinium concentrations after 1 month in the cerebellum (gadodiamide, 2.65 nmol/g; P < .001 vs both macrocyclics) combined with only 15% washout after 12 months (gadodiamide, 2.25 nmol/g) and with gadolinium detected bound to macromolecules. Elemental bioimaging enabled visualization of gadolinium deposition patterns colocalized with iron. Conclusion Gadopiclenol and gadobutrol demonstrated similar in vivo distribution and washout of gadolinium in the healthy rat brain, markedly differing from gadodiamide up to 12 months after the last injection. © RSNA, 2022 Online supplemental material is available for this article.

Mild Dissolution/Recomplexation Strategy for Speciation Analysis of Gadolinium from MR Contrast Agents in Bone Tissues by Means of HPLC-ICP-MS.

A species-dependent and total gadolinium quantification strategy for the analysis of bone and bone marrow samples was developed and applied to femurs of rats previously treated with different gadolinium-based contrast agents (GBCAs). A combined mild dissolution/recomplexation strategy allows the quantification of total Gd as well as the quantification of intact GBCA in bones within one analysis for the first time. Samples of rat bones and bone marrow were dissolved in low concentrations of hydrochloric acid and diethylenetriamine pentaacetate (DTPA). This is followed by the addition of excess In(III) to recomplex all free ligands, previously added DTPA as well as the ligands of GBCAs that were not stable during the dissolution step. Separation and quantification were carried out by means of high-performance liquid chromatography (HPLC) on a hydrophilic interaction liquid chromatography (HILIC) column with subsequent inductively coupled plasma-mass spectrometry (ICP-MS). The results show that the investigated GBCA with a macrocyclic ligand shows a higher tendency to stay intact in the bone tissues over time, while a GBCA with a linear ligand is decomplexed more rapidly four weeks after GBCA administration. Additionally, for all macrocyclic GBCAs, a similar limited gadolinium accumulation was observed in the bone and bone marrow. Whereas linear GBCAs showed a higher gadolinium accumulation, a difference was observed between bone and bone marrow, indicating a different biodistribution behavior.

Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review.

The unexpected appearance of T1 hyperintensities, mostly in the dentate nucleus and the globus pallidus, during nonenhanced MRI was reported in 2014. This effect is associated with prior repeated administrations of gadolinium (Gd)-based contrast agents (GBCAs) in patients with a functional blood-brain barrier (BBB). It is widely assumed that GBCAs do not cross the intact BBB, but the observation of these hypersignals raises questions regarding this assumption. This review critically discusses the mechanisms of Gd accumulation in the brain with regard to access pathways, Gd species, tissue distribution, and subcellular location. We propose the hypothesis that there is early access of Gd species to cerebrospinal fluid, followed by passive diffusion into the brain parenchyma close to the cerebral ventricles. When accessing areas rich in endogenous metals or phosphorus, the less kinetically stable GBCAs would dissociate, and Gd would bind to endogenous macromolecules, and/or precipitate within the brain tissue. It is also proposed that Gd species enter the brain parenchyma along penetrating cortical arteries in periarterial pial-glial basement membranes and leave the brain along intramural peri-arterial drainage (IPAD) pathways. Lastly, Gd/GBCAs may access the brain parenchyma directly from the blood through the BBB in the walls of capillaries. It is crucial to distinguish between the physiological distribution and drainage pathways for GBCAs and the possible dissociation of less thermodynamically/kinetically stable GBCAs that lead to long-term Gd deposition in the brain. LEVEL OF EVIDENCE: 5. TECHNICAL EFFICACY STAGE: 3.

One-year Retention of Gadolinium in the Brain: Comparison of Gadodiamide and Gadoterate Meglumine in a Rodent Model.

Purpose To compare the long-term brain elimination kinetics and gadolinium species in healthy rats after repeated injections of the contrast agents gadodiamide (a linear contrast agent) or gadoterate (a macrocyclic contrast agent). Materials and Methods Nine-week-old rats received five doses of 2.4 mmol gadolinium per kilogram of body weight over 5 weeks and were followed for 12 months with T1-weighted MRI (n = 140 rats, corresponding to seven time points, two contrast agents, and 10 rats per group). Animals were sacrificed at 1 week, 1 month, and 2, 3, 4, 5, and 12 months after the last injection. Brain and plasma were sampled to determine the total gadolinium concentration by using inductively coupled plasma mass spectrometry (ICP-MS). For the cerebellum, gadolinium speciation analysis was performed after mild extraction at four time points (1 month and 3, 5, and 12 months after the last injection) by using size exclusion chromatography and hydrophilic interaction liquid chromatography, both coupled to ICP-MS. Tissue gadolinium kinetics were fitted to estimate the area under the curves and tissue elimination half-lives over the 12-month injection-free period. Results T1 hyperintensity of the deep cerebellar nuclei was observed only in gadodiamide-treated rats and remained stable from the 1st month after the last injection (the ratio of the signal intensity of the deep cerebellar nuclei to the signal intensity of the brain stem at 1 year: 1.101 ± 0.023 vs 1.037 ± 0.022 before injection, P < .001). Seventy-five percent of the total gadolinium detected after the last injection of gadodiamide (3.25 nmol/g ± 0.30) was retained in the cerebellum at 1 year (2.45 nmol/g ± 0.35), with binding of soluble gadolinium to macromolecules. No T1 hyperintensity was observed with gadoterate, consistent with a rapid, time-dependent washout of the intact gadolinium chelate down to background levels (0.07 nmol/g ± 0.03). Conclusion After repeated administration of gadodiamide, a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. After repeated injection of gadoterate, only traces of the intact chelated gadolinium were observed with time-dependent clearance. Online supplemental material is available for this article.

Detection of Brain Metastases by Contrast-Enhanced MRI: Comparison of Gadopiclenol and Gadobenate in a Mouse Model.

OBJECTIVES: The aim of this study was to evaluate the capacity of gadopiclenol, a high-relaxivity gadolinium-based contrast agent to detect brain metastases in mice as a function of dose (0.08 mmol/kg or 0.1 mmol/kg) compared with gadobenate at 0.1 mmol/kg. MATERIALS AND METHODS: Brain metastases were induced by ultrasound-guided intracardiac implantation of 1.10 5 MDA-MB-231Br cells in the left ventricle of 18 anesthetized Balb/c Nude nu/nu female mice. At day 28 ± 3 after cell injection, each mouse received 2 crossover intravenous injections at 24-hour intervals, randomly selected from 2 doses of gadopiclenol (0.08 mmol/kg or 0.1 mmol/kg) and gadobenate (0.1 mmol/kg) with n = 6 mice/group (3 groups). Brain magnetic resonance imaging sessions were performed at 4 weeks on a 2.35 T magnet with a 3-dimensional T1-weighted high-resolution gradient echo sequence, before and after each injection. Images were blindly and randomly analyzed to detect enhancing lesions. Contrast-to-noise ratio between the metastases and the surrounding healthy parenchyma was calculated, based on region-of-interest signal measurements. In 2 animals per group, an early time point was added to the protocol (day 22 ± 3) to evaluate the sensitivity of detection as a function of time. After the last imaging session, the presence and location of whole-brain metastases were confirmed by histology in 4 mice. RESULTS: After gadopiclenol, approximately twice as many metastases were detected compared with gadobenate, regardless of the dose. Contrast-to-noise ratios of the detected metastases were 2.3 and 3.3 times higher with gadopiclenol at 0.08 mmol/kg and 0.1 mmol/kg, respectively, compared with gadobenate at 0.1 mmol/kg ( P < 0.0001). Gadopiclenol at the dose of 0.1 mmol/kg resulted in a 1.4-fold higher contrast compared with gadopiclenol at 0.08 mmol/kg ( P < 0.02). In a subset of mice that were imaged 1 week earlier, 2 metastases were detected with gadopiclenol and not with gadobenate. CONCLUSIONS: The high-relaxivity macrocyclic gadolinium-based contrast agent gadopiclenol allowed higher diagnostic performance for detecting brain enhancing metastases in terms of contrast-to-noise ratio and number of detected metastases compared with gadobenate, at both equal (0.1 mmol/kg) dose and 20% lower Gd dose (0.08 mmol/kg). Tumor detection was higher after gadopiclenol at the dose of 0.1 mmol/kg compared with 0.08 mmol/kg.

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.

Small Brain Lesion Enhancement and Gadolinium Deposition in the Rat Brain: Comparison Between Gadopiclenol and Gadobenate Dimeglumine.

OBJECTIVES: The aim of the set of studies was to compare gadopiclenol, a new high relaxivity gadolinium (Gd)-based contrast agent (GBCA) to gadobenate dimeglumine in terms of small brain lesion enhancement and Gd retention, including T1 enhancement in the cerebellum. MATERIALS AND METHODS: In a first study, T1 enhancement at 0.1 mmol/kg body weight (bw) of gadopiclenol or gadobenate dimeglumine was evaluated in a small brain lesions rat model at 2.35 T. The 2 GBCAs were injected in an alternated and cross-over manner separated by an interval of 4.4 ± 1.0 hours (minimum, 3.5 hours; maximum, 6.1 hours; n = 6). In a second study, the passage of the GBCAs into cerebrospinal fluid (CSF) was evaluated by measuring the fourth ventricle T1 enhancement in healthy rats at 4.7 T over 23 minutes after a single intravenous (IV) injection of 1.2 mmol/kg bw of gadopiclenol or gadobenate dimeglumine (n = 6/group). In a third study, Gd retention at 1 month was evaluated in healthy rats who had received 20 IV injections of 1 of the 2 GBCAs (0.6 mmol/kg bw) or a similar volume of saline (n = 10/group) over 5 weeks. T1 enhancement of the deep cerebellar nuclei (DCN) was assessed by T1-weighted magnetic resonance imaging at 2.35 T, performed before the injection and thereafter once a week up to 1 month after the last injection. Elemental Gd levels in central nervous system structures, in muscle and in plasma were determined by inductively coupled plasma mass spectrometry (ICP-MS) 1 month after the last injection. RESULTS: The first study in a small brain lesion rat model showed a ≈2-fold higher number of enhanced voxels in lesions with gadopiclenol compared with gadobenate dimeglumine. T1 enhancement of the fourth ventricle was observed in the first minutes after a single IV injection of gadopiclenol or gadobenate dimeglumine (study 2), resulting, in the case of gadopiclenol, in transient enhancement during the injection period of the repeated administrations study (study 3). In terms of Gd retention, T1 enhancement of the DCN was noted in the gadobenate dimeglumine group during the month after the injection period. No such enhancement of the DCN was observed in the gadopiclenol group. Gadolinium concentrations 1 month after the injection period in the gadopiclenol group were slightly increased in plasma and lower by a factor of 2 to 3 in the CNS structures and muscles, compared with gadobenate dimeglumine. CONCLUSIONS: In the small brain lesion rat model, gadopiclenol provides significantly higher enhancement of brain lesions compared with gadobentate dimeglumine at the same dose. After repeated IV injections, as expected for a macrocyclic GBCA, Gd retention is minimalized in the case of gadopiclenol compared with gadobenate dimeglumine, resulting in no T1 hypersignal in the DCN.

Safety and Gadolinium Distribution of the New High-Relaxivity Gadolinium Chelate Gadopiclenol in a Rat Model of Severe Renal Failure.

OBJECTIVE: The aim of this study was to investigate the toxicological profile of gadopiclenol, a new high-relaxivity macrocyclic gadolinium-based contrast agent (GBCA), in renally impaired rats, in comparison with 2 other macrocyclic GBCAs, gadoterate meglumine and gadobutrol, and 1 linear and nonionic GBCA, gadodiamide. METHODS: Renal failure was induced by adding 0.75% wt/wt adenine to the diet for 3 weeks. During the second week of adenine-enriched diet, the animals (n = 8/group × 5 groups) received 5 consecutive intravenous injections of GBCA at 2.5 mmol/kg per injection, resulting in a cumulative dose of 12.5 mmol/kg or saline followed by a 3-week treatment-free period after the last injection. The total (elemental) gadolinium (Gd) concentration in different tissues (brain, cerebellum, femoral epiphysis, liver, skin, heart, kidney, spleen, plasma, urine, and feces) was measured by inductively coupled plasma mass spectrometry. Transmission electron microscopy (and electron energy loss spectroscopy analysis of metallic deposits) was used to investigate the presence and localization of Gd deposits in the skin. Relaxometry was used to evaluate the presence of dissociated Gd in the skin, liver, and bone. Skin histopathology was performed to investigate the presence of nephrogenic systemic fibrosis-like lesions. RESULTS: Gadodiamide administrations were associated with high morbidity-mortality but also with macroscopic and microscopic skin lesions in renally impaired rats. No such effects were observed with gadopiclenol, gadoterate, or gadobutrol. Overall, elemental Gd concentrations were significantly higher in gadodiamide-treated rats than in rats treated with the other GBCAs for all tissues except the liver (where no significant difference was found with gadopiclenol) and the kidney and the heart (where statistically similar Gd concentrations were observed for all GBCAs). No plasma biochemical abnormalities were observed with gadopiclenol or the control GBCAs. Histopathology revealed a normal skin structure in the rats treated with gadopiclenol, gadoterate, and gadobutrol, contrary to those treated with gadodiamide. No evidence of Gd deposits on collagen fibers and inclusions in fibroblasts was found with gadopiclenol and its macrocyclic controls, unlike with gadodiamide. Animals of all test groups had Gd-positive lysosomal inclusions in the dermal macrophages. However, the textures differed for the different products (speckled texture for gadodiamide and rough-textured appearance for the 2 tested macrocyclic GBCAs). CONCLUSIONS: No evidence of biochemical toxicity or pathological abnormalities of the skin was observed, and similar to other macrocyclic GBCAs, gadoterate and gadobutrol, tissue retention of Gd was found to be low (except in the liver) in renally impaired rats treated with the new high-relaxivity GBCA gadopiclenol.

Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and Adult Rats.

OBJECTIVES: The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods. MATERIALS AND METHODS: A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals. RESULTS: Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect. CONCLUSIONS: No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate.

Gadolinium Retention, Brain T1 Hyperintensity, and Endogenous Metals: A Comparative Study of Macrocyclic Versus Linear Gadolinium Chelates in Renally Sensitized Rats.

OBJECTIVES: This preclinical study was designed to compare gadolinium (Gd) brain uptake after repeated injections of a macrocyclic Gd-based contrast agent (GBCA) (gadoterate meglumine) or 2 linear GBCAs (L-GBCAs) (gadobenate dimeglumine or gadodiamide) on a translational model of moderate renal impairment in rats. METHODS: The study was carried out in subtotally nephrectomized rats. Animals received 4 intravenous injections per week of GBCA (gadoterate meglumine, gadobenate dimeglumine, or gadodiamide) for 5 weeks, resulting in a cumulative dose of 12 mmol/kg, followed by a 1-month injection-free period. T1 hyperintensity in the deep cerebellar nuclei (DCNs) was investigated, and brain structures were carefully dissected to determine elemental Gd, iron (Fe), copper (Cu), and zinc (Zn) distribution by mass spectrometry. Urinary excretion of endogenous metals was also investigated soon after GBCA administration and several days later in order to assess a potential transmetalation phenomenon. RESULTS: Unlike gadoterate, repeated injections of L-GBCAs gadobenate and gadodiamide both induced T1 hyperintensity in the DCNs. Fine dissection of cerebral and cerebellar structures demonstrated very low levels or absence of Gd after repeated injections of gadoterate, in contrast to the two L-GBCAs, for which the highest total Gd concentration was demonstrated in the DCNs (Gd concentration in DCNs after 4.5 weeks of injection-free period: 27.1 ± 6.5 nmol/g for gadodiamide [P < 0.01 vs saline and P < 0.05 vs gadoterate]; 12.0 ± 2.6 nmol/g for gadobenate [P < 0.09 vs saline]; compared with 1.4 ± 0.2 nmol/g for gadoterate [ns vs saline]). The distribution of Gd concentration among the various brain structures dissected was also well correlated with the Fe distribution in these structures. No difference in endogenous metal levels in brain structures was observed. However, injection of gadobenate or gadodiamide resulted in an increase in urinary Zn excretion (urinary Zn concentrations: 57.9 ± 20.5 nmol/mL with gadobenate [P < 0.01 vs gadoterate and saline] and 221.6 ± 83.3 nmol/L with gadodiamide [P < 0.0001 vs all other treatments] vs 8.1 ± 2.3 nmol/L with saline and 10.6 ± 4.8 nmol/L with gadoterate]). CONCLUSIONS: In a model of renally impaired rats, only traces of gadoterate meglumine were detected in the brain with no T1 hyperintensity of the DCNs, whereas marked Gd retention was observed in almost all brain areas after injections of the L-GBCAs, gadobenate dimeglumine and gadodiamide. Brain structures with higher Gd uptake corresponded to those structures containing more Fe. Urinary Zn excretion was significantly increased after a single injection of L-GBCAs.

Multimodal Imaging Study of Gadolinium Presence in Rat Cerebellum: Differences Between Gd Chelates, Presence in the Virchow-Robin Space, Association With Lipofuscin, and Hypotheses About Distribution Pathway.

PURPOSE: The aim of this study was to investigate, based on in-depth multimodal imaging, the presence of Gd deposits, their ultrastructure, location, and co-location with endogenous elements, in the cerebellum, after repeated administrations of gadolinium-based contrast agents (GBCAs). METHODS: Rats sensitized by subtotal nephrectomy received 20 daily intravenous injections of 0.6 mmol Gd/kg for 5 weeks of commercial forms of either gadoterate, gadobenate or gadodiamide, or saline (n = 2/group). The study was randomized and blinded. Magnetic resonance imaging examination was performed weekly. One month after the last injection, electron microscopy analysis of the deep cerebellar nuclei, the granular layer of cerebellar cortex, and the choroid plexus was performed. Elemental analysis of deposits was carried out by electron energy loss spectroscopy. Secondary ion mass spectroscopy was used for complementary chemical mapping. RESULTS: A T1 hypersignal was evidenced in the deep cerebellar nuclei of rats treated with linear GBCAs, and Gd deposits were identified in all the studied cerebellar structures with gadobenate and gadodiamide (except in the granular layer in gadobenate-treated rats). No such effect was found with the macrocyclic GBCA gadoterate. Most of the Gd deposits revealed a characteristic spheroid "sea urchin-like" morphology, rich in phosphorus, and were localized in the basal lamina of microvessels, in the perivascular Virchow-Robin space, and in the interstitium. Gd was also identified in the glial cells, associated with lipofuscin pigments, for these same groups. CONCLUSIONS: Transmission electron microscopy analysis of cerebellums of renally impaired rats repeatedly injected with gadobenate and gadodiamide revealed the presence of Gd. Spheroid Gd depositions consisting of a filamentous meshwork were observed in the wall of microvessels, in perivascular Virchow-Robin space, and in the interstitium. Gd was also found in choroid plexus and was associated with pigments (likely lipofuscin) in glial cells. This is consistent with the involvement of the glymphatic distribution pathway for GBCAs. No insoluble Gd deposits were detected in rats injected with the macrocyclic GBCA gadoterate and controls.

Methodological Aspects for Preclinical Evaluation of Gadolinium Presence in Brain Tissue: Critical Appraisal and Suggestions for Harmonization-A Joint Initiative.

Gadolinium (Gd)-based contrast agents (GBCAs) are pharmaceuticals that have been approved for 30 years and used daily in millions of patients worldwide. Their clinical benefits are indisputable. Recently, unexpected long-term presence of Gd in the brain has been reported by numerous retrospective clinical studies and confirmed in preclinical models particularly after linear GBCA (L-GBCA) compared with macrocyclic GBCA (M-GBCA). Even if no clinical consequences of Gd presence in brain tissue has been demonstrated so far, in-depth investigations on potential toxicological consequences and the fate of Gd in the body remain crucial to potentially adapt the clinical use of GBCAs, as done during the nephrogenic systemic fibrosis crisis. Preclinical models are instrumental in the understanding of the mechanism of action as well as the potential safety consequences. However, such models may be associated with risks of biases, often related to the protocol design. Selection of adequate terminology is also crucial. This review of the literature intends to summarize and critically discuss the main methodological aspects for accurate design and translational character of preclinical studies.

Moderate Renal Failure Accentuates T1 Signal Enhancement in the Deep Cerebellar Nuclei of Gadodiamide-Treated Rats.

OBJECTIVES: The purpose of this preclinical study was to investigate whether moderate chronic kidney disease is a factor in potentiating gadolinium (Gd) uptake in the brain. MATERIALS AND METHODS: A comparative study was performed on renally impaired (subtotal nephrectomy) rats versus rats with normal renal function. The animals received 4 daily injections of 0.6 mmol Gd/kg a week for 5 weeks (cumulative dose of 12 mmol Gd/kg) of gadodiamide or saline solution. The MR signal enhancement in the deep cerebellar nuclei was monitored by weekly magnetic resonance imaging examinations. One week after the final injection, the total Gd concentration was determined by inductively coupled plasma mass spectrometry in different regions of the brain including the cerebellum, plasma, cerebrospinal fluid, parietal bone, and femur. RESULTS: After the administration of gadodiamide, the subtotal nephrectomy group presented a significantly higher T1 signal enhancement in the deep cerebellar nuclei and a major increase in the total Gd concentration in all the studied structures, compared with the normal renal function group receiving the same linear Gd-based contrast agent. Those potentiated animals also showed a pronounced hypersignal in the choroid plexus, still persistent 6 days after the last injection, whereas low concentration of Gd was found in the cerebrospinal fluid (<0.05 µmol/L) at this time point. Plasma Gd concentration was then around 1 µmol/L. Interestingly, plasma Gd was predominantly in a dissociated and soluble form (around 90% of total Gd). Total Gd concentrations in the brain, cerebellum, plasma, and bones correlated with creatinine clearance in both the gadodiamide-treated groups. CONCLUSIONS: Renal insufficiency in rats potentiates Gd uptake in the cerebellum, brain, and bones.

Safety profiles of gadolinium chelates in juvenile rats differ according to the risk of dissociation.

This study was designed to compare the safety of two gadolinium chelates (GCs), used as contrast agents for magnetic resonance imaging, in juvenile rats. Juvenile rats received five intravenous administrations (between postnatal day [PND] 4 and 18) of gadoteric acid (macrocyclic ionic GC), gadodiamide (linear nonionic GC) or saline, and sacrificed at PND 25. Gadodiamide induced mortality, alopecia and hyperpigmentation of dorsal skin. Two gadodiamide-treated rats presented severe epidermal and dermal lesions. No abnormal signs were detected following administration of gadoteric acid. Higher tissue gadolinium concentrations were found in the gadodiamide group compared to the gadoteric acid group. Dissociation of gadodiamide was observed in skin and liver, with the presence of dissociated and soluble gadolinium. In conclusion, repeated administration of gadoteric acid was well tolerated by juvenile rats. In contrast, gadodiamide induced significant toxicity and more marked tissue gadolinium retention (at least partly in the dissociated and soluble form).