Administration Of Gadopentetate Dimeglumine Research Articles

Combination of Contrast-enhanced FlAIR and Contrast-enhanced T1WI: A Quick and Efficient Method in Detecting Brain Metastases of Lung Cancers.

Some patients with suspected brain metastases (BM) could not tolerate longer scanning examinations according to the standardized MRI protocol. The purpose of this study was to evaluate the clinical value of contrast-enhanced fast fluid-attenuated inversion recovery (CE FLAIR) imaging in combination with contrast-enhanced T1 weighted imaging (CE T1WI) in detecting BM of lung cancer and explore a quick and effective MRI protocol. In 201 patients with lung cancers and suspected BM, T1WI and FLAIR were performed before and after administration of gadopentetate dimeglumine. Two radiologists reviewed pre- and post-contrast images to determine the presence of abnormal contrast enhancement or signal intensity and decided whether it was metastatic or not on CE T1WI (Group 1) and CE FLAIR (Group 2). The number, locations and features of abnormal findings in two groups were recorded. Receiver Operating Characteristic (ROC) analyses were conducted in three groups: Group 1, 2 and 3(combination of CE FLAIR and CE T1WI). A total of 714 abnormal findings were revealed, of which 672 were considered as BM and 42 nonmetastatic. Superficial and small metastases(≤10mm) in parenchyma and ependyma, leptomeningeal and non-expansive skull metastases were typically better seen on CE FLAIR. The areas under ROC in the three groups were 0.720,0.887 and 0.973, respectively. Group 3 was significantly better in diagnostic efficiency of BMs than Group 1 (p<0.0001) or Group 2 (p=0.0006). The combination of CE T1WI and CE FLAIR promotes diagnostic performance and results in better observation and characterization of BM in patients with lung cancers. It provides a quick and efficient way of detecting BM.

Different Impact of Gadopentetate and Gadobutrol on Inflammation-Promoted Retention and Toxicity of Gadolinium Within the Mouse Brain.

ObjectivesUsing a murine model of multiple sclerosis, we previously showed that repeated administration of gadopentetate dimeglumine led to retention of gadolinium (Gd) within cerebellar structures and that this process was enhanced with inflammation. This study aimed to compare the kinetics and retention profiles of Gd in inflamed and healthy brains after application of the macrocyclic Gd-based contrast agent (GBCA) gadobutrol or the linear GBCA gadopentetate. Moreover, potential Gd-induced neurotoxicity was investigated in living hippocampal slices ex vivo.Materials and MethodsMice at peak of experimental autoimmune encephalomyelitis (EAE; n = 29) and healthy control mice (HC; n = 24) were exposed to a cumulative dose of 20 mmol/kg bodyweight of either gadopentetate dimeglumine or gadobutrol (8 injections of 2.5 mmol/kg over 10 days). Magnetic resonance imaging (7 T) was performed at baseline as well as at day 1, 10, and 40 post final injection (pfi) of GBCAs. Mice were sacrificed after magnetic resonance imaging and brain and blood Gd content was assessed by laser ablation-inductively coupled plasma (ICP)-mass spectrometry (MS) and ICP-MS, respectively. In addition, using chronic organotypic hippocampal slice cultures, Gd-induced neurotoxicity was addressed in living brain tissue ex vivo, both under control or inflammatory (tumor necrosis factor α [TNF-α] at 50 ng/μL) conditions.ResultsNeuroinflammation promoted a significant decrease in T1 relaxation times after multiple injections of both GBCAs as shown by quantitative T1 mapping of EAE brains compared with HC. This corresponded to higher Gd retention within the EAE brains at 1, 10, and 40 days pfi as determined by laser ablation-ICP-MS. In inflamed cerebellum, in particular in the deep cerebellar nuclei (CN), elevated Gd retention was observed until day 40 after last gadopentetate application (CN: EAE vs HC, 55.06 ± 0.16 μM vs 30.44 ± 4.43 μM). In contrast, gadobutrol application led to a rather diffuse Gd content in the inflamed brains, which strongly diminished until day 40 (CN: EAE vs HC, 0.38 ± 0.08 μM vs 0.17 ± 0.03 μM). The analysis of cytotoxic effects of both GBCAs using living brain tissue revealed an elevated cell death rate after incubation with gadopentetate but not gadobutrol at 50 mM. The cytotoxic effect due to gadopentetate increased in the presence of the inflammatory mediator TNF-α (with vs without TNF-α, 3.15% ± 1.18% vs 2.17% ± 1.14%; P = 0.0345).ConclusionsIn the EAE model, neuroinflammation promoted increased Gd retention in the brain for both GBCAs. Whereas in the inflamed brains, efficient clearance of macrocyclic gadobutrol during the investigated time period was observed, the Gd retention after application of linear gadopentetate persisted over the entire observational period. Gadopentetate but not gadubutrol appeared to be neurotoxic in an ex vivo paradigm of neuronal inflammation.

Gadolinium Retention in the Brain of Mother and Pup Mouse: Effect of Pregnancy and Repeated Administration of Gadolinium-Based Contrast Agents.

BackgroundThe association of repeated administration of gadolinium‐based contrast agents (GBCAs) with the gadolinium (Gd) retention in the brains of mother and fetus remains unclear.PurposeTo investigate the effects of pregnancy and repeated administration of GBCAs on Gd retention in the brains of mother and pup mice.Study typeCross‐sectional cohort toxicity study.Animal ModelFrom gestational days 16–19, pregnant (n = 48) BALB/c mice.Field StrengthA 9.4 T and fast spin echo sequence.AssessmentHalf of the mother mice (n = 24) were killed at postnatal day 1 (P1) for inductively coupled plasma mass spectrometry (ICP‐MS) and transmission electron microscopy (TEM). Besides the ICP‐MS and TEM, four pups were randomly selected from each mother and killed at P1 for ultraperformance liquid chromatography mass spectrometry (UPLC‐MS) and Nissl staining.Statistical TestsOne‐way analysis of variance and unpaired t‐test.ResultsIn the group of gadodiamide, retention of Gd in the brains of pregnant mice was significantly lower than that of nonpregnant mice in the area of the deep cerebellar nuclei (DCN) (10.35 ± 2.16 nmol/g vs. 18.74 ± 3.65 nmol/g). Retention of Gd in the DCN of pups whose mothers were administered gadoterate meglumine was significantly lower than that of pups whose mothers were administered gadodiamide (0.21 ± 0.09 nmol/g vs. 6.15 ± 3.21 nmol/g) at P1. In mice treated with gadodiamide, most of the retained Gd in the brain tissue was insoluble (19.5% ± 9.5% of the recovered amount corresponded to the intact complex in the DCN).Data ConclusionIn different brain areas of the mother and pup mice, the retention of Gd after gadoterate meglumine administration was lower than that of gadodiamide and gadopentetate dimeglumine administration, and almost all the detected Gd in pups' brains was intact soluble GBCAs.Evidence Level1Technical EfficacyStage 2

Monthly triple-dose gadolinium administration: potential associations with leukopenia, hypophosphatemia, and bone marrow T1 hyperintensity.

ObjectiveMonthly scanning with triple-dose gadopentetate dimeglumine has been shown to be associated with progressive increases in bone T1 hyperintensity, hypophosphatemia, and leukopenia. This study was performed to retrospectively investigate the potential associations among these phenomena.MethodsThis retrospective analysis involved patients who had received monthly triple-dose gadopentetate dimeglumine for up to 2 years as part of treatment for multiple sclerosis. Monthly magnetic resonance imaging scans of the brain (n = 67) were segmented to evaluate the signal intensity in the cranial marrow. Potential associations among the marrow T1 hyperintensity, serum phosphate concentration, and white blood cell count were examined.ResultsPatients in the no leukopenia group showed a statistically significant mean monthly increase in the bone marrow signal-to-noise ratio of 0.0430/month. Patients in the leukopenia group showed a mean monthly increase in the bone marrow signal-to-noise ratio of 0.0398/month, but this was not statistically significant. Patients in the hypophosphatemia group were significantly less likely to develop leukopenia than patients who had never developed hypophosphatemia.ConclusionsAlthough monthly administration of triple-dose gadopentetate dimeglumine over 13 months has been associated with progressive increases in leukopenia, hypophosphatemia, and T1 signal intensity of bone, this study showed an inverse relationship between leukopenia and hypophosphatemia.

A prospective study to evaluate the role of multiparametric magnetic resonance imaging in the grading of gliomas using magnetic resonance imaging perfusion and diffusion and multivoxel magnetic resonance spectroscopy

Abstract Background: The primary aim of this study was to evaluate the individual and combined efficacy of magnetic resonance imaging (MRI) parameters, which include MRI perfusion, MRI diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS) in the grading of gliomas as low grade versus high grade. The pre-operative imaging-based grading of gliomas by multiparametric MRI was compared with the gold standard histopathological studies. Methods: A total of 22 patients referred to the radiology department for multiparametric MRI of the brain with presumptive diagnosis of glioma on computed tomography/MRI were included in the study. Conventional T1, T2 and fluid-attenuated inversion recovery images were obtained followed by perfusion MRI using gadopentetate dimeglumine (Magnevist) administration. This was followed by DWI and MRS. Results: Our statistical analysis demonstrated that a cut-off of apparent diffusion coefficient value of 954.085 (10–6 mm2/Sec) provides a sensitivity and specificity of 87.5% and 85.7%, respectively, in differentiating low-grade gliomas (LGGs) from high-grade gliomas (HGGs). A choline/creatine ratio cut-off value of 2 provides sensitivity and specificity of 100% and 92.9%, respectively, while a cut-off value of 1.45 of choline/N-acetylaspartate ratio provides both sensitivity and specificity of 100% in differentiating LGG from HGG. A cut-off of 1.9 for maximum relative cerebral blood volume (rCBV) value provides both sensitivity and specificity of 100% in differentiating LGGs from HGGs. Conclusions: We concluded that perfusion MRI (rCBV) was the best parameter among perfusion MRI, DWI and MRI spectroscopy in differentiating HGGs from LGGs. Combined multiparametric results showed a diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of 86.4%, 82.4%, 100%, 100% and 62.5%, respectively, on comparison with gold standard histopathological grading.

Evaluation of the effect of multiple administrations of gadopentetate dimeglumine or gadoterate meglumine on brain T1-weighted hyperintensity in pediatric patients.

Repeated administrations of linear gadolinium-based contrast media (GBCM) are associated with T1-weighted (T1-W) signal intensity change in brain structures. The purpose of this study was to compare different brain structures in children after unconfounded, repeated administrations of either a macrocyclic or linear GBCM. We performed a retrospective cohort study, identifying subjects with ≥5 unconfounded administrations of gadoterate meglumine. We matched subjects with repeated administrations of gadopentetate dimeglumine to the gadoterate meglumine arm based on the number of unconfounded GBCM administrations. Two reviewers drew regions of interest on 27 structures in and around the brain. We recorded demographic, modality and study parameters and evaluated them to determine whether they were associated with T1-W signal intensity (SI) changes. Linear mixed effects models evaluated the relationships between the number of GBCM doses and T1-W SI ratio. Finally, we identified differences in the rate of T1-W SI ratio change among individuals using a linear mixed effects model with random slope. We included a total of 52 patients (age range at first MRI: 6.0months to 17.1years), 26 in each arm. We detected a significant change in the T1-W SI ratio with repeated administrations of GBCM in one location in the gadoterate meglumine arm and in four locations in the gadopentetate dimeglumine arm. Patient gender and age were not associated with T1-W SI change. Modality vendor, imaging sequence and field strength were variably associated with a systematic difference in the ability to detect a T1-W SI change. Finally, linear mixed effects model with random slope showed that there were individual differences in the slope of SI change at various structures among individuals for both arms. This effect was present in more brain structures in the gadopentetate dimeglumine arm (14 vs. 8). There is a significant change in the T1-W SI ratio over time in multiple brain structures after repeated gadopentetate dimeglumine administrations. This effect was only seen in one ratio after repeated administrations of gadoterate meglumine. There are individual differences in the rate of change of SI ratios over time after repeated administration of gadopentetate dimeglumine and gadoterate meglumine, suggesting that individual differences are present.

Dentate nucleus signal intensity changes on T1-weighted MRI after repeated administrations of linear and macrocyclic gadolinium-based contrast agents: a pediatric intraindividual case-control study.

An association between consecutive administrations of macrocyclic gadolinium-based contrast agent (mcGBCA) gadobutrol and linear (L)-GBCA gadopentetate dimeglumine and gadolinium retention in the pediatric brain remains incompletely understood. To compare signal intensity (SI) changes in the dentate nucleus (DN) on unenhanced T1-weighted imaging (T1WI) in children who obtained mcGBCA gadobutrol with those who had previously received L-GBCA gadopentetate dimeglumine. This retrospective study included 27 children who received L-GBCA gadopentetate dimeglumine followed by mcGBCA gadobutrol and two different control groups matched for age and sex for both periods, each involving 27 individuals with no GBCA administration from January 2010 to January 2020. DN-to-middle cerebellar peduncle (MCP) SI ratios on T1WI were determined. A repeated-measures ANOVA was performed to compare the T1WI SI ratio between children exposed to GBCA in each of the two periods and controls. Pearson correlation analysis was conducted to determine any correlation between SI ratios and confounding parameters. T1WI SI ratio was significantly higher in those who had only L-GBCA (1.005±0.087) or subsequent mcGBCA gadobutrol (1.002±0.104) than in control groups 1 (0.927±0.041; P<0.001) and 2 (0.930±0.041; P=0.002), respectively, but no significant difference of the T1WI SI ratio was noted between L-GBCA period and subsequent mcGBCA gadobutrol period (P=0.917). T1WI SI ratios and the L-GBCA administration number revealed a modest but significant correlation (correlation coefficient=0.034; P=0.016). Previous administration of gadopentetate dimeglumine is associated with increased T1WI SI in the DN, while subsequent administration of gadobutrol does not demonstrate any additional SI increase in the pediatric brain.

Susceptibility-Weighted Imaging of the Pediatric Brain after Repeat Doses of Gadolinium-Based Contrast Agent.

Gadolinium complexes have paramagnetic properties; thus, we aimed to determine the susceptibility changes in the globus pallidus and dentate nucleus following administration of linear or macrocyclic gadolinium-based contrast agents in children. Thirty-three patients with linear gadolinium-based contrast agent gadopentetate dimeglumine administration, 33 age- and sex-matched patients with macrocyclic gadolinium-based contrast agent gadobutrol administration, and 33 age- and sex-matched control subjects without gadolinium exposure were enrolled in this retrospective study. The signal intensity on SWI and T1WI was determined in the dentate nucleus, middle cerebellar peduncle, globus pallidus, and pulvinar of the thalamus in an ROI-based analysis to calculate dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios. A repeated measures ANOVA was performed to compare SWIminimum, SWImean, and T1WI signal intensity ratios between gadolinium-based contrast agent groups and control subjects. Pearson correlation analysis was performed to determine any correlation between signal intensity ratios and variables. Dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios for both SWImean and SWIminimum were lower for the linear gadolinium-based contrast agent group compared with macrocyclic gadolinium-based contrast agent and control groups (P < .05). No significant difference of the SWImean and SWIminimum ratios were noted between the macrocyclic gadolinium-based contrast agent group and the control group (P > .05). Both dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios on T1WI in the linear gadolinium-based contrast agent group were higher than in the control group and the macrocyclic gadolinium-based contrast agent group (P < .05). A negative correlation was identified between SWImean and SWIminimum ratios and the number of linear gadolinium-based contrast agent administrations (dentate nucleus-to-middle cerebellar peduncle ratio: SWImean, r = -0.43, P = .005; SWIminimum, r = -0.38, P = .011; globus pallidus-to-thalamus ratio: SWImean, r = -0.39, P = .009; SWIminimum, r = -0.33, P = .017). SWI analysis of the pediatric brain demonstrated a statistically significant decrease in SWIminimum and SWImean values for the dentate nucleus and globus pallidus after administration of linear gadolinium-based contrast agents but not macrocyclic gadolinium-based contrast agents.

A retrospective cohort evaluation of the effect of multiple administrations of gadopentetate dimeglumine on brain magnetic resonance imaging T1-weighted signal.

Gadolinium deposition occurs following repeated administration of gadolinium-based contrast media. However, few studies have evaluated factors that lead to increased detection of deposition or the individual differences among patients. To measure the effect of repeated dosages of gadopentetate dimeglumine on pediatric brains and to determine the factors that influence signal intensity changes. A retrospective study evaluated magnetic resonance imaging (MRI) in patients <18years of age who received >5 doses of gadopentetate dimeglumine. Regions of interest were placed in 30 locations in the brain on axial precontrast T1 images. Signal intensity ratios were evaluated throughout the brain. The effect of increasing gadopentetate dimeglumine exposure on signal intensity ratios was assessed using linear mixed models adjusted for gender, age, imaging sequence type (fast spin echo or gradient echo), MRI manufacturer (General Electric, Philips or Siemens), and field strength (1.5 tesla [T] or 3T). Finally, the variance of the random slope in the linear mixed models was tested to determine if there were differences in the rate of signal intensity ratio change among individuals. Fifty patients (M:F=25:25; mean age at first imaging: 6.4years) with a mean of 21.5 gadopentetate dimeglumine administrations (range: 6-86) were included. There were significant increases in T1 signal in the globus pallidus, dentate nucleus and pulvinar with an increasing number of contrast administrations. Patient gender, age, and MRI field strength were not associated with changing signal intensity ratios. However, MRI sequence type and vendor significantly impacted some measured signal intensity ratios. Finally, significant differences in the slopes of the ratios were present among patients for multiple locations. Repeated administration of gadopentetate dimeglumine is associated with T1 hyperintense signal in the dentate nucleus, globus pallidus and pulvinar. Detection is significantly affected by MRI sequence type and scanner vendor. Even when accounting for these differences, there are individual differences in the slope of signal intensity change suggesting a patient-level effect influences gadolinium deposition.

MRI demonstration of gadolinium deposition in bone after monthly triple-dose gadopentetate dimeglumine and correlation with frequency of hypophosphatemia

ObjectivesWe retrospectively analyzed data of the BECOME trial to investigate whether serial administration of triple-dose (3-dose) gadopentetate dimeglumine would result in the development of T1 signal-to-noise (S/N) changes in the cranial diploic space and whether S/N changes correlated with on-study hypophosphatemia. MethodsSignal intensity analysis was performed on the first year's data of the BECOME trial using 3-dose Gd (14 months, maximum number of doses, 39, mean: 36). Routine blood and urine tests were obtained each month for safety monitoring. Linear mixed regression modeling with random intercept was used to analyze monthly signal-to-noise ratio (S/N = Bone/Air) using an ROI of the diploic space created from T2W images and overlaid on T1FS (T1 fat-saturated) images. Incidence of phosphate abnormalities was analyzed using the general estimation equation; correlation of phosphate and S/N change was achieved with type 3 test of fixed effects. ResultsCranial diploic space T1FS S/N increased over 14 months: S/N = 0.039 mean monthly increase (S.E. 0.008; p < 0.0001). Subjects with consistently normal phosphate levels (n = 32) experienced more of a S/N increase than patients with at least one episode of hypophosphatemia (n = 35) (0.057 vs. 0.023, respectively, p = 0.037). Those with moderate hypophosphatemia demonstrated no significant S/N increase. ConclusionMonthly administration of 3-dose gadopentetate dimeglumine is associated with development of increased S/N on T1FS imaging in the cranial diploic space, suggesting Gd retention in bone. Our data suggests MRI could be used as a noninvasive method of tracking Gd retention in bone, which was more pronounced in patients with normal phosphate levels.

Case 273.

HistoryA 55-year-old man with a history of chronic pancreatitis secondary to chronic alcohol abuse presented to the hospital with acute abdominal pain, generalized weakness, weight loss, and pyrexia. A clinical examination revealed he was tender to touch in the upper abdomen. Laboratory tests revealed a serum alkaline phosphatase level of 370 U/L (6.1 µkat/L) (normal range, 30-130 U/L [0.5-2.2 µkat/L]), a lipase level of 172 U/L (2.9 µkat/L) (normal range, 0-60 U/L [0-1.0 µkat/L]), a C-reactive protein level of 159 mg/L (1514 nmol/L) (normal value, <8.0 mg/L [76.2 nmol/L]), and a white cell count of 7 × 109/L (normal range, [4-11] × 109/L). During the present admission, the patient underwent urgent CT for his acute symptoms. His relevant medical history included a hospital admission 2 months earlier for abdominal discomfort. Given his history of chronic pancreatitis, baseline abdominal MRI was performed to determine the cause of his symptoms and to assess the pancreas (Figs 1-3).Figure 1a:(a, b) Images from axial fat-suppressed T2-weighted MRI (repetition time msec/echo time msec, 1000/87; section thickness, 6 mm) of the upper abdomen obtained 2 months prior to admission. (c, d) Images from axial fat-suppressed T1-weighted MRI (3.69/1.62; section thickness, 4 mm) of the upper abdomen acquired 60 seconds after intravenous administration of gadopentetate dimeglumine (0.1 mL per kilogram of body weight; Magnevist; Bayer Healthcare, East Mississauga, Ontario) during the current admission.Figure 1b:(a, b) Images from axial fat-suppressed T2-weighted MRI (repetition time msec/echo time msec, 1000/87; section thickness, 6 mm) of the upper abdomen obtained 2 months prior to admission. (c, d) Images from axial fat-suppressed T1-weighted MRI (3.69/1.62; section thickness, 4 mm) of the upper abdomen acquired 60 seconds after intravenous administration of gadopentetate dimeglumine (0.1 mL per kilogram of body weight; Magnevist; Bayer Healthcare, East Mississauga, Ontario) during the current admission.Figure 1c:(a, b) Images from axial fat-suppressed T2-weighted MRI (repetition time msec/echo time msec, 1000/87; section thickness, 6 mm) of the upper abdomen obtained 2 months prior to admission. (c, d) Images from axial fat-suppressed T1-weighted MRI (3.69/1.62; section thickness, 4 mm) of the upper abdomen acquired 60 seconds after intravenous administration of gadopentetate dimeglumine (0.1 mL per kilogram of body weight; Magnevist; Bayer Healthcare, East Mississauga, Ontario) during the current admission.Figure 1d:(a, b) Images from axial fat-suppressed T2-weighted MRI (repetition time msec/echo time msec, 1000/87; section thickness, 6 mm) of the upper abdomen obtained 2 months prior to admission. (c, d) Images from axial fat-suppressed T1-weighted MRI (3.69/1.62; section thickness, 4 mm) of the upper abdomen acquired 60 seconds after intravenous administration of gadopentetate dimeglumine (0.1 mL per kilogram of body weight; Magnevist; Bayer Healthcare, East Mississauga, Ontario) during the current admission.Figure 2:Coronal T2-weighted MRI (repetition time msec/echo time msec, 1000/89; section thickness, 4 mm) of the upper abdomen obtained 2 months prior to admission.Figure 3:Coronal CT image of the abdomen acquired 60 seconds after administration of intravenous contrast material (100 mL of iohexol, Omnipaque 350; GE Healthcare, Princeton, NJ). This CT examination was performed during the current admission.

Gadolinium Retention and Clearance in the Diabetic Brain after Administrations of Gadodiamide, Gadopentetate Dimeglumine, and Gadoterate Meglumine in a Rat Model

Purpose To evaluate gadolinium (Gd) retention and clearance in the brain of diabetic rats after administrations of gadodiamide, gadopentetate dimeglumine, and gadoterate meglumine. Materials and Methods Both diabetic rats (n = 52) and normal rats (n = 52) intravenously received 20 injections of 0.6 mmol Gd/kg gadodiamide, gadopentetate dimeglumine, gadoterate meglumine, or saline. Both diabetic rats and normal rats were divided into 2 subgroups of 24 and 28 rats for the 7-day and 42-day evaluations (i.e., they were sacrificed at 7 days (n = 6 per group) and 42 days (n = 7 per group)), respectively, after the last injection. For the 7-day subgroup, 6 rats were euthanized for inductively coupled plasma mass spectrometry (ICP-MS) analysis. For the 42-day subgroup, 6 rats underwent T1-weighted magnetic resonance imaging (MRI) and ICP-MS, and 1 rat was analyzed by transmission electron microscopy (TEM). ResultsThe T1 enhancements in the deep cerebellar nuclei (DCNs) of diabetic rats were lower than those of normal rats in both linear Gd-based contrast agent (GBCA) groups (p < 0.05). The average Gd concentrations in the brains of diabetic rats were significantly lower than those of healthy rats in both the short-term groups and long-term groups (p < 0.05). The highest Gd retentions were in the olfactory bulb, DCN, and striatum with gadodiamide. Compared with the results obtained 7 days after the last injection, the residual Gd concentrations of the 42-day subgroups in the brains of diabetic rats showed no significant difference in both linear GBCA groups (p>0.05). Conclusions Compared with normal rats, the diabetic status decreased the residual Gd concentrations in the brain after multiple administrations of gadodiamide, gadopentetate dimeglumine, and gadoterate meglumine. The clearable fraction of Gd in the brain was eliminated faster in diabetic rats than in normal rats.

Increased Retention of Gadolinium in the Inflamed Brain After Repeated Administration of Gadopentetate Dimeglumine: A Proof-of-Concept Study in Mice Combining ICP-MS and Micro- and Nano-SR-XRF.

The aim of this study was to determine in vivo if brain inflammation leads to increased gadolinium (Gd) retention in brain tissue after repeated applications of Gd-based contrast agents (GBCAs). Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice (n = 6). Experimental autoimmune encephalomyelitis and healthy control mice (n = 4) received 2.5 mmol/kg Gd-DTPA over 10 days (8 injections, cumulated dose of 20 mmol/kg), starting at day 14 post immunization when EAE mice reached the maximal clinical disability. In a group of mice, T1-weighted 2-dimensional RARE images were acquired before the first GBCA injection and 1 day after the last injection. Mice were killed either 1 day or 10 days after the last Gd application. From each single animal, a brain hemisphere was used for Gd detection using inductively coupled plasma mass spectrometry, whereas the other hemisphere was processed for histology and synchrotron x-ray fluorescence spectroscopy (SR-XRF) analysis. Gadolinium deposition in inflamed brains was mapped by SR-XRF 1 day after the last Gd-DTPA injections, although only mild signal hyperintensity was found on unenhanced T1-weighted images. In addition, using inductively coupled plasma mass spectrometry, we detected and quantified Gd in both healthy and EAE brains up to 10 days after the last injections. However, EAE mouse brains showed higher levels of Gd (mean ± SD, 5.3 ± 1.8 μg/g; range, 4.45-8.03 μg/g) with respect to healthy controls (mean ± SD, 2.4 ± 0.6 μg/g; range, 1.8-3.2 μg/g). By means of micro-SR-XRF, we identified submicrometric Gd hotspots in all investigated samples containing up to 5893 μg Gd/g tissue. Nano-SR-XRF further indicated that Gd small hotspots had an average size of ~160 nm diameter and were located in areas of high inflammatory activity. After repeated administrations of Gd-DTPA, ongoing inflammation may facilitate the retention of Gd in the brain tissue. Thus, neuroinflammation should be considered as a risk factor in the recommendation on use of linear GBCA-enhanced MRI.

Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents

PurposeTo quantitate gadolinium deposits in gliomas and adjacent normal brain specimens, and to evaluate their association with tumor contrast enhancement and the type of gadolinium-based contrast agent (GBCA) used.MethodsA total of 69 patients with primary glioma who underwent contrast-enhanced magnetic resonance imaging (MRI) prior to surgery were included in this retrospective study. Gadolinium was measured from histologically viable tumor, normal brain, and necrosis within the sample, when available, using inductively coupled plasma mass spectrometry (ICP-MS). Tumor contrast enhancement was categorized as none, minimal, or noticeable. Differences in gadolinium deposits by contrast enhancement and GBCA type were assessed.ResultsSeven patients received linear GBCA and 62 macrocyclic, respectively. At the time of surgery, gadolinium deposits were detected in 39 out of 69 (57%) tumor samples, 8 out of 13 (62%) normal brain, and 12 out of 14 (86%) necrotic specimens. Gadolinium was detected in both enhancing and non-enhancing tumors, but was greatest in gliomas with noticeable enhancement (p = 0.02). Administration of linear agents gadodiamide and gadopentetate dimeglumine resulted in significantly higher tumor gadolinium relative to macrocyclic gadoterate meglumine (p < 0.01 and p < 0.05, respectively). Normal brain and necrosis also showed higher gadolinium after exposure to linear gadodiamide (both p < 0.05). In multivariate regression, GBCA type (linear/macrocyclic) was the most powerful predictor of tumor gadolinium retention (p < 0.001).ConclusionGadolinium can be detected in both enhancing and non-enhancing gliomas, neighboring normal brain, and necrosis. Gadolinium retention is higher after exposure to linear GBCAs compared with the macrocyclic gadoterate meglumine.

Progressive T1 Shortening of the Dentate Nucleus in Patients With Multiple Sclerosis: Result of Multiple Administrations of Linear Gadolinium Contrast Agents Versus Intrinsic Disease.

The purpose of this article is to study the effect of the administration of multiple IV doses of gadolinium-based contrast agent on the intrinsic T1 hyperintensity in the dentate nucleus and globus pallidus in patients with multiple sclerosis (MS). A retrospective review of imaging in patients with relapsing-remitting MS was performed. Images of 20 patients who received four or more doses of gadolinium-based contrast agent were reviewed. Patients received the linear agent gadopentetate dimeglumine before 2011 and the macrocyclic agent gadobutrol from 2011 onward. Dentate nucleus-to-pons and globus pallidus-to-thalamus signal intensity (SI) ratios were evaluated. SI ratios were compared over time with multiple injections of gadolinium. Similar SI ratios were evaluated for six patients who received gadopentetate dimeglumine and then underwent multiple subsequent MRI studies without contrast agent administration. The increase in the dentate nucleus-to-pons SI ratio after multiple administrations of the linear agent gadopentetate dimeglumine (mean = 1.44; SD = 2.50) was significantly higher than that with the macrocyclic agent gadobutrol (mean = -0.11; SD = 2.33) (p < 0.001). The globus pallidus-to-thalamus and dentate nucleus-to-CSF ratios also increased with multiple contrast injections over time, but the changes were not found to be statistically significant. The increase in SI in the dentate nucleus was not observed in patients who stopped receiving contrast injections, after showing a previous increase over time with gadolinium. In patients with MS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images and was significantly greater with the administration of a linear agent than with a macrocyclic agent. This increase in SI over time is likely a reflection of gadolinium deposition and not due to intrinsic disease, as previously postulated.

Gadolinium deposition within the paediatric brain: no increased intrinsic T1-weighted signal intensity within the dentate nucleus following the administration of a minimum of four doses of the macrocyclic agent gadobutrol.

To determine whether repeated administration of the macrocyclic gadolinium-based contrast agent (GBCA) gadobutrol in children is associated with T1-weighted hyperintensity within the dentate nucleus, an imaging surrogate for gadolinium deposition. With institutional review board approval, we identified a cohort of eight patients aged 18 years or younger who underwent at least four gadobutrol-enhanced magnetic resonance imaging (MRI) examinations of the brain from 2013 to 2017. For comparison, we identified a cohort of 19 patients who underwent at least four gadopentetate dimeglumine-enhanced MRI examinations. For each examination, both dentate nuclei were contoured on unenhanced images; the mean dentate-to-pons signal intensity (DN-P SI) ratio was calculated. DN-P SI ratios from the first and last MRI exams were compared using Wilcoxon signed ranks tests and linear regression analyses. In the gadobutrol cohort, there was no significant change in the mean DN-P SI ratio from the first to the last scan (1.02 vs 1.02, p = 1.00). In the gadopentetate dimeglumine cohort, there was a significant increase in the mean DN-P SI ratio from the first to the last scan (1.05 vs 1.13, p = 0.003). After controlling for potentially confounding variables, the change in DN-P SI ratio from the first to the last scan was significantly lower for patients in the gadobutrol group than in the gadopentetate dimeglumine group (β = -0.08, p = 0.04). Repeated administration of the macrocyclic GBCA gadobutrol in children was not associated with T1-weighted dentate hyperintensity, while the repeated administration of the linear GBCA gadopentetate dimeglumine was associated with T1-weighted dentate hyperintensity, presumably due to gadolinium deposition. • Gadolinium-based contrast agents are routinely used in magnetic resonance imaging. • Repeated administration of the macrocyclic agent gadobutrol in children was not associated with T1-weighted dentate hyperintensity.

Dentate nucleus T1 hyperintensity in early relapsing-remitting multiple sclerosis patients is associated with cumulative gadopentetate dimeglumine (Gd-DTPA) administration (S6.007)

Dentate nucleus T1 hyperintensity in early relapsing-remitting multiple sclerosis patients is associated with cumulative gadopentetate dimeglumine (Gd-DTPA) administration (S6.007)

Pediatric Brain: Gadolinium Deposition in Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted Images Is Dependent on the Type of Contrast Agent.

The aim of this study was to identify the signal intensity (SI) changes in the dentate nucleus (DN) and the globus pallidus (GP) on unenhanced T1-weighted magnetic resonance (MR) images after multiple administration of gadolinium-based contrast agents (GBCAs) in children and compare those changes between linear and macrocyclic GBCAs. This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. We identified 92 children who underwent at least 4 consecutive MR examinations exclusively using either linear GBCA (gadodiamide or gadopentetate dimeglumine, n = 41) or macrocyclic GBCA (gadoterate meglumine, n = 51). Signal intensity ratio changes in the DN to pons and GP to thalamus between the first and last MR examinations were calculated. The SI ratios in the linear group increased significantly between the first and last MR examinations (mean difference: DN to pons, 0.0461 ± 0.0480, P < 0.001; GP to thalamus, 0.0332 ± 0.0385, P < 0.001), but not in the macrocyclic group (mean difference: DN to pons, -0.0010 ± 0.0371, P = 0.855; GP to thalamus, 0.0007 ± 0.0294, P = 0.867). In the linear regression analysis, the numbers of administrations of gadodiamide and gadopentetate dimeglumine were highly associated with the differences in SI ratios (DN to pons, P < 0.001 and P = 0.003; GP to thalamus, P < 0.001 and P = 0.002, respectively). The SIs of the DN and GP on unenhanced T1-weighted images increased after serial administrations of linear GBCA, but not macrocyclic GBCA, in children. The number of linear GBCA administration had a linear association with the SI changes in the DN and GP.

Dentate Nucleus Signal Intensity Decrease on T1-weighted MR Images after Switching from Gadopentetate Dimeglumine to Gadobutrol.

Purpose To determine if the increased dentate nucleus signal intensity following six or more doses of a linear gadolinium-based contrast agent (GBCA) (gadopentetate dimeglumine) changes at follow-up examinations performed with a macrocyclic GBCA (gadobutrol). Materials and Methods This retrospective study included 13 patients with increased dentate nucleus signal intensity following at least six (range, 6-18) gadopentetate dimeglumine administrations who then underwent at least 12 months of follow-up imaging with multiple (range, 3-29) gadobutrol-enhanced magnetic resonance (MR) examinations. Dentate nucleus-to-pons and dentate nucleus-to-cerebellar peduncle signal intensity ratios were measured by two radiologists blinded to all patient information, and changes were analyzed by using the paired t test and linear regression. Results The mean dentate nucleus-to-pons and dentate nucleus-to-cerebellar peduncle signal intensity ratios increased after gadopentetate dimeglumine administration, from 0.98 ± 0.03 to 1.10 ± 0.03 (P < .0001) and from 0.98 ± 0.030 to 1.09 ± 0.02 (P < .0001), respectively. With gadobutrol, the mean dentate nucleus-to-pons and dentate nucleus-to-cerebellar peduncle signal intensity ratios decreased to 1.03 ± 0.03 and 1.02 ± 0.04, respectively (P < .0001). With use of a mixed effects model linear regression allowing for each patient to have a different y intercept, mean dentate nucleus-to-pons and dentate nucleus-to-cerebellar peduncle signal intensity ratios decreased with follow-up time (dentate nucleus-to-pons: slope = -0.2% per month [95% confidence interval: -0.0024, -0.0015], R2 = 0.58, P < .0001 for nonzero slope; dentate nucleus-to-cerebellar peduncle: slope = -0.2% per month [95% confidence interval: -0.0024, -0.0015], R2 = 0.61, P < .0001 for nonzero slope). Conclusion Dentate signal intensity increased with at least six gadopentetate dimeglumine-enhanced MR examinations and decreased after switching from a linear (gadopentetate dimeglumine) to a macrocyclic (gadobutrol) GBCA. © RSNA, 2018 Online supplemental material is available for this article.

Intraindividual Analysis of Signal Intensity Changes in the Dentate Nucleus After Consecutive Serial Applications of Linear and Macrocyclic Gadolinium-Based Contrast Agents.

Recent studies reported an increase in the dentate nucleus (DN)-to-pons signal intensity (SI) ratio (DN-pons SI ratio) on unenhanced T1-weighted images in patients who received consecutive serial injections of linear gadolinium-based contrast agents (GBCAs). In contrast, most studies found no increase in the DN-pons SI ratio when patients were treated with consecutive serial injections of macrocyclic GBCAs. However, the potential difference between macrocyclic and linear GBCAs has never been assessed in individuals who received subsequent applications of both contrast agents. In this retrospective study, we assessed the evolution of the DN-pons SI ratio change in patients that were treated with a comparable number of serial consecutive injections of the linear GBCA gadopentetate dimeglumine and subsequent serial injections of the macrocyclic GBCAs gadobutrol and gadoterate meglumine. Data of 36 patients was analyzed. All patients underwent at least 5 consecutive administrations of the linear GBCA gadopentetate dimeglumine followed by an equal number of consecutive administrations of the macrocyclic GBCA gadobutrol. In 12 of the 36 patients, 5 or more final consecutive injections of the macrocyclic GBCA gadoterate meglumine were analyzed additionally. The difference of DN-pons SI ratios on unenhanced T1-weighted images was calculated by subtracting the ratio at the first examination from the ratio at the last examination in each of the 3 periods. The mean DN-pons SI ratio difference in the gadopentetate dimeglumine period was significantly greater than 0 (mean ± SD, 0.0448 ± 0.0345; P < 0.001), whereas the mean DN-pons SI ratio difference in the subsequent gadobutrol and gadoterate meglumine period was significantly smaller than 0 (gadobutrol: -0.0178 ± 0.0459, P = 0.026; gadoterate meglumine: -0.0250 ± 0.0284, P = 0.011). In this observational study, the application of the linear GBCA gadopentetate dimeglumine was associated with a DN-pons SI ratio increase, whereas subsequent applications of the macrocyclic GBCAs gadobutrol or gadoterate meglumine in the same patients were not. Rather, the current data tentatively suggest a decrease in preexisting hyperintensities over time when linear GBCAs are changed to macrocyclic GBCAs, potentially indicating a washout effect or precipitation of gadolinium. Future patient studies need to include control groups to replicate the present results, and additional animal studies should be conducted to clarify the underlying mechanism of the proposed SI decrease.