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The dentate nucleus (arrows) in unenhanced T1-weighted images (a), qR1 relaxation rate maps (b) and qT2 relaxation time maps (c), at the first time point (upper row) and after 14 administrations of gadobutrol (lower row). No signal change is observable between the first and last time point in either T1w, qR1 or qT2 images. The images are of subject 7, a 39-year-old female who underwent the longest follow-up (85 weeks) and the highest number (14) of contrast agent administrations
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Purpose:
To assess if ratios of T1-weighted (T1w) signal intensity (SI) and quantitative T1 relaxometry (qT1) change on serial administration of macrocyclic gadobutrol.
Methods:
A total of 17 glioblastoma patients were scanned at 3.0 T magnetic resonance imaging (MRI) every 6 weeks after tumor resection with standard MRI and T1 and T2 relaxometr...
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Citations
... T1-and T2-relaxometry of the DN and GP has been reported as robust quantitative methods for this purpose. [28][29][30][31] Quantitative susceptibility mapping (QSM), based on paramagnetic effects of gadolinium, also captures signal changes in the DN following multiple GBCA administrations and has recently been shown to outperform T1-weighted imaging. 32,33 Magnetization transfer (MT) is another quantitative MRI technique that may have a meaningful role in the evaluation of gadolinium retention. ...
... Another quantitative MRI approach that has been successfully applied and warrants further exploration is T1/T2 relaxometry. [28][29][30][31] A strength of this proof-of-concept study is that the enrolled MS cohort had received a relatively high number of GBCA administrations, increasing the likelihood of being able to demonstrate dose-dependent associations to MRI signal abnormalities. Another strength is the existence of a well-matched healthy control group without any GBCA administrations. ...
Background and Purpose: Evidence of brain gadolinium retention has affected
gadolinium-based contrast agent usage. It is, however, unclear towhat extentmacrocyclic
agents are retained andwhether their in vivo detectionmay necessitate nonconventional
MRI. Magnetization transfer (MT) could prove suitable to detect gadolinium-related signal
changes since dechelated gadolinium ions bind to macromolecules. Therefore, this
study aimed to investigate associations of prior gadolinium administrations with MT and
T1 signal abnormalities.
Methods: A cohort of 23 persons with multiple sclerosis (MS) (18 females, 5 males,
57 8.0 years) with multiple past gadolinium administrations (median 6, range 3-12)
and 23 age- and sex-matched healthy controls underwent 1.5 Tesla MRI with MT, T1-
weighted 2-dimensional spin echo, and T1-weighted 3-dimensional gradient echo. The
signal intensity index was assessed byMRI in gadolinium retention predilection sites.
Results: There were dose-dependent associations of the globus pallidus signal on gradient
echo (r = .55, p < .001) and spin echo (r = .38, p = .013) T1-weighted imaging, but
not on MT. Relative to controls, MS patients had higher signal intensity index in the dentate
nucleus on T1-weighted gradient echo (1.037 0.040 vs. 1.016 0.023, p = .04)
with a similar trend in the globus pallidus on T1-weighted spin echo (1.091 0.034 vs.
1.076 0.014, p = .06).MT detected no group differences.
Conclusions: Conventional T1-weighted imaging provided dose-dependent associations
with gadolinium administrations in MS, while these could not be detected with
2-dimensional MT. Future studies could explore newer MT techniques like 3D and inhomogenous
MT. Notably, these associations were identified with conventional MRI even
though most patients had not received gadolinium administrations in the preceding
9 years, suggestive of long-term retention.
... Evaluations of quantitative relaxometry data after exclusively serial macrocyclic CA administrations remain sparse with inconclusive results between studies. [30][31][32][33][34][35][36][37] Further, retrospective studies often lack age-matched control groups with no prior exposure to GBCAs. The reported ambiguous outcomes for macrocyclic GBCAs regarding T1 shortening spur the need for further thorough research. ...
... Clinical and preclinical studies have been conducted to evaluate the short-and long-term effect of repeated GBCA injections on MRI parameters, to assess a potential safety concern regarding gadolinium accumulation in the brain. 25,[27][28][29][30][31][32][33][34][35][36][37][38][54][55][56] The conclusiveness of these studies is challenged by controversial results regarding the existence of permanent changes of T1-weighted SIs and T1 values after exclusively serial macrocyclic CA administrations, [30][31][32][33][34][35][36][37] as well as the correlation of age with a signal change in T1-weighted MRI, [30][31][32][33]42,43 specifically in the GP and DCN region of the brain. ...
... Clinical and preclinical studies have been conducted to evaluate the short-and long-term effect of repeated GBCA injections on MRI parameters, to assess a potential safety concern regarding gadolinium accumulation in the brain. 25,[27][28][29][30][31][32][33][34][35][36][37][38][54][55][56] The conclusiveness of these studies is challenged by controversial results regarding the existence of permanent changes of T1-weighted SIs and T1 values after exclusively serial macrocyclic CA administrations, [30][31][32][33][34][35][36][37] as well as the correlation of age with a signal change in T1-weighted MRI, [30][31][32][33]42,43 specifically in the GP and DCN region of the brain. ...
Objectives:
The aim of the study was to investigate the possible influence of changes in the brain caused by age on relaxometric and relaxation time-weighted magnetic resonance imaging (MRI) parameters in the deep cerebellar nuclei (DCN) and the globus pallidus (GP) of Gd-exposed and control rats over the course of 1 year.
Materials and methods:
Twenty-five Wistar-Han rats were equally subdivided into 5 groups and initially received 8 injections on 4 consecutive days per week of either 3.6 mL/kg body weight saline (group I-III) or 1.8 mmol Gd/kg body weight gadobutrol (group IV) or gadodiamide (group V). T1- and T2-weighted scans, as well as relaxation maps, were acquired at 1 week (all groups); 5, 12, 20, and 26 weeks (saline II, gadobutrol, gadodiamide); and at 35, 44, and 52 weeks (saline III, gadobutrol, gadodiamide) after the last administration. Saline I was euthanized after 1 week, saline II after 26 weeks, and the remaining groups after 52 weeks. Signal intensities (SIs) were evaluated for the DCN/pons (P) and the GP/piriform cortex (PC) ratios, and relaxation times for the DCN and the GP. Brain tissue was extracted, and the gadolinium, iron, and manganese contents were quantified with inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation-ICP-MS imaging.
Results:
T1-weighted SI ratios did not show any significant trend with age in any region. The between-group analysis at 52 weeks resulted in a significant difference for the DCN/P and GP/PC region ratio between gadodiamide and its comparators. T1 relaxation times dropped with increasing age in the GP with a 10% to 20% difference between first and last measurement for all groups, and in the DCN <10% with a significant decrease for the gadodiamide group only (DCN: P = 0.0158). Group-related differences were observed at the last measurement time point for T1 values between gadodiamide and saline III in the DCN (P = 0.0153) and gadodiamide and gadobutrol in the GP (P = 0.0287). Analysis of the SI ratios of the T2-weighted images revealed a significant increase for the DCN/P and a decrease for the GP/PC with increasing age for all groups and no differences at 52 weeks after the last injection between groups. T2 values of the GP showed a significant linear decrease over time for all groups (saline I-III: P = 0.0101; gadobutrol: P = 0.0001; gadodiamide: P = 0.0142) in the aging rat brain. Quantitative imaging of manganese and iron by laser ablation-ICP-MS showed a linear increase for the saline groups in the GP for both metals (Fe: P < 0.0001; Mn: P = 0.0306) and in the DCN for manganese only (P = 0.0187), but no differences between groups at 52 weeks.
Conclusions:
Extensive MRI evaluation did not reveal an indication of SI or relaxation time changes associated with multiple exposure to the macrocyclic-chelated GBCA gadobutrol in the DCN and the GP. With increasing age, a T1 and T2 shortening in the GP and an increase in T2-weighted SI ratio in the DCN/P, as well as a decrease in the GP/PC, were observed for all groups. Such age-related changes can potentially bias MRI results as an indicator for gadolinium presence in the brain.
... Recently, many studies have reported an association between increased signal intensities (SI) on unenhanced T1weighted images in the dentate nucleus (DN), globus pallidus (GP) and other brain regions and the history of repeated intravenous administrations of linear GBCAs in patients with normal renal function [8][9][10][11][12][13][14][15][16][17][18][19][20]. Conversely, the more stable macrocyclic GBCAs were not associated with brain SI increase [10,12,16,18,[21][22][23][24], suggesting that the molecular structure of the GBCA is a crucial factor for the SI increase. In fact, in July 2017 the European Medicines Agency (EMA) concluded its review on GBCAs, confirming recommendations to restrict the use of linear gadolinium agents used in body MRI, including the heart (EMA/457616/2017). ...
PurposeA prospective study was conducted to evaluate signal changes in the dentate nucleus, globus pallidus, pons, and thalamus (normalized to the deep cerebellum white matter) in T1-weighted magnetic resonance (MR) images after serial injections of gadobutrol in patients with thalassemia without neurological lesions.Methods
In this study three groups were scanned at both 1.5 T and 3 T: 15 thalassemia patients transfused and chelated with ≥4 gadobutrol administrations at a high dose (0.2 mmol/kg per scan) for late gadolinium enhancement (LGE) cardiovascular MR, 8 thalassemia patients and 13 healthy subjects who had never received gadolinium-based contrast agents (GBCA).ResultsSignal intensity (SI) ratios at 1.5 T in all regions were comparable among the three groups and were not correlated with the number of gadobutrol administrations.In healthy subjects SI ratios were significantly different among the 4 regions, being higher in the pallidus.The SI ratios at 1.5 T were significantly higher and not correlated with SI ratios at 3 T or with iron overload in the same regions assessed by the T2* technique.Conclusion
This article describes the lack of increased SI in T1-weighted MR images after repeated administration of gadobutrol for cardiovascular MR studies in a high-risk population (high dose per scan, iron overload that can facilitate the transmetalation of gadolinium) scanned at 3 T and 1.5 T.
... Histopathologic studies have shown that gadolinium retention is widespread and also occurs in brain regions that are often used as a reference, such as the thalami. 9 Relaxometry provides the means to study gadolinium retention quantitatively without the need for a reference region, but so far, there are only a few T1-relaxometry studies in the context of gadolinium retention, 10,11 and no T2relaxometry studies. While chelated GBCAs lead to a shortening of T1, they also cause a shortening of T2. 12 The clinical significance of the retained gadolinium is debated, but medical authorities have used the precaution of moderating the use of mainly the linear GBCAs. ...
... Macrocyclic agents have histopathologically been shown to be retained to a lower degree than linear GBCAs and have previously shown weaker or no associations in imaging studies. 2,3,11,31,32 However, the lack of significant associations within the macrocyclic group might also be caused by the small number of patients (n ϭ 15) and the relatively few administrations of macrocyclic GBCAs (median, 3) in the current study. Meanwhile, significant associations were found in the linear group, which was even smaller (n ϭ 11), illustrating that the methodology used in this study is sensitive in picking up signal changes related to previous GBCA administrations and that the lack of significant results in the macrocyclic group may indeed reflect differences in the degree of retention between linear and macrocyclic GBCAs. ...
Background and purpose:
Brain gadolinium retention is consistently reported for linear gadolinium-based contrast agents, while the results for macrocyclics are contradictory and potential clinical manifestations remain controversial. Furthermore, most previous studies are based on conventional T1-weighted MR imaging. We therefore aimed to quantitatively investigate longitudinal and transversal relaxation in the brain in relation to previous gadolinium-based contrast agent administration and explore associations with disability in multiple sclerosis.
Materials and methods:
Eighty-five patients with MS and 21 healthy controls underwent longitudinal and transverse relaxation rate (R1 and R2) relaxometry. Patients were divided into linear, mixed, and macrocyclic groups based on previous gadolinium-based contrast agent administration. Neuropsychological testing was performed in 53 patients. The dentate nucleus, globus pallidus, caudate nucleus, and thalamus were manually segmented. Repeatability measures were also performed.
Results:
The relaxometry was robust (2.0% scan-rescan difference) and detected higher R1 (dentate nucleus, globus pallidus, caudate nucleus, thalamus) and R2 (globus pallidus, caudate nucleus) in patients receiving linear gadolinium-based contrast agents compared with controls. The number of linear gadolinium-based contrast agent administrations was associated with higher R1 and R2 in all regions (except R2 in the thalamus). No similar differences and associations were found for the macrocyclic group. Higher relaxation was associated with lower information-processing speed (dentate nucleus, thalamus) and verbal fluency (caudate nucleus, thalamus). No associations were found with physical disability or fatigue.
Conclusions:
Previous linear, but not macrocyclic, gadolinium-based contrast agent administration is associated with higher relaxation rates in a dose-dependent manner. Higher relaxation in some regions is associated with cognitive impairment but not physical disability or fatigue in MS. The findings should be interpreted with care but encourage studies into gadolinium retention and cognition.
... Again, this discrepant finding might be explained by the thalamus as reference area. In contrast Müller et al. found no changes in relaxation time in 17 subjects with a mean of 8 gadobutrol administrations, even by using the frontal white matter for normalization 18 . Although the number of adminstrations is comparable to Kang's study and our study, the number of patients is distinctly lower, which might explain the different results. ...
The aim of the study was to investigate the signal-intensity-(SI)-ratio changes in the basal ganglia, the pulvinar thalami (PN), and the dentate nucleus (DN) using frontal white matter (FWM) as reference area, in patients with multiple sclerosis after frequent administrations of gadobutrol. A control group (group I) was compared to three stratified patient groups (group II: mean applications of gadobutrol 3.7; group III: 7.5 applications; group IV: 13.8 applications). SI-ratios of the pallidum, putamen, caudate nucleus, and pulvinar thalami were calculated with: 1. FWM, and 2. PN. DN-to-pons and DN-to-FWM ratios were also calculated. The most significant SI-ratio-changes were found by comparing group I and IV for both reference values. However, by using FWM as reference an SI-ratio increase was observed, while an SI-ratio decrease was seen if referenced to the PN. DN-to-FWM showed an SI-ratio increase, too. The PN revealed a significant SI-ratio increase itself, correlating with the number of gadolinium applications, when referenced to FWM. Therefore, SI-ratio calculations using the thalamus as reference might be flawed. In addition, a minor gadolinium accumulation is possible, if FWM was used as reference area. Further studies are necessary to verify our results.
... To express their appreciation, the nine articles following this laudation [1][2][3][4][5][6][7][8][9] in this edition of the journal are dedicated to you from your admirers in Frankfurt, Bonn and Hannover. ...
Introduction and aims
Contradictory results have been reported about hyperintensity of the globus pallidus and/or dentate nucleus on unenhanced T1-weighted magnetic resonance (MR) images after exposure to various gadolinium-based contrast agents. This change in signal intensity varies with different gadolinium-based contrast agents. We aimed to determine whether signal intensity in the dentate nucleus is increased in unenhanced T1-weighted images in patients who have undergone multiple studies with the macrocyclic gadolinium-based contrast agent gadoterate meglumine. We thoroughly reviewed the literature to corroborate our results.
Materials and methods
We included patients who had undergone more than 10 MR studies with gadoterate meglumine. We quantitatively analyzed the signal intensity in unenhanced T1-weighted MR images measured in regions of interest placed in the dentate nucleus and the pons, and we calculated the dentate nucleus-to-pons signal intensity ratios and the differences between the ratio in the first MR study and the last MR study. We used t-tests to evaluate whether the differences between the signal intensity ratios were different from 0. We also analyzed the subgroups of patients who had been administered <15 and ≥15 doses of gadoterate meglumine. We used Pearson correlation to determine the relationships between the differences in the signal intensity ratios and the number of doses of gadoterate meglumine administered.
Results
The 54 patients (26 men) had received a mean of 13.8 ± 3.47 doses (range, 10−23 doses). The difference in the dentate nucleus-pons signal intensity ratio between the first and last MR study was -0.0275 ± 0.1917 (not significantly different from 0; p = 0.2968) in the entire group, -0.0357 ± 0.2204 (not significantly different from 0; p = 0.351 in the patients who had received <15 doses (n = 34), and -0.0135 ± 0.1332 (not significantly different from 0; p = 0.655) in those who had received ≥15 doses (n = 20). Differences in signal intensity ratios did not correlate significantly with the accumulated dose of gadoterate meglumine (P = 0.9064; ρ = -0.0164 [95%]).
Conclusions
Receiving more than 10 doses of gadoterate meglumine was not associated with increased signal intensity in the dentate nucleus.
Introduction and aims:
Contradictory results have been reported about hyperintensity of the globus pallidus and/or dentate nucleus on unenhanced T1-weighted magnetic resonance (MR) images after exposure to various gadolinium-based contrast agents. This change in signal intensity varies with different gadolinium-based contrast agents. We aimed to determine whether signal intensity in the dentate nucleus is increased in unenhanced T1-weighted images in patients who have undergone multiple studies with the macrocyclic gadolinium-based contrast agent gadoterate meglumine. We thoroughly reviewed the literature to corroborate our results.
Materials and methods:
We included patients who had undergone more than 10 MR studies with gadoterate meglumine. We quantitatively analyzed the signal intensity in unenhanced T1-weighted MR images measured in regions of interest placed in the dentate nucleus and the pons, and we calculated the dentate nucleus-to-pons signal intensity ratios and the differences between the ratio in the first MR study and the last MR study. We used t-tests to evaluate whether the differences between the signal intensity ratios were different from 0. We also analyzed the subgroups of patients who had been administered<15 and ≥15 doses of gadoterate meglumine. We used Pearson correlation to determine the relationships between the differences in the signal intensity ratios and the number of doses of gadoterate meglumine administered.
Results:
The 54 patients (26 men) had received a mean of 13.8±3.47 doses (range, 10-23 doses). The difference in the dentate nucleus-pons signal intensity ratio between the first and last MR study was -0.0275±0.1917 (not significantly different from 0; p=0.2968) in the entire group, -0.0357±0.2204 (not significantly different from 0; p=0.351 in the patients who had received <15 doses (n=34), and -0.0135±0.1332 (not significantly different from 0; p=0.655) in those who had received ≥15 doses (n=20). Differences in signal intensity ratios did not correlate significantly with the accumulated dose of gadoterate meglumine (P=0.9064; ρ=-0.0164 [95%]).
Conclusions:
Receiving more than 10 doses of gadoterate meglumine was not associated with increased signal intensity in the dentate nucleus.
Objectives:
Quantitative T1 relaxometry is the benchmark in imaging potential gadolinium deposition and known to be superior to semiquantitative signal intensity ratio analyses. However, T1 relaxometry studies are rare, commonly limited to a few target structures, and reported results are inconsistent.We systematically investigated quantitative T1 relaxation times (qT1) of a variety of brain nuclei after serial application of gadobutrol.
Materials and methods:
Retrospectively, qT1 measurements were performed in a patient cohort with a mean number of 11 gadobutrol applications (n = 46) and compared with a control group with no prior gadolinium-based contrast agent administration (n = 48). The following target structures were evaluated: dentate nucleus, globus pallidus, thalamus, hippocampus, putamen, caudate, amygdala, and different white matter areas. Subsequently, multivariate regression analysis with adjustment for age, presence of brain metastases and previous cerebral radiotherapy was performed.
Results:
No assessed site revealed a significant correlation between qT1 and number of gadobutrol administrations in multivariate regression analysis. However, a significant negative correlation between qT1 and age was found for the globus pallidus as well as anterior and lateral thalamus (P < 0.05 each).
Conclusions:
No T1 relaxation time shortening due to gadobutrol injection was found in any of the assessed brain structures after serial administration of 11 doses of gadobutrol.
Les chélates de Gd sont largement utilisés en tant qu’agents de contraste en imagerie par résonance magnétique. En 2015, un lien a été établi entre l’observation d’hypersignaux T1 de certaines structures cérébrales et le nombre d’administrations préalables de ces chélates de Gd reçues par les patients. Cette observation fortuite pose la question de la tolérance à long-terme de ces molécules. L’ion Gd³⁺ ayant un rayon ionique très proche de celui du Ca²⁺, il interfère avec de nombreux processus biologiques Ca²⁺-dépendants. Sa chélation par un ligand améliore considérablement sa tolérance. Les chélates de Gd sont répartis en 2 classes : macrocycliques et linéaires, différant par leur stabilité thermodynamique et donc leur tendance à se dissocier. Il est classiquement admis que les chélates de Gd ne traversent pas la barrière hémato-encéphalique saine. L’observation de ces hypersignaux au niveau du noyau dentelé du cervelet, du globus pallidus et parfois d’autres structures, remet en cause ce postulat.Les travaux de cette thèse visent à étudier le mécanisme d’accumulation du Gd dans le système nerveux central (voies de passage, localisations, spéciation du Gd accumulé). Les potentiels effets neurotoxiques associés à la présence de Gd dans le cerveau ont aussi été recherchés.Nous avons mis en évidence chez le Rat que l’accumulation cérébrale est d’autant plus importante que la stabilité thermodynamique du chélate de Gd est faible, confirmant les observations cliniques. Les hypersignaux T1 sont en effet liés à des injections répétées de chélates linéaires de Gd. Nous avons aussi établi qu’une insuffisance rénale modérée potentialise la capture cérébrale de Gd dans le cas d’un chélate de Gd linéaire. Nous avons observé que les structures cérébrales accumulent d’autant plus de Gd qu’elles sont riches en fer endogène. Une augmentation de la zincurie, après administration de chélates de Gd linéaires, a également été observée, suggérant un phénomène de transmétallation.La combinaison des techniques de fluorescence X (XRF), de microscopie électronique en transmission (TEM) et du NanoSIMS, a permis l’observation des dépôts de Gd à différentes échelles et sous différentes formes. Cela a permis de documenter les voies de passage du Gd, le rôle des métaux endogènes et du phosphore. L’analyse XRF a permis d’observer qu’au sein des noyaux cérébelleux profonds du Rat, la majorité du Gd est accumulée sous la forme de structures allongées et ramifiées. Ces structures pourraient être des vaisseaux sanguins. Le Gd serait accumulé dans l’espace périvasculaire. En TEM, des dépôts insolubles de Gd ont été observés dans les lames basales de vaisseaux, dans l’interstitium cérébelleux, et dans l’espace périvasculaire. Ces dépôts à l’apparence épineuse sont riches en phosphore, suggérant des dépôts de GdPO₄. Du Gd et du phosphore ont également été identifiés dans des cellules gliales, au sein de pigments intracellulaires de lipofuscine. Aucun dépôt de Gd n’a été trouvé chez des rats traités par un chélate de Gd macrocyclique.L’hypothèse mécanistique établie consiste en l’accès précoce des chélates de Gd au liquide céphalo-rachidien (LCR), puis leur diffusion passive dans le parenchyme proche des ventricules cérébraux, à travers l’épendyme. Arrivés dans des zones riches en métaux endogènes et/ou en phosphore, leschélates de Gd les moins stables thermodynamiquement se dissocieraient, le Gd se liant à des macromolécules endogènes, ou précipitant. La circulation du LCR le long des artérioles pénétrantes piègerait également du Gd au niveau périvasculaire. Les chélates de Gd intacts seraient éliminés par le système glymphatique périvasculaire ou « drainage périartériel intrapariétal ». On retrouve aussi du Gd probablement dissocié à ce niveau.Hormis une hypoactivité, non spécifique, les études neurocomportementales, histopathologiques et neurochimiques menées chez le Rat n’ont pas permis de mettre en évidence une toxicité avérée, même à des doses élevées.
