François Lersy
email: francois.lersy@hotmail.fr

Anne-Lise Diepenbroek
email: annelise.diepenbroek@gmail.com

Julien Lamy
email: lamy@unistra.fr

Thibauilt Willaume

Guillaume Bierry
email: guillaume.bierry@chru-strasbourg.fr

Francois Cotton
email: francois.cotton@chu-lyon.fr

Stephane Kremer
email: stephane.kremer@chru-strasbourg.fr

Thibault Willaume
email: thibault.willaume@chru-strasbourg.fr

François Cotton

Stéphane Kremer

Signal changes in enhanced T1-weighted images related to gadolinium retention: A three-time-point imaging study

Keywords:

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Contrast-enhanced magnetic resonance imaging (MRI) plays a major role in the diagnosis and follow-up of patients with a variety of neurological diseases and is routinely used in neuroimaging through the administration of gadolinium-based contrast agents (GBCAs) [START_REF] Kanal | Gadolinium Contrast Agents for CNS Imaging: Current Concepts and Clinical Evidence[END_REF][START_REF] Chazot | Brain MRIs make up the bulk of the gadolinium footprint in medical imaging[END_REF][START_REF] Brisset | New OFSEP recommendations for MRI assessment of multiple sclerosis patients: Special consideration for gadolinium deposition and frequent acquisitions[END_REF]. Over the past 7 years [START_REF] Kanda | High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material[END_REF], concern has grown worldwide after the finding of gadolinium deposits in the brain.

In 2013, Kanda et al. [START_REF] Kanda | High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material[END_REF] were the first to report the existence of intracranial gadolinium retention, based on the findings of high signal intensities on T1-weighted (W) images in two brain structures, the dentate nucleus (DN) and the globus pallidus (GP). They used the dentate nucleus-to-pons (DN/P) and the globus pallidus-to-thalamus (GP/T) signal intensity (SI) ratios in patients receiving repeated doses of linear GBCAs (gadopentetate dimeglumine, Magnevist®, Bayer; gadodiamide, Omniscan®, GE). Since then, multiple retrospective studies [START_REF] Kanda | High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration[END_REF][START_REF] Ramalho | High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents[END_REF] have confirmed these findings after five injections or more of gadopentetate dimeglumine, gadodiamide, or gadobenate dimeglumine (Multihance®, Bracco). Some studies have exclusively assessed exposure to macrocyclic GBCAs (gadoteridol, Prohance®, Bracco; gadoterate meglumine, Dotarem®, Guerbet; gadobutrol, Gadovist®, Bayer) and did not find any increased SI [START_REF] Kanda | High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration[END_REF][START_REF] Radbruch | Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent[END_REF][START_REF] Radbruch | No Signal Intensity Increase in the Dentate Nucleus on Unenhanced T1-weighted MR Images after More than 20 Serial Injections of Macrocyclic Gadolinium-based Contrast Agents[END_REF]. Correlation between the SI increase and gadolinium deposition in the neural tissue was further confirmed by histopathological correlation studies in postmortem tissue samples [START_REF] Murata | Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function[END_REF][START_REF] Kanda | Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy[END_REF]. This retention depends on the type of gadolinium chelate used. Macrocyclic GBCAs are deposited in tiny amounts without inducing an appreciable increase in the T1 signal. This discrepancy can mostly be attributed to the higher thermodynamic and kinetic stabilities of the macrocyclic GBCAs, which are therefore less prone to releasing dissociated Gd3+ in tissues [START_REF] Morcos | Extracellular gadolinium contrast agents: differences in stability[END_REF][START_REF] Idée | Role of thermodynamic and kinetic parameters in gadolinium chelate stability[END_REF]. However, the mechanism of gadolinium deposition in brain tissues remains unclear, and several related questions are left unanswered, including the form and the stability over time of this accumulation and the potential clearance of gadolinium from the brain ("wash-out" effect). Only a single clinical study to date [START_REF] Radbruch | Intraindividual Analysis of Signal Intensity Changes in the Dentate Nucleus After Consecutive Serial Applications of Linear and Macrocyclic Gadolinium-Based Contrast Agents[END_REF] has investigated the evolution of signal changes over time in patients receiving injections of GBCAs during follow-up examinations. The latter showed a DN/P SI ratio increase after administering gadopentetate dimeglumine, not found after subsequent applications of macrocyclic agents in the same patients.

Therefore, we conducted a three-time-point retrospective, multicenter, longitudinal study to explore T1 signal changes over time in the DN and GP using automatic segmentation. In order to investigate the signal variations, we compared SI ratios at the baseline, fifth, and tenth MRI examinations after injection of two classes of gadolinium chelates (either a macrocyclic agent, gadoterate meglumine, or a linear agent, gadobenate dimeglumine).

MATERIALS AND METHODS

The local ethics committee approved the design and the execution of this multicenter, retrospective, longitudinal study. The requirement to obtain written informed consent was waived because this was a retrospective study. The study was registered with ClinicalTrials.gov, NCT number: NCT02992847.

Study design and population

Two study groups were identified, comprising 18 patients (Department of Medical Imaging, Strasbourg University Medical Center) and 19 patients (Department of Medical Imaging, Lyon University Medical Center).

To compose these groups, we searched for subjects fulfilling the inclusion criteria in our electronic database of MRI examinations conducted between February 2008 and December

2016.

Inclusion criteria were: (a) history of at least ten injections of either gadoterate meglumine (Group 1, Strasbourg) or gadobenate dimeglumine (Group 2, Lyon); (b) all consecutive MRI examinations were performed in the same center.

After examining the medical records, we chose to exclude patients who had (a) undergone contrast agent administration outside our institutions or had undergone MRI with other GBCAs.

To avoid possible confounding factors, we excluded (b) patients with diseases that may result in T1 shortening in the deep gray matter (Wilson disease, Rendu-Osler-Weber disease, manganese toxicity, hemodialysis, total parenteral nutrition, and neurofibromatosis). Other exclusion criteria included (c) unsatisfactory images due to MRI artifacts or brain lesions involving the GP, the ND, the thalamus, or the pons, (d) renal insufficiency defined as an estimated glomerular filtration rate (eGFR) lower than 60 mL/min per 1.73 m2 in a blood sample with respect to the date of the MRI examination, and (e) history of liver disease (increased liver values were defined as increased serum levels of the liver transaminases or GGT).

Age, sex, diagnosis, renal function, liver values, total dosage of GBCAs, and time intervals between first and middle and first and last MRI examinations were gathered for all patients included in the study.

For the first center, Strasbourg, we extracted data for 48 patients who underwent a minimum of ten MRI examinations and for whom every instance of contrast agent administration exclusively involved gadoterate meglumine. Of these 48 patients, 18 were included, 30 patients were excluded owing to excessive distortion in regions of interest (ROIs) or because the fifth MRI examination was missing. This group consisted of 11 males and seven females (mean age: 38.3 ± 17.3 years). The cumulated mean injected volume of GBCAs was 159 ± 37 mL, and the mean interval between the first and fifth administration was 1 ± 0.6 years, amounting to 2.4 ± 1.5 years between the first and tenth injection. A total of 17 patients presented with an eGFR of more than 90 mL/min per 1.73m2; one patient had an eGFR of <90, but >60, and no increased liver values were found.

For the second center, Lyon, we extracted data for 21 patients who underwent a minimum of ten MRI examinations using gadobenate dimeglumine administration. A total of 19 patients were finally included; one was excluded because of renal dysfunction and one because of excessive distortion in the ROIs. This group consisted of 12 males and seven females (mean age: 51.7 ± 11.7 years). The cumulated mean injected volume was 145 ± 12 mL, and the mean interval between the first and fifth administration was 1.9 ± 0.7 years, amounting to 3.9 ± 1.2 years between the first and tenth injection. Of these patients, 19 presented with an eGFR of more than 90 mL/min per 1.73m2, and no increased liver values were found.

For both groups, most of the patients underwent successive brain MRI for the follow-up of primary brain tumors (Group 1, n=15; Group 2, n=17); the other diagnoses included screening for metastases (Group 1, n=3; Group 2, n=2). Ten patients from each group received tumorselective brain radiation therapy.

The demographic and clinical characteristics of the study patients are shown in Table 1.

In order to assess signal variation, we decided to collect and analyze data at three-time points: MRI1, baseline, before any injection of GBCAs; MRI2, after five injections of GBCAs; and MRI3, after ten injections of GBCAs. We chose to realize the first analysis after five injections since changes in signal are generally observed at this point [START_REF] Radbruch | Intraindividual Analysis of Signal Intensity Changes in the Dentate Nucleus After Consecutive Serial Applications of Linear and Macrocyclic Gadolinium-Based Contrast Agents[END_REF].

MRI and GBCAs administration

All patients underwent brain imaging performed on one of the MR instruments dedicated to neuroradiologic imaging using either a 1.5-T or 3-T MRI system (Magnetom Avanto 1.5T, Siemens, Aera 1.5T Siemens, Signa 3T GE, Achieva 3T Philips, Ingenia 3T, or 1.5T Philips).

The MRI protocol for the patients varied according to the center and the clinical indications, but all protocols included enhanced three-dimensional (3D) gradient-echo T1-W images, and GBCAs were injected in the MRI room. Unenhanced 3D T1 sequences were not available, as they were not part of the MRI protocols used for the patients in this study. Therefore, SI was measured on 3D-enhanced T1 sequences acquired after intravenous injection of a standardized dose of 15 or 20 mL GBCAs per contrast-enhanced MRI study. This approach was used in previous studies that yielded consistent results [START_REF] Jaulent | Weekly enhanced T1-weighted MRI with Gadobutrol injections in MS patients: Is there a signal intensity increase in the dentate nucleus and the globus pallidus?[END_REF][START_REF] Tanaka | Increased Signal Intensity in the Dentate Nucleus of Patients with Multiple Sclerosis in Comparison with Neuromyelitis Optica Spectrum Disorder after Multiple Doses of Gadolinium Contrast[END_REF], and it is suitable for long-term longitudinal analysis.

MRI data analysis and MR image segmentation

Quantitative analysis was performed using DN/P and GP/T ratios [START_REF] Kanda | High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material[END_REF]. We applied an automatic segmentation method as an alternative to manual ROIs delineation as it is more reproducible and gives more consistent results across all examinations. This technique allowed for the analysis of the entire structure, instead of measurements on subjectively selected two-dimensional (2D) slices through each ROIs. The different brain structures were defined with the SPL atlas (based on data of a healthy 42-year-old male volunteer) [START_REF] Halle | Multi-modality MRI-based Atlas of the Brain[END_REF]. The left and right structures were considered as a single region for the statistical analyses. The T1-W images of all subjects were registered to the SPL template using the diffeomorphic registration method of the advanced normalization tools (ANTs) [START_REF] Avants | Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain[END_REF]. The resulting geometric transform was then applied to the ROIs to transport them to the subject-specific space. A final check of the transform quality using 3D Slicer software [18,[START_REF] Fedorov | 3D Slicer as an image computing platform for the Quantitative Imaging Network[END_REF] was made by consensus of two radiologists (a resident with 4.5 years of experience and a senior specialist with 7.5 years of experience), who were trained and supervised by a neuroradiology expert (with more than 20 years of experience). An example of segmentation of DN/P and GP/T using 3D Slicer is shown in Online Supplement Figures 1 and2. The mean intensity of each structure at each time point was used to define the DN/P and GP/T ratios. As shown on Figure 1, the ratio not only varies along time but also with the contrast agent (different levels and different profiles on each row), and with the ROIs (different levels on each column, the profiles are however similar).

Statistical analysis

All following analyses were done with R (version 3.4; R Foundation for Statistical Computing). The evolution of the signal intensity ratios was investigated using a single mixed-effects linear model with a random intercept for the subject, and with fixed effects for the contrast agent, the time point, the ROI, as well as their second-and third-level interactions (lmer function from the lme4 package, using the formula ratio ~ agent* timepoint*roi + (1|subject)). An ANOVA was computed on the model to evaluate the effect of each predictor (anova.lmerModLmerTest of the lmerTest package). For each contrast agent and for each ROI, the SI ratio difference between the first and respectively the fifth and the tenth time point was computed, along with the 95% confidence interval (CI) and the p-value with the null hypothesis being that the difference is equal to 0.

The pvalues were adjusted for multiple comparisons by Dunnett's procedure, using the emmeans package.

RESULTS

The registration and subsequent segmentation were performed correctly for all subjects.

The model assumptions were validated from a Q-Q plot of the model residuals versus a normal distribution. The model ANOVA indicated that the signal intensity varies differently along time across the contrast agents (interaction of the agent and time point predictors, p=0.025), that the mean level for each ROI is different (ROI predictor, p<0.001), and that the signal varies similarly along time across the ROIs (interaction of the ROI and time point predictors, p=0.858). Table 2 shows the effect of all model variables.

The DN/P SI ratios tended to increase after the fifth administration of gadobenate dimeglumine (95% CI [-0.002, 0.078], p=0.064). After the tenth administration, the SI ratio was still slightly higher than the first time point (95% CI [-0.018, 0.062], p=0.379). Similar variations were found in the GP/T SI ratios, albeit with smaller differences: the difference between the fifth and the first administration had a 95% CI of [-0.020, 0.060] (p=0.427), and the difference between the tenth and the first administration had a 95% CI of [-0.033, 0.048] (p=0.866).

For the gadoterate meglumine group, the values of the DN/P SI ratios were decreased after the fifth administration (95% CI [-0.082, 0.000], p=0.053), and were still slightly lower than the first time point after the tenth administration (95% CI [-0.064, 0.018], p=0.359). As in the gadobenate dimeglumine group, the variations in the GP/T SI ratios were much smaller although following the same pattern: the difference between the fifth and the first administration had a 95% CI of [-0.066, 0.016] (p=0.302), and the difference between the tenth and the first administration had a 95% CI of [-0.069, 0.014] (p=0.246).

These results are summarized in Table 3a for the gadobenate dimeglumine group and Table 3b for the gadoterate meglumine group.

DISCUSSION

This multicenter, retrospective study shows that exposure to gadobenate dimeglumine, a linear GBCA, tends to increase the DN/P and GP/T SI ratios after the fifth administration of the agent. These findings are in line with previous studies, which have reported the deposition of linear agents in the brain, seen as high signal intensities on T1-W images [START_REF] Kanda | High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material[END_REF][START_REF] Kanda | High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration[END_REF][START_REF] Ramalho | High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents[END_REF]. Increased SI in the DN and GP after multiple exposures to a linear GBCAs seems to reflect a residual or progressive accumulation of GBCAs in those structures, as confirmed in animal studies [START_REF] Smith | Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study[END_REF][START_REF] Kartamihardja | Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model[END_REF] and human brain autopsies [START_REF] Kanda | Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy[END_REF]. Nevertheless, our study failed in highlighting a significant increase, and several reasons can explain this result. First, the limited number of patients (n=19) can alone explain the lack of significance. Second, the use of injected sequences for signal measurements must be considered as a potential bias. Third, the follow-up was performed with different machines and field strength and, therefore, with changes in the parameters of the sequences. Lastly, changes in the signal secondary to tumoral evolution or related to treatments (e.g., brain radiation therapy) can also be discussed.

After the tenth administration, the SI ratio was lower than after the fifth administration.

These results suggest that, after a period of accumulation, retained gadolinium may slowly wash out of the brain or slowly change form (possibly dechelating), causing the signal to fade.

To our knowledge, only a few studies to date [START_REF] Radbruch | Intraindividual Analysis of Signal Intensity Changes in the Dentate Nucleus After Consecutive Serial Applications of Linear and Macrocyclic Gadolinium-Based Contrast Agents[END_REF][START_REF] Smith | Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study[END_REF][START_REF] Kartamihardja | Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model[END_REF][START_REF] Jost | Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model[END_REF] have investigated whether gadolinium accumulation in brain tissue was permanent or could be cleared. The wash-out hypothesis is consistent with the findings of prospective animal studies [START_REF] Smith | Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study[END_REF][START_REF] Kartamihardja | Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model[END_REF][START_REF] Jost | Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model[END_REF], notably by Smith et al. [START_REF] Smith | Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study[END_REF], who used inductively coupled plasma mass spectroscopy to measure the amount of gadolinium deposition and its potential clearance from the brain in healthy rats. Small amounts of gadolinium were present in brain tissue after repeated administration of gadodiamide (a linear GBCA), which then partially cleared over the 20 weeks of follow-up (diminished by approximately 50%).

Even if a wash-out does occur, the dechelation hypothesis probably plays a role both in accumulation and in the elimination of gadolinium from the brain. The dechelation of free gadolinium from its ligand is a process mainly defined by kinetic and thermodynamic stabilities. It can be influenced by the presence of competitors, such as endogenous metals ions (Fe3+, Cu2+, or Zn2+). These agents compete with the gadolinium chelate, bound to the ligand, leading to gadolinium dissociation and deposition in the body [START_REF] Hao | MRI contrast agents: basic chemistry and safety[END_REF][START_REF] Hernández Mdel | Identification of mineral deposits in the brain on radiological images: a systematic review[END_REF][START_REF] Tweedle | Reaction of gadolinium chelates with endogenously available ions[END_REF][START_REF] Cacheris | The relationship between thermodynamics and the toxicity of gadolinium complexes[END_REF][START_REF] Abraham | Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis[END_REF], which then causes a signal increase.

The SI decrease could be explained by a transition of formerly chelated gadolinium or gadolinium bound to macromolecules with high relaxivity to gadolinium-binding molecules with negligible relaxivity, causing the T1 signal to fade.

Regarding macrocyclic GBCAs, no increase in signal was found in both DN/P and GP/T after repeated administration, confirming the higher thermodynamic stability of this type of GBCAs, which is less prone to gadolinium accumulation. This is in line with previous studies, notably those of Kanda et al. [START_REF] Kanda | High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration[END_REF] and Rabruch et al. [START_REF] Radbruch | Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent[END_REF], who stated that gadolinium deposition in the brain depends mainly on the molecular structure of the GBCAs. However, current animal and human autopsy studies provided evidence of both linear and macrocyclic retention, suggesting that all GBCAs are associated with gadolinium accumulation, even if no appreciable mean increase in SI was seen on MRI examination when using macrocyclic agents. This could be explained by the minimal amount of macrocyclic retention compared with the linear agents, and it also reflects that MRI has a relatively limited sensitivity to detect gadolinium deposition in brain tissue.

We found, instead, a trend in a decrease in SI in the DN and GP after the fifth and tenth administrations of gadoterate meglumine. Such a signal decrease has been reported by few studies only [START_REF] Cao | Signal Change in the Dentate Nucleus on T1-Weighted MR Images After Multiple Administrations of Gadopentetate Dimeglumine Versus Gadobutrol[END_REF][START_REF] Schlemm | Gadopentetate but not gadobutrol accumulates in the dentate nucleus of multiple sclerosis patients[END_REF][START_REF] Kelemen | T1-weighted Grey Matter Signal Intensity Alterations After Multiple Administrations of Gadobutrol in Patients with Multiple Sclerosis, Referenced to White Matter[END_REF]. Reasons for this phenomenon can be put forward, such as the hypothesis of precipitation of the GBCAs or an increased signal in the pons and thalami. Before exploring these theories, we considered the possible influence of the MR field strength, since examinations were acquired either at 1.5 T or 3 T. Even if the signal differed slightly between 1.5 T and 3 T, the use of ratios limits this effect without having an impact on the appearance of an increased signal [START_REF] Adin | Hyperintense Dentate Nuclei on T1-Weighted MRI: Relation to Repeat Gadolinium Administration[END_REF]. One of the theories put forward was the precipitation of the macrocyclic complex. Indeed, as seen previously, macrocyclic agents are retained in brain structures, even in small amounts, and are subsequently eliminated over time. It is established that macrocyclic agents are more stable, less prone to dechelation, and mostly accumulate in a soluble intact form [START_REF] Frenzel | Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents: Comparative Study in Rats[END_REF]. However, if this complex precipitates over time as a phosphate or carbonate complex, which does not induce an increase in the signal, or if dechelation occurs, which leads to the creation of complexes bound to macromolecules with negligible relaxivity, this will cause the signal to fade. Regarding the increase in the signal within the pons or thalamus, this effect was not found in our study. Indeed, no isolated increase in the value of these denominators, which could have resulted in a decrease in the DN/P and GP/T ratios, was found.

Our study has several limitations, as previously mentioned, including the small number of subjects and the fact that retrospective studies may contain observer bias. However, in this multicentric study, all subjects were exclusively exposed to a single contrast agent. This prerequisite and the fact that each patient had an equal number of administrations with a high mean volume injected, increased the power of our study, and allowed us to compare the GBCAs directly. Furthermore, we used data compiled since 2008 from two centers; hence not all examinations were conducted at the same field strength (1.5 T or 3 T), and no pre-contrast 3D T1 unenhanced images were acquired. The use of 3D T1 contrast-enhanced images for SI analysis and the inhomogeneous field strength thereby may have led to variations in the interpretation of our results. However, our results are in line with previous studies using unenhanced T1-W imaging. Thereby, as Ramalho [START_REF] Ramalho | Gadolinium Deposition and Chronic Toxicity[END_REF] underlines in analyzing the study of Tanaka et al. [START_REF] Tanaka | Increased Signal Intensity in the Dentate Nucleus of Patients with Multiple Sclerosis in Comparison with Neuromyelitis Optica Spectrum Disorder after Multiple Doses of Gadolinium Contrast[END_REF], no significant differences were found throughout the comparison of the SI ratio of the DN/P on both unenhanced T1-W and postgadolinium T1-W sequences, suggesting that the effect of gadolinium accumulation in the brain could be analyzed on enhanced T1-W images. This approach can be very useful for long-term analysis, as seen in a previous study [START_REF] Jaulent | Weekly enhanced T1-weighted MRI with Gadobutrol injections in MS patients: Is there a signal intensity increase in the dentate nucleus and the globus pallidus?[END_REF].

Our study failed in highlighting significant differences that could probably have been highlighted if the delay between the different MRIs had been longer. Despite the limitations discussed here, the strength of our study lies in the use of 3D T1 imaging with an automatic segmentation technique, allowing us to analyze the signal of each wholebrain structure, right and left, in a more reliable and reproducible way as compared with the use of subjective unilateral ROI placement on 2D slices.

CONCLUSION

Our three-time-point, longitudinal, retrospective, multicenter study using automatic segmentation found no measurable SI increase in the DN and GP on T1-W MR images of patients exposed exclusively to gadoterate meglumine, thus confirming the stability of macrocyclic agents, which are less prone to being retained in the brain. Instead, we found, a trend in a decrease in SI, which confirms the assumption for a significative gadolinium elimination over time.

After exposure to a linear GBCAs (gadobenate dimeglumine ), the SI tended to increase after the fifth injection owing to gadolinium accumulation. After the tenth administration, the SI ratio was lower than after the fifth administration supporting the hypothesis of a slow elimination of the previously retained gadolinium (wash-out effect) from the brain or of a change in form (by dechelation), causing the signal to fade.

Formatting of funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

  Abbreviations:

Figure 1 :

 1 Figure 1: Signal variation between timepoints

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.