Progressive Increase of T1 Signal Intensity of the Dentate Nucleus on Unenhanced Magnetic Resonance Images Is Associated With Cumulative Doses of Intravenously Administered Gadodiamide in Patients With Normal Renal Function, Suggesting Dechelation

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Abstract
The purpose of this study was to assess the association between the serial number of gadolinium-enhanced magnetic resonance imaging (MRI) examinations and the signal hyperintensity of the dentate nucleus on unenhanced T1-weighted images in patients with multiple sclerosis (MS) and those with brain metastases (BMs). A group of 38 patients with MS and 37 patients with BM who had undergone at least 2 consecutive enhanced MRI examinations in our institution were examined for this retrospective observational study. The average T1 signal intensity of the dentate nuclei and the pons was obtained, and the dentate nuclei-to-pons (DNP) signal intensity ratio was calculated. These values were compared between patients with less than 6 and 6 enhanced MRI scans or more (eMRI). Relative changes of the DNP were plotted against the number of enhanced MRI scans (eMRIn). A progressive increase in the T1 signal intensity of the DNP ratio was observed both in the MS group and in the BM group. The DNP ratios of the last eMRI scans in the subgroup of patients with 6 eMRI scans or more were significantly higher than those of the first eMRI scan in the MS group (P < 0.001) and in the BM group (P < 0.01). Relative changes of the DNP showed a positive correlation with the eMRIn with a Spearman ρ of 0.96 (P < 0.001) in the MS group and that of 0.88 (P < 0.001) in the BM group. Curve regression analyses of the relative change of DNP ratios showed linear models to best fit the data with r(2) of 0.89 in the MS group and r(2) of 0.74 in the BM group. Our study shows that the increase in the unenhanced T1 signal intensity has a linear relationship with the eMRIn in patients with MS and BM. Indeed, we estimated a linear regression model to fit the progressive increase in T1 signal intensity of the dentate nucleus after multiple enhanced MRI scans. This finding suggests substantial dechelation of gadodiamide in patients with normal renal function, raising further concerns regarding the stability of this agent. Further comparative studies with other gadolinium chelates, specifically both linear and macrocyclic, are strongly recommended.

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