Regional and global assessment on relaxometric quantitative MRI in patients with previous administration of a linear gadolinium-based contrast agent
Hirofumi Kuno1, Hernan Jara1, Karen Buch1, Andrew Mills1, Muhammad Mustafa Quresh1, Neil Thayil 1, Margaret N Chapman1, and Osamu Sakai1

1Radiology, Boston University, Boston Medical Center, Boston, MA, United States

Synopsis

To assess potential regional and global correlations between brain relaxation times and the number of prior administrations of linear gadolinium-based contrast agents (GBCA) using quantitative MRI. The subjects consisted of 40 patients (7 patients with multiple prior linear GBCA exposures and 33 patients with no prior GBCA exposures) with brain MRI using the mixed turbo spin-echo pulse sequence. T1 and T2 relaxation times were assessed in selected regions of brain parenchyma (GP, DN, thalamus, and pons) and the whole brain, and were demonstrated to be associated with the number of gadolinium administrations. A stronger relationship was demonstrated in gray matter.

Purpose

Recently it has become apparent that patients with normal renal function may exhibit progressively increased signal intensity in selected regions of the brain on T1-weighted images obtained in the setting of repeated MR studies using gadolinium-based contrast agents (GBCA), especially linear GBCAs (1-5). Prior studies used only qualitative measures based on weighted signal intensities in selected regions of interest without a quantitative assessment of the true relaxation times. The purpose of this work was to assess potential regional and global correlations between brain relaxation times, using T1 and T2 quantitative MRI sequences, and the number of prior administrations of linear GBCA.

Methods

This IRB approved, HIPAA compliant retrospective study conducted in 2008-2014 evaluated 40 patients (17 men, 23 women; 3.8–87 years; median age, 27 years) with brain MRI acquired using the mixed turbo spin-echo pulse sequence at a 1.5T unit. For regional assessment, regions-of-interest (ROIs) were placed on a T1 map by a single blinded neuroradiologist in the globus pallidus (GP), thalamus, dentate nucleus (DN), and centrally within the pons. Using an in-house developed Mathcad (PTC, Needham, MA) program, the T1 and T2 relaxation times within each of these structures were calculated using the same ROIs. For global measurement, the whole brain, including white (WM) and gray matter (GM), was segmented using a 3-channel dual-clustering algorithm programmed in Mathcad (6). T1 and T2 relaxation time histograms of all segments were generated and modeled with Gaussian functions. The mean T1 of WM/GM and T2 of the whole brain were measured. Regression analysis was performed (Stata ver. 12.1, Stata Corp LP, College Station, TX, USA) to assess whether an association exists between the regional and global T1 and T2 relaxation times and the number of prior GBCA administrations.

Results

Of 40 subjects, 7 patients (4 men, 3 women; 7–77 years; median age, 47) received linear GBCA (Magnevist®) administrations (range 1 to 8 times). No patients received macrocyclic GBCAs. The remaining 33 patients had no history of GBCA exposure. Scatterplots of T1 values versus the number of previous GBCA administrations in the GP, DN, thalamus and pons are shown in Figure 1. The GP (P<.001), DN (P=.03), and thalamus (P<.002) showed significant correlations with the number of previous gadolinium-based contrast material administrations in T1 relaxation times. T2 relaxation time changes versus number of previous linear GBCA administrations in the GP, DN, thalamus and pons are shown in Figure 2. The GP, DN, thalamus, and pons demonstrated an inverse relationship between T2 relaxation times and the number of previous gadolinium administrations, with a significant correlation found in the DN (P=.01), thalamus (P<.001), and pons (P<.01). The relationship between the globally quantitative T1/T2 relaxation times and previous linear GBCA administrations are shown in Figures 3 and 4. Whole brain evaluation in patients with prior GBCA exposure showed an inverse relationship between T1 relaxation times and the number of previous gadolinium administrations, especially for grey matter (P=.06), though this trend did not achieve statistical significance. T1 relaxation times of grey matter were significantly shorter in patients with prior GBCA exposure than those of patients with none (with prior GBCA 939±72ms, without prior GBCA 1001±73ms, P=.043). T2 relaxation times were also significantly shorter in patients with prior GBCA exposure than those of patients without exposure (with prior GBCA 105.6±9.3ms, without prior GBCA 112.7±7.9ms, P=.044), and also showed a significant correlation between T2 and the number of previous gadolinium administrations (P<.003).

Discussion

In this work, T1 and T2 relaxation times were assessed in selected regions of brain parenchyma (GP, DN, thalamus and pons) and the whole brain, and were demonstrated to be associated with the number of prior gadolinium administrations. A stronger relationship was demonstrated in gray matter. These results suggest that gadolinium accumulation may be seen in the whole brain, as shown in several recent studies using brain specimen analysis, which showed gadolinium deposition in several brain regions (1,2,4,5,7,8). Prior works have focused on imaging assessment using selected normalized signal intensity ratios from specific regions of interest on T1 weighted images, such as the GP:thalamus and DN:pons ratios (2,4,5,9,10). Herein, we show that prior observations with qualitative MR images are further corroborated with fully quantitative measures of T1 and T2 relaxation times.

Conclusions

Quantitative assessment using changes in T1 and T2 relaxation times demonstrated an association with the number of prior gadolinium-based contrast agent administrations. Additional studies are needed to investigate the clinical significance of these findings with large sample size. Quantitative MRI may potentially be a useful method for noninvasive assessment of gadolinium accumulation in the brain.

Acknowledgements

No acknowledgement found.

References

1. Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. 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. Radiology 2013;270(3):834-841.

2. Errante Y, Cirimele V, Mallio CA, Di Lazzaro V, Zobel BB, Quattrocchi CC. 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. Investigative radiology 2014;49(10):685-690.

3. Xia D, Davis RL, Crawford JA, Abraham JL. Gadolinium released from MR contrast agents is deposited in brain tumors: in situ demonstration using scanning electron microscopy with energy dispersive X-ray spectroscopy. Acta Radiologica 2010;51(10):1126-1136.

4. Kanda T, Osawa M, Oba H, Toyoda K, Kotoku J, Haruyama T, Takeshita K, Furui S. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: Association with linear versus macrocyclic gadolinium chelate administration. Radiology 2015; 275(3):803-809.

5. Adin M, Kleinberg L, Vaidya D, Zan E, Mirbagheri S, Yousem D. Hyperintense Dentate Nuclei on T1-Weighted MRI: Relation to Repeat Gadolinium Administration. American Journal of Neuroradiology 2015;36(10):1859-1865.

6. Suzuki S, Sakai O, Jara H. Combined volumetric T1, T2 and secular-T2 quantitative MRI of the brain: age-related global changes (preliminary results). Magnetic Resonance Imaging 2006;24(7):877-887.

7. McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, Williamson EE, Eckel LJ. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275(3):772-782.

8. Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku Ji, Haruyama T, Kitajima K, Furui S. 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. Radiology 2015;276(1):228-232.

9. Ramalho J, Castillo M, AlObaidy M, Nunes RH, Ramalho M, Dale BM, Semelka RC. High signal intensity in globus pallidus and dentate nucleus on unenhanced T1-weighted MR images: evaluation of two linear gadolinium-based contrast agents. Radiology 2015;276(3):836-844.

10. Radbruch A, Weberling LD, Kieslich PJ, Eidel O, Burth S, Kickingereder P, Heiland S, Wick W, Schlemmer H-P, Bendszus M. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015;275(3):783-791.

Figures

Figure 1. T1 relaxation time associated with number of linear GBCA administrations. Scatter-plots show selected region in globus pallidus (a), dentate nucleus (b), thalamus (c) and pons (d) versus number of previous linear GBCA administrations. In each plot, the solid line represents linear regression and the dashed lines indicate 95% confidence limits.

Figure 2. T2 relaxation time associated with number of linear GBCA administrations. Scatter-plots show selected region in globus pallidus (a), dentate nucleus (b), thalamus (c) and pons (d) versus number of previous linear GBCA administrations. In each plot, the solid line represents linear regression and the dashed lines indicate 95% confidence limits.

Figure 3. (a, b) Scatter-plots of T1 relaxation time of the gray and white matter of whole brain versus number of previous linear GBCA administrations. (c) Scatter-plots of T2 relaxation time of the gray and white matter of whole brain versus number of previous linear GBCA administrations. In each plot, the solid line represents linear regression and the dashed line indicates 95% confidence limits.

Figure 4. (a, b) Box plots of T1 relaxation time of the gray and white matter between with and without previous linear GBCA administrations. (c) T2 relaxation time of the whole brain between with and without previous linear GBCA administrations.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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