T1 relaxometry indicate cerebral gadolinium retention after multiple administration of a macrocyclic Gd-based contrast agent: A Retrospective Study in 27 patients with Glioblastoma Multiforme

Svein Are Vatnehol¹, Inge Rasmus Groote¹, Christopher Larsson¹, Magne Kleppestø¹, Jonas Vardal¹, and Atle Bjørnerud^1,2

¹The Intervention Center, Oslo University Hospital, Oslo, Norway, ²Department of Physics, University of Oslo, Oslo, Norway

Synopsis

Recent publications have shown an increase in signal intensity on non-enhanced T1w-images for the Dentate Nucleus and Globus Pallidus. This effect seems to be linked to multiple administrations of linear gadolinium chelate. In this retrospective study we have analyzed the quantitative T1 values (qT1) and the normalized native T1 signal intensity (nSI) for the Globus Pallidus and the nSI for the Dentate Nucleus in patients with multiple injections of gadobutrol (Gadovist™). Our analysis suggest a significant change in the qT1 and nSI for the Globus Pallidus as well as in the nSI for the Dentate Nucleus

Introduction

Recent reports based on examining serial normalized T1 signal intensity (SI) measurements in unenhanced T1-weighted images suggest that gadolinium (Gd) can be retained in the brain after repeated contrast administrations (1-6) The clinical implications of cerebral Gd-retention is unknown, and the effect has mainly been observed using linear gadolinium chelates and not in macrocyclic gadolinium chelates (3,6). Previous publications have only used normalized T1 SI, but suggestions have been made to also include quantitative T1-analysis (qT1) (6) Here, we investigate the effect of multiple injections of a macrocyclic Gd-agent using both native non-enhanced T1 images, and qT1.

Materials and Methods

The study was approved by the regional ethics committee. As part of a retrospective study investigating treatment response with multiple MRI methods, we performed comprehensive MRI in 27 patients with Glioblastoma Multiforme receiving 3-19 double-dose (0.2 mmol/kg b.w) injections of gadobutrol (Gadovist™) over a time-period of 2-36 months. In addition to 3D-T1-weighted series, qT1 maps were generated using a 3D Look-Locker (LL) sequence (8). We evaluated quantitative T1-values from LL sequence (qT1) and normalized SI values (nSI) from 3D-T1w series for globus pallidus (GP) (SI normalized to thalamus) and additionally nTI for nucleus dentatus (ND) (SI normalized to pons). Two patients had less than 3 injections between the first and last available qT1 measurements and was therefore excluded for this part of the analysis. Both scans were acquired immediately before Gd-administration for each scan session. Ellipsoid ROIs were placed on the contralateral side of the bulk tumor on reconstructed transversal T1w-images from the first timepoint by a MRI-radiographer with 9 years experience in neuro MRI. If structures where unclear, co registered FLAIR images was used to assist ROI placement. Successive qT1-maps and native T1-images was co registered to the first timepoint and the ROIs where copied to the correlated images to ensure the same positions of the ROIs for each timepoint. In case of structure displacement due to bulk tumor growth the ROI was manually adapted.

Changes in qT1 and nSI were plotted against number of Gd-injections and mixed linear models were used to investigate presence of significant changes in the two metrics between baseline (before first Gd-injection) and last contrast administration. Additionally, possible correlation between the difference in qT1 and nSI between last time-point and baseline scan versus total number of injections received by each subject was investigated using Spearman correlation. Imaging was performed at 3T using a Philips Achieva system. NordiceICE (Nordic Neuro lab AS) was used for image co registration and analysis.

Results

qT1-analysis revealed an average (95% ci) reduction in T1 of DN of 42 ms (8-77 ms (p=.019) between baseline and last MR examination. A significant correlation was observed between T1-reduction in GP and number of Gd-injections received (fig1) (rho=-.54, p=.010). No change in T1 of thalamus was observed (p=.32). nSI showed a significant increase in nSI of GP (p=.005) and also an increase in nSI of DN (p=.001). nSI showed a significant correlation between increase in nSI of DN and number of Gd-injections (rho=.44, p=.019), but not in GP (rho=.19, p=.35). Due to limited slice coverage, qT1 data could not be obtained from DN or pons.

Discussion

This is to our knowledge the first study where quantitative T1 relaxometry is used to investigate possible Gd-retention following multiple contrast injections. Using T1 relaxometry and T1-SI measurements normalized to thalamus and pons values, we found evidence of subtle, but significant (p<0.02) dose-dependent Gd-retention in the investigated brain areas after repeated administration of gadobutrol; an effect to date only associated with linear Gd-chelates (1-7). No significant change in qT1 of the thalamus was detected, supporting the use of this structure as a reference region for SI normalization. Further studies with T1-relaxometry and whole brain coverage are warranted to substantiate our findings

Acknowledgements

No acknowledgement found.

References

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2. Errante et al. Progressive Increase of T1 Signal Intensity of the Dentate Nucleus on Unenhanced Magnetic Resonance Images Is Associated With Cumulative Doses Of Intrevenously Administered Gadolinium In Patients With Normal Renal Function, Suggestin Dechelation. Invest Radiol 2014 49 (10)

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Figures

Relative change in T1 in GP vs number of Gd-injections.

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

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