T. Kanda, H. Oba, K. Toyoda and S. Furui
Department of Radiology
Teikyo University School of Medicine
Itabashi-ku, Japan

We wish to comment on the August 2015 article of Adin et al¹ in the American Journal of Neuroradiology (AJNR) entitled “Hyperintense Dentate Nuclei on T1-Weighted MRI: Relation to Repeat Gadolinium Administration.” The authors reported the relationship between the hyperintense dentate nucleus on unenhanced T1WI and past gadolinium based–contrast agent (GBCA) administration. This relationship was first reported by our group on December 7, 2013.² Since then, several important reports have been published, and knowledge regarding gadolinium deposition has increased remarkably.

Our group³ and Radbruch et al⁴ evaluated the difference in the signal change between patients repeatedly administered linear GBCA and macrocyclic GBCA. A change in the signal intensity of the dentate nucleus was observed in the former, but not in the latter. McDonald et al⁵ and our group⁶ evaluated the brain tissue from postmortem specimens, and gadolinium deposition was verified from the brain tissue.⁷ Robert et al⁸injected GBCA 20 times into rats and evaluated the signal-intensity change of the dentate nucleus on T1WI and gadolinium concentration in the brain. A hyperintense dentate nucleus was observed in rats with repeat linear GBCA administration, but not with repeat macrocyclic GBCA administration. The gadolinium concentration of the brain with repeat linear GBCA administration was 14 times greater than that with repeat macrocyclic GBCA administration.⁸ The work of Adin et al¹ was confirmed in our first study. It was accepted by AJNR on February 19, 2015, and was published on-line on August 20, 2015. In this short period, studies on gadolinium deposition advance so rapidly, a more prompt publication schedule from AJNR would be desirable.

In previous studies (our study), a hyperintense dentate nucleus on T1WI was detected in subjects with >5 previous administrations of gadodiamide or gadopentetate dimeglumine. In contrast, in this study, some of the subjects with >12 previous administrations of GBCA did not show hyperintensity in the dentate nucleus. One reason may be the use of macrocyclic GBCAs in these subjects. In addition, the detectability of the hyperintense dentate nucleus on various sequences of T1WI may have influenced their results. According to our experience with several cases, the detectability of high signal intensity in the dentate nucleus differs between spin-echo T1WI and T1 FLAIR (Fig 1). Adin et al¹ evaluated the hyperintense dentate nucleus with various T1WI sequences, such as MPRAGE, spin-echo, and T1 FLAIR. The different detectabilities of hyperintense dentate nuclei on these sequences may have influenced their results.

References

1. Adin ME, Kleinberg L, Vaidya D, et al. Hyperintense dentate nuclei on T1-weighted MRI: relation to repeat gadolinium administration. AJNR Am J Neuroradiol 2015 Aug 20. [Epub ahead of print] » Abstract/FREE Full Text
2. Kanda T, Ishii K, Kawaguchi H, et al. 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 2014;270:834–41 » CrossRef » Medline
3. Kanda T, Osawa M, Oba H, et al. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 2015;275:803–09 » CrossRef » Medline
4. Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015;275:783–91 » CrossRef » Medline
5. McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275:772–82 » CrossRef » Medline
6. Kanda T, Fukusato T, Matsuda M, et al. 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;276:228–32 » CrossRef » Medline
7. Kanal E, Tweedle MF. Residual or retained gadolinium: practical implications for radiologists and our patients. Radiology 2015;275:630–34 » CrossRef » Medline
8. Robert P, Lehericy S, Grand S, et al. T1-weighted hypersignal in the deep cerebellar nuclei after repeated administrations of gadolinium-based contrast agents in healthy rats: difference between linear and macrocyclic agents. Invest Radiol 2015;50:473–80 » CrossRef » Medline

Reply

M.E. Adin
Division of Neuroradiology
The Russell H. Morgan Department of Radiology and Radiological Science
The Johns Hopkins Medical Institutions
Baltimore, Maryland

L. Kleinberg
bDepartment of Radiation Oncology and Radiation Molecular Sciences
The Johns Hopkins Medical Institutions
Baltimore, Maryland

D. Vaidya
cJohns Hopkins Bloomberg School of Public Health
The Johns Hopkins Medical Institutions
Baltimore, Maryland

E. Zan, S. Mirbagheri and D.M. Yousem
Division of Neuroradiology
The Russell H. Morgan Department of Radiology and Radiological Science
The Johns Hopkins Medical Institutions
Baltimore, Maryland

Our study commenced in the last quarter of 2013, concluded in May 2014, and was presented at the Symposium Neuroradiologicum held in Istanbul on September 7–12, 2014. As a result of multipdisciplinary authorship and distant collaborations, the manuscript was finally submitted to the American Journal of Neuroradiology in December 2014. At the initial period of our study, there were 2 articles in the literature concluding that hyperintense dentate nuclei (HDN) on T1-weighted MR imaging were secondary to rapidly progressive MS and radiation therapy (RT) effect.^1,2 We, therefore, investigated this entity in a large cohort of irradiated individuals and found no apparent associations between HDN and RT. During the data gathering and after the submission of our manuscript, several studies were published on this topic, mainly arguing the possible association of HDN and repeated performance of gadolinium-enhanced MR imaging.^3,4 McDonald et al⁵ were the first to show actual gadolinium deposition in the human brain by using inductively coupled plasma mass spectrometry in postmortem subjects. Although linear gadolinium-based contrast agents were reported to be associated with HDN, the exact mechanism and clinical ramifications remain unclear.^6⇓–8

T1-weighted FLAIR is a recently described MR imaging sequence.⁹ In brain imaging, it is mainly used to better differentiate gray and white matter, owing to its improved contrast difference. In our institution, it is not a part of the standard brain MR imaging protocol and is mainly performed for epilepsy. Because our cohort was obtained from those with a history of RT for underlying tumoral lesions, only a handful of the subjects were imaged with the T1 FLAIR sequence. As far as the authors’ qualitative assessment, differentiating HDN from normal dentate nuclei (NDN) on axial T1 FLAIR images was not a matter of debate in any of subjects included in our study (Fig 1). On sagittal T1 FLAIR images, given the enhanced brightness of white matter, qualitative differentiation of faint HDN and NDN could be doubtful, particularly if the reader is not familiar with appearance of HDN. Nevertheless, without specific research on this topic, we do not speculate on the superiority of one technique (T1 FSE, FLAIR, MPRAGE, and so forth) over another in differentiating faint HDN from NDN. From our study cohort, we randomly looked into 7 subjects with NDN who underwent at least 6 contrast-enhanced MR imaging examinations by using linear gadolinium agents (Table). Not a single case was imaged with T1 FLAIR, practically excluding the possibility of HDN being misinterpreted as NDN.

The mechanism of gadolinium retention in the dentate nuclei is unknown, and individual factors contributing to the normal appearance of the dentate nuclei in some patients, despite the large amount of gadolinium administered, remain unclear.