Published Online:

Our findings demonstrate that gadolinium deposition in neuronal tissues occurs even in the absence of intracranial abnormalities among patients exposed to multiple gadolinium-enhanced MR examinations.


To determine whether gadolinium deposits in neural tissues of patients with intracranial abnormalities following intravenous gadolinium-based contrast agent (GBCA) exposure might be related to blood-brain barrier integrity by studying adult patients with normal brain pathologic characteristics.

Materials and Methods

After obtaining antemortem consent and institutional review board approval, the authors compared postmortem neuronal tissue samples from five patients who had undergone four to 18 gadolinium-enhanced magnetic resonance (MR) examinations between 2005 and 2014 (contrast group) with samples from 10 gadolinium-naive patients who had undergone at least one MR examination during their lifetime (control group). All patients in the contrast group had received gadodiamide. Neuronal tissues from the dentate nuclei, pons, globus pallidus, and thalamus were harvested and analyzed with inductively coupled plasma mass spectrometry (ICP-MS), transmission electron microscopy with energy-dispersive x-ray spectroscopy, and light microscopy to quantify, localize, and assess the effects of gadolinium deposition.


Tissues from the four neuroanatomic regions of gadodiamide-exposed patients contained 0.1–19.4 μg of gadolinium per gram of tissue in a statistically significant dose-dependent relationship (globus pallidus: ρ = 0.90, P = .04). In contradistinction, patients in the control group had undetectable levels of gadolinium with ICP-MS. All patients had normal brain pathologic characteristics at autopsy. Three patients in the contrast group had borderline renal function (estimated glomerular filtration rate <45 mL/min/1.73 m2) and hepatobiliary dysfunction at MR examination. Gadolinium deposition in the contrast group was localized to the capillary endothelium and neuronal interstitium and, in two cases, within the nucleus of the cell.


Gadolinium deposition in neural tissues after GBCA administration occurs in the absence of intracranial abnormalities that might affect the permeability of the blood-brain barrier. These findings challenge current understanding of the biodistribution of these contrast agents and their safety.

© RSNA, 2017


  • 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 2014;270(3):834–841. LinkGoogle Scholar
  • 2. 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(1):228–232. LinkGoogle Scholar
  • 3. McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275(3):772–782. LinkGoogle Scholar
  • 4. Murata N, Gonzalez-Cuyar LF, Murata K, et al. 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. Invest Radiol 2016;51(7):447–453. Crossref, MedlineGoogle Scholar
  • 5. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130(6):461–470. Crossref, MedlineGoogle Scholar
  • 6. R Development Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2012. Google Scholar
  • 7. Ray DE, Cavanagh JB, Nolan CC, Williams SC. Neurotoxic effects of gadopentetate dimeglumine: behavioral disturbance and morphology after intracerebroventricular injection in rats. AJNR Am J Neuroradiol 1996;17(2):365–373. MedlineGoogle Scholar
  • 8. Rogosnitzky M, Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals 2016;29(3):365–376. Crossref, MedlineGoogle Scholar
  • 9. Caillé JM, Lemanceau B, Bonnemain B. Gadolinium as a contrast agent for NMR. AJNR Am J Neuroradiol 1983;4(5):1041–1042. MedlineGoogle Scholar
  • 10. Tweedle MF. Physicochemical properties of gadoteridol and other magnetic resonance contrast agents. Invest Radiol 1992;27(Suppl 1):S2–S6. MedlineGoogle Scholar
  • 11. 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. Invest Radiol 2014;49(10):685–690. Crossref, MedlineGoogle Scholar
  • 12. Ginat DT, Meyers SP. Intracranial lesions with high signal intensity on T1-weighted MR images: differential diagnosis. RadioGraphics 2012;32(2):499–516. LinkGoogle Scholar
  • 13. Kanda T, Nakai Y, Aoki S, et al. Contribution of metals to brain MR signal intensity: review articles. Jpn J Radiol 2016;34(4):258–266. Crossref, MedlineGoogle Scholar
  • 14. Bourne GW, Trifaró JM. The gadolinium ion: a potent blocker of calcium channels and catecholamine release from cultured chromaffin cells. Neuroscience 1982;7(7):1615–1622. Crossref, MedlineGoogle Scholar
  • 15. Rim KT, Koo KH, Park JS. Toxicological evaluations of rare earths and their health impacts to workers: a literature review. Saf Health Work 2013;4(1):12–26. Crossref, MedlineGoogle Scholar
  • 16. Palmer RJ, Butenhoff JL, Stevens JB. Cytotoxicity of the rare earth metals cerium, lanthanum, and neodymium in vitro: comparisons with cadmium in a pulmonary macrophage primary culture system. Environ Res 1987;43(1):142–156. Crossref, MedlineGoogle Scholar
  • 17. Hare DJ, George JL, Bray L, et al. The effect of paraformaldehyde fixation and sucrose cryoprotection on metal concentration in murine neurological tissue. J Anal At Spectrom 2014;29(3):565–570. CrossrefGoogle Scholar
  • 18. Dugar A, Farley ML, Wang AL, et al. The effect of paraformaldehyde fixation on the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) measurement. J Orthop Res 2009;27(4):536–539. Crossref, MedlineGoogle Scholar
  • 19. Manning GS. Electrostatic free energy of the DNA double helix in counterion condensation theory. Biophys Chem 2002;101–102:461–473. Crossref, MedlineGoogle Scholar
  • 20. Port M, Idée JM, Medina C, Robic C, Sabatou M, Corot C. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals 2008;21(4):469–490. Crossref, MedlineGoogle Scholar
  • 21. Kanda T, Oba H, Toyoda K, Furui S. Macrocyclic gadolinium-based contrast agents do not cause hyperintensity in the dentate nucleus. AJNR Am J Neuroradiol 2016;37(5):E41. Crossref, MedlineGoogle Scholar
  • 22. 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(3):803–809. LinkGoogle Scholar
  • 23. 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(3):783–791. LinkGoogle Scholar
  • 24. Radbruch A, Weberling LD, Kieslich PJ, et al. High-signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evaluation of the macrocyclic gadolinium-based contrast agent gadobutrol. Invest Radiol 2015;50(12):805–810. Crossref, MedlineGoogle Scholar
  • 25. 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(8):473–480. Crossref, MedlineGoogle Scholar
  • 26. Robert P, Violas X, Grand S, et al. Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Invest Radiol 2016;51(2):73–82. Crossref, MedlineGoogle Scholar
  • 27. Birka M, Wehe CA, Hachmöller O, Sperling M, Karst U. Tracing gadolinium-based contrast agents from surface water to drinking water by means of speciation analysis. J Chromatogr A 2016;1440:105–111. Crossref, MedlineGoogle Scholar

Article History

Received July 24, 2016; revision requested October 17; revision received March 8, 2017; accepted March 20; final version accepted March 27.
Published online: June 27 2017
Published in print: Nov 2017