• 1. Kuriashkin IV, Losonsky JM. Contrast enhancement in magnetic resonance imaging using intravenous paramagnetic contrast media: a review. Vet Radiol Ultrasound 2000;41:47.

    • Search Google Scholar
    • Export Citation
  • 2. Brady TJ, Reimer P. Contrast agents in whole body magnetic resonance: an overview. In: Young IR, ed. Methods in biomedical magnetic resonance imaging and spectroscopy. Ann Arbor, Mich: Wiley, 2000;693698.

    • Search Google Scholar
    • Export Citation
  • 3. McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275:772782.

    • Search Google Scholar
    • Export Citation
  • 4. Robertson I. Optimal magnetic resonance imaging of the brain. Vet Radiol Ultrasound 2011;52:S15S22.

  • 5. Niendorf H, Brasch R. Gd-DTPA tolerance and clinical safety. In: Brasch R, ed. MRI contrast enhancement in the central nervous system: a case study approach. New York: Raven Press, 1993;1121.

    • Search Google Scholar
    • Export Citation
  • 6. Caravan P, Ellison JJ, McMurry TJ, et al. Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 1999;99:22932352.

    • Search Google Scholar
    • Export Citation
  • 7. Ramalho J, Semelka RC, Ramalho M, et al. Gadolinium-based contrast agent accumulation and toxicity: an update. AJNR Am J Neuroradiol 2016;37:11921198.

    • Search Google Scholar
    • Export Citation
  • 8. Gulani V, Calamante F, Shellock FG, et al. Gadolinium deposition in the brain: summary of evidence and recommendations. Lancet Neurol 2017;16:564570.

    • Search Google Scholar
    • Export Citation
  • 9. 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;50:473480.

    • Search Google Scholar
    • Export Citation
  • 10. 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;275:783791.

    • Search Google Scholar
    • Export Citation
  • 11. Ramalho J, Castillo M, AlObaidy M, et al. 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;276:836844.

    • Search Google Scholar
    • Export Citation
  • 12. Ray DE, Holton JL, Nolan CC, et al. Neurotoxic potential of gadodiamide after injection into the lateral cerebral ventricle of rats. AJNR Am J Neuroradiol 1998;19:14551462.

    • Search Google Scholar
    • Export Citation
  • 13. Roman-Goldstein SM, Barnett PA, McCormick CI, et al. Effects of gadopentetate dimeglumine administration after osmotic blood-brain barrier disruption: toxicity and MR imaging findings. AJNR Am J Neuroradiol 1991;12:885890.

    • Search Google Scholar
    • Export Citation
  • 14. Kanal E, Tweedle MF. Residual or retained gadolinium: practical implications for radiologists and our patients. Radiology 2015;275:630634.

    • Search Google Scholar
    • Export Citation
  • 15. 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;270:834841.

    • Search Google Scholar
    • Export Citation
  • 16. Errante Y, Cirimele V, Mallio CA, et al. 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;49:685690.

    • Search Google Scholar
    • Export Citation
  • 17. Quattrocchi CC, Mallio CA, Errante Y, et al. Gadodiamide and dentate nucleus T1 hyperintensity in patients with meningioma evaluated by multiple follow-up contrast-enhanced magnetic resonance examinations with no systemic interval therapy. Invest Radiol 2015;50:470472.

    • Search Google Scholar
    • Export Citation
  • 18. 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;275:803809.

    • Search Google Scholar
    • Export Citation
  • 19. Roberts DR, Holden KR. Progressive increase of T1 signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in the pediatric brain exposed to multiple doses of gadolinium contrast. Brain Dev 2016;38:331336.

    • Search Google Scholar
    • Export Citation
  • 20. Miller JH, Hu HH, Pokorney A, et al. MRI brain signal intensity changes of a child during the course of 35 gadolinium contrast examinations. Pediatrics 2015;136:e1637e1640.

    • Search Google Scholar
    • Export Citation
  • 21. 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;276:228232.

    • Search Google Scholar
    • Export Citation
  • 22. 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;36:18591865.

    • Search Google Scholar
    • Export Citation
  • 23. 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;51:447453.

    • Search Google Scholar
    • Export Citation
  • 24. Malayeri AA, Brooks KM, Bryant LH, et al. National Institutes of Health perspective on reports of gadolinium deposition in the brain. J Am Coll Radiol 2016;13:237241.

    • Search Google Scholar
    • Export Citation
  • 25. Kasahara S, Miki Y, Kanagaki M, et al. Hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with a history of brain irradiation. Radiology 2011;258:222228.

    • Search Google Scholar
    • Export Citation
  • 26. US FDA. FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI). Safety announcement. Silver Spring, Md: US Department of Health and Human Services, 2015.

    • Search Google Scholar
    • Export Citation
  • 27. European Medicines Agency. EMA's final opinion confirms restrictions on use of linear gadolinium agents in body scans. London: European Medicines Agency, 2017.

    • Search Google Scholar
    • Export Citation
  • 28. US FDA. FDA drug safety communication: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue. Silver Spring, Md: US Department of Health and Human Services, 2017.

    • Search Google Scholar
    • Export Citation
  • 29. Dickinson PJ, LeCouteur RA, Higgins RJ, et al. Canine spontaneous glioma: a translational model system for convection-enhanced delivery. Neuro Oncol 2010;12:928940.

    • Search Google Scholar
    • Export Citation
  • 30. Potschka H, Fischer A, von Rüden E-L, et al. Canine epilepsy as a translational model? Epilepsia 2013;54:571579.

  • 31. White GW, Gibby WA, Tweedle MF. Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Invest Radiol 2006;41:272278.

    • Search Google Scholar
    • Export Citation
  • 32. Darrah TH, Prutsman-Pfeiffer JJ, Poreda RJ, et al. Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics 2009;1:479488.

    • Search Google Scholar
    • Export Citation
  • 33. Radbruch A, Haase R, Kieslich PJ, et al. No signal intensity increase in the dentate nucleus on unenhanced T1-weighted MR images after more than 20 serial injections of macrocyclic gadolinium-based contrast agents. Radiology 2017;282:699707.

    • Search Google Scholar
    • Export Citation
  • 34. Omniscan [package insert]. Oslo: GE Healthcare, 2010.

  • 35. Aime S, Caravan P. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging 2009;30:12591267.

    • Search Google Scholar
    • Export Citation
  • 36. Weinmann HJ, Laniado M, Mutzel W. Pharmacokinetics of GdDTPA/dimeglumine after intravenous injection into healthy volunteers. Physiol Chem Phys Med NMR 1984;16:167172.

    • Search Google Scholar
    • Export Citation
  • 37. Oksendal AN, Hals P-A. Biodistribution and toxicity of MR imaging contrast media. J Magn Reson Imaging 1993;3:157165.

  • 38. Radbruch A, Weberling LD, Kieslich PJ, et al. Intraindividual analysis of signal intensity changes in the dentate nucleus after consecutive serial applications of linear and macrocyclic gadolinium-based contrast agents. Invest Radiol 2016;51:683690.

    • Search Google Scholar
    • Export Citation
  • 39. Iliff JJ, Lee H, Yu M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 2013;123:12991309.

    • Search Google Scholar
    • Export Citation
  • 40. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 2012;4:147ra111.

    • Search Google Scholar
    • Export Citation
  • 41. Mendelsohn AR, Larrick JW. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases. Rejuvenation Res 2013;16:518523.

    • Search Google Scholar
    • Export Citation
  • 42. Telgmann L, Sperling M, Karst U. Determination of gadolinium-based MRI contrast agents in biological and environmental samples: a review. Anal Chim Acta 2013;764:116.

    • Search Google Scholar
    • Export Citation
  • 43. Arbughi T, Bertani F, Celeste R, et al. High-performance liquid chromatographic determination of the magnetic resonance imaging contrast agent gadobenate ion in plasma, urine, faeces, bile and tissues. J Chromatogr B Biomed Sci Appl 1998;713:415426.

    • Search Google Scholar
    • Export Citation
  • 44. Kindberg GM, Uran S, Friisk G, et al. The fate of Gd and chelate following intravenous injection of gadodiamide in rats. Eur Radiol 2010;20:16361643.

    • Search Google Scholar
    • Export Citation
  • 45. Normann PT, Hals PA. In vivo stability and excretion of gadodiamide (GdDTPA-BMA), a hydrophilic gadolinium complex used as a contrast enhancing agent for magnetic resonance imaging. Eur J Drug Metab Pharmacokinet 1995;20:307313.

    • Search Google Scholar
    • Export Citation
  • 46. Mata M, Gottschalk S. Man's best friend: utilizing naturally occurring tumors in dogs to improve chimeric antigen receptor T-cell therapy for human cancers. Mol Ther 2016;24:15111512.

    • Search Google Scholar
    • Export Citation

Advertisement

Retention of gadolinium in the brains of healthy dogs after a single intravenous administration of gadodiamide

View More View Less
  • 1 Department of Clinical Sciences, Mississippi State University, Mississippi State, MS 39762.
  • | 2 College of Veterinary Medicine, and the Institute for Imaging and Analytical Technologies, Mississippi State University, Mississippi State, MS 39762
  • | 3 Department of Radiology, Diagnostic Physics Division, Mayo Clinic, Phoenix, AZ 85054.
  • | 4 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 5 Department of Clinical Sciences, Mississippi State University, Mississippi State, MS 39762.
  • | 6 Department of Clinical Sciences, Mississippi State University, Mississippi State, MS 39762.
  • | 7 College of Veterinary Medicine, and the Institute for Imaging and Analytical Technologies, Mississippi State University, Mississippi State, MS 39762
  • | 8 Department of Pathobiology and Population Medicine, Mississippi State University, Mississippi State, MS 39762.
  • | 9 Department of Clinical Sciences, Mississippi State University, Mississippi State, MS 39762.

Abstract

OBJECTIVE To determine brain region affinity for and retention of gadolinium in dogs after administration of gadodiamide and whether formalin fixation affects quantification.

ANIMALS 14 healthy dogs.

PROCEDURES 13 dogs received gadodiamide (range, 0.006 to 0.1 mmol/kg, IV); 1 control dog received a placebo. Dogs received gadodiamide 3 to 7 days (n = 8) or 9 hours (5) before euthanasia and sample collection. Brain regions were analyzed with inductively coupled mass spectrometry (ICP-MS) and transmission electron microscopy. Associations between dose, time to euthanasia, and gadolinium retention quantities (before and after fixation in 5 dogs) were evaluated.

RESULTS Gadolinium retention was seen in all brain regions at all doses, except for the control dog. Exposure 3 to 7 days before euthanasia resulted in 1.7 to 162.5 ng of gadolinium/g of brain tissue (dose-dependent effect), with cerebellum, parietal lobe, and brainstem affinity. Exposure 9 hours before euthanasia resulted in 67.3 to 1,216.4 ng of gadolinium/g of brain tissue without dose dependency. Transmission electron microscopy revealed gadolinium in examined tissues. Fixation did not affect quantification in samples immersed for up to 69 days.

CONCLUSIONS AND CLINICAL RELEVANCE Gadodiamide exposure resulted in gadolinium retention in the brain of healthy dogs. Cerebellum, parietal lobe, and brainstem affinity was detected with dose dependency only in dogs exposed 3 to 7 days before euthanasia. Fixation had no effect on quantification when tissues were immersed for up to 69 days. Physiologic mechanisms for gadolinium retention remained unclear. The importance of gadolinium retention requires further investigation.

Abstract

OBJECTIVE To determine brain region affinity for and retention of gadolinium in dogs after administration of gadodiamide and whether formalin fixation affects quantification.

ANIMALS 14 healthy dogs.

PROCEDURES 13 dogs received gadodiamide (range, 0.006 to 0.1 mmol/kg, IV); 1 control dog received a placebo. Dogs received gadodiamide 3 to 7 days (n = 8) or 9 hours (5) before euthanasia and sample collection. Brain regions were analyzed with inductively coupled mass spectrometry (ICP-MS) and transmission electron microscopy. Associations between dose, time to euthanasia, and gadolinium retention quantities (before and after fixation in 5 dogs) were evaluated.

RESULTS Gadolinium retention was seen in all brain regions at all doses, except for the control dog. Exposure 3 to 7 days before euthanasia resulted in 1.7 to 162.5 ng of gadolinium/g of brain tissue (dose-dependent effect), with cerebellum, parietal lobe, and brainstem affinity. Exposure 9 hours before euthanasia resulted in 67.3 to 1,216.4 ng of gadolinium/g of brain tissue without dose dependency. Transmission electron microscopy revealed gadolinium in examined tissues. Fixation did not affect quantification in samples immersed for up to 69 days.

CONCLUSIONS AND CLINICAL RELEVANCE Gadodiamide exposure resulted in gadolinium retention in the brain of healthy dogs. Cerebellum, parietal lobe, and brainstem affinity was detected with dose dependency only in dogs exposed 3 to 7 days before euthanasia. Fixation had no effect on quantification when tissues were immersed for up to 69 days. Physiologic mechanisms for gadolinium retention remained unclear. The importance of gadolinium retention requires further investigation.

Contributor Notes

Address correspondence to Dr. Gambino (Gambino@cvm.msstate.edu).