DOI QR코드

DOI QR Code

Gadolinium Deposition in the Brain: Current Updates

  • Jin Woo Choi (Department of Radiology, Konkuk University Medical Center, Konkuk University School of Medicine) ;
  • Won-Jin Moon (Department of Radiology, Konkuk University Medical Center, Konkuk University School of Medicine)
  • Received : 2018.06.05
  • Accepted : 2018.09.21
  • Published : 2019.01.01

Abstract

Gadolinium-based contrast agents (GBCAs) are commonly used for enhancement in MR imaging and have long been considered safe when administered at recommended doses. However, since the report that nephrogenic systemic fibrosis is linked to the use of GBCAs in subjects with severe renal diseases, accumulating evidence has suggested that GBCAs are not cleared entirely from our bodies; some GBCAs are deposited in our tissues, including the brain. GBCA deposition in the brain is mostly linked to the specific chelate structure of the GBCA: linear GBCAs were responsible for brain deposition in almost all reported studies. This review aimed to summarize the current knowledge about GBCA brain deposition and discuss its clinical implications.

Keywords

References

  1. Matsumura T, Hayakawa M, Shimada F, Yabuki M, Dohanish S, Palkowitsch P, et al. Safety of gadopentetate dimeglumine after 120 million administrations over 25 years of clinical use. Magn Reson Med Sci 2013;12:297-304 https://doi.org/10.2463/mrms.2013-0020
  2. Murphy KJ, Brunberg JA, Cohan RH. Adverse reactions to gadolinium contrast media: a review of 36 cases. AJR Am J Roentgenol 1996;167:847-849 https://doi.org/10.2214/ajr.167.4.8819369
  3. Runge VM. Safety of approved MR contrast media for intravenous injection. J Magn Reson Imaging 2000;12:205-213 https://doi.org/10.1002/1522-2586(200008)12:2<205::AID-JMRI1>3.0.CO;2-P
  4. Runge VM. Safety of magnetic resonance contrast media. Top Magn Reson Imaging 2001;12:309-314 https://doi.org/10.1097/00002142-200108000-00007
  5. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17:2359-2362 https://doi.org/10.1681/ASN.2006060601
  6. Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21:1104-1108 https://doi.org/10.1093/ndt/gfk062
  7. Sieber MA, Lengsfeld P, Frenzel T, Golfier S, Schmitt-Willich H, Siegmund F, et al. Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol 2008;18:2164-2173 https://doi.org/10.1007/s00330-008-0977-y
  8. Perez-Rodriguez J, Lai S, Ehst BD, Fine DM, Bluemke DA. Nephrogenic systemic fibrosis: incidence, associations, and effect of risk factor assessment--report of 33 cases. Radiology 2009;250:371-377 https://doi.org/10.1148/radiol.2502080498
  9. Thomsen HS. Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am 2009;47:827-831, vi https://doi.org/10.1016/j.rcl.2009.05.003
  10. ACR Committee on Drugs and Contrast Media. Nephrogenic Systemic Fibrosis. In: ACR Committee on Drugs and Contrast Media, ed. ACR manual on contrast media, version 10.3. Reston, VA: American College of Radiology, 2017:81-89
  11. 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;270:834-841 https://doi.org/10.1148/radiol.13131669
  12. 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;49:685-690 https://doi.org/10.1097/RLI.0000000000000072
  13. Adin ME, Kleinberg L, Vaidya D, Zan E, Mirbagheri S, Yousem DM. Hyperintense dentate nuclei on T1-weighted MRI: relation to repeat gadolinium administration. AJNR Am J Neuroradiol 2015;36:1859-1865 https://doi.org/10.3174/ajnr.A4378
  14. Cao Y, Huang DQ, Shih G, Prince MR. Signal change in the dentate nucleus on T1-weighted MR images after multiple administrations of gadopentetate dimeglumine versus gadobutrol. AJR Am J Roentgenol 2016;206:414-419 https://doi.org/10.2214/AJR.15.15327
  15. Kanda T, Osawa M, Oba H, Toyoda K, Kotoku J, Haruyama T, et al. High signal intensity in dentate nucleus on unenhanced T1-weighted MR Images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 2015;275:803-809 https://doi.org/10.1148/radiol.14140364
  16. Radbruch A, Weberling LD, Kieslich PJ, Eidel O, Burth S, Kickingereder P, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015;275:783-791 https://doi.org/10.1148/radiol.2015150337
  17. Ramalho J, Castillo M, AlObaidy M, Nunes RH, Ramalho M, Dale BM, 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;276:836-844 https://doi.org/10.1148/radiol.2015150872
  18. Weberling LD, Kieslich PJ, Kickingereder P, Wick W, Bendszus M, Schlemmer HP, et al. Increased signal intensity in the dentate nucleus on unenhanced T1-weighted images after gadobenate dimeglumine administration. Invest Radiol 2015;50:743-748 https://doi.org/10.1097/RLI.0000000000000206
  19. Hu HH, Pokorney A, Towbin RB, Miller JH. Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams. Pediatr Radiol 2016;46:1590-1598 https://doi.org/10.1007/s00247-016-3646-3
  20. Radbruch A, Weberling LD, Kieslich PJ, Hepp J, Kickingereder P, Wick W, 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;51:683-690 https://doi.org/10.1097/RLI.0000000000000308
  21. Ramalho J, Ramalho M, AlObaidy M, Nunes RH, Castillo M, Semelka RC. T1 signal-intensity increase in the dentate nucleus after multiple exposures to gadodiamide: intraindividual comparison between 2 commonly used sequences. AJNR Am J Neuroradiol 2016;37:1427-1431 https://doi.org/10.3174/ajnr.A4757
  22. Ramalho J, Semelka RC, AlObaidy M, Ramalho M, Nunes RH, Castillo M. Signal intensity change on unenhanced T1-weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide. Eur Radiol 2016;26:4080-4088 https://doi.org/10.1007/s00330-016-4269-7
  23. Roberts DR, Chatterjee AR, Yazdani M, Marebwa B, Brown T, Collins H, et al. Pediatric patients demonstrate progressive T1-weighted hyperintensity in the dentate nucleus following multiple doses of gadolinium-based contrast agent. AJNR Am J Neuroradiol 2016;37:2340-2347 https://doi.org/10.3174/ajnr.A4891
  24. 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;38:331-336 https://doi.org/10.1016/j.braindev.2015.08.009
  25. Tanaka M, Nakahara K, Kinoshita M. Increased signal intensity in the dentate nucleus of patients with multiple sclerosis in comparison with neuromyelitis optica spectrum disorder after multiple doses of gadolinium contrast. Eur Neurol 2016;75:195-198 https://doi.org/10.1159/000445431
  26. Flood TF, Stence NV, Maloney JA, Mirsky DM. Pediatric brain: repeated exposure to linear gadolinium-based contrast material is associated with increased signal intensity at unenhanced T1-weighted MR imaging. Radiology 2017;282:222-228 https://doi.org/10.1148/radiol.2016160356
  27. Ichikawa S, Motosugi U, Omiya Y, Onishi H. Contrast agent-induced high signal intensity in dentate nucleus on unenhanced T1-weighted images: comparison of gadodiamide and gadoxetic acid. Invest Radiol 2017;52:389-395 https://doi.org/10.1097/RLI.0000000000000360
  28. Kuno H, Jara H, Buch K, Qureshi MM, Chapman MN, Sakai O. Global and regional brain assessment with quantitative MR imaging in patients with prior exposure to linear gadolinium-based contrast agents. Radiology 2017;283:195-204 https://doi.org/10.1148/radiol.2016160674
  29. Oner AY, Barutcu B, Aykol S,, Tali ET. Intrathecal contrast-enhanced magnetic resonance imaging-related brain signal changes: residual gadolinium deposition? Invest Radiol 2017;52:195-197 https://doi.org/10.1097/RLI.0000000000000327
  30. Zhang Y, Cao Y, Shih GL, Hecht EM, Prince MR. Extent of signal hyperintensity on unenhanced T1-weighted brain MR images after more than 35 administrations of linear gadolinium-based contrast agents. Radiology 2017;282:516-525 https://doi.org/10.1148/radiol.2016152864
  31. Drug Safety Communications. FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue. U.S. Food & Drug Administration. Retrieved from https://www.fda.gov/downloads/Drugs/DrugSafety/UCM559654.pdf. Published July 27, 2015. Accessed May 26, 2018
  32. European Medicines Agency Science Medicines Health. EMA's final opinion confirms restrictions on use of linear gadolinium agents in body scans. European Medicines Agency. Retrieved from http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/gadolinium_contrast_agents_31/Opinion_provided_by_Committee_for_Medicinal_Products_for_Human_Use/WC500231824.pdf. Published July 21, 2017. Accessed May 26, 2018
  33. European Medicines Agency Science Medicines Health. PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations. European Medicines Agency. Retrieved from http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/gadolinium_contrast_agents_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500223161.pdf. Published March 10, 2017. Accessed May 26, 2018
  34. Pharmaceuticals and Medical Devices Agency. Report on the investigation results. Pharmaceuticals and Medical Devices Agency. Retrieved from http://www.pmda.go.jp/files/000221379.pdf. Published November 11, 2017. Accessed May 26, 2018
  35. Advance notice on mandatory revision of the precautions section in the package insert of gadolinium agent. Ministry of Food and Drug Safety Web site. http://www.mfds.go.kr/brd/m_74/view.do?seq=40761. Published February 27, 2018. Accessed May 26, 2018
  36. Drug Safety Information-Gadolinium Agents. Ministry of Food and Drug Safety Decision Web site. http://www.mfds.go.kr/brd/m_545/view.do?seq=268. Published May 25, 2018. Accessed May 26, 2018
  37. Semelka RC, Ramalho M, AlObaidy M, Ramalho J. Gadolinium in humans: a family of disorders. AJR Am J Roentgenol 2016;207:229-233 https://doi.org/10.2214/AJR.15.15842
  38. Palasz A, Czekaj P. Toxicological and cytophysiological aspects of lanthanides action. Acta Biochim Pol 2000;47:1107-1114 https://doi.org/10.18388/abp.2000_3963
  39. Morcos SK. Extracellular gadolinium contrast agents: differences in stability. Eur J Radiol 2008;66:175-179 https://doi.org/10.1016/j.ejrad.2008.01.025
  40. Idee JM, Port M, Robic C, Medina C, Sabatou M, Corot C. Role of thermodynamic and kinetic parameters in gadolinium chelate stability. J Magn Reson Imaging 2009;30:1249-1258 https://doi.org/10.1002/jmri.21967
  41. Tweedle MF, Hagan JJ, Kumar K, Mantha S, Chang CA. Reaction of gadolinium chelates with endogenously available ions. Magn Reson Imaging 1991;9:409-415 https://doi.org/10.1016/0730-725X(91)90429-P
  42. Mann JS. Stability of gadolinium complexes in vitro and in vivo. J Comput Assist Tomogr 1993;17 Suppl 1:S19-S23 https://doi.org/10.1097/00004728-199301001-00004
  43. Frenzel T, Lengsfeld P, Schirmer H, Hutter J, Weinmann HJ. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37℃. Invest Radiol 2008;43:817-828 https://doi.org/10.1097/RLI.0b013e3181852171
  44. Port M, Idee 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;21:469-490 https://doi.org/10.1007/s10534-008-9135-x
  45. Roccatagliata L, Vuolo L, Bonzano L, Pichiecchio A, Mancardi GL. Multiple sclerosis: hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with the secondary progressive subtype. Radiology 2009;251:503-510 https://doi.org/10.1148/radiol.2511081269
  46. Prayer D, Grois N, Prosch H, Gadner H, Barkovich AJ. MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol 2004;25:880-891
  47. Kasahara S, Miki Y, Kanagaki M, Yamamoto A, Mori N, Sawada T, et al. Hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with a history of brain irradiation. Radiology 2011;258:222-228 https://doi.org/10.1148/radiol.10100508
  48. Lai PH, Chen C, Liang HL, Pan HB. Hyperintense basal ganglia on T1-weighted MR imaging. AJR Am J Roentgenol 1999;172:1109-1115 https://doi.org/10.2214/ajr.172.4.10587157
  49. Oikonomou A, Chatzistefanou A, Zezos P, Mintzopoulou P, Vadikolias K, Prassopoulos P. Basal ganglia hyperintensity on T1-weighted MRI in Rendu-Osler-Weber disease. J Magn Reson Imaging 2012;35:426-430 https://doi.org/10.1002/jmri.22892
  50. da Silva CJ, da Rocha AJ, Jeronymo S, Mendes MF, Milani FT, Maia AC Jr, et al. A preliminary study revealing a new association in patients undergoing maintenance hemodialysis: manganism symptoms and T1 hyperintense changes in the basal ganglia. AJNR Am J Neuroradiol 2007;28:1474-1479 https://doi.org/10.3174/ajnr.A0600
  51. Quattrocchi CC, Mallio CA, Errante Y, Cirimele V, Carideo L, Ax A, 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;50:470-472 https://doi.org/10.1097/RLI.0000000000000154
  52. Radbruch A, Weberling LD, Kieslich PJ, Hepp J, Kickingereder P, Wick W, 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;50:805-810 https://doi.org/10.1097/RLI.0000000000000227
  53. Stojanov DA, Aracki-Trenkic A, Vojinovic S, Benedeto-Stojanov D, Ljubisavljevic S. Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol. Eur Radiol 2016;26:807-815 https://doi.org/10.1007/s00330-015-3879-9
  54. Khant ZA, Hirai T, Kadota Y, Masuda R, Yano T, Azuma M, et al. T1 shortening in the cerebral cortex after multiple administrations of gadolinium-based contrast agents. Magn Reson Med Sci 2017;16:84-86
  55. McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275:772-782 https://doi.org/10.1148/radiol.15150025
  56. McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Paolini MA, Murray DL, et al. Gadolinium deposition in human brain tissues after contrast-enhanced MR imaging in adult patients without intracranial abnormalities. Radiology 2017;285:546-554 https://doi.org/10.1148/radiol.2017161595
  57. Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku J, 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;276:228-232 https://doi.org/10.1148/radiol.2015142690
  58. Lohrke J, Frisk AL, Frenzel T, Schockel L, Rosenbruch M, Jost G, et al. Histology and gadolinium distribution in the rodent brain after the administration of cumulative high doses of linear and macrocyclic gadolinium-based contrast agents. Invest Radiol 2017;52:324-333 https://doi.org/10.1097/RLI.0000000000000344
  59. Smith AP, Marino M, Roberts J, Crowder JM, Castle J, Lowery L, et al. Clearance of gadolinium from the brain with no pathologic effect after repeated administration of gadodiamide in healthy rats: an analytical and histologic study. Radiology 2017;282:743-751 https://doi.org/10.1148/radiol.2016160905
  60. McDonald JS, McDonald RJ, Jentoft ME, Paolini MA, Murray DL, Kallmes DF, et al. Intracranial gadolinium deposition following gadodiamide-enhanced magnetic resonance imaging in pediatric patients: a case-control study. JAMA Pediatr 2017;171:705-707 https://doi.org/10.1001/jamapediatrics.2017.0264
  61. Gianolio E, Bardini P, Arena F, Stefania R, Di Gregorio E, Iani R, et al. Gadolinium retention in the rat brain: assessment of the amounts of insoluble gadolinium-containing species and intact gadolinium complexes after repeated administration of gadolinium-based contrast agents. Radiology 2017;285:839-849 https://doi.org/10.1148/radiol.2017162857
  62. Frenzel T, Apte C, Jost G, Schockel L, Lohrke J, Pietsch H. Quantification and assessment of the chemical form of residual gadolinium in the brain after repeated administration of gadolinium-based contrast agents: comparative study in rats. Invest Radiol 2017;52:396-404 https://doi.org/10.1097/RLI.0000000000000352
  63. Greenberg SA. Zinc transmetallation and gadolinium retention after MR imaging: case report. Radiology 2010;257:670-673 https://doi.org/10.1148/radiol.10100560
  64. Swaminathan S. Gadolinium toxicity: iron and ferroportin as central targets. Magn Reson Imaging 2016;34:1373-1376 https://doi.org/10.1016/j.mri.2016.08.016
  65. Kanda T, Nakai Y, Oba H, Toyoda K, Kitajima K, Furui S. Gadolinium deposition in the brain. Magn Reson Imaging 2016;34:1346-1350 https://doi.org/10.1016/j.mri.2016.08.024
  66. Robert P, Lehericy S, Grand S, Violas X, Fretellier N, Idee JM, 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;50:473-480 https://doi.org/10.1097/RLI.0000000000000181
  67. Robert P, Violas X, Grand S, Lehericy S, Idee JM, Ballet S, et al. Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Invest Radiol 2016;51:73-82 https://doi.org/10.1097/RLI.0000000000000241
  68. Kartamihardja AA, Nakajima T, Kameo S, Koyama H, Tsushima Y. Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model. Br J Radiol 2016;89:20160509
  69. Kartamihardja AA, Nakajima T, Kameo S, Koyama H, Tsushima Y. Impact of impaired renal function on gadolinium retention after administration of gadolinium-based contrast agents in a mouse model. Invest Radiol 2016;51:655-660 https://doi.org/10.1097/RLI.0000000000000295
  70. Swaminathan S, Horn TD, Pellowski D, Abul-Ezz S, Bornhorst JA, Viswamitra S, et al. Nephrogenic systemic fibrosis, gadolinium, and iron mobilization. N Engl J Med 2007;357:720-722 https://doi.org/10.1056/NEJMc070248
  71. Swaminathan S, Shah SV. New insights into nephrogenic systemic fibrosis. J Am Soc Nephrol 2007;18:2636-2643 https://doi.org/10.1681/ASN.2007060645
  72. Kanda T, Oba H, Toyoda K, Kitajima K, Furui S. Brain gadolinium deposition after administration of gadolinium-based contrast agents. Jpn J Radiol 2016;34:3-9 https://doi.org/10.1007/s11604-015-0503-5
  73. Valdes Hernandez Mdel C, Maconick LC, Tan EM, Wardlaw JM. Identification of mineral deposits in the brain on radiological images: a systematic review. Eur Radiol 2012;22:2371-2381 https://doi.org/10.1007/s00330-012-2494-2
  74. Bressler JP, Olivi L, Cheong JH, Kim Y, Maerten A, Bannon D. Metal transporters in intestine and brain: their involvement in metal-associated neurotoxicities. Hum Exp Toxicol 2007;26:221-229 https://doi.org/10.1177/0960327107070573
  75. Jost G, Lenhard DC, Sieber MA, Lohrke J, Frenzel T, Pietsch H. Signal increase on unenhanced T1-weighted images in the rat brain after repeated, extended doses of gadolinium-based contrast agents: comparison of linear and macrocyclic agents. Invest Radiol 2016;51:83-89 https://doi.org/10.1097/RLI.0000000000000242
  76. Mamourian AC, Hoopes PJ, Lewis LD. Visualization of intravenously administered contrast material in the CSF on fluid-attenuated inversion-recovery MR images: an in vitro and animal-model investigation. AJNR Am J Neuroradiol 2000;21:105-111
  77. Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 2013;123:1299-1309 https://doi.org/10.1172/JCI67677
  78. Eide PK, Ringstad G. MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain. Acta Radiol Open 2015;4:2058460115609635
  79. Naganawa S, Nakane T, Kawai H, Taoka T. Gd-based contrast enhancement of the perivascular spaces in the basal ganglia. Magn Reson Med Sci 2017;16:61-65 https://doi.org/10.2463/mrms.mp.2016-0039
  80. Eisele P, Alonso A, Szabo K, Ebert A, Ong M, Schoenberg SO, et al. Lack of increased signal intensity in the dentate nucleus after repeated administration of a macrocyclic contrast agent in multiple sclerosis: an observational study. Medicine (Baltimore) 2016;95:e4624
  81. Kromrey ML, Liedtke KR, Ittermann T, Langner S, Kirsch M, Weitschies W, et al. Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5 years. Eur Radiol 2017;27:772-777 https://doi.org/10.1007/s00330-016-4418-z
  82. Lee JY, Park JE, Kim HS, Kim SO, Oh JY, Shim WH, et al. Up to 52 administrations of macrocyclic ionic MR contrast agent are not associated with intracranial gadolinium deposition: multifactorial analysis in 385 patients. PLoS One 2017;12:e0183916
  83. Yoo RE, Sohn CH, Kang KM, Yun TJ, Choi SH, Kim JH, et al. Evaluation of gadolinium retention after serial administrations of a macrocyclic gadolinium-based contrast agent (gadobutrol): a single-institution experience with 189 patients. Invest Radiol 2018;53:20-25 https://doi.org/10.1097/RLI.0000000000000404
  84. Schlemm L, Chien C, Bellmann-Strobl J, Dorr J, Wuerfel J, Brandt AU, et al. Gadopentetate but not gadobutrol accumulates in the dentate nucleus of multiple sclerosis patients. Mult Scler 2017;23:963-972 https://doi.org/10.1177/1352458516670738
  85. Ryu YJ, Choi YH, Cheon JE, Lee WJ, Park S, Park JE, et al. Pediatric brain: gadolinium deposition indentate nucleus and globus pallidus on unenhanced T1-weighted images is dependent on the type of contrast agent. Invest Radiol 2018;53:246-255 https://doi.org/10.1097/RLI.0000000000000436
  86. Kahn J, Posch H, Steffen IG, Geisel D, Bauknecht C, Liebig T, et al. Is there long-term signal intensity increase in the central nervous system on T1-weighted images after MR imaging with the hepatospecific contrast agent gadoxetic acid? A cross-sectional study in 91 patients. Radiology 2017;282:708-716 https://doi.org/10.1148/radiol.2016162535
  87. Conte G, Preda L, Cocorocchio E, Raimondi S, Giannitto C, Minotti M, et al. Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study. Eur Radiol 2017;27:4372-4378 https://doi.org/10.1007/s00330-017-4810-3
  88. Kang KM, Choi SH, Hwang M, Yun TJ, Kim JH, Sohn CH. T1 shortening in the globus pallidus after multiple administrations of gadobutrol: assessment with a multidynamic multiecho sequence. Radiology 2018;287:258-266 https://doi.org/10.1148/radiol.2017162852
  89. Rossi Espagnet MC, Bernardi B, Pasquini L, Figa-Talamanca L, Toma P, Napolitano A. Signal intensity at unenhanced T1-weighted magnetic resonance in the globus pallidus and dentate nucleus after serial administrations of a macrocyclic gadolinium-based contrast agent in children. Pediatr Radiol 2017;47:1345-1352 https://doi.org/10.1007/s00247-017-3874-1
  90. Murata N, Gonzalez-Cuyar LF, Murata K, Fligner C, Dills R, Hippe D, 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;51:447-453 https://doi.org/10.1097/RLI.0000000000000252
  91. McDonald RJ, McDonald JS, Dai D, Schroeder D, Jentoft ME, Murray DL, et al. Comparison of gadolinium concentrations within multiple rat organs after intravenous administration of linear versus macrocyclic gadolinium chelates. Radiology 2017;285:536-545 https://doi.org/10.1148/radiol.2017161594
  92. Rasschaert M, Idee JM, Robert P, Fretellier N, Vives V, Violas X, et al. Moderate renal failure accentuates T1 signal enhancement in the deep cerebellar nuclei of gadodiamide-treated rats. Invest Radiol 2017;52:255-264 https://doi.org/10.1097/RLI.0000000000000339
  93. Boyken J, Frenzel T, Lohrke J, Jost G, Pietsch H. Gadolinium accumulation in the deep cerebellar nuclei and globus pallidus after exposure to linear but not macrocyclic gadolinium-based contrast agents in a retrospective pig study with high similarity to clinical conditions. Invest Radiol 2018;53:278-285 https://doi.org/10.1097/RLI.0000000000000440
  94. Bussi S, Coppo A, Botteron C, Fraimbault V, Fanizzi A, De Laurentiis E, et al. Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats. J Magn Reson Imaging 2018;47:746-752 https://doi.org/10.1002/jmri.25822
  95. Cao Y, Zhang Y, Shih G, Zhang Y, Bohmart A, Hecht EM, et al. Effect of renal function on gadolinium-related signal increases on unenhanced T1-weighted brain magnetic resonance imaging. Invest Radiol 2016;51:677-682 https://doi.org/10.1097/RLI.0000000000000294
  96. Tibussek D, Rademacher C, Caspers J, Turowski B, Schaper J, Antoch G, et al. Gadolinium brain deposition after macrocyclic gadolinium administration: a pediatric case-control study. Radiology 2017;285:223-230 https://doi.org/10.1148/radiol.2017161151
  97. Tedeschi E, Palma G, Canna A, Cocozza S, Russo C, Borrelli P, et al. In vivo dentate nucleus MRI relaxometry correlates with previous administration of Gadolinium-based contrast agents. Eur Radiol 2016;26:4577-4584 https://doi.org/10.1007/s00330-016-4245-2
  98. Hinoda T, Fushimi Y, Okada T, Arakawa Y, Liu C, Yamamoto A, et al. Quantitative assessment of gadolinium deposition in dentate nucleus using quantitative susceptibility mapping. J Magn Reson Imaging 2017;45:1352-1358 https://doi.org/10.1002/jmri.25490
  99. Welk B, McArthur E, Morrow SA, MacDonald P, Hayward J, Leung A, et al. Association between gadolinium contrast exposure and the risk of parkinsonism. JAMA 2016;316:96-98 https://doi.org/10.1001/jama.2016.8096
  100. Bauer K, Lathrum A, Raslan O, Kelly PV, Zhou Y, Hewing D, et al. Do gadolinium-based contrast agents affect 18F-FDG PET/CT uptake in the dentate nucleus and the globus pallidus? A pilot study. J Nucl Med Technol 2017;45:30-33 https://doi.org/10.2967/jnmt.116.180844
  101. Semelka RC, Ramalho J, Vakharia A, AlObaidy M, Burke LM, Jay M, et al. Gadolinium deposition disease: initial description of a disease that has been around for a while. Magn Reson Imaging 2016;34:1383-1390 https://doi.org/10.1016/j.mri.2016.07.016
  102. Muldoon LL, Neuwelt EA. Dose-dependent neurotoxicity (seizures) due to deposition of gadolinium-based contrast agents in the central nervous system. Radiology 2015;277:925-926 https://doi.org/10.1148/radiol.2015151028
  103. Roman-Goldstein SM, Barnett PA, McCormick CI, Ball MJ, Ramsey F, Neuwelt EA. Effects of gadopentetate dimeglumine administration after osmotic blood-brain barrier disruption: toxicity and MR imaging findings. AJNR Am J Neuroradiol 1991;12:885-890
  104. Gong E, Pauly JM, Wintermark M, Zaharchuk G. Deep learning enables reduced gadolinium dose for contrast-enhanced brain MRI. J Magn Reson Imaging 2018;48:330-340 https://doi.org/10.1002/jmri.25970
  105. Tweedle MF. Science to practice: will gadolinium chelates be replaced by iron chelates in MR imaging? Radiology 2018;286:409-411 https://doi.org/10.1148/radiol.2017172305
  106. Chan KW, McMahon MT, Kato Y, Liu G, Bulte JW, Bhujwalla ZM, et al. Natural D-glucose as a biodegradable MRI contrast agent for detecting cancer. Magn Reson Med 2012;68:1764-1773 https://doi.org/10.1002/mrm.24520
  107. Jahng GH, Li KL, Ostergaard L, Calamante F. Perfusion magnetic resonance imaging: a comprehensive update on principles and techniques. Korean J Radiol 2014;15:554-577 https://doi.org/10.3348/kjr.2014.15.5.554
  108. Ramalho J, Ramalho M. Gadolinium deposition and chronic toxicity. Magn Reson Imaging Clin N Am 2017;25:765-778 https://doi.org/10.1016/j.mric.2017.06.007
  109. ACR Committee on Drugs and Contrast Media. Appendix A - Contrast media specifications. ACR manual on contrast media, version 10.3. Reston, VA: American College of Radiology, 2017:123-125
  110. Huckle JE, Altun E, Jay M, Semelka RC. Gadolinium deposition in humans: when did we learn that gadolinium was deposited in vivo? Invest Radiol 2016;51:236-240 https://doi.org/10.1097/RLI.0000000000000228
  111. Ramalho J, Semelka RC, Ramalho M, Nunes RH, AlObaidy M, Castillo M. Gadolinium-based contrast agent accumulation and toxicity: an update. AJNR Am J Neuroradiol 2016;37:1192-1198 https://doi.org/10.3174/ajnr.A4615
  112. Gulani V, Calamante F, Shellock FG, Kanal E, Reeder SB; International Society for Magnetic Resonance in Medicine. Gadolinium deposition in the brain: summary of evidence and recommendations. Lancet Neurol 2017;16:564-570 https://doi.org/10.1016/S1474-4422(17)30158-8