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Clinical Neuroradiology

, Volume 28, Issue 2, pp 159–169 | Cite as

A Review of the Current Evidence on Gadolinium Deposition in the Brain

  • Richard PullicinoEmail author
  • Mark Radon
  • Shubhabrata Biswas
  • Maneesh Bhojak
  • Kumar Das
Review Article

Abstract

Over the past 3 years, gadolinium-based contrast agents have been linked to MRI signal changes in the brain, which have been found to be secondary to gadolinium deposition in the brain, particularly in the dentate nuclei and globus pallidus even in patients having an intact blood-brain barrier and a normal renal function. This tends to occur more in linear agents than with macrocyclic agents. Nonetheless, there has been no significant evidence that this has any clinical consequence. We reviewed the current evidence related to this new phenomenon and the precautionary approach taken by regulatory agencies.

Keywords

Gadolinium-based contrast agents Gadolinium deposition Pharmacokinetics Dentate nucleus Regulation 

Abbreviations

BBB

Blood-brain barrier

CMSC

Consortium of Multiple Sclerosis Centers

CSF

Cerebrospinal fluid

DN

Dentate nucleus

EMA

European Medicines Agency

FDA

U.S. Food and Drug Administration

Fe

Iron

GBCA

Gadolinium-based contrast agent

Gd

Gadolinium

GP

Globus pallidus

ICP-MS

Inductively coupled plasma mass spectrometry

LA-ICP-MS

Laser ablation inductively coupled plasma mass spectrometry

MRI

Magnetic resonance imaging

MS

Multiple sclerosis

NSF

Nephrogenic systemic fibrosis

QSM

Quantitative-susceptibility mapping

SEM/EDS

Scanning electron microscopy/energy dispersive X‑ray spectroscopy

Notes

Conflict of interest

R. Pullicino, M. Radon, S. Biswas, M. Bhojak and K. Das declare that they have no competing interests.

References

  1. 1.
    Laniado M, Weinmann HJ, Schörner W, Felix R, Speck U. First use of GdDTPA/dimeglumine in man. Physiol Chem Phys Med Nmr. 1984;16:157–65.PubMedGoogle Scholar
  2. 2.
    Runge VM, Clanton JA, Price AC, Herzer WA, Allen JH, Partain CL, James AE Jr. Dyke Award. Evaluation of contrast-enhanced MR imaging in a brain-abscess model. AJNR Am J Neuroradiol. 1985;6:139–47.PubMedGoogle Scholar
  3. 3.
    Runge VM. Safety of the gadolinium-based contrast agents for magnetic resonance imaging, focusing in part on their accumulation in the brain and especially the dentate nucleus. Invest Radiol. 2016;51:273–9.PubMedGoogle Scholar
  4. 4.
    Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2000;356:1000–1.CrossRefPubMedGoogle Scholar
  5. 5.
    Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21:1104–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Marckmann P. An epidemic outbreak of nephrogenic systemic fibrosis in a Danish hospital. Eur J Radiol. 2008;66:187–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Bennett CL, Qureshi ZP, Sartor AO, Norris LB, Murday A, Xirasagar S, Thomsen HS. Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease. Clin Kidney J. 2012;5:82–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, Williamson EE, Eckel LJ. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology. 2015;275:772–82.CrossRefPubMedGoogle Scholar
  9. 9.
    Xia D, Davis RL, Crawford JA, Abraham JL. Gadolinium released from MR contrast agents is deposited in brain tumors: in situdemonstration using scanning electron microscopy with energy dispersive X‑ray spectroscopy. Acta Radiol. 2010;51:1126–36.CrossRefPubMedGoogle Scholar
  10. 10.
    Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku J, Haruyama T, Kitajima K, Furui S. 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.CrossRefPubMedGoogle Scholar
  11. 11.
    Kanal E. Gadolinium based contrast agents (GBCA): safety overview after 3 decades of clinical experience. Magn Reson Imaging. 2016;34:1341–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Lenkinski RE. Gadolinium Retention and Deposition Revisited: How the Chemical Properties of Gadolinium-based Contrast Agents and the Use of Animal Models Inform Us about the Behavior of These Agents in the Human Brain. Radiology. 2017;285:721–4.CrossRefGoogle Scholar
  13. 13.
    Tedeschi E, Caranci F, Giordano F, Angelini V, Cocozza S, Brunetti A. Gadolinium retention in the body: what we know and what we can do. Radiol Med. 2017;122:589–600.CrossRefPubMedGoogle Scholar
  14. 14.
    Kanda T, Nakai Y, Hagiwara A, Oba H, Toyoda K, Furui S. Distribution and chemical forms of gadolinium in the brain: a review. Br J Radiol. 2017;90:20170115.CrossRefPubMedGoogle Scholar
  15. 15.
    Olchowy C, Cebulski K, Łasecki M, Chaber R, Olchowy A, Kałwak K, Zaleska-Dorobisz U. The presence of the gadolinium-based contrast agent depositions in the brain and symptoms of gadolinium neurotoxicity—a systematic review. PLoS One. 2017;12:e171704.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Aime S, Caravan P. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging. 2009;30:1259–67.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tweedle MF, Hagan JJ, Kumar K, Mantha S, Chang CA. Reaction of gadolinium chelates with endogenously available ions. Magn Reson Imaging. 1991;9:409–15.CrossRefPubMedGoogle Scholar
  18. 18.
    Sherry AD, Caravan P, Lenkinski RE. Primer on gadolinium chemistry. J Magn Reson Imaging. 2009;30:1240–8.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Penfield JG, Reilly RF. What nephrologists need to know about gadolinium. Nat Rev Nephrol. 2007;3:654–68.CrossRefGoogle Scholar
  20. 20.
    Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann HJ. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37°C. Invest Radiol. 2008;43:817–28.CrossRefPubMedGoogle Scholar
  21. 21.
    Tóth É, Brücher E, Lázár I, Tóth I. Kinetics of formation and dissociation of lanthanide (III)-DOTA complexes. Inorganic chemistry. 1994;33:4070–6.CrossRefGoogle Scholar
  22. 22.
    Sarka L, Burai L, Király R, Zékány L, Brücher E. Studies on the kinetic stabilities of the Gd(3+) complexes formed with the N‑mono(methylamide), N′-mono(methylamide) and N,N″-bis(methylamide) derivatives of diethylenetriamine-N,N,N′,N′,N′-pentaacetic acid. J Inorg Biochem. 2002;91:320–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium(III) chelates as MRI contrast agents:  structure, dynamics, and applications. Chem Rev. 1999;99:2293–352.CrossRefPubMedGoogle Scholar
  24. 24.
    Puttagunta NR, Gibby WA, Smith GT. Human in vivo comparative study of zinc and copper transmetallation after administration of magnetic resonance imaging contrast agents. Invest Radiol. 1996;31:739–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Gibby WA, Gibby KA, Gibby WA. Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Invest Radiol. 2004;39:138–42.CrossRefPubMedGoogle Scholar
  26. 26.
    Laurent S, Elst LV, Muller RN. Comparative study of the physicochemical properties of six clinical low molecular weight gadolinium contrast agents. Contrast Media Mol Imaging. 2006;1:128–37.CrossRefPubMedGoogle Scholar
  27. 27.
    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;251:503–10.CrossRefPubMedGoogle Scholar
  28. 28.
    Absinta M, Rocca MA, Filippi M. Dentate nucleus T1 hyperintensity in multiple sclerosis. AJNR Am J Neuroradiol. 2011;32:E120–1.CrossRefPubMedGoogle Scholar
  29. 29.
    Kasahara S, Miki Y, Kanagaki M, Yamamoto A, Mori N, Sawada T, Taoka T, Okada T, Togashi K. Hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with a history of brain irradiation. Radiology. 2011;258:222–8.CrossRefPubMedGoogle Scholar
  30. 30.
    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;270:834–41.CrossRefPubMedGoogle Scholar
  31. 31.
    Leray E, Moreau T, Fromont A, Edan G. Epidemiology of multiple sclerosis. Rev Neurol (Paris). 2016;172:3–13.CrossRefGoogle Scholar
  32. 32.
    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;282:516–25.CrossRefPubMedGoogle Scholar
  33. 33.
    Khant ZA, Hirai T, Kadota Y, Masuda R, Yano T, Azuma M, Suzuki Y, Tashiro K. T1 shortening in the cerebral cortex after multiple administrations of gadolinium-based contrast agents. Magn Reson Med Sci. 2017;16:84–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Tedeschi E, Palma G, Canna A, Cocozza S, Russo C, Borrelli P, Lanzillo R, Angelini V, Postiglione E, Morra VB, Salvatore M, Brunetti A, Quarantelli M. In vivo dentate nucleus MRI relaxometry correlates with previous administration of gadolinium-based contrast agents. Eur Radiol. 2016;26:4577–84.CrossRefPubMedGoogle Scholar
  35. 35.
    Hinoda T, Fushimi Y, Okada T, Arakawa Y, Liu C, Yamamoto A, Okada T, Yoshida K, Miyamoto S, Togashi K. Quantitative assessment of gadolinium deposition in dentate nucleus using quantitative susceptibility mapping. J Magn Reson Imaging. 2016;45:1352–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Tedeschi E, Cocozza S, Borrelli P, Ugga L, Morra VB, Palma G. Longitudinal assessment of dentate nuclei relaxometry during massive gadobutrol exposure. Magn Reson Med Sci. 2018;17:100–4.CrossRefPubMedGoogle Scholar
  37. 37.
    RRadbruch A, Haase R, Kieslich PJ, Weberling LD, Kickingereder P, Wick W, Schlemmer HP, Bendszus M. 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;282:699–707.CrossRefPubMedGoogle Scholar
  38. 38.
    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;282:222–8.CrossRefPubMedGoogle Scholar
  39. 39.
    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;46:1590–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Roberts DR, Chatterjee AR, Yazdani M, Marebwa B, Brown T, Collins H, Bolles G, Jenrette JM, Nietert PJ, Zhu X. Pediatric patients demonstrate progressive T1-weighted hyperintensity in the dentate nucleus following multiple doses of gadolinium-based contrast agent. AJNR Am J Neuroradiol. 2016;37:2340–7.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tibussek D, Rademacher C, Caspers J, Turowski B, Schaper J, Antoch G, Klee D. Gadolinium brain deposition after macrocyclic gadolinium administration: a pediatric case-control study. Radiology. 2017;285:223–30.CrossRefPubMedGoogle Scholar
  42. 42.
    Radbruch A, Haase R, Kickingereder P, Bäumer P, Bickelhaupt S, Paech D, Wick W, Schlemmer HP, Seitz A, Bendszus M. Pediatric brain: no increased signal intensity in the dentate nucleus on unenhanced T1-weighted MR images after consecutive exposure to a macrocyclic gadolinium-based contrast agent. Radiology. 2017;283:828–36.CrossRefPubMedGoogle Scholar
  43. 43.
    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;26:807–15.CrossRefPubMedGoogle Scholar
  44. 44.
    Agris J, Pietsch H, Balzer T. What evidence is there that gadobutrol causes increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W MRI in patients with RRMS? Eur Radiol. 2016;26:816–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Radbruch A, Weberling LD, Kieslich PJ, Hepp J, Kickingereder P, Wick W, Schlemmer HP, Bendszus M. 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;51:683–90.CrossRefPubMedGoogle Scholar
  46. 46.
    Cao Y, Huang DQ, Shih G, Prince MR. Signal change in the dentate nucleus on T1-weighted MR images after multiple administrations of gadopentetate fimeglumine versus gadobutrol. AJR Am J Roentgenol. 2016;206:414–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Kanda T, Osawa M, Oba H, Toyoda K, Kotoku J, Haruyama T, Takeshita K, Furui S. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology. 2015;275:803–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Schneider GK, Stroeder J, Roditi G, Colosimo C, Armstrong P, Martucci M, Buecker A, Raczeck P. T1 signal measurements in pediatric brain: findings after multiple exposures to gadobenate dimeglumine for imaging of nonneurologic disease. AJNR Am J Neuroradiol. 2017;38:1799–806.CrossRefPubMedGoogle Scholar
  49. 49.
    Rossi Espagnet MC, Bernardi B, Pasquini L, Figà-Talamanca L, Tomà 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;47:1345–52.CrossRefPubMedGoogle Scholar
  50. 50.
    Radbruch A, Quattrocchi CC. Interpreting signal-intensity ratios without visible T1 hyperintensities in clinical gadolinium retention studies. Pediatr Radiol. 2017;47:1688–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Frenzel T, Apte C, Jost G, Schöckel 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.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Roberts DR, Welsh CA, LeBel DP, Davis WC. Distribution map of gadolinium deposition within the cerebellum following GBCA administration. Neurology. 2017;88:1206–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Rossi Espagnet MC, Tomà P, Napolitano A. Reply to Radbruch et al.: ‘interpreting signal-intensity ratios without visible T1 hyperintensities in clinical gadolinium retention studies’. Pediatr Radiol. 2017;47:1690–1.CrossRefPubMedGoogle Scholar
  54. 54.
    Nonaka H, Akima M, Hatori T, Nagayama T, Zhang Z, Ihara F. The microvasculature of the human cerebellar meninges. Acta Neuropathol. 2002;104:608–14.PubMedGoogle Scholar
  55. 55.
    McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Paolini MA, Murray DL, Williamson EE, Eckel LJ. Gadolinium deposition in human brain tissues after contrast-enhanced MR imaging in adult patients without Intracranial abnormalities. Radiology. 2017;285:546–54.CrossRefPubMedGoogle Scholar
  56. 56.
    Murata N, Gonzalez-Cuyar LF, Murata K, Fligner C, Dills R, Hippe D, Maravilla KR. 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;51:447–53.CrossRefPubMedGoogle Scholar
  57. 57.
    Robert P, Lehericy S, Grand S, Violas X, Fretellier N, Idée JM, Ballet S, Corot C. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    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;51:83–9.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Robert P, Violas X, Grand S, Lehericy S, Idée JM, Ballet S, Corot C. Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Invest Radiol. 2016;51:73–82.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Smith AP, Marino M, Roberts J, Crowder JM, Castle J, Lowery L, Morton C, Hibberd MG, Evans PM. 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;282:743–51.CrossRefPubMedGoogle Scholar
  61. 61.
    Prybylski JP, Maxwell E, Coste Sanchez C, Jay M. Gadolinium deposition in the brain: lessons learned from other metals known to cross the blood-brain barrier. Magn Reson Imaging. 2016;34:1366–72.CrossRefGoogle Scholar
  62. 62.
    Ramalho J, Castillo M, AlObaidy M, Nunes RH, Ramalho M, Dale BM, Semelka RC. 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;276:836–44.CrossRefPubMedGoogle Scholar
  63. 63.
    Weberling LD, Kieslich PJ, Kickingereder P, Wick W, Bendszus M, Schlemmer HP, Radbruch A. Increased signal intensity in the dentate nucleus on unenhanced T1-weighted images after gadobenate dimeglumine administration. Invest Radiol. 2015;50:743–8.CrossRefPubMedGoogle Scholar
  64. 64.
    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;38:331–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Radbruch A. Are some agents less likely to deposit gadolinium in the brain? Magn Reson Imaging. 2016;34:1351–4.CrossRefPubMedGoogle Scholar
  66. 66.
    Schlemm L, Chien C, Bellmann-Strobl J, Dörr J, Wuerfel J, Brandt AU, Paul F, Scheel M. Gadopentetate but not gadobutrol accumulates in the dentate nucleus of multiple sclerosis patients. Mult Scler. 2017;23:963–72.CrossRefPubMedGoogle Scholar
  67. 67.
    Kahn J, Posch H, Steffen IG, Geisel D, Bauknecht C, Liebig T, Denecke T. 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;282:708–16.CrossRefPubMedGoogle Scholar
  68. 68.
    Takeda A, Akiyama T, Sawashita J, Okada S. Brain uptake of trace metals, zinc and manganese. Brain Res. 1994;640:341–4.CrossRefPubMedGoogle Scholar
  69. 69.
    Aoki I, Wu YJ, Silva AC, Lynch RM, Koretsky AP. In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI. Neuroimage. 2004;22:1046–59.CrossRefPubMedGoogle Scholar
  70. 70.
    Jost G, Frenzel T, Lohrke J, Lenhard DC, Naganawa S, Pietsch H. Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue. Eur Radiol. 2017;27:2877–85.CrossRefPubMedGoogle Scholar
  71. 71.
    Wardlaw JM, Farrall A, Armitage PA, Carpenter T, Chappell F, Doubal F, Chowdhury D, Cvoro V, Dennis MS. Changes in background blood-brain barrier integrity between lacunar and cortical ischemic stroke subtypes. Stroke. 2008;39:1327–32.CrossRefPubMedGoogle Scholar
  72. 72.
    Naganawa S, Kawai H, Taoka T, Sone M. Improved HYDROPS: imaging of endolymphatic hydrops after intravenous administration of gadolinium. Magn Reson Med Sci. 2017;16:357–61.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4:147ra111.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123:1299–309.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Rasschaert M, Emerit A, Fretellier N, Factor C, Robert P, Idée JM, Corot C. Gadolinium retention, brain T1 hyperintensity, and endogenous metals: a comparative study of macrocyclic versus linear gadolinium chelates in renally sensitized rats. Invest Radiol. 2018 Jan 12. [Epub ahead of print]PubMedCentralCrossRefPubMedGoogle Scholar
  76. 76.
    Fretellier N, Poteau N, Factor C, Mayer JF, Medina C, Port M, Idée JM, Corot C. Analytical interference in serum iron determination reveals iron versus gadolinium transmetallation with linear gadolinium-based contrast agents. Invest Radiol. 2014;49:766–72.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Boehm-Sturm P, Haeckel A, Hauptmann R, Mueller S, Kuhl CK, Schellenberger EA. Low-molecular-weight iron chelates may be an alternative to gadolinium-based contrast agents for T1-weighted contrast-enhanced MR imaging. Radiology. 2018;286:537–46.CrossRefPubMedGoogle Scholar
  78. 78.
    Prybylski JP, Semelka RC, Jay M. Can gadolinium be re-chelated in vivo? Considerations from decorporation therapy. Magn Reson Imaging. 2016;34:1391–3.CrossRefGoogle Scholar
  79. 79.
    Larson KN, Gagnon AL, Darling MD, Patterson JW, Cropley TG. Nephrogenic systemic fibrosis manifesting a decade after exposure to gadolinium. Jama Dermatol. 2015;151:1117–20.CrossRefPubMedGoogle Scholar
  80. 80.
    Thomson LK, Thomson PC, Kingsmore DB, Blessing K, Daly CD, Cowper SE, Roditi GH. Diagnosing nephrogenic systemic fibrosis in the post-FDA restriction era. J Magn Reson Imaging. 2015;41:1268–71.CrossRefPubMedGoogle Scholar
  81. 81.
    Habas C. Functional imaging of the deep cerebellar nuclei: a review. Cerebellum. 2009;9:22–8.CrossRefPubMedGoogle Scholar
  82. 82.
    Münchau A, Mathen D, Cox T, Quinn NP, Marsden CD, Bhatia KP. Unilateral lesions of the globus pallidus: report of four patients presenting with focal or segmental dystonia. J Neurol Neurosurg Psychiatr. 2000;69:494–8.CrossRefGoogle Scholar
  83. 83.
    Welk B, McArthur E, Morrow SA, MacDonald P, Hayward J, Leung A, Lum A. Association between gadolinium contrast exposure and the risk of parkinsonism. JAMA. 2016;316:96–3.CrossRefPubMedGoogle Scholar
  84. 84.
    Forslin Y, Shams S, Hashim F, Aspelin P, Bergendal G, Martola J, Fredrikson S, Kristoffersen-Wiberg M, Granberg T. Retention of gadolinium-based contrast agents in multiple sclerosis: retrospective analysis of an 18-year longitudinal study. AJNR Am J Neuroradiol. 2017;38:1311–6.CrossRefPubMedGoogle Scholar
  85. 85.
    Helwick C. Brain gadolinium deposition varies with contrast agent in MS. Medscape. 2017. http://www.medscape.com/viewarticle/880649. Accessed 25 May 2017.Google Scholar
  86. 86.
    Rovira A, Auger C, Huerga E, Corral JF, Mitjana R, Sastre-Garriga J, Tintoré M, Montalban X. Cumulative dose of macrocyclic gadolinium-based contrast agent improves detection of enhancing lesions in patients with multiple sclerosis. AJNR Am J Neuroradiol. 2017;38:1486–93.CrossRefPubMedGoogle Scholar
  87. 87.
    Savarino E, Chianca V, Bodini G, Albano D, Messina C, Tontini GE, Sconfienza LM7. Gadolinium accumulation after contrast-enhanced magnetic resonance imaging: which implications in patients with Crohn’s disease? Dig Liver Dis. 2017;49:728–30.CrossRefPubMedGoogle Scholar
  88. 88.
    Semelka RC, Ramalho M, AlObaidy M, Ramalho J. Gadolinium in Humans: A Family of Disorders. AJR Am J Roentgenol. 2016;207:229–33.CrossRefPubMedGoogle Scholar
  89. 89.
    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;37:1192–8.CrossRefPubMedGoogle Scholar
  90. 90.
    Forgács A, Regueiro-Figueroa M, Barriada JL, Esteban-Gómez D, de Blas A, Rodríguez-Blas T, Botta M, Platas-Iglesias C. Mono-, bi-, and trinuclear bis-hydrated Mn(2+) complexes as potential MRI contrast agents. Inorg Chem. 2015;54:9576–87.CrossRefPubMedGoogle Scholar
  91. 91.
    Nguyen HV, Chen Q, Paletta JT, Harvey P, Jiang Y, Zhang H, Boska MD, Ottaviani MF, Jasanoff A, Rajca A, Johnson JA. Nitroxide-based macromolecular contrast agents with unprecedented transverse relaxivity and stability for magnetic resonance imaging of tumors. Acs Cent Sci. 2017;3:800–11.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    U.S. Food and Drug Administration. Center for Drug Evaluation and Research. FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI). 2015. http://www.fda.gov/Drugs/DrugSafety/ucm455386.htm#collapseOne. Accessed 21 Dec 2016.Google Scholar
  93. 93.
    U.S. Food and Drug Administration. FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings. 2017. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM589442.pdf. Accessed 19 Dec 2017.Google Scholar
  94. 94.
    Gulani V, Calamante F, Shellock FG, Kanal E, Reeder SB. Gadolinium deposition in the brain: summary of evidence and recommendations. Lancet Neurol. 2017;16:564–70.CrossRefPubMedGoogle Scholar
  95. 95.
    Radbruch A, Roberts DR, Clement O, Rovira A, Quattrocchi CC. Chelated or dechelated gadolinium deposition. Lancet Neurol. 2017;16:955.CrossRefPubMedGoogle Scholar
  96. 96.
    European Medicines Agency. EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/gadolinium_contrast_agents_31/European_Commission_final_decision/WC500240575.pdf. Accessed 17 Nov 2017.Google Scholar
  97. 97.
    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;49:685–90.CrossRefPubMedGoogle Scholar
  98. 98.
    Radbruch A, Weberling LD, Kieslich PJ, Hepp J, Kickingereder P, Wick W, Schlemmer HP, Bendszus M. High-signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images. Invest Radiol. 2015;50:805–10.CrossRefPubMedGoogle Scholar
  99. 99.
    Quattrocchi CC, Mallio CA, Errante Y, Cirimele V, Carideo L, Ax A, Zobel BB. 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;50:470–2.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neuroradiology DepartmentThe Walton Centre NHS Foundation TrustLiverpoolUK

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