Start Submission Become a Reviewer

Reading: Gadolinium Deposition in the Brain and Body


A- A+
Alt. Display

Short Abstracts

Gadolinium Deposition in the Brain and Body


Aart J. van der Molen

Department of Radiology, Leiden University Medical Center, NL
X close


How to Cite: van der Molen AJ. Gadolinium Deposition in the Brain and Body. Journal of the Belgian Society of Radiology. 2019;103(1):71. DOI:
  Published on 18 Nov 2019
 Accepted on 29 Sep 2019            Submitted on 10 Sep 2019

Gadolinium Deposition in the Brain

Clinical studies

In 2014, it was suggested that the retrospectively observed hyperintensity of the dentate nucleus and the globus pallidus relative to the pons (dentate nucleus to pons [DNP] ratio) on unenhanced T1-weighted images of a population of patients with brain tumours was related to repeated administrations of linear Gadolinium-Based Contrast Agents (GBCAs) [1]. Almost simultaneously, another group reported similar findings on unenhanced T1-weighted brain images after multiple injections of gadodiamide in patients with multiple sclerosis and patients with brain metastases [2].

After these initial reports, a multitude of retrospective studies have found increased SI ratios in the dentate nucleus and or globus pallidus for linear GBCA. No such increases were found for macrocyclic GBCA, even after large doses [3, 4, 5]. In a recent systematic review of these studies by the ESMRMB Gadolinium Research and Education Committee (ESMRMB-GREC) it was shown that there was large variety in sequence type and evaluation methodologies [6].

One of the biggest problems is that increased SI ratios at unenhanced T1-weighted MRI are a poor biomarker for gadolinium deposition, as SI ratios do not have a linear relationship with Gd concentration, and are highly dependent on the magnetic resonance imaging (MRI) parameters used during acquisition. Absolute signal intensity in MRI depends on many MRI parameters such as field strength, sequence type/parameters, coil sensitivity/filling factor, coil tuning/matching drift, etc. Because little is known about which forms of gadolinium are present (speciation), signal intensities, or changes thereof, will not reflect true changes in gadolinium content [6, 7].

Preclinical studies

In post-mortem human brain samples, gadolinium was shown to be deposited in neuronal tissue after intravenous GBCA administration [8].

Preclinical studies in rat brains have highlighted the importance of in vivo dechelation of Gd3+ ions from less stable GBCAs, regardless of the presence of a renal dysfunction and with a clear dose-effect relationship. All quantities were in the nmol/g tissue range. They have also shown that differences exist in the amount of total gadolinium retained in the brain when comparing different GBCA compounds [9, 10, 11, 12].

To date, it is unclear what forms are responsible for the increased T1w signal increase (gadolinium speciation). Recently, it was shown that for gadolinium in the rat brain three different chemical forms have to be distinguished: intact chelate, gadolinium bound to macromolecules, and insoluble gadolinium salts [13]. The intact chelates were found for both linear and macrocyclic GBCA, but the other forms only for linear GBCA. As precipitated gadolinium does not induce any MRI signal when excitated, it is likely that the gadolinium bound to macromolecules is responsible for the visible T1w hyperintensity in clinical MRI [14].

Well-conducted long-term animal studies demonstrated that for linear GBCA, a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. For macrocyclic GBCA, only traces of the intact chelated gadolinium were present, with complete washout in time [15, 16].

Intact GBCA does not cross the intact blood-brain barrier. It is now believed that GBCA can reach the CSF via the choroid plexus [17] and ciliary body and can reach the brain interstitium via the glympathic system along perineural sheaths and perivascular spaces of penetrating cortical arteries. GBCA distributed into the cerebrospinal fluid cavity via the glymphatic system may remain in the eye or brain tissue for a longer duration compared to the GBCA in systemic circulation. The glympathic system may be responsible for deposition in linear GBCA as well as for GBCA clearance [18, 19].

Gadolinium Deposition in the Body

Preclinical Studies

Gadolinium deposition in bone

Lanthanide metals (gadolinium, samarium, europium, and cerium) have long been known to deposit in bone tissue and have effects on osteoblasts and osteoclasts, but the exact mechanisms are not yet well understood [20].

Gadolinium deposits have been found in samples of bone tissues of humans at higher concentrations than in brain tissue after administration of linear and macrocyclic GBCA, whereby linear GBCA deposit 4 to 25 times more than macrocyclic GBCA [21, 22, 23, 24].

The bone residence time for macrocyclic GBCA (up to 30 days) is much shorter than for linear GBCA (up to eight years) [22, 25]. Bone may serve as a storage compartment from which Gd is later released in the body [26, 27]. It is postulated that the long-term reservoir of gadolinium in bones might implicate that some patients with high bone turnover, such as menopausal women and patients with osteoporosis, may be more vulnerable to gadolinium deposition [22].

Gadolinium deposition in skin

Gadolinium depositions in skin have been demonstrated ever since the association of GBCA with nephrogenic systemic fibrosis in 2006. In skin biopsies of NSF patients, gadolinium was found along collagen bundles but also as insoluble apatite-like deposits, suggesting dechelation [26, 27, 28, 29]. After linear GBCA, gadolinium deposits were found up to 40–180 times more frequently than after macrocyclic GBCA, histologic changes are more extensive, and also products of dechelation of GBCA can be found [23, 30].

Recently, gadolinium has also been found in the skin of patients with normal renal function after high cumulative GBCA doses [31]. With normal renal function, even a case of ‘gadolinium-associated plaques’ has been described, which suggest that gadolinium deposition in the skin after linear GBCA might give clinically relevant symptoms [32].

Gadolinium deposition in other organs

Thus far, very little is published about the effects of gadolinium deposition in other organs.

In a clinical study in the liver, gadolinium deposits have been associated with iron overload in the livers of paediatric stem cell transplantation patients with normal renal function, reacting well to iron dechelation therapy [33].

Based on animal studies, it has been suggested that residual Gd is also present in tissues samples of kidney, liver, spleen, and testis [23, 34, 35, 36, 37, 38]. While deposition in the brain was only 2 to 7 μg Gd, the amounts in other organs varied 168 to 2134 μg Gd for kidney, 16 to 388 μg Gd for liver, and 18 to 354 μg Gd for spleen, all per gram of tissue. In all tissues the level was highest for the linear GBCA gadodiamide [35].

Self-reported clinical symptoms

Thus far, gadolinium deposition has not been associated with clinical symptoms.

Online gadolinium toxicity support groups in the USA have claimed that their members have manifested symptoms analogous to NSF and have prolonged excretion of Gd in urine following administration of GBCA. Surveys have shown variable symptoms that occur either directly or within six weeks of GBCA administration. Most frequently reported symptoms are a burning sensation and bone pain in lower arms and limbs, central torso pain, headache with vision/hearing changes, and skin thickening and discoloration [39, 40].

This complex of symptoms was coined ‘gadolinium deposition disease (GDD)’. The critical findings are the presence of gadolinium in the body beyond 30 days, combined with at least three of the following features, with onset after the administration of GBCA: i) central torso pain, ii) headache and clouded mentation, iii) peripheral leg and arm pain, iv) peripheral leg and arm thickening and discoloration, and v) bone pain [40].

Significant differences in gadolinium levels in bone and urine have been observed between individuals experiencing symptoms and those who are not [41]. A large study with a control population found more new symptoms within 24 hours after exposure to GBCA than after unenhanced MRI. From the GDD-like symptoms, only fatigue and mental confusion were more frequently reported after enhanced MRI, questioning the term GDD [42].

Gadolinium metabolism and deposition still has many knowledge gaps for which an international research agenda is important. The 2018 ACR/NIH/RSNA Meeting has made a good inventory of where future research should be aimed [7, 43].

The effect of NSF and the EMA ruling

In many European countries, the described association between NSF and exposure to linear GBCAs in 2006 has resulted in the fact that most hospitals switched early (from 2007) to macrocyclic GBCA use only, most often gadoterate or gadobutrol. After the series of publications describing increased signal intensities in the brain nuclei on unenhanced T1-weighted imaging after multiple linear GBCA exposures and post-mortem studies revealing the presence of small amounts of gadolinium in neural tissues, the European Medicines Agency instituted an article 31 procedure which eventually led to the withdrawal of EU market authorizations of the high-risk linear GBCA gadodiamide and gadoversetamide, as well as restrictions on the use of gadopentetate (MR arthrography only) and gadobenate (liver imaging only) [44, 45]. Therefore, for general use in MRI only macrocyclic GBCA are available, while the linear GBCA gadoxetate and gadobenate are available for liver-specific MRI.

For clinical practice, there are several recent guidelines to refer to [46, 47, 48, 49].

Competing Interests

Author is member of the ESUR Contrast Media Safety Committee and member of the ESMRMB-GREC committee. No grants, support, or stocks received for the JBSR 2019 meeting.


  1. Kanda, T, Ishii, K, Kawaguchi, H, Kitajima, K and 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. DOI: 

  2. Errante, Y, Cirimele, V, Mallio, CA, Di Lazzaro, V, Zobel, BB and 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. DOI: 

  3. 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: 805–810. DOI: 

  4. 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: 699–707. DOI: 

  5. Ramalho, J, Semelka, RC, Al-Obaidy, M, Ramalho, M, Nunes, RH and 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. DOI: 

  6. Quattrocchi, CC, Ramalho, J, van der Molen, AJ, Rovira, À, Radbruch, A, GREC, European Gadolinium Retention Evaluation Consortium and the ESNR, European Society of Neuroradiology. Standardized assessment of the signal intensity increase on unenhanced T1-weighted images in the brain: The European Gadolinium Retention Evaluation Consortium (GREC) Task Force position statement. Eur Radiol. 2019; 29: 3959–3967. DOI: 

  7. McDonald, RJ, Levine, D, Weinreb, J, et al. Gadolinium retention: A research roadmap from the 2018 NIH/ACR/RSNA workshop on gadolinium chelates. Radiology. 2018; 289: 517–534. DOI: 

  8. McDonald, RJ, McDonald, J, Kallmes, D, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology. 2015; 275: 772–782. DOI: 

  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: 473–480. DOI: 

  10. 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: 73–82. DOI: 

  11. Jost, G, Lenhard, DC, Sieber, MA, Lohrke, J, Frenzel, T and 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. DOI: 

  12. Smith, AP, Marino, M, Roberts, J, 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. DOI: 

  13. Frenzel, T, Apte, C, Jost, G, Schöckel, L, Lohrke, J and 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. DOI: 

  14. Gianolio, E, Bardini, P, Arena, F, 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. DOI: 

  15. Robert, P, Fingerhut, S, Factor, C, et al. One-year retention of gadoliniumin the brain: Comparison of gadodiamide and gadoterate meglumine in a rodent model. Radiology. 2018; 288: 424–433. DOI: 

  16. Jost, G, Frenzel, T, Boyken, J, Lohrke, J, Nischwitz, V and Pietsch, H. Long-term excretion of gadolinium-based contrast agents: Linear versus macrocyclic agents in an experimental rat model. Radiology. 2019; 290: 340–348. DOI: 

  17. Jost, G, Frenzel, T, Lohrke, J, Lenhard, DC, Naganawa, S and 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. Eur Radiol. 2017; 27: 2877–2885. DOI: 

  18. Taoka, T and Naganawa, S. Gadolinium-based contrast media, cerebrospinal fluid and the glymphatic system: Possible mechanisms for the deposition of gadolinium in the brain. Magn Reson Med Sci. 2018; 17: 111–119. DOI: 

  19. Deike-Hofmann, K, Reuter, J, Haase, R, et al. Glymphatic pathway of gadolinium-based contrast agents through the brain: Overlooked and misinterpreted. Invest Radiol. 2019; 54: 229–237. DOI: 

  20. Vidaud, C, Bourgeois, D and Meyer, D. Bone as target organ for metals: The case of f-elements. Chem Res Toxicol. 2012; 25: 1161–1175. DOI: 

  21. White, GW, Gibby, WA and 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: 272–278. DOI: 

  22. Darrah, TH, Prutsman-Pfeiffer, JJ, Poreda, RJ, Ellen Campbell, M, Hauschka, PV and Hannigan, RE. Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics. 2009; 1: 479–488. DOI: 

  23. Wang, YX, Schroeder, J, Siegmund, H, et al. Total gadolinium tissue deposition and skin structural findings following the administration of structurally different gadolinium chelates in healthy and ovariectomized female rats. Quant Imaging Med Surg. 2015; 5: 534–545. 

  24. 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. Invest Radiol. 2016; 51: 447–453. DOI: 

  25. Lancelot, E. Revisiting the pharmacokinetic profiles of gadolinium-based contrast agents. Invest Radiol. 2016; 51: 691–700. DOI: 

  26. Thakral, C, Alhariri, J and Abraham, JL. Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: Case report and implications. Contrast Media Mol Imaging. 2007; 2: 199–205. DOI: 

  27. Thakral, C and Abraham, JL. Nephrogenic systemic fibrosis: Histology and gadolinium detection. Radiol Clin North Am. 2009; 47: 841–853. DOI: 

  28. Sieber, MA, Lengsfeld, P, Frenzel, T, 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. DOI: 

  29. Pietsch, H, Lengsfeld, P, Jost, G, Frenzel, T, Hütter, J and Sieber, MA. Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents. Eur Radiol. 2009; 19: 1417–1424. DOI: 

  30. Haylor, J, Schroeder, J, Wagner, B, et al. Skin gadolinium following use of MR contrast agents in a rat model of Nephrogenic Systemic Fibrosis. Radiology. 2012; 263: 107–116. DOI: 

  31. Roberts, DR, Lindhorst, SM, Welsh, CT, et al. High levels of gadolinium deposition in the skin of a patient with normal renal function. Invest Radiol. 2016; 51: 280–289. DOI: 

  32. Gathings, RM, Reddy, R, Santa Cruz, D and Brodell, RT. Gadolinium-associated plaques: A new, distinctive clinical entity. JAMA Dermatol. 2015; 151: 316–319. DOI: 

  33. Maximova, N, Gregori, M, Zennaro, F, Sonzogni, A, Simeone, R and Zanon, D. Hepatic gadolinium deposition and reversibility after contrast agent-enhanced MR imaging of pediatric hematopoietic stem cell transplant recipients. Radiology. 2016; 281: 418–426. DOI: 

  34. Tweedle, MF, Wedeking, P and Kumar, K. Biodistribution of radiolabeled, formulated gadopentetate, gadoteridol, gadoterate, and gadodiamide in mice and rats. Invest Radiol. 1995; 30: 372–380. DOI: 

  35. McDonald, RJ, McDonald, JS, Dai, D, et al. Comparison of gadolinium concentrations within multiple rat organs after intravenous administration of linear versus macrocyclic gadolinium chelates. Radiology. 2017; 285: 536–545. DOI: 

  36. Di Gregorio, E, Ferrauto, G, Furlan, C, et al. The issue of gadolinium retained in tissues insights on the role of metal complex stability by comparing metal uptake in murine tissues upon the concomitant administration of lanthanum- and gadolinium-diethylene-triaminopenta-acetate. Invest Radiol. 2018; 53: 167–172. DOI: 

  37. Mercantepe, T, Tümkaya, L, Çeliker, FB, et al. Effects of gadolinium-based MRI contrast agents on liver tissue. J Magn Reson Imaging. 2018; 48: 1367–1374. DOI: 

  38. Çeliker, FB, Tumkaya, L, Mercantepe, T, Beyazal, M, Turan, A, Beyazal Polat, H, et al. Effects of gadodiamide and gadoteric acid on rat kidneys: A comparative study. J Magn Reson Imaging. 2019; 49: 382–389. DOI: 

  39. Burke, LM, Ramalho, M, Al Obaidy, M, Chang, E, Jay, M and Semelka, RC. Self-reported gadolinium toxicity: A survey of patients with chronic symptoms. Magn Reson Imaging. 2016; 34: 1078–1080. DOI: 

  40. Semelka, RC, Ramalho, J, Vakharia, A, et al. Gadolinium deposition disease: Initial description of a disease that has been around for a while. Magn Reson Imaging. 2016; 34: 1383–1390. DOI: 

  41. Lord, ML, Chettle, DR, Gräfe, JL, Noseworthy, MD and McNeill, FE. Observed deposition of gadollinium in bone using a new noninvasive in vivo biomedical device: Results of small pilot feasibility study. Radiology. 2018; 287: 96–103. DOI: 

  42. Parillo, M, Sapienza, M, Arpaia, F, et al. A structured survey on adverse events occurring within 24 hours after intravenous exposure to gadodiamide or gadoterate meglumine: A controlled prospective comparison study. Invest Radiol. 2019; 54: 191–197. DOI: 

  43. Le Fur, M and Caravan, P. The biological fate of gadolinium-based MRI contrast agents: A call to action for bioinorganic chemists. Metallomics. 2019; 11: 240–254. DOI: 

  44. European Medicines Agency. EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans (21 july 2017). Available at: Last accessed: 23 September 2019. 

  45. Dekkers, IA, Roos, R and van der Molen, AJ. Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency. Eur Radiol. 2018; 28: 1579–1584. DOI: 

  46. American College of Radiology. ACR Manual on contrast media, v10.3. Available at: Last accessed: 23 September 2019. 

  47. European Society of Urogenital Radiology Contrast Media Safety Committee. ESUR Guidelines on contrast safety, v10. Available at: Last accessed: 23 September 2019. 

  48. Costa, AF, van der Pol, CB, Maralani, PJ, et al. Gadolinium deposition in the brain: A systematic review of existing guidelines and Policy Statement issued by the Canadian Association of Radiologists. Can Assoc Radiol J. 2018; 69: 373–382. DOI: 

  49. Schieda, N, Maralani, PJ, Hurrell, C, Tsampalieros, AK and Hiremath, S. Updated clinical practice guideline on use of Gadolinium-Based Contrast Agents in kidney disease issued by the Canadian Association of Radiologists. Can Assoc Radiol J. 2019; 70: 226–232. DOI: 

comments powered by Disqus