Advertisement

The Cerebellum

, Volume 17, Issue 3, pp 247–251 | Cite as

The Effects of Gadolinium-Based Contrast Agents on the Cerebellum: from Basic Research to Neurological Practice and from Pregnancy to Adulthood

  • Winda Ariyani
  • Miski Aghnia Khairinisa
  • Gaetano Perrotta
  • Mario Manto
  • Noriyuki KoibuchiEmail author
Editorial

Abstract

Gadolinium (Gd)-based contrast agents (GBCAs) are used in magnetic resonance imaging (MRI) to increase the diagnostic yield. Current reports using animal models or human subjects have shown that GBCAs may be deposited in brain including the cerebellum. Although further studies may be required to clarify the toxicity of GBCAs, we should be more cautious to use these agents particularly in patients who more likely to have repeated enhanced MRI along their lifespan. In this editorial, current studies to clarify the toxicity of GBCAs in the cerebellum are introduced.

Gadolinium (Gd)-based contrast agents (GBCAs) are used in magnetic resonance imaging (MRI) to increase the diagnostic yield. Studies using animal models have shown that GBCAs may be deposited in the brain after repeated injections [1, 2, 3]. Tissue depositions of linear GBCAs are much higher than those of macrocyclic GBCA. Among brain regions, the dentate nucleus of the cerebellum has been considered as a primary region for such deposition on the basis of human studies [4, 5]. Animal MRI studies also revealed the same phenomenon [3, 6]. Furthermore, the Gd deposition has also been observed in the cerebellar cortex [3, 7]. Gd compounds deposited in the cerebellum consist of both soluble and insoluble forms [1, 2]. Soluble form may be intact GBCA, whereas insoluble form may be Gd bound with organic or inorganic anions, although the exact chemical nature of insoluble form has not yet fully clarified. A large fraction of linear GBCAs is transformed to insoluble form and deposited in the cerebellum.

In addition to Gd deposition in the adult brain which has become a matter of concern for the clinical community, attention should also be paid for fetal GBCA deposition during pregnancy. Indeed, in recent studies using pregnant mice, Gd was deposited in the brain of dams and pups with higher concentration in the pup brain after GBCA injection [8, 9]. Higher levels of Gd deposition in the fetal brain may be due to the immaturity of the blood-brain barrier [10] and the blood-cerebrospinal fluid barrier, both of which are not fully developed in the perinatal period [6, 11].

Although the Gd toxicity on cerebellar development and function has not been demonstrated yet, recent studies have provided novel information [8, 12]. One such information is that Gd may disrupt the action of thyroid hormone (TH), which plays a critical role on cerebellar development [13]. Low dose (10−7 M) of gadodiamide (linear GBCA) augmented TH receptor (TR)-mediated transcription, whereas high dose (10−4 M) suppressed it [12]. In contrast, no significant change on TR-mediated transcription was observed by gadoterate meglumine (macrocyclic GBCA). In T4-treated primary cerebellar culture, low dose (10−7 M) of gadodiamide augmented dendrite arborization of Purkinje cell (Fig. 1a), whereas high dose (10−4 M) suppressed it [12]. However, no significant change on dendrite arborization of Purkinje cell was observed by gadoterate meglumine. In T3-treated primary cerebellar culture, both gadodiamide and gadoterate meglumine suppressed the dendrite arborization of Purkinje cell and total Purkinje cell number [12]. According to previous studies, it is unlikely that GBCAs or Gd enters into the cell. Thus, Gd may not directly inhibit TR action. It may disrupt calcium signaling by blocking Ca2+ channel which then affects Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV)-mediated augmentation of TR action [14] or bind to integrin αVβ3 that is known as TH-binding site [15]. On the other hand, another in vivo study, when gadoterate meglumine or gadodiamide was intravenously injected into dams during perinatal period (embryonic day 15–19, single injection/day), which is the critical period for the functional organization of neuronal circuits, both GBCAs disrupted motor coordination and impaired memory function [8]. The magnitude of disruption was higher with gadodiamide. Motor coordination examined by rotarod was significantly disrupted (Fig. 1b), whereas memory functions examined by object recognition and object-in-location were also disrupted [8]. These behavioral alterations indicate that GBCAs affect the development of several brain regions such as the cerebellum and hippocampus. Taken together with in vitro results, GBCAs, particularly linear form, may cause toxic effects in the developing brain at least in part by disrupting the action of THs to induce behavioral alterations in mice. Therefore, GBCAs may be administered during pregnancy only when the benefit significantly outweighs the risk of exposure.
Fig. 1

a Representative photomicrographs showing the effects of gadodiamide (Gd-DTPA-BMA), gadoterate meglumine (Gd-DOTA), or GdCl3 on Purkinje cell morphology. Bars indicate 50 μm. b The effect of perinatal GBCA exposure on motor coordination. Male mice (aged 70 days), whose mother received GBCA injection during gestational days 15–19, showed a significant decrease in the time spent on the rotarod on day 3 in both GBCA-treated groups (gadoterate meglumine-treated group, p < 0.001 and gadodiamide-treated group, p < 0.001, by ANOVA followed by Bonferroni test) compared with that in the control group. ***p < 0.001

In humans, the evidence of gadolinium accumulation in brain structures after repeated administrations of GBCAs has raised important concerns about the safety of these products. Although no evidence of clinically relevant consequences has been provided to date, the scientific and medical community recommendations underline that physicians should be cautious regarding the administration of these products, especially in patients who are expected to receive several MRI scans. This is the case for both children and adults.

After (a) repeated reports of signal intensity (SI) increase in the dentate nuclei and basal ganglia on brain T1-weighted images of pediatric patients who underwent several contrast-enhanced MRI scans with administration of linear products [16, 17, 18, 19] and (b) a study with no SI after gadobenate administration [20], an autoptic study of three children has confirmed the deposition of gadolinium in the dentate nucleus, globus pallidus, and at a smaller concentration in the thalamus and pons, after more than 3 administrations of gadodiamide, a linear GBCA [21]. Pathological changes were also observed in the dentate nuclei (gliosis, axonal spheroids). However, these signs of damage and deterioration could possibly be due to previous radiotherapy rather than the administration of GBCA. A previous single case report in a pediatric patient who received 4 administrations of a linear GBCA (gadopentetate and possibly gadodiamide) described similar observations [22]. Gadolinium deposition seems to be class-dependent, as no brain MRI modification is visible in subjects who received several doses of macrocyclic agents [18, 23, 24, 25]. Nevertheless, after an average of 10 macrocyclic GBCA administrations, a SI increase has been quantitatively measured in the dentate nucleus and globus pallidus of 50 children [26]. Anatomopathological studies after repeated macrocyclic administrations in the pediatric population are still lacking. We also miss detailed clinical/neurological reports in children exposed to GBCAs. The cerebellum of children is also in development and possible long-term impacts of gadolinium deposits on the cerebellar functions fully deserve the attention of the medical community.

First descriptions of SI increase in the cerebellum and basal ganglia were obtained from analysis of brain MRI T1-weighted images of adult patients who received more than 5 GBCA administrations [27], in comparison to subjects who underwent an equal number of unenhanced MRI scans. SI increase in adults is clearly associated to linear compound administration [28, 29].

Macrocyclic agents do not modify the signal intensity in the cerebellum and basal ganglia on MRI images [30, 31], while anatomopathological findings from autoptic studies suggest that gadolinium accumulation could occur even after administration of these molecules, both in rodents and in humans [32, 33]. However, the extent of accumulation is clearly smaller with macrocyclic than with linear GBCAs [32, 33, 34], and the clinical meaning of these findings remains uncertain. In a detailed retrospective analysis of 10 patients who received an average of more than 28 doses of gadoterate, a macrocyclic agent, Perrotta et al. did not find any argument for a de novo cerebellar syndrome triggered by gadoterate [35]. In a larger retrospective study focusing on patients who underwent at least one enhanced MRI scan, no significant association was found between GBCA exposure and risk of developing movement disorders such as parkinsonian symptoms [36]. So far, no unequivocal report of neurological symptoms occurring after intracranial gadolinium accumulation has been published. Nevertheless, some functional modifications are suggested by Bauer and colleagues who showed a hypometabolism in the dentate nuclei and globi pallidi of subjects who received GBCAs when compared to naïve controls [37].

Overall, clinical consequences of gadolinium deposition in brain structures clearly need further studies evaluating prospectively motor, cognitive, and effective functions. In addition, mechanisms of gadolinium deposition and washout pathways should also be elucidated, thus providing the basis for potential therapies in case of appearance of neurological deficits, especially cerebellar ataxia. The research community should take advantage of the clinically silent phase to speed up research and set up international registries. The myriad of functions played by the cerebellum requires a specific attention by the cerebellum community and dedicated studies.

For the moment, clinicians should be cautious particularly in patients who more likely to have repeated enhanced MRI along their lifespan. The indication of GBCA administration should be systematically challenged, and the type of GBCA which will be used should be discussed. The general leading opinion is to avoid linear agents. The brain is not the sole potential target for deposits. A tissue retention occurs also in the bone, skin, and kidney. Patients with renal failure are particularly vulnerable [38]. The risk of developing nephrogenic systemic fibrosis (NSF) should be minimized to the maximum. We should also keep in mind that cerebellar patients themselves might be a vulnerable population also!

References

  1. 1.
    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(3):839–49.  https://doi.org/10.1148/radiol.2017162857.CrossRefPubMedGoogle Scholar
  2. 2.
    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. Investig Radiol. 2017;52(7):396–404.  https://doi.org/10.1097/RLI.0000000000000352.CrossRefGoogle Scholar
  3. 3.
    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(2):536–45.  https://doi.org/10.1148/radiol.2017161594.CrossRefPubMedGoogle Scholar
  4. 4.
    Mcdonald RJ, Mcdonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Neuroradiology. 2015;275(3):772–82.Google Scholar
  5. 5.
    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(2):546–54.  https://doi.org/10.1148/radiol.2017161595.CrossRefPubMedGoogle Scholar
  6. 6.
    Rasschaert M, Idée J, 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. Investig Radiol. 2017;52(5):255–64.  https://doi.org/10.1097/RLI.0000000000000339.CrossRefGoogle Scholar
  7. 7.
    Lohrke J, Frisk A-L, Frenzel T, Schöckel 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. Investig Radiol. 2017;52(6):324–33.  https://doi.org/10.1097/RLI.0000000000000344.CrossRefGoogle Scholar
  8. 8.
    Khairinisa MA, Takatsuru Y, Amano I, Erdene K, Nakajima T, Kameo S, et al. The effect of perinatal gadolinium-based contrast agents on adult mice behavior. Investig Radiol. 2017:1.  https://doi.org/10.1097/RLI.0000000000000417.
  9. 9.
    Erdene K, Nakajima T, Kameo S, Khairinisa MA, Lamid-Ochir O, Tumenjargal A, et al. Organ retention of gadolinium in mother and pup mice: effect of pregnancy and type of gadolinium-based contrast agents. Jpn J Radiol. 2017;35(10):568–73.  https://doi.org/10.1007/s11604-017-0667-2.CrossRefPubMedGoogle Scholar
  10. 10.
    Saunders NR, Liddelow SA, Dziegielewska KM. Barrier mechanisms in the developing brain. Front Pharmacol. 2012;3(46):1–18.Google Scholar
  11. 11.
    Ek CJ, Dziegielewska KM, Habgood MD, Saunders NR. Barriers in the developing brain and neurotoxicology. Neurotoxicology. 2012;33(3):586–604.  https://doi.org/10.1016/j.neuro.2011.12.009.CrossRefPubMedGoogle Scholar
  12. 12.
    Ariyani W, Iwasaki T, Miyazaki W, Khongorzul E, Nakajima T, Kameo S, et al. Effects of gadolinium-based contrast agents on thyroid hormone receptor action and thyroid hormone-induced cerebellar Purkinje cell morphogenesis. Front Endocrinol (Lausanne). 2016;7(115)Google Scholar
  13. 13.
    Koibuchi N. The role of thyroid hormone on cerebellar development. Cerebellum. 2008;7(4):530–3.  https://doi.org/10.1007/s12311-008-0069-1.CrossRefPubMedGoogle Scholar
  14. 14.
    Kuno-Murata M, Koibuchi N, Fukuda H, Murata M, Chin WW. Augmentation of thyroid hormone receptor-mediated transcription by Ca2+/calmodulin-dependent protein kinase type IV. Endocrinology. 2000;141(6):2275–8.  https://doi.org/10.1210/endo.141.6.7612.CrossRefPubMedGoogle Scholar
  15. 15.
    Davis PJ, Goglia F, Leonard JL. Nongenomic actions of thyroid hormone. Nat Rev Endocrinol. 2016;12(2):111–21.  https://doi.org/10.1038/nrendo.2015.205.CrossRefPubMedGoogle Scholar
  16. 16.
    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(12):2340–7.  https://doi.org/10.3174/ajnr.A4891.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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(1):222–8.  https://doi.org/10.1148/radiol.2016160356.CrossRefPubMedGoogle Scholar
  18. 18.
    Renz DM, Kümpel S, Böttcher J, Pfeil A, Streitparth F, Waginger M, et al. Comparison of unenhanced t1-weighted signal intensities within the dentate nucleus and the globus pallidus after serial applications of gadopentetate dimeglumine versus gadobutrol in a pediatric population. Investig Radiol. 2017:1.  https://doi.org/10.1097/RLI.0000000000000419.
  19. 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(11):1590–8.CrossRefGoogle Scholar
  20. 20.
    Schneider GK, Stroeder J, Roditi G, Colosimo C, Armstrong P, Martucci M, et al. T1 signal measurements in pediatric brain: findings after multiple exposures to gadobenate dimeglumine for imaging of nonneurologic disease. AJNR Am J Neuroradiol. 2017;38(9):1799–806.  https://doi.org/10.3174/ajnr.A5270.CrossRefPubMedGoogle Scholar
  21. 21.
    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(7):705–7.  https://doi.org/10.1001/jamapediatrics.2017.0264.CrossRefPubMedGoogle Scholar
  22. 22.
    Roberts DR, Welsh CA, LeBel DP, Davis WC. Distribution map of gadolinium deposition within the cerebellum following GBCA administration. Neurology. 2017;88(12):1206–8.  https://doi.org/10.1212/WNL.0000000000003735.CrossRefPubMedGoogle Scholar
  23. 23.
    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(8):e0183916.  https://doi.org/10.1371/journal.pone.0183916.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Radbruch A, Haase R, Kieslich PJ, Weberling LD, Kickingereder P, Wick W, 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(3):699–707.  https://doi.org/10.1148/radiol.2016162241.CrossRefPubMedGoogle Scholar
  25. 25.
    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(1):223–30.  https://doi.org/10.1148/radiol.2017161151.CrossRefPubMedGoogle Scholar
  26. 26.
    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(10):1345–52.  https://doi.org/10.1007/s00247-017-3874-1.CrossRefPubMedGoogle Scholar
  27. 27.
    Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology. 2014;270(3):834–41.  https://doi.org/10.1148/radiol.13131669.CrossRefPubMedGoogle Scholar
  28. 28.
    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(2):414–9.  https://doi.org/10.2214/AJR.15.15327.CrossRefPubMedGoogle Scholar
  29. 29.
    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(3):803–9.  https://doi.org/10.1148/radiol.14140364.CrossRefPubMedGoogle Scholar
  30. 30.
    Kromrey M-L, 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(2):772–7.  https://doi.org/10.1007/s00330-016-4418-z.CrossRefPubMedGoogle Scholar
  31. 31.
    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(3):783–91.  https://doi.org/10.1148/radiol.2015150337.CrossRefPubMedGoogle Scholar
  32. 32.
    Robert P, Lehericy S, Grand S, Violas X, Fretellier N, Idée 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. Investig Radiol. 2015;50(8):473–80.  https://doi.org/10.1097/RLI.0000000000000181.CrossRefGoogle Scholar
  33. 33.
    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. Investig Radiol. 2016;51(7):447–53.  https://doi.org/10.1097/RLI.0000000000000252.CrossRefGoogle Scholar
  34. 34.
    Robert P, Violas X, Grand S, Lehericy S, Idée JM, Ballet S, et al. Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Investig Radiol. 2016;51(2):73–82.  https://doi.org/10.1097/RLI.0000000000000241.CrossRefGoogle Scholar
  35. 35.
    Perrotta G, Metens T, Absil J, Lemort M, Manto M. Absence of clinical cerebellar syndrome after serial injections of more than 20 doses of gadoterate, a macrocyclic GBCA: a monocenter retrospective study. J Neurol. 2017;264(11):2277–83.  https://doi.org/10.1007/s00415-017-8631-8.CrossRefPubMedGoogle Scholar
  36. 36.
    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(1):96–8.  https://doi.org/10.1001/jama.2016.8096.CrossRefPubMedGoogle Scholar
  37. 37.
    Bauer K, Lathrum A, Raslan O, et al. Do gadolinium-based contrast agents affect (18)f-fdg pet/ct uptake in the dentate nucleus and the globus pallidus? A pilot study. J Nucl Med Technol. 2017;45(1):302–5.CrossRefGoogle Scholar
  38. 38.
    Naito S, Tazaki H, Okamoto T, Takeuchi K, Kan S, Takeuchi Y, et al. Comparison of nephrotoxicity between two gadolinium-contrasts, gadodiamide and gadopentetate in patients with mildly diminished renal failure. J Toxicol Sci. 2017;42(3):379–84.  https://doi.org/10.2131/jts.42.379.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Integrative PhysiologyGunma University Graduate School of MedicineMaebashiJapan
  2. 2.Service de NeurologieHôpital ErasmeBruxellesBelgium
  3. 3.FNRS, ULB-ErasmeBruxellesBelgium
  4. 4.Service des NeurosciencesUMonsMonsBelgium

Personalised recommendations