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Gadolinium-based contrast agents induce gadolinium deposits in cerebral vessel walls


Gadolinium based MRI contrast agents (GBCAs) are used to enhance the images and allow physicians interpreting the exam to distinguish blood vessels from nearby tissue. Safety claims for the GBCAs are based on the high stability of the agents and the high solubility leading to rapid excretion in an intact state. Yet, recent studies showed gadolinium depositions following serial administrations of GBCAs in various parts of the brain with the dentate nucleus (DN) being most affected. While there is currently no evidence that gadolinium deposition in the brain has caused any harm to patients, an intensive debate developed about the consequences of such retention. Regulatory bodies in Europe, the US and Japan have therefore called the manufacturers to study the retention and its effect on health.

The new study:
The aim of the current study was to specify the gadolinium distribution in brain tissue of patients who received serial injections of GBCAs in the low-μm range and to explore any potential pathological tissue changes caused by gadolinium deposits.

The German researchers identified thirteen autopsy cases — eight receiving GBCA administrations, five serving as controls — from the archives of the Institute of Neuropathology, University Hospital Münster, Germany. For all patients, total gadolinium quantification after acidic digestion by means of inductively coupled plasma mass spectrometry (ICP-MS) was performed. Six cases were selected for the spatially resolved quantification of gadolinium within the cerebellum and the basal ganglia by means of high-resolution laser ablation (LA)-ICP-MS. Quantitative bioimaging of tissue sections for these cases by LA-ICP-MS revealed gadolinium depositions in the walls of small blood vessels of the DN in all GBCA exposed patients, while no gadolinium was found in the control group. Additionally, the detection of phosphorus and metals like copper, zinc and iron provides evidence that transmetalation reactions might have occurred.

Figure: Results for the LA-ICP-MS analysis of a cryo autopsy brain section of patient E. Microscopic images of the cerebellum (a, b). The red rectangle represents the analyzed area within the cerebellum. Corresponding quantitative distribution map of gadolinium (c) and qualitative distribution maps of phosphorus (d), copper (e), zinc (f) and iron (g). LA-ICP-MS analysis was performed with a spot size of 20 μm. Relevant areas for the analysis of the DN are marked with dotted lines (b)

Apart from the analysis of the Gd retention, histopathological and immunohistochemical examinations were performed to determine tissue reactions. No significant pathological changes of the brain tissue in the vicinity of the DN with respect to micro-/astrogliosis and neuronal loss were found in any of the patients. The absence of pathological changes was observed even for a patient who died from nephrogenic systemic fibrosis exhibiting extremely high gadolinium concentrations within the DN. Alltogether the results show that gadolinium depositions in the brain are restricted to blood vessel walls, while the neuropil is spared and apparent cellular reactions are absent.

The original studies

Stefanie Fingerhut, Michael Sperling, Markus Holling, Thomas Niederstadt, Thomas Allkemper, Alexander Radbruch, Walter Heindel, Werner Paulus, Astrid Jeibmann, Uwe Karst, Gadolinium‑based contrast agents induce gadolinium deposits in cerebral vessel walls, while the neuropil is not affected: an autopsy study, Acta Neuropathol., (2018). DOI: 10.1007/s00401-018-1857-4

Related studies (newest first)

S. Fingerhut, A.C. Niehoff, M. Sperling, A. Jeibmann, W. Paulus, T. Niederstadt, T. Allkemper, W. Heindel, M. Holling, U. Karst, Spatially resolved quantification of gadolinium deposited in the brain of a patient treated with gadolinium-based contrast agents. J. Trace Elem. Med. Biol., 45 (2018) 125–130. DOI: 10.1016/j.jtemb .2017.10.004

T. Frenzel, C. Apte, G. Jost, L. Schockel, J. Lohrke, H. Pietsch, Quantification and assess-ment of the chemical form of residualgadolinium in the brain after repeated administration of gadolinium-based contrast agents comparative study in rats. Invest. Radiol.,  52 (2017) 396–404. DOI: 10.1097/Rli.0000000000000352

G. Jost, T. Frenzel, J. Lohrke, D.C. Lenhard, S. Naganawa, H. Pietsch, 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., 27 (2017) 2877–2885.
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J. Lohrke, A.L. Frisk, T. Frenzel, L. Schöckel, M. Rosenbruch, G. Jost, D.C. Lenhard, M.A. Sieber, V. Nischwitz, A. Küppers, H.Pietsch, 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.,  52 (2017) 324–333. DOI: 10.1097/Rli.0000000000000344

R.J. McDonald, J.S. McDonald, D. Dai, D. Schroeder, M.E. Jentoft,D.L. Murray, R. Kadirvel, L.J. Eckel, D.F. Kallmes, Comparison of gadolinium concentrations within multiple rat organs after intravenous administration of linear versus macrocyclic gadolinium chelates. Radiology, 285 (2017) 536-545. DOI: 10.1148/radiol.2017161594

A. Radbruch, R. Haase, P.J. Kieslich, L.D. Weberling, P. Kickingereder, W. Wick, H.P. Schlemmer, M. Bendszus, 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, 282 (2017) 699–707. DOI: 10.1148/radiol.2016162241

D.R. Roberts, C.A. Welsh, D.P. LeBel 2nd, W.C. Davis, Distribution map of gadolinium deposition within the cerebellum following GBCA administration. Neurology, 88 (2017) 1206–1208. DOI: 10.1212/WNL.0000000000003735

V.M. Runge, Critical questions regarding gadolinium deposition in the brain and body after injections of the gadolinium-based contrast agents, safety, and clinical recommendations in consideration of the EMA’s pharmacovigilance and risk assessment committee recommendation for suspension of the marketing authorizations for 4 linear agents. Invest. Radiol., 52 (2017) 317–323. DOI: 10.1097/Rli.0000000000000374

Donna R. Roberts, Kenton R. Holden, 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., 38/3 (2016) 331–336. DOI: 10.1016/j.braindev.2015.08.009

Philippe Robert, Xavier Violas, Sylvie Grand, Stéphane Lehericy, Jean-Marc Idée, Sébastien Ballet, Claire Corot, Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats, Invet. Radiol., 51/2 (2016) 73-82. DOI: 10.1097/RLI.0000000000000241

Y. Cao, Y. Zhang, G. Shih, Y. Zhang, A. Bohmart, E.M. Hecht, M.R. Prince, Effect of renal function on gadolinium-related signal increases on unenhanced T1-weighted brain magnetic resonance imaging. Invest. Radiol., 51 (2016) 677–682. DOI: 10.1097/Rli.0000000000000294

Y. Cao, D.Q. Huang, G. Shih, M.R. Prince, Signal change in the dentate nucleus on T1-weighted MR images after multiple administrationsof gadopentetate dimeglumine versus gadobutrol. Am. J. Roentgenol., 206 (2016) 414–419. DOI: 10.2214/Ajr.15.15327

G. Jost, D.C. Lenhard, M.A. Sieber, J. Lohrke, T. Frenzel, H. Pietsch,  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., 51 (2016) 83–89. DOI: 10.1097/Rli.0000000000000242

N. Murata, L.F. Gonzalez-Cuyar, K. Murata, C. Fligner, R. Dills,D. Hippe, K.R. Maravilla, Macrocyclic and other nongroup 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., 51 (2016) 447-4523. DOI: 10.1097/rli.0000000000000252

M. Birka, K.S. Wentker, E. Lusmöller, B. Arheilger, C.A. Wehe, M. Sperling, R. Stadler, U. Karst, Diagnosis of nephrogenic systemic fibrosis by means of elemental bioimaging and speciation analysis. Anal. Chem., 87 (2015) 3321–3328. DOI: 10.1021/ac504488k

A. Radbruch, L.D. Weberling, P.J. Kieslich, O. Eidel, S. Burth, P. Kickingereder, S. Heiland, W. Wick, H.P. Schlemmer, M. Bendszus, Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology, 275 (2015) 783–791. DOI: 10.1148/radiol.2015150337

A. Radbruch, L.D. Weberling, P.J. Kieslich, J. Hepp, P. Kickingereder, W. Wick, H.P. Schlemmer, M. Bendszus, 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., 50 (2015) 805–810. DOI: 10.1097/Rli.0000000000000227

J. Ramalho, M. Castillo, M. AlObaidy, R.H. Nunes, M. Ramalho, B.M. Dale, R.C. Semelka, High signal intensity in globus pallidus and dentate nucleus on unenhanced T1-weighted MR images: evaluation of two linear gadolinium-based contrast agents. Radiology, 276 (2015) 836–844. DOI: 10.1148/radiol.2015150872

P. Robert, S. Lehericy, S. Grand, X. Violas, N. Fretellier, J.M. Idee, S. Ballet, C. Corot, 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., 50 (2015) 473–480. DOI: 10.1097/Rli.0000000000000181

T. Kanda, T. Fukusato, M. Matsuda, K. Toyoda, H. Oba, J. Kotoku, T. Haruyama, K. Kitajima, S. Furui, 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, 276 (2015) 228–232. DOI: 10.1148/radiol.2015142690

T. Kanda, M. Osawa, H. Oba, K. Toyoda, J. Kotoku, T. Haruyama, K. Takeshita, S. Furui, High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology, 275 (2015) 803–809. DOI: 10.1148/radiol.14140364

R.J. McDonald, J.S. McDonald, D.F. Kallmes, M.E. Jentoft, D.L. Murray, K.R. Thielen, E.E. Williamson, L.J. Eckel, Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology, 275 (2015) 772–782. DOI: 10.1148/radiol.15150025

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