Skip to main content

Advertisement

SpringerLink
Log in

Gadolinium presence, MRI hyperintensities, and glucose uptake in the hypoperfused rat brain after repeated administrations of gadodiamide

  • Diagnostic Neuroradiology
  • Published:
Neuroradiology Aims and scope Submit manuscript

Abstract

Purpose

The discussed topic about gadolinium-based contrast agents (GBCA) safety has recently been revived due to the evidence of hyperintensities observed in the dentate nucleus (DN) and globus pallidus (GP) in the brain of patients with normal kidney function. Several preclinical studies have been conducted to understanding how the use of GBCAs can promote the gadolinium deposition in the brain. Here, we evaluate the impact of chronic cerebral hypoperfusion on gadolinium presence.

Methods

T1 hyperintensities and BBB integrity were evaluated by MRI in chronically hypoperfused and healthy rats injected with either gadodiamide or hypertonic saline. Additionally, the assessment of glucose metabolism by PET imaging and the gadolinium content by ICP-MS was performed after the last MR scan.

Results

Chronically hypoperfused rats displayed a greater MRI T1w signal in the DCN and hippocampus compared to Sham-operated animals, suggesting gadolinium accumulation. Dynamic contrast-enhanced (DCE) MRI assessment of BBB permeability revealed loss of integrity (high Ktrans) after rat injury in the dentate nuclei and hippocampus. Ex vivo tissue analysis showed greater gadolinium retention in the cerebellum and subcortical regions, supporting the imaging finding. FDG-PET imaging of the cerebellum did not reveal abnormal uptake in the DCN after chronic cerebral hypoperfusion.

Conclusion

Higher signal intensity followed by higher Gd concentration observed in DCN and hippocampus of animals subjected to cerebral injury can be associated with an increase in BBB permeability due to the applied vascular dementia animal model. Nonetheless, no glucose metabolism abnormalities were detected in chronically hypoperfused cerebellum.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, Williamson EE, Eckel LJ (2015) Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 275(3):772–782. https://doi.org/10.1148/radiol.15150025

    Article  PubMed  Google Scholar 

  2. Errante Y, Cirimele V, Mallio CA, Di Lazzaro V, Zobel BB, Quattrocchi CC (2014) 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. Investig Radiol 49(10):685–690

    Article  CAS  Google Scholar 

  3. Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D (2014) 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 270(3):834–841. https://doi.org/10.1148/radiol.13131669

    Article  PubMed  Google Scholar 

  4. Quattrocchi CC, Mallio CA, Errante Y, Cirimele V, Carideo L, Ax A, Zobel BB (2015) 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. Investig Radiol 50(7):470–472. https://doi.org/10.1097/RLI.0000000000000154

    Article  Google Scholar 

  5. Kalaria RN, Akinyemi R, Ihara M (2012) Does vascular pathology contribute to Alzheimer changes? J Neurol Sci 322(1–2):141–147. https://doi.org/10.1016/j.jns.2012.07.032

    Article  CAS  PubMed  Google Scholar 

  6. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85(2):296–302. https://doi.org/10.1016/j.neuron.2014.12.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jost G, Lenhard DC, Sieber MA, Lohrke J, Frenzel T, Pietsch H (2016) 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(2):83–89. https://doi.org/10.1097/RLI.0000000000000242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gianolio E, Bardini P, Arena F, Stefania R, Di Gregorio E, Iani R, Aime S (2017) 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 162857. https://doi.org/10.1148/radiol.2017162857

  9. Robert P, Fingerhut S, Factor C, Vives V, Letien J, Sperling M, Rasschaert M, Santus R, Ballet S, Idee JM, Corot C, Karst U (2018) One-year retention of gadolinium in the brain: comparison of gadodiamide and gadoterate meglumine in a rodent model. Radiology 172746:424–433. https://doi.org/10.1148/radiol.2018172746

    Article  Google Scholar 

  10. Robert P, Frenzel T, Factor C, Jost G, Rasschaert M, Schuetz G, Fretellier N, Boyken J, Idee JM, Pietsch H (2018) Methodological aspects for preclinical evaluation of gadolinium presence in brain tissue: critical appraisal and suggestions for harmonization-a joint initiative. Investig Radiol 53:499–517. https://doi.org/10.1097/RLI.0000000000000467

    Article  CAS  Google Scholar 

  11. Farkas E, Luiten PG, Bari F (2007) Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 54(1):162–180. https://doi.org/10.1016/j.brainresrev.2007.01.003

    Article  CAS  PubMed  Google Scholar 

  12. Wang ZQ, Fan J, Wang J, Li YX, Duan D, Du G, Wang QS (2016) Chronic cerebral hypoperfusion induces long-lasting cognitive deficits accompanied by long-term hippocampal silent synapses increase in rats. Behav Brain Res 301:243–252. https://doi.org/10.1016/j.bbr.2015.12.047

    Article  PubMed  Google Scholar 

  13. Soria G, Tudela R, Marquez-Martin A, Camon L, Batalle D, Munoz-Moreno E, Eixarch E, Puig J, Pedraza S, Vila E, Prats-Galino A, Planas AM (2013) The ins and outs of the BCCAo model for chronic hypoperfusion: a multimodal and longitudinal MRI approach. PLoS One 8(9):e74631. https://doi.org/10.1371/journal.pone.0074631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guidance for industry. Estimating the maximum safe. Starting dose in initial clinical trials for therapeutics in adult healthy volunteers (2005) U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER)

  15. Faraco G, Blasi F, Min W, Wang ZQ, Moroni F, Chiarugi A (2010) Brain ischemic preconditioning does not require PARP-1. Stroke 41(1):181–183. https://doi.org/10.1161/STROKEAHA.109.567826

    Article  PubMed  Google Scholar 

  16. Choki JI, Yamaguchi T, Takeya Y, Morotomi Y, Omae T (1977) Effect of carotid artery ligation on regional cerebral blood flow in normotensive and spontaneously hypertensive rats. Stroke 8(3):374–379

    Article  CAS  PubMed  Google Scholar 

  17. Brookes JA, Redpath TW, Gilbert FJ, Murray AD, Staff RT (1999) Accuracy of T1 measurement in dynamic contrast-enhanced breast MRI using two- and three-dimensional variable flip angle fast low-angle shot. J Magn Reson Imaging 9(2):163–171

    Article  CAS  PubMed  Google Scholar 

  18. Paxinos GWC (ed) (2008) The rat brain in stereotaxic coordinates, 6th edn. San Diego, CA

    Google Scholar 

  19. Blasi F, Oliveira BL, Rietz TA, Rotile NJ, Day H, Naha PC, Cormode DP, Izquierdo-Garcia D, Catana C, Caravan P (2015) Radiation dosimetry of the fibrin-binding probe (6)(4)Cu-FBP8 and its feasibility for PET imaging of deep vein thrombosis and pulmonary embolism in rats. J Nucl Med 56(7):1088–1093. https://doi.org/10.2967/jnumed.115.157982

    Article  CAS  PubMed  Google Scholar 

  20. Loening AM, Gambhir SS (2003) AMIDE: a free software tool for multimodality medical image analysis. Mol Imaging 2(3):131–137

    Article  PubMed  Google Scholar 

  21. Longo DL, Bartoli A, Consolino L, Bardini P, Arena F, Schwaiger M, Aime S (2016) In vivo imaging of tumor metabolism and acidosis by combining PET and MRI-CEST pH imaging. Cancer Res 76(22):6463–6470. https://doi.org/10.1158/0008-5472.CAN-16-0825

    Article  CAS  PubMed  Google Scholar 

  22. Tsuchiya M, Sako K, Yura S, Yonemasu Y (1992) Cerebral blood flow and histopathological changes following permanent bilateral carotid artery ligation in Wistar rats. Exp Brain Res 89(1):87–92

    Article  CAS  PubMed  Google Scholar 

  23. Larsson HB, Courivaud F, Rostrup E, Hansen AE (2009) Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, using dynamic contrast-enhanced T(1)-weighted MRI at 3 tesla. Magn Reson Med 62(5):1270–1281. https://doi.org/10.1002/mrm.22136

    Article  PubMed  Google Scholar 

  24. Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku J, Haruyama T, Kitajima K, Furui S (2015) 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(1):228–232. https://doi.org/10.1148/radiol.2015142690

    Article  PubMed  Google Scholar 

  25. Radbruch A, Weberling LD, Kieslich PJ, Eidel O, Burth S, Kickingereder P, Heiland S, Wick W, Schlemmer HP, Bendszus M (2015) Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 275(3):783–791. https://doi.org/10.1148/radiol.2015150337

    Article  PubMed  Google Scholar 

  26. Robert P, Violas X, Grand S, Lehericy S, Idee JM, Ballet S, Corot C (2016) Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Investig Radiol 51(2):73–82. https://doi.org/10.1097/RLI.0000000000000241

    Article  CAS  Google Scholar 

  27. Robert P, Lehericy S, Grand S, Violas X, Fretellier N, Idee JM, Ballet S, Corot C (2015) 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 50(8):473–480. https://doi.org/10.1097/RLI.0000000000000181

    Article  CAS  Google Scholar 

  28. Roberts DR, Lindhorst SM, Welsh CT, Maravilla KR, Herring MN, Braun KA, Thiers BH, Davis WC (2016) High levels of gadolinium deposition in the skin of a patient with normal renal function. Investig Radiol 51(5):280–289. https://doi.org/10.1097/RLI.0000000000000266

    Article  CAS  Google Scholar 

  29. Sharma HS (2003) Blood-spinal cord and brain barriers in health and disease. 1st Edition edn.,

  30. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin a. Nature 485(7399):512–516. https://doi.org/10.1038/nature11087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li W, Watts L, Long J, Zhou W, Shen Q, Jiang Z, Li Y, Duong TQ (2016) Spatiotemporal changes in blood-brain barrier permeability, cerebral blood flow, T2 and diffusion following mild traumatic brain injury. Brain Res 1646:53–61. https://doi.org/10.1016/j.brainres.2016.05.036

    Article  CAS  PubMed  Google Scholar 

  32. Reimer MM, McQueen J, Searcy L, Scullion G, Zonta B, Desmazieres A, Holland PR, Smith J, Gliddon C, Wood ER, Herzyk P, Brophy PJ, McCulloch J, Horsburgh K (2011) Rapid disruption of axon-glial integrity in response to mild cerebral hypoperfusion. J Neurosci 31(49):18185–18194. https://doi.org/10.1523/JNEUROSCI.4936-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Aksoy D, Bammer R, Mlynash M, Venkatasubramanian C, Eyngorn I, Snider RW, Gupta SN, Narayana R, Fischbein N, Wijman CA (2013) Magnetic resonance imaging profile of blood-brain barrier injury in patients with acute intracerebral hemorrhage. J Am Heart Assoc 2(3):e000161. https://doi.org/10.1161/JAHA.113.000161

    Article  PubMed  PubMed Central  Google Scholar 

  34. Montagne A, Toga AW, Zlokovic BV (2016) Blood-brain barrier permeability and gadolinium: benefits and potential pitfalls in research. JAMA neurology 73(1):13–14. https://doi.org/10.1001/jamaneurol.2015.2960

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mosconi L, Mistur R, Switalski R, Tsui WH, Glodzik L, Li Y, Pirraglia E, De Santi S, Reisberg B, Wisniewski T, de Leon MJ (2009) FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease. Eur J Nucl Med Mol Imaging 36(5):811–822. https://doi.org/10.1007/s00259-008-1039-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Alavi JB, Alavi A, Chawluk J, Kushner M, Powe J, Hickey W, Reivich M (1988) Positron emission tomography in patients with glioma. A predictor of prognosis. Cancer 62(6):1074–1078

    Article  CAS  PubMed  Google Scholar 

  37. Bauer K, Lathrum A, Raslan O, Kelly PV, Zhou Y, Hewing D, Botkin C, Turner JA, Osman M (2017) 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 45(1):30–33. https://doi.org/10.2967/jnmt.116.180844

    Article  PubMed  Google Scholar 

  38. Naganawa S (2017) Effect of gadolinium deposition on (18)F-FDG PET/CT of dentate nucleus and globus pallidus. J Nucl Med Technol 45(2):173–17173. https://doi.org/10.2967/jnmt.116.187591

    Article  PubMed  Google Scholar 

  39. Kanal E, Tweedle MF (2015) Residual or retained gadolinium: practical implications for radiologists and our patients. Radiology 275(3):630–634. https://doi.org/10.1148/radiol.2015150805

    Article  PubMed  Google Scholar 

  40. Gulani V, Calamante F, Shellock FG, Kanal E, Reeder SB, International Society for Magnetic Resonance in M (2017) Gadolinium deposition in the brain: summary of evidence and recommendations. Lancet Neurol 16(7):564–570. https://doi.org/10.1016/S1474-4422(17)30158-8

    Article  PubMed  Google Scholar 

  41. Kanal E, Maravilla K, Rowley HA (2014) Gadolinium contrast agents for CNS imaging: current concepts and clinical evidence. AJNR Am J Neuroradiol 35(12):2215–2226. https://doi.org/10.3174/ajnr.A3917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. PB and FB contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biotechnology and Health Sciences, University of Torino (Italy), via Nizza 52, 10126, Torino, Italy

    Francesca Arena, Paola Bardini, Eliana Gianolio, Giada M. Marini, Francesca La Cava & Silvio Aime

  2. Department of Molecular Biotechnology and Health Sciences, Centro di Eccellenza di Imaging Preclinico (CEIP)- University of Torino (Italy), c/o BioIndustry Park of Canavese, Via Ribes 5, 10010, Colleretto Giacosa, TO, Italy

    Francesca Arena, Paola Bardini, Giada M. Marini & Francesca La Cava

  3. Bracco Research Centre, Bracco Imaging SpA, Via Ribes 5, 10010, Colleretto Giacosa, TO, Italy

    Francesco Blasi

  4. Ephoran Imaging Solutions S.r.l., c/o BioIndustry Park of Canavese, Via Ribes 5, 10010, Colleretto Giacosa, TO, Italy

    Giovanni Valbusa

  5. IBB-CNR, Sede secondaria c/o MBC, Via Nizza 52, 10126, Torino, Italy

    Silvio Aime

Authors
  1. Francesca Arena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Bardini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Blasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eliana Gianolio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giada M. Marini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francesca La Cava
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giovanni Valbusa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Silvio Aime
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesca Arena.

Ethics declarations

Funding

No funding was received for this study.

Conflict of interest

SA consults for Bracco Imaging (Milan, Italy).

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed (L.D. 26/2014; Directives 2010/63/EU). Every effort was made to minimize the number of animals used and their suffering.

Informed consent

Statement of informed consent was not applicable since the manuscript does not contain any patient data.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arena, F., Bardini, P., Blasi, F. et al. Gadolinium presence, MRI hyperintensities, and glucose uptake in the hypoperfused rat brain after repeated administrations of gadodiamide. Neuroradiology 61, 163–173 (2019). https://doi.org/10.1007/s00234-018-2120-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00234-018-2120-3

Keywords

Search

Navigation