Research Article

Optimization of Detection of Gadodiamide Brain Retention in Rats Using Quantitative T₂ Mapping and Intraperitoneal Administration

Corresponding Author

Serguei M. Liachenko MD, PhD

[email protected]

orcid.org/0000-0002-0683-5442

Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

Address reprint requests to: S.L., 3900 NCTR Rd, Jefferson, AR 72079, USA. E-mail: [email protected]

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Natalya V. Sadovova PhD,

Natalya V. Sadovova PhD

Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

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Arnold Tripp,

Arnold Tripp

Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

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Suman Ghorai PhD,

Suman Ghorai PhD

Nanotechnology Core Facility, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

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Anil K. Patri PhD,

Anil K. Patri PhD

Nanotechnology Core Facility, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

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Joseph P. Hanig PhD,

Joseph P. Hanig PhD

Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland, USA

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Jonathan E. Cohen PhD,

Jonathan E. Cohen PhD

Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland, USA

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Ira Krefting MD,

Ira Krefting MD

Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland, USA

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Serguei M. Liachenko MD, PhD,

Corresponding Author

Serguei M. Liachenko MD, PhD

[email protected]

orcid.org/0000-0002-0683-5442

Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

Address reprint requests to: S.L., 3900 NCTR Rd, Jefferson, AR 72079, USA. E-mail: [email protected]

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Natalya V. Sadovova PhD,

Natalya V. Sadovova PhD

Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

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Arnold Tripp,

Arnold Tripp

Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

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Suman Ghorai PhD,

Suman Ghorai PhD

Nanotechnology Core Facility, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

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Anil K. Patri PhD,

Anil K. Patri PhD

Nanotechnology Core Facility, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA

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Joseph P. Hanig PhD,

Joseph P. Hanig PhD

Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland, USA

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Jonathan E. Cohen PhD,

Jonathan E. Cohen PhD

Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland, USA

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Ira Krefting MD,

Ira Krefting MD

Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland, USA

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First published: 12 March 2022

https://doi.org/10.1002/jmri.28149

This article reflects the views of the authors and should not be construed to represent US FDA's views or policies.

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Abstract

Background

Currently, the gadolinium retention in the brain after the use of contrast agents is studied by T₁-weighted magnetic resonance imaging (MRI) (T₁w) and T₁ mapping. The former does not provide easily quantifiable data and the latter requires prolonged scanning and is sensitive to motion. T₂ mapping may provide an alternative approach. Animal studies of gadolinium retention are complicated by repeated intravenous (IV) dosing, whereas intraperitoneal (IP) injections might be sufficient.

Hypothesis

T₂ mapping will detect the changes in the rat brain due to gadolinium retention, and IP administration is equivalent to IV for long-term studies.

Study Type

Prospective longitudinal.

Animal Model

A total of 31 Sprague–Dawley rats administered gadodiamide IV (N = 8) or IP (N = 8), or saline IV (N = 6) or IP (N = 9) 4 days per week for 5 weeks.

Field strength/sequences

A 7 T, T₁w, and T₂ mapping.

Assessment

T₂ relaxation and image intensities in the deep cerebellar nuclei were measured pre-treatment and weekly for 5 weeks. Then brains were assessed for neuropathology (N = 4) or gadolinium content using inductively coupled plasma mass spectrometry (ICP-MS, N = 12).

Statistical tests

Repeated measures analysis of variance with post hoc Student–Newman–Keuls tests and Hedges' effect size.

Results

Gadolinium was detected by both approaches; however, T₂ mapping was more sensitive (effect size 2.32 for T₂ vs. 0.95 for T₁w), and earlier detection (week 3 for T₂ vs. week 4 for T₁w). ICP-MS confirmed the presence of gadolinium (3.076 ± 0.909 nmol/g in the IV group and 3.948 ± 0.806 nmol/g in the IP group). There was no significant difference between IP and IV groups (ICP-MS, P = 0.109; MRI, P = 0.696). No histopathological abnormalities were detected in any studied animal.

Conclusion

T₂ relaxometry detects gadolinium retention in the rat brain after multiple doses of gadodiamide irrespective of the route of administration.

Evidence Level

Technical Efficacy

Stage 1

References

1Mallio CA, Rovira A, Parizel PM, Quattrocchi CC. Exposure to gadolinium and neurotoxicity: Current status of preclinical and clinical studies. Neuroradiology 2020; 62(8): 925-934.
10.1007/s00234-020-02434-8
PubMed Web of Science® Google Scholar
2Olchowy C, Cebulski K, Lasecki M, et al. The presence of the gadolinium-based contrast agent depositions in the brain and symptoms of gadolinium neurotoxicity - a systematic review. PLoS One 2017; 12(2):e0171704.
10.1371/journal.pone.0171704
PubMed Web of Science® Google Scholar
3Kanda T, Fukusato T, Matsuda M, et al. 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(1): 228-232.
10.1148/radiol.2015142690
PubMed Web of Science® Google Scholar
4Kanda 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): 834-841.
10.1148/radiol.13131669
PubMed Web of Science® Google Scholar
5Quattrocchi CC, Mallio CA, Errante Y, Beomonte ZB. High T1 signal intensity in dentate nucleus after multiple injections of linear gadolinium chelates. Radiology 2015; 276(2): 616-617.
10.1148/radiol.2015150464
PubMed Web of Science® Google Scholar
6Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015; 275(3): 783-791.
10.1148/radiol.2015150337
PubMed Web of Science® Google Scholar
7Arena 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 2019; 61(2): 163-173.
10.1007/s00234-018-2120-3
PubMed Web of Science® Google Scholar
8Bolles GM, Yazdani M, Stalcup ST, et al. Development of high signal intensity within the globus pallidus and dentate nucleus following multiple administrations of Gadobenate Dimeglumine. AJNR Am J Neuroradiol 2018; 39(3): 415-420.
10.3174/ajnr.A5510
CAS PubMed Web of Science® Google Scholar
9Hu 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): 1590-1598.
10.1007/s00247-016-3646-3
PubMed Web of Science® Google Scholar
10Olchowy C, Maciag EJ, Sanchez-Montanez A, Olchowy A, Delgado I, Vazquez E. Measurements of signal intensity of globus pallidus and dentate nucleus suggest different deposition characteristics of macrocyclic GBCAs in children. PLoS One 2018; 13(12):e0208589.
10.1371/journal.pone.0208589
CAS PubMed Web of Science® Google Scholar
11Rasschaert M, Emerit A, Fretellier N, et al. Gadolinium retention, brain T1 Hyperintensity, and endogenous metals: A comparative study of macrocyclic versus linear gadolinium chelates in renally sensitized rats. Invest Radiol 2018; 53(6): 328-337.
10.1097/RLI.0000000000000447
CAS PubMed Web of Science® Google Scholar
12Robert 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(8): 473-480.
10.1097/RLI.0000000000000181
CAS PubMed Web of Science® Google Scholar
13Rasschaert M, Schroeder JA, Wu TD, et al. Multimodal imaging study of gadolinium presence in rat cerebellum: Differences between Gd chelates, presence in the Virchow-Robin space, association with lipofuscin, and hypotheses about distribution pathway. Invest Radiol 2018; 53(9): 518-528.
10.1097/RLI.0000000000000490
CAS PubMed Web of Science® Google Scholar
14Saake M, Hepp T, Schmidle A, et al. Influence of artifact corrections on MRI signal intensity ratios for assessment of gadolinium brain retention. Acad Radiol 2019; 27: 744-749.
10.1016/j.acra.2019.07.013
PubMed Web of Science® Google Scholar
15Quattrocchi CC, Ramalho J, van der Molen AJ, et al. 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(8): 3959-3967.
10.1007/s00330-018-5803-6
PubMed Web of Science® Google Scholar
16Saake M, Schmidle A, Kopp M, et al. MRI brain signal intensity and relaxation times in individuals with prior exposure to Gadobutrol. Radiology 2019; 290(3): 659-668.
10.1148/radiol.2018181927
PubMed Web of Science® Google Scholar
17Forslin Y, Martola J, Bergendal A, Fredrikson S, Wiberg MK, Granberg T. Gadolinium retention in the brain: An MRI Relaxometry study of linear and macrocyclic gadolinium-based contrast agents in multiple sclerosis. AJNR Am J Neuroradiol 2019; 40(8): 1265-1273.
10.3174/ajnr.A6112
CAS PubMed Web of Science® Google Scholar
18Robert 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(2): 73-82.
10.1097/RLI.0000000000000241
CAS PubMed Web of Science® Google Scholar
19Noebauer-Huhmann IM, Kraff O & Juras V Proc Intl Soc Mag Reson Med 2008; 16: 1457.
Google Scholar
20Burtea C, Laurent S, Vander Elst L, Muller RN. Contrast agents: magnetic resonance. Handb Exp Pharmacol 2008; 185 Pt 1: 135-165.
10.1007/978-3-540-72718-7_7
PubMed Google Scholar
21Pintaske J, Martirosian P, Graf H, et al. Relaxivity of Gadopentetate Dimeglumine (Magnevist), Gadobutrol (Gadovist), and Gadobenate Dimeglumine (MultiHance) in human blood plasma at 0.2, 1.5, and 3 tesla. Invest Radiol 2006; 41(3): 213-221.
10.1097/01.rli.0000197668.44926.f7
PubMed Web of Science® Google Scholar
22Al Shoyaib A, Archie SR, Karamyan VT. Intraperitoneal route of drug administration: Should it be used in experimental animal studies? Pharm Res 2019; 37(1): 12.
10.1007/s11095-019-2745-x
PubMed Web of Science® Google Scholar
23Nolan TE, Klein HJ. Methods in vascular infusion biotechnology in research with rodents. ILAR J 2002; 43(3): 175-182.
10.1093/ilar.43.3.175
CAS PubMed Google Scholar
24Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016; 7(2): 27-31.
10.4103/0976-0105.177703
PubMed Google Scholar
25Hanig J, Paule MG, Ramu J, et al. The use of MRI to assist the section selections for classical pathology assessment of neurotoxicity. Regul Toxicol Pharmacol 2014; 70(3): 641-647.
10.1016/j.yrtph.2014.09.010
CAS PubMed Web of Science® Google Scholar
26Doty FD, Entzminger G Jr, Hauck CD. Error-tolerant RF litz coils for NMR/MRI. J Magn Reson 1999; 140(1): 17-31.
10.1006/jmre.1999.1828
CAS PubMed Web of Science® Google Scholar
27Liachenko S, Ramu J. Quantification and reproducibility assessment of the regional brain T2 relaxation in naive rats at 7T. J Magn Reson Imaging 2017; 45(3): 700-709.
10.1002/jmri.25378
PubMed Web of Science® Google Scholar
28Gray EP, Coleman JG, Bednar AJ, Kennedy AJ, Ranville JF, Higgins CP. Extraction and analysis of silver and gold nanoparticles from biological tissues using single particle inductively coupled plasma mass spectrometry. Environ Sci Technol 2013; 47(24): 14315-14323.
10.1021/es403558c
CAS PubMed Web of Science® Google Scholar
29Switzer RC. Application of silver degeneration stains for neurotoxicity testing. Toxicol Pathol 2000; 28(1): 70-83.
10.1177/019262330002800109
CAS PubMed Web of Science® Google Scholar
30Klein S, Staring M, Murphy K, Viergever MA, Pluim JP. Elastix: A toolbox for intensity-based medical image registration. IEEE Trans Med Imaging 2010; 29(1): 196-205.
10.1109/TMI.2009.2035616
PubMed Web of Science® Google Scholar
31Hedges LV, Olkin I. CHAPTER 5 - estimation of a single effect size: Parametric and nonparametric methods. In: LV Hedges, I Olkin, editors. Statistical methods for meta-analysis. San Diego: Academic Press; 1985. p 75-106.
10.1016/B978-0-08-057065-5.50010-5
Google Scholar
32Kuno H, Jara H, Buch K, Qureshi MM, Chapman MN, Sakai O. Global and regional brain assessment with quantitative MR imaging in patients with prior exposure to linear gadolinium-based contrast agents. Radiology 2017; 283(1): 195-204.
10.1148/radiol.2016160674
PubMed Web of Science® Google Scholar
33DiResta GR, Lee J, Lau N, Ali F, Galicich JH, Arbit E. Measurement of brain tissue density using pycnometry. Acta Neurochir Suppl (Wien) 1990; 51: 34-36.
CAS PubMed Google Scholar
34Smith 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(3): 743-751.
10.1148/radiol.2016160905
PubMed Web of Science® Google Scholar

Volume56, Issue5

November 2022

Pages 1499-1504

Optimization of Detection of Gadodiamide Brain Retention in Rats Using Quantitative T₂ Mapping and Intraperitoneal Administration

Abstract

Background

Hypothesis

Study Type

Animal Model

Field strength/sequences

Assessment

Statistical tests

Results

Conclusion

Evidence Level

Technical Efficacy

References

References

Information

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Optimization of Detection of Gadodiamide Brain Retention in Rats Using Quantitative T2 Mapping and Intraperitoneal Administration

Abstract

Background

Hypothesis

Study Type

Animal Model

Field strength/sequences

Assessment

Statistical tests

Results

Conclusion

Evidence Level

Technical Efficacy

References

References

Related

Information

Optimization of Detection of Gadodiamide Brain Retention in Rats Using Quantitative T₂ Mapping and Intraperitoneal Administration