Skip to main content

Advertisement

SpringerLink
Log in

Imaging Copper Metabolism Imbalance in Atp7b −/− Knockout Mouse Model of Wilson’s Disease with PET-CT and Orally Administered 64CuCl2

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Objectives

This study aims to determine the feasibility and utility of functional imaging of copper metabolism imbalance in Atp7b −/− knockout mouse model of Wilson’s disease (WD) with positron emission tomography-computed tomography (PET-CT) using orally administered copper-64 chloride (64CuCl2) as a tracer.

Procedures

Atp7b −/− KO mice (N = 5) were subjected to PET scanning using a hybrid PET-CT scanner, after oral administration of 64CuCl2 as a tracer. Time-dependent PET quantitative analysis was performed to assess gastrointestinal absorption and biodistribution of 64Cu radioactivity in the Atp7b −/− KO mice, using C57BL wild-type (WT) mice (N = 5) as a normal control. Estimates of human radiation dosimetry were calculated based on biodistribution of 64Cu radioactivity in live animals.

Results

PET-CT analysis demonstrated higher 64Cu radioactivity in the liver of Atp7b −/− knockout mice compared with that in the control C57BL WT mice (p < 0.001), following oral administration of 64CuCl2 as a tracer. In addition, 64Cu radioactivity in the lungs of the Atp7b −/− knockout mice was slightly higher than those in the control C57BL WT mice (p = 0.01). Despite initially higher renal clearance of 64Cu, there was no significant difference of 64Cu radioactivity in the kidneys of the Atp7b −/− KO mice and the control C57BL WT mice at 24 h post-oral administration of 64CuCl2 (p = 0.16). There was no significant difference in low 64Cu radioactivity in the blood, brain, heart, and muscles between the Atp7b −/− knockout mice and control C57BL WT mice (p > 0.05). Based on the biodistribution of 64Cu radioactivity in C57BL WT mice, radiation dosimetry estimates of 64Cu in normal human subjects were obtained. An effective dose (ED) of 42.4 μSv/MBq (weighted dose over 22 organs) was calculated and the lower large intestines were identified as the critical organ for radiation exposure (120 μGy/MBq for males and 135 μGy/MBq for females). Radiation dosimetry estimates for patients with WD, derived from the biodistribution of 64Cu in Atp7b −/− KO mice, showed a slightly lower ED of 37.5 μSv/MBq, with the lower large intestines as the critical organ for radiation exposure (83 μSv/MBq for male and 95 μSv/MBq for female).

Conclusions

PET-CT quantitative analysis demonstrated an increased level of 64Cu radioactivity in the liver of Atp7b −/− KO mice compared with that in the control C57BL WT mice, following oral administration of 64CuCl2 as a tracer. The results of this study suggest the feasibility and utility of PET-CT using orally administered 64CuCl2 as a tracer (64CuCl2-PET/CT) for functional imaging of copper metabolism imbalance in WD.

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

Similar content being viewed by others

References

  1. Olivares M, Uauy R (1996) Copper as an essential nutrient. Am J Clin Nutr 63(5):791S–796S

    PubMed  CAS  Google Scholar 

  2. Uauy R, Olivares M, Gonzalez M (1998) Essentiality of copper in humans. Am J Clin Nutr 67(5 Suppl):952S–959S

    PubMed  CAS  Google Scholar 

  3. Uriu-Adams JY, Scherr RE, Lanoue L, Keen CL (2010) Influence of copper on early development: prenatal and postnatal considerations. Biofactors 36(2):136–152

    PubMed  CAS  Google Scholar 

  4. Dunlap WM, James GW III, Hume DM (1974) Anemia and neutropenia caused by copper deficiency. Ann Intern Med 80:470–476

    PubMed  CAS  Google Scholar 

  5. Li Y, Wang L, Schuschke DA, Zhou Z, Saari JT, Kang YJ (2005) Marginal dietary copper restriction induces cardiomyopathy in rats. J Nutr 135(9):2130–2136

    PubMed  CAS  Google Scholar 

  6. Kumar N, Gross JB Jr, Ahlskog JE (2003) Myelopathy due to copper deficiency. Neurology 61:273–274

    Article  PubMed  Google Scholar 

  7. Kumar N, Gross JB Jr, Ahlskog JE (2004) Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 63:33–39

    Article  PubMed  CAS  Google Scholar 

  8. Kumar N (2006) Copper deficiency myelopathy (human swayback). Mayo Clin Proc 81:1371–1384

    Article  PubMed  CAS  Google Scholar 

  9. Prodan CI, Holland NR, Wisdom PJ, Burstein SA, Bottomley SS (2002) CNS demyelination associated with copper deficiency and hyperzincemia. Neurology 59:1453–1456

    Article  PubMed  CAS  Google Scholar 

  10. Tan JC, Burns DL, Jones RH (2006) Severe ataxia, myelopathy, and peripheral neuropathy due to acquired copper deficiency in a patient with history of gastrectomy. J Parenter Enteral Nutr 30(5):446–450

    Article  Google Scholar 

  11. Juhasz-Pocsine K, Rudnicki SA, Archer RL, Harik SI (2007) Neurologic complications of gastric bypass surgery for morbid obesity. Neurology 68(21):1843–1850

    Article  PubMed  Google Scholar 

  12. Khaleeli Z, Healy DG, Briddon A, Lunn MP, Reilly MM, Land J, Giovannoni G (2010) Copper deficiency as a treatable cause of poor balance. Br Med J 340:c508

    Article  Google Scholar 

  13. Goez HR, Jacob FD, Fealey RD, Patterson MC, Ramaswamy V, Persad R, Johnson ES, Yager JY (2011) An unusual presentation of copper metabolism disorder and a possible connection with Niemann–Pick type C. J Child Neurol 26:518–521

    Article  PubMed  Google Scholar 

  14. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5:327–337

    Article  PubMed  CAS  Google Scholar 

  15. Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, Romano DM, Parano E, Pavone L, Brzustowicz LM (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5:344–350

    Article  PubMed  CAS  Google Scholar 

  16. Harris ED (2000) Cellular copper transport and metabolism. Annu Rev Nutr 20:291–310

    Article  PubMed  CAS  Google Scholar 

  17. Puig S, Thiele DJ (2002) Molecular mechanisms of copper uptake and distribution. Curr Opin Chem Biol 6:171–180

    Article  PubMed  CAS  Google Scholar 

  18. Lutsenko S (2010) Human copper homeostasis: a network of interconnected pathways. Curr Opin Chem Biol 14:1–7

    Article  Google Scholar 

  19. Cartwright GE, Wintrobe MM (1964) Copper metabolism in normal subjects. Am J Clin Nutr 14:224–232

    PubMed  CAS  Google Scholar 

  20. Turnlund JR (1998) Human whole-body copper metabolism. Am J Clin Nutr 67(5 Suppl):960S–964S

    PubMed  CAS  Google Scholar 

  21. Owen CA Jr (1964) Distribution of copper in the rat. Am J Physiol 207:446–448

    PubMed  CAS  Google Scholar 

  22. Owen CA Jr (1965) Metabolism of radiocopper (Cu64) in the rat. Am J Physiol 209:900–904

    PubMed  CAS  Google Scholar 

  23. Dunn MA, Green MH, Leach RM Jr (1991) Kinetics of copper metabolism in rats: a compartmental model. Am J Physiol 261(1 Pt 1):E115–E125

    PubMed  CAS  Google Scholar 

  24. Turnlund JR, Keyes WR, Erson HL, Acord LL (1989) Copper absorption and retention in young men at three levels of dietary copper using the stable isotope 65Cu. Am J Clin Nutr 49:870–878

    PubMed  CAS  Google Scholar 

  25. Bush JA, Mahoney JP, Markowitz H, Gubler CJ, Cartwright GE, Wintrobe MM (1955) Studies on copper metabolism. XIV. Radioactive copper studies in normal subjects and in patients with hepatolenticular degeneration. J Clin Invest 34(12):1766–1778

    Article  PubMed  CAS  Google Scholar 

  26. Tauxe WN, Goldstein NP, Randall RV, Gross JB (1966) Radiocopper studies in patients with Wilson’s disease and their relatives. Am J Med 41(3):375–380

    Article  PubMed  CAS  Google Scholar 

  27. Vierling JM, Shrager R, Rumble WF, Aamodt R, Berman MD, Jones EA (1978) Incorporation of radiocopper into ceruloplasmin in normal subjects and in patients with primary biliary cirrhosis and Wilson’s disease. Gastroenterology 74(4):652–660

    PubMed  CAS  Google Scholar 

  28. Osborn SB, Szaz KF, Walshe JM (1996) Studies with radioactive copper (64Cu and 67Cu): abdominal scintiscans in patients with Wilson’s disease. Q J Med 38:467–474

    Google Scholar 

  29. Skromne-Kadlubik G, Diaz JF, Celis C (1975) Basal ganglia scans in the human. J Nucl Med 16(8):787–788

    PubMed  CAS  Google Scholar 

  30. Walshe JM, Potter G (1977) The pattern of the whole body distribution of radioactive copper (67Cu, 64Cu) in Wilson’s disease and various control groups. Q J Med 46:445–462

    PubMed  CAS  Google Scholar 

  31. Bissig KD, Honer M, Zimmermann K, Summer KH, Solioz M (2005) Whole animal copper flux assessed by positron emission tomography in the Long–Evans cinnamon rat—a feasibility study. Biometals 18(1):83–88

    Article  PubMed  CAS  Google Scholar 

  32. Peng F, Lutsenko S, Sun X, Muzik O (2011) Positron emission tomography of copper metabolism in the Atp7b −/− knock-out mouse model of Wilson’s disease. Mol Imag Biol. doi:10.1007/s11307-011-0476-4

  33. Huster D, Finegold MJ, Morgan CT, Burkhead JL, Nixon R, Vanderwerf SM, Gilliam CT, Lutsenko S (2006) Consequences of copper accumulation in the livers of the Atp7b-/(Wilson disease gene) knockout mice. Am J Pathol 168(2):423–434

    Article  PubMed  CAS  Google Scholar 

  34. Stabin MG (1996) MIRDOSE: personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 37:538–546

    PubMed  CAS  Google Scholar 

  35. Stabin MB, Siegel JA (2003) Physical models and dose factors for use in internal dose assessment. Health Phys 85:294–310

    Article  PubMed  CAS  Google Scholar 

  36. Hays MT, Watson EE, Thomas SR, Stabin M (2002) Radiation absorbed dose estimates from 18F-FDG. J Nucl Med 43:210–214

    PubMed  CAS  Google Scholar 

  37. Blower PJ, Lewis JS, Zweit J (1996) Copper radionuclides and radiopharmaceuticals in nuclear medicine. Nucl Med Biol 23:957–980

    Article  PubMed  CAS  Google Scholar 

  38. Chelly J, Tumer Z, Tonnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N, Horn N, Monaco AP (1993) Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet 3:14–19

    Article  PubMed  CAS  Google Scholar 

  39. Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J (1993) Isolation of a candidate gene for Menke’s disease and evidence that it encodes a copper-transporting. Nat Genet 3:7–13

    Article  PubMed  CAS  Google Scholar 

  40. Mercer JF, Livingston J, Hall B, Paynter JA, Begy C, Chandrasekharappa S, Lockhart P, Grimes A, Bhave M, Siemieniak D (1993) Isolation of a partial candidate gene for Menke’s disease by positional cloning. Nat Genet 3:20–25

    Article  PubMed  CAS  Google Scholar 

  41. Prasad AS, Brewer GJ, Schoomaker EB, Rabbani P (1978) Hypocupremia induced by zinc therapy in adults. JAMA 240:2166–2168

    Article  PubMed  CAS  Google Scholar 

  42. Jayakumar S, Micallef-Eynaud PD, Lyon TD, Cramb R, Jilaihawi AN, Prakash D (2005) Acquired copper deficiency following prolonged jejunostomy feeds. Ann Clin Biochem 42(3):227–231

    Article  PubMed  CAS  Google Scholar 

  43. Spinazzi M, De Lazzari F, Tavolato B, Angelini C, Manara R, Armani M (2007) Myelo-optico-neuropathy in copper deficiency occurring after partial gastrectomy: do small bowel bacterial overgrowth syndrome and occult zinc ingestion tip the balance? J Neurol 254:1012–1017

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Anjali Gupta for technical support in PET-CT scanning. This project was funded partially by the Department of Radiology, University of Texas Southwestern Medical Center at Dallas, Texas, USA, and National Institutes of Health (R56DK084510 to SL). The production of Cu-64 at Washington University School of Medicine is supported by NCI grant R24 CA86307.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Hines Blvd, Dallas, TX, 75390-8542, USA

    Fangyu Peng & Xiankai Sun

  2. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Fangyu Peng & Xiankai Sun

  3. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Fangyu Peng

  4. Department of Physiology, Johns Hopkins University, Baltimore, MD, USA

    Svetlana Lutsenko

  5. Carman & Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI, USA

    Otto Muzik

  6. Department of Radiology, School of Medicine, Wayne State University, Detroit, MI, USA

    Otto Muzik

Authors
  1. Fangyu Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Svetlana Lutsenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiankai Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Otto Muzik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fangyu Peng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peng, F., Lutsenko, S., Sun, X. et al. Imaging Copper Metabolism Imbalance in Atp7b −/− Knockout Mouse Model of Wilson’s Disease with PET-CT and Orally Administered 64CuCl2 . Mol Imaging Biol 14, 600–607 (2012). https://doi.org/10.1007/s11307-011-0532-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-011-0532-0

Key words

Search

Navigation