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Age-dependent changes of cerebral copper metabolism in Atp7b −/− knockout mouse model of Wilson’s disease by [64Cu]CuCl2-PET/CT

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Abstract

Copper is a nutritional metal required for brain development and function. Wilson’s disease (WD), or hepatolenticular degeneration, is an inherited human copper metabolism disorder caused by a mutation of the ATP7B gene. Many WD patients present with variable neurological and psychiatric symptoms, which may be related to neurodegeneration secondary to copper metabolism imbalance. The objective of this study was to explore the feasibility and use of copper-64 chloride ([64C]CuCl2) as a tracer for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD using an Atp7b −/− knockout mouse model of WD and positron emission tomography/computed tomography (PET/CT) imaging. Continuing from our recent study of biodistribution and radiation dosimetry of [64C]CuCl2 in Atp7b −/− knockout mice, PET quantitative analysis revealed low 64Cu radioactivity in the brains of Atp7b −/− knockout mice at 7th weeks of age, compared with 64Cu radioactivity in the brains of age- and gender-matched wild type C57BL/6 mice, at 24 h (h) post intravenous injection of [64C]CuCl2 as a tracer. Furthermore, age-dependent increase of 64Cu radioactivity was detected in the brains of Atp7b −/− knockout mice from the 13th to 21th weeks of age, based on the data derived from a longitudinal [64C]CuCl2-PET/CT study of Atp7b −/− knockout mice with orally administered [64Cu]CuCl2 as a tracer. The findings of this study support clinical use of [64Cu]CuCl2-PET/CT imaging as a tool for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD patients presenting with variable neurological and psychiatric symptoms.

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Acknowledgements

The authors thank Xiankai Sun for use of the ICP-MS instrument. This research project was partially supported by the National Institutes of Health (1R21NS074394-01A1 and 1R21AG047953-01 to F.P). The production of [64Cu]CuCl2 at Washington University School of Medicine was supported by NIH/NCI grant R24 CA86307.

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Authors and Affiliations

  1. Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9140, USA

    Fang Xie, Yin Xi & Fangyu Peng

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

    Fangyu Peng

  3. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Juan M. Pascual

  4. Carman & Ann Adams Department of Pediatrics, Wayne State University, Detroit, MI, USA

    Otto Muzik

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

    Otto Muzik

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  1. Fang Xie
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Correspondence to Fangyu Peng.

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Xie, F., Xi, Y., Pascual, J.M. et al. Age-dependent changes of cerebral copper metabolism in Atp7b −/− knockout mouse model of Wilson’s disease by [64Cu]CuCl2-PET/CT. Metab Brain Dis 32, 717–726 (2017). https://doi.org/10.1007/s11011-017-9956-9

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  • DOI: https://doi.org/10.1007/s11011-017-9956-9

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