nach oben

Metabolic Brain Disease

Erschienen in:

27.01.2017 | Original Article

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

verfasst von: Fang Xie, Yin Xi, Juan M. Pascual, Otto Muzik, Fangyu Peng

Erschienen in: Metabolic Brain Disease | Ausgabe 3/2017

Einloggen, um Zugang zu erhalten

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.

Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML (2007) Wilson's disease. Lancet 369:397–408CrossRefPubMed

Buiakova OI, Xu J, Lutsenko S, Zeitlin S, Das K, Das S et al (1999) Null mutation of the murine ATP7B (Wilson disease) Gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. Hum Mol Genet 8:1665–1671CrossRefPubMed

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 5:327–337CrossRefPubMed

Capasso E, Durzu S, Piras S, Zandieh S, Knoll P, Haug A, Hacker M, Meleddu C, Mirzaei S (2015) Role of ⁶⁴CuCl₂ PET/CT in staging of prostate cancer. Ann Nucl Med 29(6):482–488CrossRefPubMed

Choi BS, Zheng W (2009) Copper transport to the brain by the blood-brain barrier and blood-CSF barrier. Brain Res 1248:14–21CrossRefPubMed

Chuang N, Mori S, Yamamoto A, Jiang H, Ye X, Xu X, Richards LJ, Nathans J, Miller MI, Toga AW, Sidman RL, Zhang J (2011) An MRI-based atlas and database of the developing mouse brain. NeuroImage 54:80–89CrossRefPubMed

Dong Y, Shi SS, Chen S, Ni W, Zhu M, Wu ZY (2015) The discrepancy between the absence of copper deposition and the presence of neuronal damage in the brain of Atp7b ^−/− mice. Metallomics 7:283–288CrossRefPubMed

Faa G, Lisci M, Caria MP, Ambu R, Sciot R, Nurchi VM, Silvagni R, Diaz A, Crisponi G, Silvagni SS (2001) Brain copper, iron, magnesium, zinc, calcium, sulfur and phosphorus storage in Wilson's disease. J Trace Elem Med Biol 15:155–160CrossRefPubMed

Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D, Phelps ME, Weber WA (2006) Impact of animal handling on the results of ¹⁸F-FDG PET studies in mice. J Nucl Med 47:999–1006PubMed

Gray LW, Peng F, Molloy SA, Pendyala VS, Muchenditsi A, Muzik O, Lee J, Kaplan JH, Lutsenko S (2012) Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load. PLoS One 7:e38327CrossRefPubMedPubMedCentral

Hawkins RA, Mazziotta JC, Phelps ME (1987) Wilson's disease studied with FDG and positron emission tomography. Neurology 37(11):1707–1711

Hermann W (2014) Morphological and functional imaging in neurological and non-neurological Wilson's patients. Ann N Y Acad Sci 1315:24–29CrossRefPubMed

Hermann W, Barthel H, Hesse S, Grahmann F, Kühn HJ, Wagner A, Villmann T (2002) Comparison of clinical types of Wilson's disease and glucose metabolism in extrapyramidal motor brain regions. J Neurol 249(7):896–901CrossRefPubMed

Litwin T, Gromadzka G, Szpak GM, Jabłonka-Salach K, Bulska E, Członkowska A (2013) Brain metal accumulation in Wilson's disease. J Neurol Sci 329:55–58CrossRefPubMed

Lorincz MT (2010) Neurologic Wilson's disease. Ann N Y Acad Sci 1184:173–187CrossRefPubMed

Lutsenko S (2008) Atp7b ^−/− mice as a model for studies of Wilson’s disease. Biochem Soc Trans 36:1233–1238CrossRefPubMed

Lutsenko S (2014) Modifying factors and phenotypic diversity in Wilson’s disease. Ann N Y Acad Sci 1315:56–63CrossRefPubMedPubMedCentral

Lutsenko S, Bhattacharjee A, Hubbard AL (2010) Copper handling machinery of the brain. Metallomics 2:596–608CrossRefPubMed

Madsen E, Gitlin JD (2007) Copper and iron disorders of the brain. Annu Rev Neurosci 30:317–337CrossRefPubMed

Manrique-Arias JC, Carrasco-Hernández J, Reyes PG, Ávila-Rodríguez MA (2016) Biodistribution in rats and estimates of doses to humans from ⁶⁴CuCl₂, a potential theranostic tracer. Appl Radiat Isot 115:18–22CrossRefPubMed

Nomura S, Nozaki S, Hamazaki T, Takeda T, Ninomiya E, Kudo S, Hayashinak E, Wada Y, Hiroki T, Fujisawa C, Kodama H, Shintaku H, Watanabe Y (2014) PET imaging analysis with ⁶⁴Cu in disulfiram treatment for aberrant copper biodistribution in Menkes disease mouse model. J Nucl Med 55:845–851CrossRefPubMed

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

Peng F, Lutsenko S, Sun X, Muzik O (2012a) Positron emission tomography of copper metabolism in the Atp7b ^−/− knock-out mouse model of Wilson's disease. Mol Imaging Biol 14:70–78CrossRefPubMedPubMedCentral

Peng F, Lutsenko S, Sun X, Muzik O (2012b) Imaging copper metabolism imbalance in Atp7b ^−/− knockout mouse model of Wilson's disease with PET-CT and orally administered ⁶⁴CuCl₂. Mol Imaging Biol 14:600–607CrossRefPubMed

Peng F, Muzik O, Gatson J, Kernie SG, Diaz-Arrastia R (2015) Assessment of traumatic brain injury by increased ⁶⁴Cu uptake on ⁶⁴CuCl₂ PET/CT. J Nucl Med 56:1252–1257CrossRefPubMedPubMedCentral

Przybyłkowski A, Gromadzka G, Wawer A, Bulska E, Jabłonka-Salach K, Grygorowicz T, Schnejder-Pachołek A, Członkowski A (2013) Neurochemical and behavioral characteristics of toxic milk mice: an animal model of Wilson's disease. Neurochem Res 38:2037–2045CrossRefPubMedPubMedCentral

Roberts EA, Schilsky ML (2008) Diagnosis and treatment of Wilson disease: an update. Hepatology 47:2089–2111CrossRefPubMed

Som P, Atkins HL, Bandoypadhyay D, Fowler JS, MacGregor RR, Matsui K, Oster ZH, Sacker DF, Shlue CY, Turner H, Wan CN, Wolf AP, Zabinski SV (1980) A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection. J Nucl Med 21:670–675PubMed

Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, Romano DM, Parano E, Pavone L, Brzustowicz LM, Devoto M, Peppercorn J, Bush AI, Sternlieb I, Pirastu M, Gusella JF, Evgrafov O, Penchaszadeh GK, Honig B, Edelman IS, Soares MB, Scheinberg IH, Gilliam TC (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5:344–350CrossRefPubMed

Terwel D, Löschmann YN, Schmidt HH, Schöler HR, Cantz T, Heneka MT (2011) Neuroinflammatory and behavioural changes in the Atp7b mutant mouse model of Wilson's disease. J Neurochem 118:105–112CrossRefPubMed

Toyama H, Ichise M, Liow JS, Vines DC, Seneca NM, Modell KJ, Seidel J, Green MV, Innis RB (2004) Evaluation of anesthesia effects on [¹⁸F]FDG uptake in mouse brain and heart using small animal PET. Nucl Med Biol 31(2):251–256CrossRefPubMed

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

Wang LM, Becker JS, Wu Q, Oliveira MF, Bozza FA, Schwager AL, Hoffman JM, Morton KA (2010) Bioimaging of copper alterations in the aging mouse brain by autoradiography, laser ablation inductively coupled plasma mass spectrometry and immunohistochemistry. Metallomics 2:348–353CrossRefPubMed

Yamaguchi Y, Heiny ME, Gitlin JD (1993) Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biochem Biophys Res Commun 197:271–277CrossRefPubMed

Zhou B, Gitschier J (1997) hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci U S A 94:7481–7486CrossRefPubMedPubMedCentral

Zhou XX, Li XH, Qin H, Li GD, Huang HW, Liang YY, Liang XL, Pu XY (2016) Diffusion tensor imaging of the extracorticospinal network in the brains of patients with Wilson disease. J Neurol Sci 362:292–298CrossRefPubMed

Zhu M, Dong Y, Ni W, Wu ZY (2015) Defective roles of ATP7B missense mutations in cellular copper tolerance and copper excretion. Mol Cell Neurosci 67:31–36CrossRefPubMed

Titel: Age-dependent changes of cerebral copper metabolism in Atp7b −/− knockout mouse model of Wilson’s disease by [64Cu]CuCl2-PET/CT
verfasst von: Fang Xie
Yin Xi
Juan M. Pascual
Otto Muzik
Fangyu Peng
Publikationsdatum: 27.01.2017
Verlag: Springer US
Erschienen in: Metabolic Brain Disease / Ausgabe 3/2017
Print ISSN: 0885-7490
Elektronische ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-017-9956-9

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Akuter Schwindel: Wann lohnt sich eine MRT?

28.04.2024 Schwindel Nachrichten

Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Frühe Alzheimertherapie lohnt sich

25.04.2024 AAN-Jahrestagung 2024 Nachrichten

Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.

Viel Bewegung in der Parkinsonforschung

25.04.2024 Parkinson-Krankheit Nachrichten

Neue arznei- und zellbasierte Ansätze, Frühdiagnose mit Bewegungssensoren, Rückenmarkstimulation gegen Gehblockaden – in der Parkinsonforschung tut sich einiges. Auf dem Deutschen Parkinsonkongress ging es auch viel um technische Innovationen.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2017

Efficacy and safety of escitalopram in treatment of severe depression in Chinese population

The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): Kill two birds with one stone

Characterization of the CA1 pyramidal neurons in rat model of hepatic cirrhosis: insights into their electrophysiological properties

Sitagliptin down-regulates retinol-binding protein 4 and reduces insulin resistance in gestational diabetes mellitus: a randomized and double-blind trial

Peripheral and central administration of T3 improved the histological changes, memory and the dentate gyrus electrophysiological activity in an animal model of Alzheimer’s disease

Diabetic brain or retina? Visual psychophysical performance in diabetic patients in relation to GABA levels in occipital cortex