Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and Disease    2018, Vol. 9 Issue (1) : 109-118     DOI: 10.14336/AD.2017.1025
Orginal Article |
Alteration of Copper Fluxes in Brain Aging: A Longitudinal Study in Rodent Using 64CuCl2-PET/CT
Fangyu Peng1,2,*,Fang Xie1,Otto Muzik3,4
1Department of Radiology, and
2Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX75390, USA
3Department of Pediatrics and
4 Department of Radiology, Wayne State University, Detroit, MI 48202, USA
Download: PDF(846 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    

Brain aging is associated with changes of various metabolic pathways. Copper is required for brain development and function, but little is known about changes in copper metabolism during brain aging. The objective of this study was to investigate alteration of copper fluxes in the aging mouse brain with positron emission tomography/computed tomography using 64CuCl2 as a radiotracer (64CuCl2-PET/CT). A longitudinal study was conducted in C57BL/6 mice (n = 5) to measure age-dependent brain and whole-body changes of 64Cu radioactivity using PET/CT after oral administration of 64CuCl2 as a radiotracer. Cerebral 64Cu uptake at 13 months of age (0.17 ± 0.05 %ID/g) was higher than the cerebral 64Cu uptake at 5 months of age (0.11 ± 0.06 %ID/g, p < 0.001), followed by decrease to (0.14 ± 0.04 %ID/g, p = 0.02) at 26 months of age. In contrast, cerebral 18F-FDG uptake was highest at 5 months of age (7.8 ± 1.2 %ID/g) and decreased to similar values at 12 (5.2 ± 1.1 %ID/g, p < 0.001) and 22 (5.6 ± 1.1 %ID/g, p < 0.001) months of age. The findings demonstrated alteration of copper fluxes associated with brain aging and the time course of brain changes in copper fluxes differed from changes in brain glucose metabolism across time, suggesting independent underlying physiological processes. Hence, age-dependent changes of cerebral copper fluxes might represent a novel metabolic biomarker for assessment of human brain aging process with PET/CT using 64CuCl2 as a radiotracer.

Keywords Positron emission tomography      brain aging      Alzheimer’s disease      copper fluxes      glucose metabolism      copper-64 chloride     
Corresponding Authors: Fangyu Peng   
Issue Date: 01 February 2018
E-mail this article
E-mail Alert
Articles by authors
Fangyu Peng
Fang Xie
Otto Muzik
Cite this article:   
Fangyu Peng,Fang Xie,Otto Muzik. Alteration of Copper Fluxes in Brain Aging: A Longitudinal Study in Rodent Using 64CuCl2-PET/CT[J]. A&D, 2018, 9(1): 109-118.
URL:     OR
[1] Camandola S, Mattson MP (2017). Brain metabolism in health, aging, and neurodegeneration. EMBO J, 36:1474-1492.
[2] Chetelat G, Landeau B, Salmon E, Yakushev I, Bahri MA, Mezenge F, et al (2013). Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity. NeuroImage, 76:167-177.
[3] Trotta N, Archambaud F, Goldman S, Baete K, Van Laere K, Wens V, et al (2016). Functional integration changes in regional brain glucose metabolism from childhood to adulthood. Hum Brain Mapp, 37(8):3017-3030.
[4] Berti V, Mosconi L, Pupi A (2014). Brain: normal variations and benign findings in fluorodeoxyglucose-PET/computed tomography imaging. PET clin, 9(2):129-140.
[5] Buijs M, Doan NT, van Rooden S, Versluis MJ, van Lew B, Milles J, et al (2017). In vivo assessment of iron content of the cerebral cortex in healthy aging using 7-Tesla T2*-weighted phase imaging. Neurobiol Aging, 53:20-26.
[6] Olivares M, Uauy R (1996). Copper as an essential nutrient. Am J Clin Nutr, 63(5): 791S-796S.
[7] Uauy R, Olivares M, Gonzalez M (1998). Essentiality of copper in humans. Am J Clin Nutr, 67(5 Suppl): 952S-959S.
[8] Trumbo P, Yates AA, Schlicker S, Poos M (2011). Dietary Reference Intakes. J Am Diet Assoc, 101(3):294-301.
[9] Lutsenko S, Bhattacharjee A, Hubbard AL (2010). Copper handling machinery of the brain. Metallomics, 2(9):596-608.
[10] Vlachová V, Zemková H, Vyklický L (1996). Copper Modulation of NMDA Responses in Mouse and Rat Cultured Hippocampal Neurons. Eur J Neurosci, 8(11):2257-2264.
[11] Chelly J, Tumer Z, Tonnesen T, Petterson A, Ishikawa-Brush Y, Tommerup Net al (1993). Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat genet, 3(1):14-19.
[12] Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J (1993). Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat genet, 3(1):7-13.
[13] Mercer JF, Livingston J, Hall B, Paynter JA, Begy C, Chandrasekharappa S, et al (1993). Isolation of a partial candidate gene for Menkes disease by positional cloning. Nat genet, 3(1):20-25.
[14] Kaler SG (2001). ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol, 7(1):15-29.
[15] 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(4):327-337.
[16] Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, et al (1993). The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat genet, 5(4):344-350.
[17] 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(1):271-277.
[18] 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(9):1665-1671.
[19] Lorincz MT (2010). Neurologic Wilson's disease. Ann NY Acad Sci, 1184:173-187.
[20] Faa G, Lisci M, Caria MP, Ambu R, Sciot R, Nurchi VM, et al (2001). Brain copper, iron, magnesium, zinc, calcium, sulfur and phosphorus storage in Wilson's disease. J Trace Elem Med Biol, 15(2-3):155-160.
[21] Litwin T, Gromadzka G, Szpak GM, Jablonka-Salach K, Bulska E, Czlonkowska A (2013). Brain metal accumulation in Wilson's disease. J Neurol Sci, 329(1-2): 55-58.
[22] Peng F (2014). Positron emission tomography for measurement of copper fluxes in live organisms. Ann NY Acad Sci, 1314:24-31.
[23] Peng F, Lutsenko S, Sun X, Muzik O (2012). Imaging copper metabolism imbalance in Atp7b-/- knockout mouse model of Wilson's disease with PET-CT and orally administered 64CuCl2. Mol Imaging Biol, 14(5):600-607.
[24] Peng F, Lutsenko S, Sun X, Muzik O (2012). Positron emission tomography of copper metabolism in the Atp7b-/- knock-out mouse model of Wilson's disease. Mol Imaging Biol, 14(1):70-78.
[25] Xie F, Xi Y, Pascual JM, Muzik O,Peng F (2017). 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(3):717-726.
[26] Som P, Atkins H, Bandoypadhyay D, Fowler J, MacGregor R, Matsui K, et al (1980). A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection. J Nucl Med, 21(7):670-675.
[27] Chuang N, Mori S, Yamamoto A, Jiang H, Ye X, Xu X, et al (2011). An MRI-based atlas and database of the developing mouse brain. Neuroimage, 54(1):80-89.
[28] 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(8):1252-1257.
[29] Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011). Alzheimer's disease. Lancet, 377(9770):1019-1031.
[30] Torres JB, Andreozzi EM, Dunn JT, Siddique M, Szanda I, Howlett DR, Sunassee K, Blower PJ (2016). PET Imaging of copper trafficking in a mouse model of Alzheimer’s disease. J Nucl Med, 57:109-114.
[31] Johnson PE, Milne DB, Lykken GI (1992). Effects of age and sex on copper absorption, biological half-life, and status in humans. Am J Clin Nutr, 56(5):917-925.
[32] Choi BS, Zheng W (2009). Copper transport to the brain by the blood-brain barrier and blood-CSF barrier. Brain Res, 1248:14-21.
[33] Davies KM, Hare DJ, Cottam V, Chen N, Hilgers L, Halliday G, Mercer JF, Double KL (2013). Localization of copper and copper transporters in the human brain. Metallomics, 5(1):43-51.
[1] Daichi Sone,Etsuko Imabayashi,Norihide Maikusa,Masayo Ogawa,Noriko Sato,Hiroshi Matsuda,Japanese-Alzheimer’s Disease Neuroimaging Initiative. Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) on 3-tesla Normal Database: Diagnostic Accuracy in Two Independent Cohorts with Early Alzheimer’s Disease[J]. A&D, 2018, 9(4): 755-760.
[2] Fabiana Morroni,Giulia Sita,Agnese Graziosi,Eleonora Turrini,Carmela Fimognari,Andrea Tarozzi,Patrizia Hrelia. Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway[J]. A&D, 2018, 9(4): 605-622.
[3] Yangqi Xu,Xiaoli Liu,Junyi Shen,Wotu Tian,Rong Fang,Binyin Li,Jianfang Ma,Li Cao,Shengdi Chen,Guanjun Li,Huidong Tang. The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia[J]. A&D, 2018, 9(4): 696-705.
[4] Qiong Ding,Kitora Tanigawa,Jun Kaneko,Mamoru Totsuka,Yoshinori Katakura,Etsuko Imabayashi,Hiroshi Matsuda,Tatsuhiro Hisatsune. Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4[J]. A&D, 2018, 9(3): 334-345.
[5] Ting Shen,Yuyi You,Chitra Joseph,Mehdi Mirzaei,Alexander Klistorner,Stuart L. Graham,Vivek Gupta. BDNF Polymorphism: A Review of Its Diagnostic and Clinical Relevance in Neurodegenerative Disorders[J]. A&D, 2018, 9(3): 523-536.
[6] Diana L Castillo-Carranza,Ashley N Nilson,Candice E Van Skike,Jordan B Jahrling,Kishan Patel,Prajesh Garach,Julia E Gerson,Urmi Sengupta,Jose Abisambra,Peter Nelson,Juan Troncoso,Zoltan Ungvari,Veronica Galvan,Rakez Kayed. Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer’s Disease and Related Tauopathies[J]. A&D, 2017, 8(3): 257-266.
[7] Zohara Sternberg,Zihua Hu,Daniel Sternberg,Shayan Waseh,Joseph F. Quinn,Katharine Wild,Kaye Jeffrey,Lin Zhao,Michael Garrick. Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease[J]. A&D, 2017, 8(2): 215-227.
[8] Jianhui Wang,Xiaorui Cheng,Ju Zeng,Jiangbei Yuan,Zhongfu Wang,Wenxia Zhou,Yongxiang Zhang. LW-AFC Effects on N-glycan Profile in Senescence-Accelerated Mouse Prone 8 Strain, a Mouse Model of Alzheimer’s Disease[J]. A&D, 2017, 8(1): 101-114.
[9] Annamaria Zaia,Pierluigi Maponi,Giuseppina Di Stefano,Tiziana Casoli. Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Focus on Mitochondrial DNA and Alzheimer’s Disease[J]. A&D, 2017, 8(1): 44-56.
[10] Murat Serdar Gurses,Mustafa Numan Ural,Mehmet Akif Gulec,Omer Akyol,Sumeyya Akyol. Pathophysiological Function of ADAMTS Enzymes on Molecular Mechanism of Alzheimer’s Disease[J]. A&D, 2016, 7(4): 479-490.
[11] Ryan J. Day,Katie L. McCarty,Kayla E. Ockerse,Elizabeth Head,Troy T. Rohn. Proteolytic Cleavage of Apolipoprotein E in the Down Syndrome Brain[J]. A&D, 2016, 7(3): 267-277.
[12] Arpita Konar,Padmanabh Singh,Mahendra K. Thakur. Age-associated Cognitive Decline: Insights into Molecular Switches and Recovery Avenues[J]. A&D, 2016, 7(2): 121-129.
[13] Isaac G. Onyango,Jameel Dennis,Shaharyah M. Khan. Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies[J]. A&D, 2016, 7(2): 201-214.
[14] Xu Yunqi, Wei Xiaobo, Liu Xu, Liao Jinchi, Lin Jiaping, Zhu Cansheng, Meng Xiaochun, Xie Dongsi, Chao Dongman, J Fenoy Albert, Cheng Muhua, Tang Beisha, Zhang Zhuohua, Xia Ying, Wang Qing. Low Cerebral Glucose Metabolism: A Potential Predictor for the Severity of Vascular Parkinsonism and Parkinson's Disease[J]. A&D, 2015, 6(6): 426-436.
[15] J. De Reuck,F. Auger,N. Durieux,V. Deramecourt,C. Cordonnier,F. Pasquier,C.A. Maurage,D. Leys,R. Bordet. Topography of Cortical Microbleeds in Alzheimer’s Disease with and without Cerebral Amyloid Angiopathy: A Post-Mortem 7.0-Tesla MRI Study[J]. A&D, 2015, 6(6): 437-443.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd