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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
Peng Fangyu1,2,*, Xie Fang1, Muzik Otto3,4
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
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Abstract  

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: Peng Fangyu   
About author:

These authors equally contributed to this work.

Issue Date: 01 February 2018
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Peng Fangyu
Xie Fang
Muzik Otto
Cite this article:   
Peng Fangyu,Xie Fang,Muzik Otto. Alteration of Copper Fluxes in Brain Aging: A Longitudinal Study in Rodent Using 64CuCl2-PET/CT[J]. Aging and disease, 2018, 9(1): 109-118.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1025     OR     http://www.aginganddisease.org/EN/Y2018/V9/I1/109
Figure 1.  Schematic presentation of longitudinal study of glucose metabolism and copper fluxes in C57BL/6 mice with PET/CT

Human age equivalents to mouse data were provided at the bottom.

5 months (22 weeks)13 months (59 weeks)26 months (104 weeks)
2 h24 h2 h24 h2 h24 h
Liver1.15 ± 0.381.73 ± 0.381.25 ± 0.351.35 ± 0.072.13 ± 1.101.53 ± 0.41
heart0.18 ± 0.08**0.43 ± 0.07*0.24 ± 0.010.29 ± 0.01*0.50 ± 0.26**0.56 ± 0.12
Muscle0.06 ± 0.020.05 ± 0.050.06 ± 0.010.02 ± 0.020.09 ± 0.030.12 ± 0.12
Brain0.11 ± 0.020.11 ± 0.060.14 ± 0.010.17 ± 0.050.12 ± 0.030.14 ± 0.06
Kidneys0.53 ± 0.180.95 ± 0.13*0.90 ± 0.420.81 ± 0.070.70 ± 0.530.48 ± 0.15*
Lungs0.22 ± 0.080.44 ± 0.050.28 ± 0.030.36 ± 0.010.42 ± 0.310.46 ± 0.04
Table 1  Whole body biodistribution of 64Cu (mean ± SD %ID/g) in C57BL/6 mice orally administered with 64CuCl2 by a longitudinal PET/CT.
5 months13 months26 months
Olfactory bulb0.17 ± 0.060.26 ± 0.090.18 ± 0.04
Frontal cortex0.17 ± 0.140.13 ± 0.020.17 ± 0.09
Posterior cortex0.11 ± 0.050.12 ± 0.020.12 ± 0.05
Hippocampus0.18 ± 0.050.19 ± 0.010.14 ± 0.02
Basal ganglia0.16 ± 0.060.20 ± 0.02*0.09 ± 0.03*
Thal/Hypothal0.23 ± 0.100.21 ± 0.06*0.11 ± 0.03*
Mid-brain0.12 ± 0.030.11 ± 0.010.12 ± 0.02
Brain stem0.12 ± 0.01**0.20 ± 0.04**0.19 ± 0.01
Cerebellum0.12 ± 0.040.12 ± 0.010.15 ± 0.12
Table 2  64Cu uptake (mean ± SD %ID/g) in brains of C57BL/6 mice orally administered with 64CuCl2 measured by PET at 24h PO.
Figure 2.  Biodistribution of <sup>64</sup>Cu radioactivity in C57BL/6 mice orally administered with <sup>64</sup>CuCl<sub>2</sub> by PET/CT imaging

(A) At 24h PO, prominent 64Cu radioactivity in the liver and gastrointestinal tracts were visualized on PET/CT images. Residual 64Cu radioactivity in oral cavity was also noted. (B) PET quantitative analysis determined 64Cu tissue distribution across different ages (5, 13 and 26 months of age) with 64Cu uptake in the heart and muscle at old age higher than 64Cu uptake at middle age. In contrast, 64Cu radioactivity in the kidneys at old age was lower than renal 64Cu radioactivity of C57BL/6 mice at young and middle age. Mean ± SD %ID/g: percentage of injected dose per gram tissue; PO: post oral administration of the tracer.

6 months (26 weeks)11 months (44 weeks)22 months (93 weeks)
Liver1.25 ± 0.191.4 ± 0.492.0 ± 0.34
heart1.85 ± 0.783.3 ± 1.153.4 ± 0.53
Muscle0.76 ± 0.530.65 ± 0.391.3 ± 0.36
Whole brain7.92 ± 1.19*5.33 ± 1.63*5.63 ± 1.16
Kidneys1.98 ± 0.621.33 ± 0.21**2.26 ± 0.31**
Lungs1.20 ± 0.351.48 ± 0.821.8 ± 0.36
Table 3  Whole body biodistribution of 18F-FDG (mean ± SD %ID/g) in C57BL/6 mice orally administered with 18F-FDG radiotracer by a longitudinal PET/CT.
Figure 3.  Whole brain regional <sup>64</sup>Cu uptake at different ages assessed using longitudinal PET imaging

(A) Whole brain 64Cu uptake (mean ± SD %ID/g) at 5, 13 and 26 months of age acquired at 2h and 24h post oral administration of the 64CuCl2 PET tracer. (B) Transaxial images showing regional 64Cu radioactivity (mean ± SD %ID/g) acquired 24h PO at 5, 13 and 26 months of age. Regions were shown for cerebellum (CB), Thalamus (T), olfactory bulb (OB), posterior cortex (PC), and frontal cortex (FC).

Figure 4.  Biodistribution of <sup>18</sup>F-FDG radioactivity (mean ± SD %ID/g) in C57BL/6 mice orally administered with <sup>18</sup>F-FDG by PET/CT imaging

(A) At 1h PO, prominent 18F-FDG radioactivity in the brain and gastrointestinal tracts was visualized on PET/CT images. Residual 18F-FDG was noted in oral cavity. (B) PET quantitative analysis demonstrated 18F-FDG tissue distribution across different ages (6, 11 and 22 months of age) with 18F-FDG uptake in the brain of middle and old age lower than 18F-FDG uptake in the brain of young adult C57BL/6 mice. Error bars represent SD; %ID/g: percentage of injected dose per gram tissue; PO: post oral administration of the tracer.

Figure 5.  Correlative presentation of age-dependent changes of <sup>64</sup>Cu uptake (left panel) and <sup>18</sup>F-FDG uptake (right panel) determined using longitudinal PET analysis

The figures demonstrate a significantly different time course of 64Cu and 18F-FDG uptake in the brain regions across the life span, indicating variable changes of copper fluxes and glucose metabolism in brain aging. Regions were shown for whole brain (WB), olfactory bulb (OB), basal ganglia (BG), posterior cortex (PC), and hippocampus (HC). Error bars represent SD; %ID/g, percentage of injected dose per gram tissue.

6 montsh (26 weeks)11 months (44 weeks)22 months (88 weeks)
Mid-brain8.35 ± 1.23*5.3 ± 1.72*5.3 ± 1.04
Cerebellum8.32 ± 1.33*5.4 ± 1.39*5.57 ± 1.01
Frontal cortex7.58 ± 1.66*5.23 ± 1.35*5.17 ± 1.01
Posterior cortex7.92 ± 1.56*5.6 ± 1.74*5.57 ± 1.27
Olfactory bulb7.58 ± 0.92*4.73 ± 1.10*5.9 ± 1.31
Hippocampus7.85 ± 1.59*4.93 ± 1.43*5.26 ± 1.31
Basal ganglia7.45 ± 1.125.5 ± 1.746.33 ± 1.58
Thalamus/hypothalamus7.05 ± 1.21*5.1 ± 1.39*5.27 ± 0.93
Brain stem7.85 ± 0.925.8 ± 1.915.77 ± 1.33
Table 4  Regional 18F-FDG radioactivity (mean ± SD %ID/g) in the brains of C57BL/6 mice orally administered with 18F-FDG radiotracer measured with a longitudinal PET/CT.
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