- traumatic brain injury
- copper metabolism
- neuroimaging
- positron emission tomography
- 64Cu-chloride
Traumatic brain injury (TBI) is a significant cause of neurologic disability among the U.S. population, affecting those who are in car accidents, involved in contact sports, or exposed to a blast on the battlefield (1). Neuroimaging plays an important role in the diagnosis and clinical management of TBI patients. Among the neuroimaging modalities, CT is useful for evaluating head injury features such as hemorrhages and edema (2,3); MR imaging is useful when neurologic symptoms are unexplained by the CT findings, because of higher sensitivity for microhemorrhages and subtle nonhemorrhagic lesions (4,5); and PET is highly sensitive and quantitative in the assessment of brain perfusion (6) and changes in cerebral glucose metabolism (7,8). Because the sensitivity and specificity of 18F-FDG PET in TBI may be limited by abundant physiologic 18F-FDG uptake in nontraumatized brain tissues, it is important to search for new biomarkers for PET assessment of TBI.
Copper is an essential nutrient for the function of many enzymes present in physiologic and pathophysiologic processes of mammals (9,10). The brain is the organ containing the second largest amount of copper in the human body (11), and copper plays an important role in normal brain physiology (12). Copper is required for wound repair and regeneration, and increased copper has been detected in wound tissue (13,14). The molecular mechanisms by which copper plays a role in wound repair are not fully understood but may be related to induction of vascular endothelial growth factor expression for angiogenesis (15) and to copper-containing molecules serving an essential function in cell proliferation in the wound-healing process. In response to TBI, there may be increased copper uptake by activated microglia secondary to posttraumatic neuroinflammation (16), copper/zinc superoxide dismutase (17), and potentially other copper transporters and chaperones defending oxidative damage (18).
We hypothesized that increased copper uptake in traumatized brain tissues may be tracked in vivo using radioactive copper and that increased uptake of 64Cu may be applied as a biomarker to assess TBI using 64CuCl2 PET/CT. This study tested our hypothesis by comparing cerebral uptake in 3 groups of mice: a group in which TBI was induced by controlled cortical impact (CCI), a normal control group without TBI, and a modified sham control group. In the modified sham procedure the skin was incised, and instead of the craniotomy performed in the regular sham control procedure, a small hole was drilled into the cranium to minimize cortical injury (19). To increase the strength of this control, after the hole had been drilled the mice received an intracortical injection of zymosan A. Although this modified sham control procedure may cause mild damage to brain tissue, we expected it to be less than that caused by the regular sham control procedure.
In an initial effort to differentiate uptake caused by the requirement for copper for wound healing from uptake caused by neuroinflammation, we assessed cerebral 64Cu uptake in TBI mice treated and not treated with minocycline, a tetracycline derivative with antiinflammatory effects in TBI (20). The results of this comparison are expected to be useful not only to investigate the molecular mechanism by which TBI increases copper uptake but also to determine whether 64CuCl2 is a useful tracer for detecting neuroinflammation in TBI with PET/CT and monitoring the therapeutic effects of minocycline and other antineuroinflammation medications.
- © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
- Received for publication February 12, 2015.
- Accepted for publication June 17, 2015.
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