PET Imaging of Copper Trafficking in a Mouse Model of Alzheimer Disease.

Abstract

Alzheimer disease (AD) is a fatal neurodegenerative disorder characterized by progressive neuronal loss and cognitive decline. The lack of reliable and objective diagnostic markers for AD hampers early disease detection and treatment. Growing evidence supports the existence of a dysregulation in brain copper trafficking in AD. The aim of this study was to investigate brain copper trafficking in a transgenic mouse model of AD by PET imaging with (64)Cu, to determine its potential as a diagnostic biomarker of the disorder. Brain copper trafficking was evaluated in 6- to 8-mo-old TASTPM transgenic mice and age-matched wild-type controls using the (64)Cu bis(thiosemicarbazone) complex (64)Cu-GTSM (glyoxalbis(N(4)-methyl-3-thiosemicarbazonato) copper(II)), which crosses the blood-brain barrier and releases (64)Cu bioreductively into cells. Animals were intravenously injected with (64)Cu-GTSM and imaged at 0-30 min and 24-25 h after injection. The images were analyzed by atlas-based quantification and texture analysis. Regional distribution of (64)Cu in the brain 24 h after injection was also evaluated via ex vivo autoradiography and compared with amyloid-β plaque deposition in TASTPM mice. Compared with controls, in TASTPM mice PET image analysis demonstrated significantly increased (by a factor of ~1.3) brain concentration of (64)Cu at 30 min (P < 0.01) and 24 h (P < 0.05) after injection of the tracer and faster (by a factor of ~5) (64)Cu clearance from the brain (P < 0.01). Atlas-based quantification and texture analysis revealed significant differences in regional brain uptake of (64)Cu and PET image heterogeneity between the 2 groups of mice. Ex vivo autoradiography showed that regional brain distribution of (64)Cu at 24 h after injection did not correlate with amyloid-β plaque distribution in TASTPM mice. The trafficking of (64)Cu in the brain after administration of (64)Cu-GTSM is significantly altered by AD-like pathology in the TASTPM mouse model, suggesting that (64)Cu-GTSM PET imaging warrants clinical evaluation as a diagnostic tool for AD and possibly other neurodegenerative disorders.