Characterization of PiB Binding to White Matter in Alzheimer Disease and Other Dementias

C-11-Pittsburgh Compound B (C-11-PiB) PET has demonstrated significantly higher PiB retention in the gray matter of Alzheimer disease (AD) patients than in healthy controls (HCs). PiB is Similarly retained within the white matter of HC and AD brains. Although the specificity of PiB for A beta plaques in gray matter has been well described, the nature of PiB binding to white matter remains unclear. In this study, we characterized the binding of PiB to human white matter homogenates. Methods: In vitro binding studies were conducted using H-3-PiB (0.1-500 nM) and white matter brain homogenates (100 mu g) from 3 AD patients and 3 HCs. Nonspecific binding was determined using PiB (1 mu M). White matter from the same patients was also analyzed by immunofluorescence/immunohistochemistry (IF/IHC) microscopy and Western blotting for A beta expression. White matter kinetics were also characterized in vivo through C-11-PiB PET studies in 27 HCs and 34 patients with dementia. IF/IHC experiments were conducted on 1 postmortem patient with dementia, to compare with the C-11-PiB distribution volume ratio data acquired 23 mo earlier. Results: In vitro saturation studies indicated that H-3-PiB binds nonspecifically to white matter brain homogenates. PiB fluorescence staining of AD and HC brain sections was consistent with absence of A beta in IHC staining. Higher gray matter-to-white matter ratios were observed in IHC images than in C-11-PiB PET images. Conclusion: These studies suggest that PiB binding to white matter is mainly nonsaturable and nonspecific and that PiB retention in the C-11-PiB PET studies is largely attributable to slower PiB white matter kinetics.