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

¹ Department of Pathology, University of Melbourne, Victoria, Australia; ² Bio21 Molecular and Biotechnology Institute, Neuroproteomics Platform, University of Melbourne, Victoria, Australia; ³ Mental Health Research Institute of Victoria, Parkville, Victoria, Australia; ⁴ Department of Nuclear Medicine, Centre for PET, Austin Hospital, Heidelberg, Victoria, Australia; ⁵ Department of Medicine (Austin Hospital), University of Melbourne, Victoria, Australia; ⁶ Department of Anatomical Pathology, Monash University and Alfred Hospital, Prahran, Victoria, Australia; ⁷ National Neuroscience Facility, University of Melbourne, Victoria, Australia; and ⁸ Centre for Neuroscience, University of Melbourne, Victoria Australia

Correspondence: For correspondence or reprints contact: Victor L. Villemagne, Department of Nuclear Medicine, Centre for PET, Austin Hospital, 145 Studley Rd., Heidelberg, Victoria, Australia 3084. E-mail: villemagne{at}petnm.unimelb.edu.au

¹¹C-Pittsburgh Compound B (¹¹C-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 Aβ 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 ³H-PiB (0.1–500 nM) and white matter brain homogenates (100 µg) from 3 AD patients and 3 HCs. Nonspecific binding was determined using PiB (1 µM). White matter from the same patients was also analyzed by immunofluorescence/immunohistochemistry (IF/IHC) microscopy and Western blotting for Aβ expression. White matter kinetics were also characterized in vivo through ¹¹C-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 ¹¹C-PiB distribution volume ratio data acquired 23 mo earlier. Results: In vitro saturation studies indicated that ³H-PiB binds nonspecifically to white matter brain homogenates. PiB fluorescence staining of AD and HC brain sections was consistent with absence of Aβ in IHC staining. Higher gray matter–to–white matter ratios were observed in IHC images than in ¹¹C-PiB PET images. Conclusion: These studies suggest that PiB binding to white matter is mainly nonsaturable and nonspecific and that PiB retention in the ¹¹C-PiB PET studies is largely attributable to slower PiB white matter kinetics.

Key Words: Pittsburgh Compound-B • Alzheimer disease • white matter • Aβ • PET

^* Contributed equally to this work.

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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