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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

View larger version (12K): [in this window] [in a new window]   FIGURE 1.  In vitro binding studies demonstrate that 3H-PiB fails to bind to white matter brain homogenates. Scatchard plots of 3H-PiB binding to gray matter (AD patients [A] and age-matched HCs [B]) and white matter (AD patients [C] and age-matched HCs [D]) brain homogenates. Scatchard analysis indicated that 3H-PiB binds to AD gray matter (dissociation constant, 3.77 nM; maximum number of binding sites, 9,254 pmol 3H-PiB/g tissue) brain homogenates. No significant binding of 3H-PiB to HC gray matter or white matter homogenates was observed. Consequently, no binding parameters could be calculated. Binding data were analyzed using software (version 1.0; GraphPad). Figure is representative of at least 3 independent experiments.

View larger version (109K): [in this window] [in a new window]   FIGURE 2.  IHC and IF analysis indicates PiB staining does not bind to white matter. Microscopy images of 2 serial sections (7 µm) from frontal cortex of AD patient (A) and centrum semiovale from age-matched HC (B) and AD patient (C). First section was immunostained with antibody to Aβ (1E8) to identify Aβ plaques; second serial section was stained with 100 µM PiB. Presence of Aβ plaques was detected in AD frontal cortex sections (black arrowheads) and colocalized with positive PiB staining (white arrowheads). Centrum semiovale sections exhibited no immunoreactivity with 1E8, indicating absence of plaques (B and C). At higher magnification, PiB staining was observed to highlight blood vessels. (D) Serial sections (5 µm) isolated from gray matter (frontal cortex; top) and white matter (centrum semiovale; bottom) of patient with DLB who underwent 11C-PiB PET 23 mo before his death. Sections (from left to right) were stained with antibodies to Aβ (1E8) to Aβ plaques, PiB, -syn (97/8), and tau-protein (Dako) and stained with PiB (100 µM). Presence of Aβ plaques was detected in DLB frontal cortex sections and colocalized with positive PiB staining. Centrum semiovale sections exhibited no immunoreactivity with any reagent used, indicating absence of Aβ plaques, Lewy bodies, or neurofibrillary tangles. Images were taken on Leica microscope. Scale bars, 50 µm. -syn = -synuclein.

View larger version (11K): [in this window] [in a new window]   FIGURE 3.  Time–activity curves demonstrate no difference in 11C-PiB clearance rates in white matter of all patients analyzed. Time–activity curves demonstrate uptake and clearance of 11C-PiB in frontal cortex (A) and white matter (B). There is greater retention of PiB in frontal cortex of AD patients and to lesser extent in DLB patients than in HCs. In contrast, there was no significant difference in rate of 11C-PiB clearance in all groups analyzed. SUV = standardized uptake value.