PIB binding in aged primate brain: Enrichment of high-affinity sites in humans with Alzheimer's disease

Division of Neuroscience, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
Neurobiology of aging (Impact Factor: 5.01). 04/2009; 32(2):223-34. DOI: 10.1016/j.neurobiolaging.2009.02.011
Source: PubMed


Aged nonhuman primates accumulate large amounts of human-sequence amyloid β (Aβ) in the brain, yet they do not manifest the full phenotype of Alzheimer's disease (AD). To assess the biophysical properties of Aβ that might govern its pathogenic potential in humans and nonhuman primates, we incubated the benzothiazole imaging agent Pittsburgh Compound B (PIB) with cortical tissue homogenates from normal aged humans, humans with AD, and from aged squirrel monkeys, rhesus monkeys, and chimpanzees with cerebral Aβ-amyloidosis. Relative to humans with AD, high-affinity PIB binding is markedly reduced in cortical extracts from aged nonhuman primates containing levels of insoluble Aβ similar to those in AD. The high-affinity binding of PIB may be selective for a pathologic, human-specific conformation of multimeric Aβ, and thus could be a useful experimental tool for clarifying the unique predisposition of humans to Alzheimer's disease.

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    • "Only increased numbers of cortical plaques usually associated with increased amounts of cortical soluble and nonplaque-associated insoluble (so called dispersible) Ab aggregates in Ab p h a s e4a n d5c a s e s[15] [16] permitted significant [ 18 F]flutemetamol retention in the cortex. The assumption of a threshold for Ab pathology to be passed for detection with amyloid PET is in agreement with the negative PIB amyloid imaging results in aged monkeys with amyloid plaques that may not exhibit sufficient degrees of amyloid pathology (as Ab phase 1–3 cases in this study) to allow detection by amyloid PET methods [33]. "
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    • "The specific binding properties of [11C]PiB are still controversial, as is the correlation with the post-mortem histology of tissue taken from disease models established in animals (Klunk et al., 2005a; Toyama et al., 2005; Bacskai et al., 2007; Rosen et al., 2011). The tracer is known to pass the blood-brain barrier with comparative ease, which renders the uptake sensitive to blood flow differences, as well as amyloid load (Blomquist et al., 2008; Gjedde et al., 2013). "
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    • "There are both high (nM) and low (μM) affinity PiB binding sites on synthetic and biological Aβ fibrils [33]. The low affinity site is more abundant in synthetic fibrils, fibrillar Aβ from transgenic mice, and the Aβ found in the brains of aged non-human primates [52] [66]. A large proportion of the PiB binding under our assay conditions (1 nM 3 H-PiB) is to the high affinity site [33]. "
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