Pittsburgh compound B and the postmortem diagnosis of alzheimer disease

Abstract

Deposition of the amyloid-β (Aβ) peptide in neuritic plaques is a requirement for the diagnosis of Alzheimer disease (AD). Although the continued development of in vivo imaging agents such as Pittsburgh compound B (PiB) is promising, the diagnosis of AD is still challenging. This can be partially attributed to our lack of a detailed understanding of the interrelationship between the various pools and species of Aβ and other common indices of AD pathology. We hypothesized that recent advances in our ability to accurately measure Aβ postmortem (for example, using PiB), could form the basis of a simple means to deliver an accurate AD diagnosis. We conducted a comprehensive analysis of the amount of Aβ40 and Aβ42 in increasingly insoluble fractions, oligomeric Aβ, and fibrillar Aβ (as defined by PiB binding), as well as plaques (diffuse and neuritic), and neurofibrillary tangles in autopsy specimens from age-matched, cognitively normal controls (n = 23) and AD (n = 22) cases, across multiple brain regions. Both PiB binding and the amount of sodium dodecyl sulfate (SDS)-soluble Aβ were able to predict disease status; however, SDS-soluble Aβ was a better measure. Oligomeric Aβ was not a predictor of disease status. PiB binding was strongly related to plaque count, although diffuse plaques were a stronger correlate than neuritic plaques. Although postmortem PiB binding was somewhat useful in distinguishing AD from control cases, SDS-soluble Aβ measured by standard immunoassay was substantially better. These findings have important implications for the development of imaging-based biomarkers of AD.