Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to beta-pleated sheet aggregates of the amyloid-beta (A beta) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimer's disease shows a regional distribution that is very similar to distribution of A beta deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of A beta-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimer's disease subjects, including one Alzheimer's disease subject who had undergone PiB-PET imaging 10 months prior to death, to evaluate region-and substrate-specific binding of the highly fluorescent PiB derivative 6-CN-PiB. These data were then correlated with region-matched A beta plaque load and peptide levels, [H-3] PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimer's disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either A beta 42 or A beta 40, and to vascular A beta deposits. 6-CN-PiB labelling was most robust in compact/cored plaques in the prefrontal and temporal cortices. While diffuse plaques, including those in caudate nucleus and presubiculum, were less prominently labelled, amorphous A beta plaques in the cerebellum were not detectable with 6-CN-PiB. Only a small subset of NFT were 6-CN-PiB positive; these resembled extracellular 'ghost' NFT. In Alzheimer's disease brain tissue homogenates, there was a direct correlation between [H-3] PiB binding and insoluble A beta peptide levels. In the Alzheimer's disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [H-3] PiB binding, insoluble A beta peptide levels, 6-CNPi-B- and A beta plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimer's disease brain, that PiB binding is highly selective for insoluble (fibrillar) A beta deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of A beta plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of A beta plaque burden.