Early AD pathology in a [C-11]PiB-negative case: a PiB-amyloid imaging, biochemical, and immunohistochemical study

Amyloid-beta (A beta) deposits are detectable in the brain in vivo using positron emission tomography (PET) and [C-11]-labeled Pittsburgh Compound B ([C-11]PiB); however, the sensitivity of this technique is not well understood. In this study, we examined A beta pathology in an individual who had clinical diagnoses of probable dementia with Lewy bodies and possible Alzheimer's disease (AD) but with no detectable [C-11]PiB PET retention ([C-11]PiB(-)) when imaged 17 months prior to death. Brain samples were processed in parallel with region-matched samples from an individual with a clinical diagnosis of probable AD and a positive [C-11]PiB PET scan ([C-11]PiB(+)) when imaged 10 months prior to death. In the [C-11]PiB(-) case, A beta plaques were sparse, occupying less than 2% cortical area, and were weakly labeled with 6-CN-PiB, a highly fluorescent derivative of PiB. In contrast, A beta plaques occupied up to 12% cortical area in the [C-11]PiB(+) case, and were intensely labeled with 6-CN-PIB. The [C-11]PiB(-) case had low levels of [H-3]PiB binding (<100 pmol/g) and A beta 1-42 (<500 pmol/g) concentration except in the frontal cortex where A beta 1-42 values (788 pmol/g) approached cortical values in the [C-11]PiB(+) case (800-1,700 pmol/g). In several cortical regions of the [C-11]PiB(-) case, A beta 1-40 levels were within the range of cortical A beta 1-40 values in the [C-11]PiB(+) case. Antemortem [C-11]PiB DVR values correlated well with region-matched postmortem measures of A beta 1-42 and A beta 1-40 in the [C-11]PiB(+), and with A beta 1-42 only in the [C-11]PiB(-) case. The low ratios of [H-3]PiB binding levels to Ab concentrations and 6-CN-PiB to Ab plaque loads in the [C-11]PiB(-) case indicate that Ab pathology in the brain may be associated with low or undetectable levels of [C-11]PiB retention. Studies in greater numbers of [C-11]PiB PET autopsy cases are needed to define the Ab concentration and [H-3]PiB binding levels required to produce a positive [C-11]PiB PET signal.