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

Amyloid-β (Aβ) 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 Aβ 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, Aβ 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, Aβ 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 Aβ1–42 (<500 pmol/g) concentration except in the frontal cortex where Aβ1–42 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, Aβ1–40 levels were within the range of cortical Aβ1–40 values in the [C-11]PiB(+) case. Antemortem [C-11]PiB DVR values correlated well with region-matched postmortem measures of Aβ1–42 and Aβ1–40 in the [C-11]PiB(+), and with Aβ1–42 only in the [C-11]PiB(−) case. The low ratios of [H-3]PiB binding levels to Aβ concentrations and 6-CN-PiB to Aβ plaque loads in the [C-11]PiB(−) case indicate that Aβ 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 Aβ concentration and [H-3]PiB binding levels required to produce a positive [C-11]PiB PET signal.