Basic Science and Pathogenesis.

Background: Brain deposits of amyloid-β (Aβ), one of the hallmark pathologies of Alzheimer disease (AD), are consistently present in people with Down syndrome (DS) after the age of 30 years. Positron emission tomography (PET) radioligands like [3H]Pittsburgh Compound-B (PiB) allow for visualizing Aβ accumulation in living people. In DS, the earliest and strongest PiB-PET retention is in the striatum, differing from late-onset AD. The neuropathological substrates of early PiB retention in DS striatum are unknown. The goal of this postmortem study is to compare histofluorescent labeling with cyano-PiB, a fluorescent derivative of PiB, in the striatum and frontal cortex of people with DS.

Method: Cyano-PiB histofluorescence load (% area) was evaluated on postmortem tissue from putamen and frontal cortex (n = 43; age 42-70 years, 24F/19M) using whole slide imaging and digital quantification. Cyano-PiB histofluorescence was combined with Aβ immunofluorescence on a subset (n = 3) of cases.

Result: After the age of 42 years, cyano-PiB loads did not increase as a function of age at death in frontal cortex (layers II-IV; p = 0.64) and putamen (p = 0.76). Cyano-PiB loads were not greater in putamen compared to frontal cortex. Putamen and frontal cortex cyano-PiB loads directly correlated (r = 0.52). Cyano-PiB labeled plaques were immunolabelled with Aβ-targeting antibodies 6E10, 12F4, and 4G8, in both putamen and frontal cortex, with less overlap observed in deep frontal cortical layers.

Conclusion: Striatal cyano-PiB load in putamen was not greater than in the frontal cortex layers II-IV in people with DS above the age of 42 years. The partial overlap of cyano-PiB labeled amyloid plaques with Aβ immunoreactive plaques suggests that only a subset of Aβ plaques were detected with cyano-PiB. Further characterization of cyano-PiB loads in deep layers of the frontal cortex as well as in DS cases at younger ages is warranted.