AbstractBackgroundThe binding substrates of [18F]flutemetamol and [11C]PiB PET consist of fibrillar amyloid‐β (Aβ) aggregates in morphologically and structurally distinct diffuse plaques (DP) and cored plaques (CP) which are present at different proportions across brain regions in Alzheimer’s disease (AD). To account for this heterogeneity, an unbiased quantitative measure integrating plaque size and density of amyloid‐β (Aβ) fibrils in plaques could help avoid false positive results, improve imaging‐to‐autopsy correlations, and further advance our understanding of pathological substrates for binding of amyloid PET tracers.MethodSixteen subjects underwent [18F]flutemetamol PET imaging in the pivotal Phase III end‐of‐life study (Study GE067‐007 and GE067‐026) and later came to autopsy (mean imaging‐to‐autopsy interval was 111 ± 87.6 days). [18F]flutemetamol SUVRpons values in four neocortical regions were correlated with region‐matched postmortem measures of cyano‐flutemetamol labeling of all plaques, as well as CP and DP separately, using percent area coverage, mean grayscale intensity of fluorescence, or a combination of the two measures referred to as integrated density.ResultIn the analysis of all cyano‐flutemetamol‐labeled plaques, [18F]flutemetamol SUVRpons values were more closely associated with integrated density measures than percent area coverage and mean grayscale values. Similarly, when CP and DP were analyzed separately, the integrated density values showed the closest association with neocortical region‐matched [18F]flutemetamol SUVRpons values. When area coverage of CP and DP were each expressed as a fraction of total plaque area coverage with or without integrating fluorescence intensity values, [18F]flutemetamol SUVRpons values within each region of interest were associated with the DP, but not the CP, area coverage measure.ConclusionThe association of antemortem [18F]flutemetamol PET and region‐matched postmortem integrated density measurements of cyano‐flutemetamol labeled plaques further supports the hypothesis that amyloid PET signal is influenced both by plaque size and Aβ fibril density within DP and CP. Further elucidating the relative contributions of each plaque type to the retention of amyloid PET radioligands could influence how a positive amyloid PET signal is interpreted in relation to postmortem pathology data.
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