Quantifying Extent, the Spatial Distribution of Flortaucipir PET Uptake, in an Autopsy Cohort and its Correspondence to Post‐Mortem Staining of Alzheimer’s Disease Biomarkers

Abstract

AbstractBackgroundIn Alzheimer’s disease, neurofibrillary tangle (NFT) burden can be characterized in postmortem staining and in vivo NFT‐specific flortaucipir PET by increases in intensity and spatial distribution. Previous work compared intensity based standard uptake value ratios (SUVRs) from Early Tau and MUBADA volumes of interest (VOIs) in detecting Braak stage pathology. We propose a measure called Extent to quantify the spatial distribution of NFT‐specific uptake in flortaucipir PET from the Phase III study AV‐1451‐A16 and compare against Early Tau and MUBADA SUVRs in detecting Braak stage pathology and post‐mortem amyloid burden.MethodsThis retrospective analysis of the AV‐1451‐A16 study included 60 subjects that underwent ante‐mortem flortaucipir imaging and post‐mortem assignment of Braak stages and Thal/CERAD scoring for amyloid burden. The processing of the flortaucipir scans and the recording of neuropathological findings were performed as previously described except cerebellum crustaneous was used as a reference region. Extent was calculated by 1) creating a Z‐score image using 16 young cognitively normal controls, 2) retaining voxel clusters with Z‐scores smaller than a false discovery corrected p‐value of 0.01, and 3) calculating the ratio of the number of surviving voxels against the total number of voxels in the mask. Flortaucipir positivity was defined as greater than 2.5 SD of the mean of young controls for Early Tau and MUBADA SUVRs and as non‐zero for Extent. Amyloid positivity was defined by a Thal/CERAD scoring of 2 or higher and compared to flortaucipir positivity using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).ResultsExtent detected subjects with flortaucipir positivity comparably to Early Tau in Braak stages I, II, and III while detecting more subjects with flortaucipir positivity in Braak stages V and VI than Early Tau and MUBADA (Table 1 and Figure 1). For amyloid positivity, Extent had the highest sensitivity (79.62%) and NPV (29.42%) while MUBADA had the highest specificity (87.50%) and PPV (97.06%) (Table 2).ConclusionBased on the Correspondence to post‐mortem staining, the Extent measure of flortaucipir spatial distribution may provide benefit over intensity based SUVRs in detecting flortaucipir and amyloid positive subjects for inclusion in future studies.