Abstract
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Objectives: Extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFT) characterize Alzheimer’s disease (AD). The combined use of Aβ and tau PET biomarkers has demonstrated that high neocortical tau is rarely observed in the absence of high Aβ. We describe the prevalence of participants with high neocortical tau PET retention (both visually and quantitatively) with a correspondingly low Aβ PET result and further characterize these participants.
Methods: Participants from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of ageing were included if they had both an Aβ and tau PET scan. A Centiloid value of <25 was used to define a low (negative) Aβ result. Tau PET SUVR was estimated in three composite regions of interest (ROI): mesial temporal (Me), temporoparietal (Te), and the rest of the neocortex (R). The 95%ile of the Aβ negative, cognitively unimpaired participants determined the threshold for each composite ROI, while the 99%ile represented the upper bound of the peri-threshold range. A subset of participants had one or more alternative biomarker (plasma Aβ, plasma pTau-217, CSF Aβ1-42, pTau, tTau or 18F-FDG PET) results available.
Results: Two hundred and eighty seven of the 466 participants who had both Aβ (18F-NAV4694) and tau (18F-MK6240) PET scans had a low Aβ PET result. Twelve Aβ- participants were above the upper bound of the peri-threshold value for tau tracer retention in both the Te and R ROI’s, and of these, four (a prevalence of 1.4% of all Aβ-) were visually positive for the presence of neocortical tau, in a pattern consistent with AD (Braak stage V-VI) (Fig 1). One participant was cognitively unimpaired (CU), while three had a clinical diagnosis of amnestic MCI or AD. Despite the low Aβ PET, one participant had high plasma Aβ, while one had low CSF Aβ1-42 in addition to high CSF pTau and tTau and a 18F-FDG PET pattern consistent with AD. High plasma pTau-217 results were observed for three of these four participants (a result was not available for one participant).
Conclusions: We have identified four participants with low Aβ PET and high neocortical tau PET retention. The alternative biomarker results in these cases are suggestive of a diagnosis of AD, despite the low Aβ PET result. We propose that in these instances, the Aβ PET ligand may not be detecting Aβ, maybe due to a different conformation of the aggregates. While infrequent, this finding has been reported using 11C-PiB. Overall, the prevalence of this discordance was <2% in the sampled cohort, suggesting it is an uncommon occurrence. However, this study is limited by the lack of alternative Aβ biomarker results. Studies in larger cohorts are necessary to validate these findings, while genetic testing and postmortem correlation will enhance our understanding of the potential explanation for this finding. Acknowledgements: The data used in the preparation of this article was obtained from the Australian Imaging Biomarkers and Lifestyle flagship study of aging (AIBL), funded by the Commonwealth Scientific and Industrial Research Organization (CSIRO), National Health and Medical Research Council of Australia (NHMRC), and participating institutions. AIBL researchers are listed at www.aibl.csiro.au. NK was supported by a cofunded PhD scholarship from Australian Rotary Health/ Bartolina Peluso.