Josephs KA, Tosakulwong N, Weigand SD, Graff-Radford J, Schwarz CG, Senjem ML, Machulda MM, Kantarci K, Knopman DS, Nguyen A, Reichard RR, Dickson DW, Petersen RC, Lowe VJ, Jack CR Jr, Whitwell JL. Flortaucipir PET uncovers relationships between tau and amyloid-β in primary age-related tauopathy and Alzheimer's disease. Sci Transl Med. 2024 Jul 24;16(757):eado8076. PubMed.
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VU University Medical Center
This is an excellent and important study reporting on the largest antemortem tau PET (combined with amyloid PET) versus autopsy dataset to date. The main goal of the study was to investigate the relationships between tau and amyloid pathology based on information derived from in vivo and postmortem data. The main strengths include i) the impressive sample size, ii) the relatively short time interval between last PET scan and death, iii) the good representation of various syndrome diagnoses, iv) the wide range of the tau/amyloid pathological burden, and v) the availability of both tau and amyloid PET in nearly all cases.
The inability of flortaucipir to detect primary age-related tauopathy (PART) is a very important observation, because the field has been misinformed by several in vivo PET studies that have used inappropriate thresholds (i.e., too low for tau PET and too high for amyloid PET) to suggest that flortaucipir can be used to detect PART in vivo. Future antemortem versus postmortem studies will be key to test whether other tau PET tracers (especially MK6240) are suitable for the detection of PART in vivo. This is plausible given the higher affinity of MK6240 as well as the high(er) proportion of A-T2+ cognitively unimpaired individuals in independent MK6240 versus flortaucipir PET studies.
View all comments by Rik OssenkoppeleLund University
This is a very comprehensive study, which was done in a careful manner by experts in the field. I have only one major concern, and that is how A plaques and tau tangle pathology are compared to flortaucipir retention. The flortaucipir PET signal is quantified in nine different regions of interest in a semiquantitative manner, as we normally do, and these SUVR-based measures should reflect the density of tau aggregates in the same nine regions. However, the neuropathological assessments are done using the standard neuropathological staging systems, Braak and Thal, which only tell us where in the brain tau aggregates and A plaques, respectively, can be found.
Of course, there is an association between Braak stage and the regional tau tangle density in different brain regions, but it is naturally far from perfect. For example, people at Braak stage III-IV, without amyloid, have a lower density of tau aggregates in the medial temporal lobe than do those with a high Ab plaque load. Therefore, comparing flortaucipir retention in different brain regions with Braak (or Thal) staging is a bit complex for me to interpret.
It would be great if a follow-up study could compare PET and neuropathological measures of the density (or concentration) of abnormal tau in the same regions. This could be done by comparing flortaucipir retention with the density of abnormal tau in the same regions as detected by immunohistochemistry, e.g., with AT8 antibody, or by quantifying the levels of abnormal tau species in fresh frozen tissue. I believe that when using both a measure of the regional density of plaques and a measure of the regional density of tau tangles and neuropil threads, only the latter will predict the regional flortaucipir retention. I do not believe that flortaucipir can detect the rather low level of tau aggregates found in Ab plaques.
View all comments by Oskar HanssonMake a Comment
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