. Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes. JAMA Neurol. 2020 Apr 27; PubMed.

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  1. A crucial step in the validation of a PET tracer for tau pathology is the comparison of in vivo tracer retention and neuropathological verification of the pathology postmortem. Adam Fleisher and colleagues have now performed a relatively large end-of-life study, showing an accuracy of approximately 88 percent to detect Braak V/VI neurofibrillary tangle pathology using visual read of flortaucipir PET images. The sensitivity of flortaucipir was generally high (range: 92 to 100 percent), but the specificity was lower for some of the readers (range 52 to 92 percent). The relatively low specificity for some of the readers was explained by the fact that they overcalled small foci with signal in the temporal lobe.

    Importantly, quantitative measurement of the images revealed a higher specificity (of 100 percent), implying that a combination of visual read and quantitative assessment might improve the outcome. The study is very well performed and supports the use of flortaucipir in the clinical diagnostic work-up of patients with cognitive impairment where AD is considered to be one of several possible etiologies. It is interesting to note that all cases in the present study who had an elevated retention of flortaucipir (according to quantitative measurement) also exhibited significant amyloid pathology according to neuropathology. Therefore, it might not be necessary to also perform an amyloid-PET scan (or CSF Aβ analysis) in a patient with an abnormal tau-PET scan, except in rare cases where, e.g., svPPA is suspected.

    A weakness of the study might be that flortaucipir was mainly compared to Braak staging, considering that this staging system mainly reflects the distribution of neurofibrillary tangles in the brain and not the actual amount/density of tau pathology in different regions, which would better reflect the in vivo retention of flortaucipir. Further, the study implies that visual read of flortaucipir is not a suitable method to detect very early tau pathology in AD, and here P-tau181 and P-tau217 in cerebrospinal fluid as well as in plasma are likely to be more accurate markers.

    Overall, the study provides solid evidence that flortaucipir PET can be used in the diagnostic work-up of patients with cognitive impairment, and increased retention of flortaucipir according to quantitative assessment indicates with high certainty that a patient has AD. Flortaucipir PET will also be very useful to determine drug target engagement of certain anti-tau therapies, and to reveal potential downstream effects of anti-amyloid therapies.

    View all comments by Ruben Smith

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