13 Introduction pathology (i.e., a combination of 3R/4R isoforms). The most widely used tracer for AD-specific tau pathology is [18F]flortaucipir. This tracer captures the paired helical filament of tau in neurofibrillary tangles. In Europe [18F]flortaucipir is currently only approved for research purposes, but In America the tracer has been approved for clinical use by the American Food & Drug Agency (FDA) in 2020 [16]. Tau PET can be used as a measure for tau pathology in the AT(N) classification, where ‘T’ status can be based on either quantitative thresholds or visual read. There are only few studies evaluating the temporal ordering of AT(N) biomarker abnormality in a longitudinal manner, using [18]flortaucipir for determination of ‘T’ status. Insight into the temporal dynamics of the biomarkers used in the diagnostic framework is important, especially for the earliest phases of disease in which pathological changes might direct future prevention or treatment strategies. Methodological aspects of Tau PET PET images can be acquired using dynamic or static protocols. Static scanning protocols consist of tracer injection, followed by a waiting period, after which a short scan is acquired. Static protocols have the advantage of clinical applicability and relative computational simplicity, but harbor the disadvantage that the parameters obtained are semi-quantitative. Dynamic PET scan protocols consist of tracer injection, while simultaneously starting a long scanning acquisition. Dynamic protocols allow for more accurate (fully) quantitative measures of specific binding of PET tracers [17, 18]. Moreover, dynamic scan protocols additionally enable computation of parametric images of tracer delivery, which can be interpreted as a proxy of relative tracer flow or relative cerebral blood flow (rCBF) (i.e. R1) [19]. R1 represents the ratio between the rate constant for ligand transfer from blood to tissue (K1) in the tissue of interest and the reference region, which is strongly correlated with metabolic activity ([18F]FDG PET) and the ‘gold standard’ for measuring flow ([15O]H 2O PET) [20-22]. A dynamic [18F]flortaucipir PET scan may thus not only provide accurate information on (regional) quantification of tau pathology, but also yields information on rCBF. Semi-quantitative measures from static scans are usually sufficient for clinical application, but accurate quantification of tracer uptake is of major importance for accurately detecting early-stage pathology, clinical trials and longitudinal studies. Longitudinal changes using static measures may be biased by blood flow changes, whereas quantitative measures are not. However, the PET tracer [18F]flortaucipir requires a relatively long dynamic acquisition period (i.e. up to 100 minutes) because of the slow tracer kinetics. This can be challenging, especially when working with a vulnerable population (like individuals with AD), and even more so when applied in a longitudinal or clinical trial setting. Ideally, one would thus prefer a relatively short dynamic scanning protocol, yielding quantitative accurately information about 1
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