231 Summary & Discussion are unreliable parameters for longitudinal studies with [11C]PiB [3]. The shortened dual-time-window protocol (0–30/80–100), on the other hand, additionally provides a flow estimate (R1) to evaluate the effect of flow and therefore is considered apt for longitudinal studies. In chapter three, we set out to assess whether flow changes also affect longitudinal [18F]flortaucipir PET parameters. Contrary to the study into longitudinal [11C]PiB PET, we did not observe such effects of flow on SUVr for [18F]flortaucipir. In fact, SUVr provided an accurate estimate of changes in specific binding over a 2-year follow-up during which changes in flow were small. Notwithstanding, simulations showed that large(r) flow changes may affect [18F]flortaucipir SUVr. Given that it is currently unknown to what order of magnitude pharmacotherapeutic interventions may induce changes in cerebral blood flow, caution may be warranted when changes in flow are potentially large(r), as in clinical trials. A suggestion for clinical trial designs would therefore be to introduce a coffee-break protocol in a subset of participants, so that the potential confounding of treatment induced flow changes can be assessed. Keeping the aforementioned notion in mind, overall, the use of static acquisition protocols for [18F]flortaucipir as is currently done in most settings, seem optimal, since they provide reliable estimates of specific binding, while limiting patient burden. Whether this will also be the case for other tau PET tracers that are currently explored in longitudinal settings is yet to be determined. Apart from the aforementioned suggestions there are some additional methodological considerations worth addressing for [18F]flortaucipir PET in this context. One of those considerations is the follow-up duration of longitudinal prospective studies. Since we know that tau pathology might develop decades before symptom onset in AD longer follow-up periods allow for a more detailed understanding of development of tau pathology. This might be relevant in the context of participant selection is trials, as information about the development of tau pathology might identify specific subtypes of disease or for example distinguish between slow- and fast-progressing individuals. Also, it would shed light on whether development of tau pathology can be considered a linear process (which is something that is often assumed as demonstrated by the type of statistical tests most often used in literature), or whether there is something like a ‘tipping point’ which might also influence treatment outcome in clinical trials. Regions of interest An actively debated methodological topic in the field of tau PET is the use of regions of interest (ROIs). For [18F]flortaucipir the hippocampus is of special interest in this regard. The hippocampus is one of the earliest regions to be affected by tau pathology and thus of importance in research settings. Off-target binding of the tracer 9
RkJQdWJsaXNoZXIy MjY0ODMw