234 Chapter 9 ASL MRI or water PET) correlate. Suggestions for future research would therefore include a within-person study focusing on the direct comparison of these measures. Cognition Interest in imaging tau pathology in vivo has largely been driven by histopathological studies showing that tau pathology, as opposed to amyloid pathology, is strongly associated with cognition in AD [20]. In this thesis we aimed to use tau PET as an in vivo imaging technique to explore the relationships of tau pathology and rCBF with (longitudinal) cognition in AD. In chapter 4 we found that tau pathology and low rCBF were both independently associated with worse cognitive performance. For tau pathology, these associations spanned widespread neocortex, while for rCBF, independent associations were restricted to lateral temporal and parietal regions and the executive functioning and attention domains. In chapter 5 we assessed whether these relationships were different for EAOD and LOAD. We found that, compared to LOAD, the degree of lateral temporal and occipitoparietal tau pathology and relative cerebral blood-flow was more strongly associated with cognition in EOAD. In this context, an important related question we answered in chapter 6 is what the predictive value of tau PET is for longitudinal cognitive trajectories. We found that both baseline and change in tau load were predictive for multi-domain longitudinal cognitive trajectories, when corrected for rCBF. Furthermore, a study into the predictive value of tau PET relative to that of amyloid PET or structural MRI demonstrated that tau PET was most strongly related to and best predicted cognition [21]. Taken together, these findings underline that tau PET is a valuable tool in predicting cognition and indicates that tau pathology and longitudinal changes in CBF are (partly) independent factors predicting cognitive decline, partially masking each other’s effect on cognition. Furthermore, our findings may have important implications for clinical trials. It is currently well recognized that age-at-onset affects the manifestation of the disease, but in this thesis we demonstrated that the association between pathology and cognition is also different between early- and late-onset AD. This might imply that effects of potential tau- or blood flow targeting therapeutic interventions might exert larger effects in early-onset AD compared to late-onset AD patients. Additionally, differences between early- and late-onset AD patients should be considered in any therapeutic intervention trial where either cognition is used as an outcome measure or where indirect effects on tau pathology or rCBF are expected, to ensure correct interpretation of results and aid in the formation of appropriate patient selection criteria.
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