233 Summary & Discussion not to decreases in relative CBF. Moreover, tau PET load at baseline was a better predictor of cortical thinning than change of tau PET signal. These results are in line with disease models proposing that tau load is a key driver of local cortical thinning and stress the need for future longitudinal studies into the role of rCBF in the pathophysiological process of AD. In the context of clinical trials, results described in chapter 7 also indicate that a single tau PET scan at baseline best predicts cortical thinning over time when compared to longitudinal tau PET imaging, which highlights the potential of a single tau PET to improve the prognosis and selection of the right target population for clinical trials. How measures of rCBF could aid in this process is not yet clear. Neuronal injury: cerebral blood flow The exact role and temporal dynamics of rCBF in AD are not fully understood yet. In our study rCBF did not change over time during the two-year follow-up period. Although we assumed that CBF alterations occur in between tau accumulation and atrophy in the pathophysiological development of AD, thus expecting changes in rCBF to occur, a recent study showed CBF alterations to be a late pathological event following both tau pathology and atrophy[10]. It could thus be that changes in cerebral blood flow did not occur yet, as they occur later on in the pathophysiological cascade. Another study assessing the relationship between longitudinal perfusion measures and tau pathology (as measured with PET) found a lack of overlap between declining perfusion and increases in tau pathology, also suggesting a lag phase between these two processes [49]. This may also be the case in our data, given that tau pathology did change over time, while CBF did not (yet). Another possibility is that changes in rCBF occur in opposed neurobiological directions (i.e., increases vs decreases) on the individuals level, representing degenerative or compensatory responses to pathology. As the response direction may differ between individuals (in- or decreases in CBF; as was observed in our data and that of others [18, 19]) they may potentially cancel each other out on group level, leading to absence of average effects or change. Understanding when and in what direction rCBF changes might allow for selection of individuals for potential (treatment) interventions in clinical trials. Whether dynamic [18F]flortaucipir PET imaging is the most optimal way to measure rCBF could be argued, as rCBF derived from tau PET also only represents a proxy. Parameters for CBF derived from for example arterial spin labelling (ASL) MRI or [15O]-water PET represent more direct measures of CBF, but in tau PET studies require additional scanning procedures compared to when the rCBF measure derived from the tau PET scan is used. Also, it is currently unknown to what extend rCBF derived from tau PET and more direct CBF measured (derived from 9
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