15 Introduction participant selection for clinical trials, but may also provide patients with a better perspective on what to expect regarding disease progression and related clinical impairment (which is currently lacking). When it comes to using tau PET as a predictive tool, this technique might also forecast neuronal injury. In line with histopathological and in vitro studies, neuroimaging studies have demonstrated strong correlations between baseline tau PET with cross-sectional atrophy in AD patients. In addition, longitudinal studies with relatively short follow-up time (i.e., 12-15 months) have shown that tau load also predicts future atrophy rates. Another aspect of neuronal injury in AD is the progressive reduction of cerebral blood flow (CBF). Previous studies indicate that baseline tau pathology is related to neuronal injury as reflected by decreased CBF as well as atrophy in AD. However, it is less well known whether (rate of) change in tau pathology also relates to (rate of) change in CBF. To better understand how tau PET and neurodegeneration are related or whether tau PET can serve as a predictive tool for future neuronal injury, it is important to study their dynamic associations over time and investigate how baseline tau load and change in tau load associate with longitudinal cortical thinning and rCBF. Aims and outline of this thesis This thesis had two general aims. First, we aimed to gain better understanding of methodological aspects of tau PET in the context of AD, in order to optimize its protocols and applications in clinical and research settings. The second aim of this thesis was to provide insight into the biological and clinical correlates of tau PET in AD, in order to optimize and direct its use in clinical (and prognostics) and research settings. The outline of this thesis starts with addressing the first aim, examining methodological aspects of tau PET in the context of AD. We first aimed to investigate whether a shorter overall scan duration for [18F]flortaucipir PET dualtime-window scans is feasible, while retaining quantitative accuracy (chapter 2). In chapter 3, we compared semi-quantitative (SUVr) and quantitative (DVR/BPND) parameters for [18F]flortaucipir PET in a longitudinal setting. In the second part of this thesis we examined aspects of clinical applications of tau PET. We investigated the (regional) association between tau pathology and rCBF, and their (independent) associations with cognitive functioning in patients with AD (chapter 4). Following this, we investigate differences between early-onset AD and late-onset AD in (1) tau pathology and rCBF and (2) the associations between tau pathology and rCBF with cognitive performance (chapter 5). In chapter 6, we extended into longitudinal applications and assessed the association between i) baseline tau pathology and rCBF, and ii) change in tau pathology and rCBF with longitudinal cognitive change in individuals along the AD spectrum. Expanding on 1
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