14 Chapter 1 both tau pathology and cerebral blood flow, while being more easily applicable in AD populations and longitudinal settings. However, whether it is feasible to shorten the dynamic tau PET scanning protocol while maintaining quantitative accuracy is yet to be determined. Furthermore, measuring R1 in longitudinal studies is especially important because blood flow changes can occur over time in AD because of disease progression or drug intervention. However, for [18F]flortaucipir the sensitivity of static measures for changes in blood flow has not been investigated and it thus remains unclear whether longitudinal [18F]flortaucipir PET studies require dynamic tracer acquisition in the context of blood flow induced bias. Biological and clinical correlates of Tau PET In contrast to amyloid-β deposition, histopathological studies have shown tau pathology correlates well with cognitive impairment and its topography is specific to the different AD clinical phenotypes (e.g. tau pathology predominantly in the occipital visual association cortex in the visual variant of AD or frontal tau pathology in the behavioral variant of AD) [23]. Some first PET studies demonstrated that high levels of regional tau PET levels [10–12], as well as low levels of rCBF (as measured with [18F]FDG PET or MRI), correlate with cognitive impairment in various domains. However, more studies in different cohorts are required to improve understanding about the relationship between tau PET and cognition in AD. Furthermore, rCBF has not been investigated yet using [18F]flortaucipir R 1 prior to this thesis. Investigating tau pathology and rCBF simultaneously by using dynamic [18F]flortaucipir PET might yield valuable information, since both pathophysiological mechanisms may contribute to cognitive impairment in AD and little is known about their interrelationships. Since clinical (cognitive) phenotypes depend on age-at-onset, clinical phenotypes may also be associated with differences in the regional distribution of tau pathology. Age-at-onset is thus closely related to both cognitive symptoms and distinct patterns of tau pathology in AD. This might imply that there could be differences in the association between tau pathology and cognitive performance depending on age-at-onset. Understanding these potential differences between EOAD and LOAD might have important implications for clinical trials, among others, since effects of potential tau- or blood flow targeting therapeutic interventions might exert different effects on cognition in EOAD compared to LOAD patients. Whether the association between tau pathology and cognitive performance is affected by age-at-onset is yet to be elucidated. Similarly, it is unknown whether age-at-onset affects the association between rCBF and cognitive performance. Another important question in the context of clinical use, but also for clinical trials, would be whether tau PET could serve as a predictive tool for future rates of cognitive decline. This would not only be useful in research context, directing
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