96 Chapter 4 DISCUSSION The present study used a single dynamic [18F]flortaucipir PET scan to examine the relationship between tau pathology, rCBF and cognition in AD. The main finding is that high levels of tau pathology and low levels of rCBF were independently associated with worse cognitive performance across various domains. Tau pathology and rCBF are independently associated with cognition in AD An important finding in the present study is that tau pathology and rCBF, at least in part, independently contribute to cognitive deficits in AD. A previous study demonstrated that tau pathology was also independently associated with specific cognitive impairment in AD in the context of neurodegeneration [29]. This leads to the notion that tau pathology may impact cognitive performance directly, but also indirectly through a variety of mechanisms [29]. One such mechanisms might be rCBF, since some of the associations found between [18F]flortaucipir BP ND and cognition in the present study disappeared when R1 was included in the model simultaneously. Other factors possibly explaining the tau pathology independent associations between rCBF and cognition in AD might be the presence of other down- or upstream pathological factors like tau-independent atrophy, vascular pathology or other proteinopathies. Vascular damage for example might lead to impaired rCBF, possibly causing an increase in amyloid-β accumulation, which in turn can lead to inflammation and neuronal dysfunction, leading to cognitive deficits [30]. Further research is required, however, to gain knowledge about the mechanisms explaining the tau-independent relationships between rCBF and cognition in AD. Associations between tau pathology, rCBF and cognition Strong (regional) associations between tau pathology and cognitive deficits in AD have been established by multiple (imaging) studies [10–12, 31], and results of the present study are generally in line with previous findings. As expected, tau pathology in the medial temporal regions showed strong associations with memory, while tau pathology in temporoparietal regions was associated with language. High levels of tau pathology in frontal regions were associated with more anteriorly based cognitive functions, like executive function and attention. Although the association between CBF and cognition in AD has not been studied using this [18F]flortaucipir PET approach before, other studies investigated these associations by using [18F]FDG PET or MRI techniques (such as arterial spin labeling (ASL)) to measure (proxies of) CBF [13, 32]. These studies demonstrated that in AD, reduced CBF is generally associated with worse global cognition [13, 32] and not with domain-specific cognitive impairments (memory, executive function, language, attention and visuospatial
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