97 Tau PET and cognition functioning) [13]. Nonetheless, it was also demonstrated that most associations with cognition were found for low CBF in parietal and occipital regions, while least associations were found for temporal and frontal CBF [13]. This is in line with our results, although we also found multiple associations between cognition and low CBF in lateral temporal regions. This might be explained by the fact that the former study used a ROI covering the entire temporal cortex and did not differentiate between medial and lateral temporal regions. Both studies used subjects from the Amsterdam Dementia Cohort and used a similar approach to assess cognition, but another striking similarity between the former and present study is the range of regression coefficients for significant associations between CBF and cognition. Standardized regression coefficients ranged from 0.22 till 0.42 across the cognitive domains in the former study [13], and ranged from 0.27 till 0.48 in the present study, indicating comparable effect sizes. Regional association between tau pathology and low rCBF Relative CBF is tightly correlated with measures of metabolic activity such as [18F]FDG PET [4, 5, 9]. Earlier studies investigating [18F]flortaucipir and [18F]FDG PET in AD found considerable overlap between higher levels of tau tracer uptake and lower levels of metabolic activity [11, 33], with moderate correlation coefficients across 30 predefined brain regions. The present study used R1 as proxy for rCBF, and in line with the previously described study [33], we also found spatial overlap between high levels of tau pathology and low rCBF, with comparable standardized regression coefficients. The overlap of high levels of tau pathology and low levels of rCBF was in both studies not completely uniform across all brain regions, suggesting that both measures represent complementary aspects of AD pathology [33]. A potential explanation might be that tau pathology may develop prior to or even (partially) drive impaired metabolic activity or CBF, creating a time-lag between both pathological mechanism leading to topographical differences [34]. Alternatively, other pathological processes besides tau pathology may contribute to impaired metabolic activity or CBF, such as other proteinopathies. Vascular pathology has been linked to AD [35] and might have an impact on for example rCBF. However, in our study, the influence of vascular pathology showed to be negligible, since no correlation between Fazekas score and tau pathology or rCBF was found, and addition of Fazekas score to the regression model assessing the association between tau pathology and rCBF did not notably change results. Strengths and limitations This study has several strengths, including the use of [18F]flortaucipir R 1 as a measure of rCBF, since this tracer has not been used in this context before, while 4
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