181 Longitudinal tau PET and atrophy INTRODUCTION Histopathological and in vitro studies have shown that tau pathology is closely associated with neuronal injury (synaptic alterations and neuronal loss) in Alzheimer’s disease (AD) [1-6]. The positron emission tomography (PET) tracer [18F]flortaucipir binds to paired helical filaments of tau and has enabled examination of the relationship between tau pathology and neuronal injury or neurodegeneration in vivo in AD [7-10]. 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 ([1, 10, 11]). 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 [2, 5, 11-13]. To better understand how tau PET and neurodegeneration are related, 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. Another aspect of neuronal injury in AD is the progressive reduction of cerebral blood flow (CBF). Dynamic scanning protocols can be utilized to obtain a measure of R1 [14, 15]. R1 is a proxy for relative cerebral blood flow (rCBF) and is closely associated with metabolic activity ([18F]FDG PET) and 15O-H 2O PET (i.e., the ‘gold standard’ for measuring flow) [16-18]. Previous studies using other imaging techniques such as Arterial Spin Labelling (ASL) to measure CBF have demonstrated decreased CBF (or cerebral perfusion) in (probable) AD patients [19, 20]. When it comes to the relationship between tau pathology and CBF (cross-sectional), it has been shown that higher levels of tau pathology are associated with locally decreased rCBF in AD [14, 21]. Taken together, these 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 established whether (rate of) change in tau pathology also relates to (rate of) change in CBF. With respect to the order of pathophysiological processes in AD, general consensus has been reached for accumulation of tau pathology (relatively early event) and atrophy (relatively late event) [4, 22]. There is less agreement regarding rCBF changes, as some studies suggest CBF to be an early biomarker of disease [19], while others suggest changes in CBF to potentially be both cause and consequence of protein accumulation [23]. Many studies suggested that neuronal injury imaging markers change relatively late in the disease process, after the first observation of protein accumulation (such as amyloid or tau pathology) on PET or in CSF [4, 21, 22, 24]. The aim of this longitudinal study was to investigate the associations between changes in tau PET with imaging biomarkers of neuronal injury (i.e., atrophy and CBF) in a cohort comprising i) amyloid negative (Aβ-) cognitively normal (CN) individ7
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