149 Cerebral blood flow, amyloid burden and cognition First, this study investigated CBF but not amyloid deposition longitudinally. Also, this study acquired images for 60 seconds once the total radioactivity counts in the brain reached threshold levels. This is a semi-quantitative method for analysis of [15O]H 2O PET data, which may have compromised the CBF measurements. Last, we used a much larger sample size, which makes our results more robust. Our study has important implications. We show that amyloid accumulation and reduction in rCBF are separate and parallel disease processes which independently contribute to cognitive decline whilst influencing each other longitudinally, without ordering one process before the other. This provides additional insight in the pathophysiology of AD. Our results suggest that, in the hypothetical biomarker model of amyloid accumulation leading to tau pathology, neuronal injury and cognitive decline, changes in CBF could be placed before or after amyloid accumulation. Since other studies also show tau pathology and rCBF are independently associated with cognition in AD, rCBF probably reflects a different aspect of AD pathology (41). It furthermore illustrates there are multiple pathways through which AD biomarkers can become abnormal. Strengths of our study include that we had a relatively large sample of cognitively normal individuals with considerable follow-up. We show that by using one dynamic [18F]florbetapir PET scan, information about two relevant biomarkers can be obtained, which both provide predictive information about future cognitive decline. Additionally, we had repeated PET scans available for a large group of participants, enabling the investigation of longitudinal trajectories of rCBF and amyloid burden. Limitations of our study include that we did not take all variables into account that potentially affect rCBF, such as diurnal variations, genetic factors and cerebrovascular risk factors. Last, although we already had a relatively long follow-up duration of 3.8 years on average, an even longer period would enable us to capture more clinically relevant changes in cognition, in this sample of cognitively normal individuals. Concluding, we showed that amyloid burden and rCBF were independently associated with cognitive decline over time in a group of initially cognitively normal individuals. Even though there were hardly any cross-sectional relationships between amyloid burden and rCBF, we observed an association between high baseline amyloid burden and a subsequent decrease in rCBF, and inversely an association between a low baseline rCBF and a subsequent increase in amyloid burden. Our results provide evidence that amyloid accumulation and decrease of CBF are separate and parallel disease processes, each of them providing unique predictive information, and enhancing the other longitudinally. 6
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