135 Cerebral blood flow, amyloid burden and cognition Image analysis Data were reconstructed while using standard LOR RAMLA reconstruction algorithm with corrections for scatter, random coincidences, attenuation, decay and dead time. Images were reconstructed with a matrix size of 128 × 128 × 90 and a voxel size of 2 × 2 × 2 mm3. Isotropic 3-dimensional T1-weighted MR images were co-registered to PET images using Vinci software (Max Planck Institute, Cologne, Germany). Next, regions of interest (ROIs) were defined on the co-registered MRI using the probabilistic Hammers brain atlas in PVElab (30). Receptor parametric mapping (RPM) was used to generate parametric BPND and R1 images with cerebellar grey matter as a reference region using PPET (24, 31-33). We calculated (volume weighted) mean cortical BPND and R1 in the following (bilateral) ROIs: frontal, temporal, parietal, occipital, and a composite ROI consisting of orbitofrontal, temporal, parietal, anterior cingulate, posterior cingulate and precuneus regions (34). The difference in time between MRI and PET was generally within one year (median time difference 0.2 years (IQR -0.5 – 0.5)). White matter hyperintensities were visually assessed using the Fazekas scale (range 0-3) (35). Microbleeds were assessed on T2-weighted images and defined as small dot-like hypointense lesions. They were counted and dichotomized into absent (0) or present (≥ 1 microbleed). Scans were reviewed by a neuroradiologist. Neuropsychological assessment All participants underwent extensive standardized neuropsychological assessments (29). For memory, we used the Visual Association Test version A (VAT-A) and the total immediate and delayed recall condition of the Dutch version of the Rey auditory verbal learning task (RAVLT). To assess language, we used category fluency (animals). For attention, we used the Trail Making Test A (TMT-A) and Stroop task I and II (naming and color naming). For executive functioning, we used the TMT-B and Stroop task III (color-word). For global cognition, we used the Mini Mental State Examination (MMSE). Raw test scores for TMT and Stroop were log transformed, because data were right-skewed. Values were subsequently inverted, so that a lower score implies worse test performance for all tests. We used available test results of visits before as well as after the PET scan, in order to accurately estimate the cognitive slope (36). This resulted in longitudinal cognitive data covering 3.8±3.1 years. Concurrent time points were defined as the visit closest to the date of the baseline PET scan (median -0.19, IQR -0.41-0.00). In total, 774 neuropsychological investigations of 187 patients were available (165 ≥2 visits, median 3). 6
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