83 Tau PET and cognition cortical gray matter regions-of-interest (ROIs) on the co-registered MR images, the Hammers template [20] incorporated in PVElab software was used (which uses the default settings of SPM to define gray matter). To generate voxel-wise parametric images of non-displaceable binding potential (BPND) and R1, receptor parametric mapping (RPM) [21] with cerebellar gray matter as reference region was applied to the dynamic 130 min PET data [22]. Our group previously demonstrated that, when compared to full kinetic modelling, RPM is the most optimal simplified parametric method for [18F]flortaucipir [23] with excellent test-retest repeatability [24]. PET images were partial volume-corrected using Van Cittert iterative deconvolution methods (IDM), combined with highly constrained back-projection (HYPR) [25]. A moving frame composite image was used for HYPR to better sustain the temporal information while denoising [26]. Uncorrected data are presented throughout the paper and partial volume-corrected data are presented in the Supplementary material. For voxel-wise analyses, using Statistical Parametric Mapping (SPM) version 12 software (Wellcome Trust Center for Neuroimaging, University College London, UK), we warped all native space parametric BPND and R1 images to Montreal Neurological Institute (MNI152) space, by using the transformation matrixes derived from warping the co-registered T1-weighted MRI scans to MNI space. Warped images underwent quality control for transformation errors. For regional analyses, the following bilateral ROIs were created a priori based on the Hammers atlas [20] (in subject space): medial temporal (hippocampus, parahippocampal and ambient gyri, anterior temporal lobe medial part), lateral temporal (superior temporal gyrus, middle and inferior temporal gyri), parietal (inferolateral remainder of parietal lobe, superior parietal gyrus, gyrus cinguli posterior part), occipital (cuneus, lingual gyrus, lateral remainder of occipital lobe) and frontal (middle frontal gyrus, orbitofrontal gyri, superior frontal gyrus) regions. As a measure of vascular pathology, white matter hyperintensities (WMHs) were visually rated by an experienced rater on subjects’ FLAIR image using the Fazekas scale, with scores ranging from 0 to 3 [27]. Cognition Cognitive domain scores were created by averaging Z-transformed test-scores (based on the current sample) of corresponding tests for memory (Immediate Recall of the Dutch version of the RAVLT, Delayed Recall of the Dutch version of the RAVLT and Visual Association Test-A), executive functioning (Stroop Colour Word test III, Phonemic Verbal Fluency (D-A-T), Digit Span Backwards and Trail Making Test (TMT)- B), language (Category Fluency Animals and Visual Association Test-Naming) and attention (TMT-A, Stroop Colour Word test I and II and the Digit Span Forward) [28]. 4
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