145 Longitudinal tau PET and cognition Germany). The Hammers and Svarer templates incorporated in PVElab software were used to define cortical gray matter regions of interest (ROIs) on the co-registered MRI scans [34, 35]. Receptor parametric mapping (RPM) was applied to the PET data to obtain parametric images of BPND and R1, with the cerebellum gray matter as a reference region [36]. We obtained BPND values (bilateral volume-weighted average) in three a priori defined regions corresponding to Braak staging regions of tau pathology (Braak I, Braak III/IV and Braak V/VI), as described previously [30, 37]. For R1 we used a composite global cortical gray matter ROI [15]. Data were not partial volume-corrected. Neuropsychological assessment All participants underwent repeated standardized neuropsychological assessments. To assess global cognition we used the mini mental state examination (MMSE) [38]. For memory, we used the total immediate recall condition of the Dutch version of the Rey Auditory Verbal Learning Task (RAVLT), as the delayed recall of the RAVLT suffers from floor effects in CI individuals. For executive functioning, we used the Trail Making Test B (TMT-B). Raw test scores for TMT-B were 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. This resulted in longitudinal cognitive data covering up to 17 years. Concurrent time points were defined as the visit closest and within one year to the date of the baseline PET scan (average -0.06 ± 0.29 years from PET). Testscores were scaled (Z-scored) prior to analyses in order to be able to compare results between cognitive tests. In total, 587 neuropsychological investigations of 129 individuals were available, with a mean follow-up time of 4.4 ± 2.1 years. When restricting to neuropsychological investigations from the baseline PET onward, a total of 345 neuropsychological investigations were available, with a mean follow-up time of 2.6 ± 1.4 years. Statistical analyses First, we assessed the association between baseline tau PET BPND or R1 with (longitudinal) cognitive test scores using linear mixed models (LMMs). Baseline tau PET BPND (per ROI) or R1 was used as determinant and scores on each of the three individual cognitive tests (MMSE, RAVLT immediate recall and TMT-B) as outcome. Models furthermore included variables age-at-PET, sex, education, time, and determinant*time. Both cross-sectional (determinant) and longitudinal (determinant*- time) coefficients were extracted from the model. To assess associations between annual change in tau PET BPND or R1 similar models were used, but now annual change in tau PET BPND or R1 were added as determinant. For this purpose, annual 6
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