210 Chapter 8 was on cognitively unimpaired individuals, we a priori decided to select this region of interest to capture the earliest changes in neocortical areas [21]. We then fit Gaussian Mixture Models with two components using the normalmixEM function in R. A threshold was derived representing the mean of the calculated mu of both components, resulting in a threshold 0.08 BPND. This threshold separated the two clusters with minimal overlap. We used the average medial temporal atrophy rating (MTA) on MRI as biomarker for N as determined by experienced neuroradiologists. Raters were blinded to amyloid status. For individuals < 65 years of age, an average MTA score of ≥ 1 was considered positive; for individuals ≥ 65 years of age, an average MTA score ≥ 1.5 was considered positive [22]. Additionally, white matter hyperintensities were visually assessed using the Fazekas scale (range 0–3) [23]. 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). Neuropsychological tests All participants underwent annual standardized neuropsychological assessments [13]. For the memory domain, 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). For the language domain, we used category fluency (animals). For the attention domain, we used the Trail Making Test A (TMTA) and Stroop task I and II (naming and color naming). For the domain of executive functioning, we used the TMT-B and Stroop task III (color-word). For global cognition, we used the Mini Mental State Examination (MMSE). Because the data were rightskewed, the raw test scores for TMT and Stroop were log transformed. Subsequently, values 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 PET scans, in order to accurately estimate the cognitive slope. The neuropsychological tests administered most closely to baseline [18F]florbetapir were defined as baseline test results. In total, we used longitudinal cognitive data covering 4.9 ± 2.8 years. The proportion of missing tests ranged from 2.7% for MMSE to 8.5% for Stroop II and III. In total, 447 neuropsychological investigations of 92 patients were available (92 ≥ 2 visits, median 4). Statistics All analyses are conducted in R version 4.0.3. We first compared demographic and clinical variables between baseline A− and A+ individuals using t-test, chi-square, or Mann-Whitney U test where appropriate. Next, we described changes in biomarker status over time. We first investigated changes in A, T, and N biomarkers separately
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