220 Chapter 8 DISCUSSION In our sample of cognitively normal individuals with SCD, we found that biomarker abnormality increased over a 2.5-year period. There was considerable variability in the order of biomarkers becoming abnormal in the ATN classification, suggesting no fixed order. Change from A− to A+ was associated with steeper decline in tests of attention and executive function. We showed that the number of individuals with an abnormal biomarker status increased for both A, T, and N, over a time course of 2.5 years. Most of these individuals changed from a negative to positive biomarker status, yet of note, a smaller number of individuals changed from positive to negative. There are not many longitudinal studies investigating changes in the ATN classification; hence, the phenomenon of change from a positive to a negative status has not yet received much attention. One study investigating amyloid burden excluded individuals who were amyloid positive at one time point, and negative at the next, but did not specify the number of individuals [9]. Another excluded the 5% of individuals with borderline amyloid PET burden, reducing the risk of individuals crossing the threshold due to small changes [5]. Other studies investigating amyloid accumulation rate as continuous measure showed a negative slope in some individuals but did not address the possibility of reverting amyloid status and explained the negative slope by random variation, noise, or actual clearance of amyloid [7, 8]. One potential explanation for the five individuals changing from a positive to negative amyloid status by visual rating (positive-negative) could be that these scans were false-positive at baseline. While the quantitative measures might not have changed much over time, scan could be visually assessed differently at the two time points due to an imperfect intra-rater agreement [24–26]. This is part of clinical practice, especially in early disease stages. Therefore, acquiring follow-up scans is highly useful in individuals with equivocal scans with grey zone amyloid burden. Of note, one could also argue that also the negative-positive scans could be the result of rater variability and that their changing from negative to positive does not necessarily reflect clinical relevance. However, a substantial portion of these individuals had grey zone amyloid burden at baseline, which is already associated with a changed slope in memory function, as shown by our group previously [6]. We found that this group has a steeper decline in performance on Stroop I and III, which are indicative of attention and executive functioning. This is in line with other studies showing that amyloid burden in the subthreshold range is associated with cognitive decline and highlights the clinical relevance of grey zone amyloid burden [7, 8]. In general, an amyloid status based on visual assessment is not identical to an amyloid status based on a threshold for quantitative measures. Quantitative measures are not directly affected by rater
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