72 Chapter 3 and found evidence for a diminished practice effect in grey zone amyloid burden. Last, although BPND and SUVr are widely used continuous measures, it is difficult to compare tracers and sites due to the large variability in methodology previously mentioned. The aim of the Centiloid Project is to provide a method with which this is possible. In this method, all outcome measures are standardized by scaling them to a 0 to 100 scale (53, 54). For future research, it would be of interest to explore how our results translate to the centiloid scale (55). Our demonstration of the potential significance of grey zone amyloid burden may have several clinical consequences. Especially for individuals with amyloid burden within the grey zone, a single threshold might not be very good at distinguishing individuals with a high and a low risk of cognitive decline (4, 40). When a binary division is warranted, our results imply that only lower thresholds that include the grey zone capture all individuals at risk of memory decline, which corresponds to a previous study that showed existing thresholds for Pittsburgh compound B (PIB) seem too high (24). When a high threshold is used (e.g. 0.29 BPND) that classifies 16% as amyloid positive, 9% of individuals that are actually also at risk are labelled amyloid negative. This means a total of 25% of individuals is at risk of future deterioration. When considering that the 4th subgroup of the 5-way division also already demonstrates a diminished practice effect, even up to 40% might be at risk (4th and 5th subgroup together). This could have consequences for clinical trials that only include amyloid positive individuals. Excluding grey zone individuals would lower recruitment rates and means loss of valuable information. In addition, these subjects could benefit the most from disease modifying drugs as they are very early in the disease course. In summary, we showed that various thresholds correspond well to visual assessment in our sample, particularly for BPND thresholds. We furthermore show that not only a high amyloid burden, but also grey zone amyloid burden has an effect on longitudinal memory function. We therefore suggest, when the same methodology is used, to use a low BPND threshold of 0.19 when a binary classification is needed, to also include the grey zone.
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