70 Chapter 3 DISCUSSION In this sample of cognitively normal individuals with SCD, we observed that grey zone amyloid burden contains relevant clinical information. Furthermore, we obtained thresholds for amyloid positivity based on both SUVr and BPND, which corresponded well with visual assessment of amyloid deposition. We investigated the association between grey zone amyloid burden and memory function. We found that cognitively healthy individuals with low amyloid levels showed improved memory performance over time, which could be due to a practice effect. By contrast, individuals with substantial amyloid burden showed memory decline over time. Individuals with grey zone amyloid burden had slopes in between, showing neither decline, nor improvement in memory. This implies that these individuals did not benefit from a practice effect, like amyloid negative individuals do. The absence of a practice effect is not an innocent finding, as it has previously been demonstrated as a predictor of future deterioration (34-37). Although for all subgroups, the estimated annual change was relatively small, the fact that differences could already be measured in this very early stage provides evidence for the concept of a grey zone. Furthermore, some individuals might already experience a subclinical decline in test scores, while the test scores themselves are still within normal limits. This illustrates the relevance of longitudinal research to capture within-subject changes over time. Comparison to other studies is complicated because there is not one universal grey zone definition. Studies that focused on peri- or subthreshold amyloid levels have had different approaches, for example studying amyloid negative subthreshold individuals (25, 26, 38), or CSF/PET discordant cases (39). In a recent article, the grey zone is proposed as a region of uncertainty around the threshold for which more data is needed to actually estimate the risk of cognitive decline or clinical progression (40). These previous studies found that individuals in the subthreshold range can be on the path to further neurodegeneration (i.e. atrophy, tau pathology, hypometabolism) (38, 41), and are at risk of further amyloid accumulation, cognitive decline and clinical progression (25, 26, 39). In the present study, we defined the grey zone making use of two thresholds obtained in a data-driven way. In a second approach, we subdivided the data using divisions based on quantiles. Irrespective of the approach, our findings showed that the negative relationship between amyloid and memory performance is not merely driven by the small number of individuals with high amyloid burden, but rather that the variability in amyloid burden, even within normal limits, has potential clinical value.
RkJQdWJsaXNoZXIy MjY0ODMw