182 Chapter 8 SUMMARY In chapter 2, we investigated the relationship between the ATN classification system, risk of dementia and cognitive decline in individuals with SCD. Six hundred ninety-three individuals were classified into ATN profiles, as determined by amyloid PET or CSF amyloid-β (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (MTA; N). We found that Alzheimer’s continuum profiles (A+T-N-, A+T-N+, A+T+N-, A+T+N+) together make up one fifth, and non-AD pathologic change profiles (A-T-N+, A-T+N-, A-T+N+) one third of cases. Most frequent was the profile with all biomarkers normal, observed in more than half of participants. Compared to A-T-N-, individuals in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Individuals in A+ profiles also showed a steeper decline on tests addressing memory, attention, language, and executive functions. These findings implicate that in individuals with SCD, the ATN classification can help to identify which individuals are at risk of dementia and which individuals are highly unlikely to show progression over time. In chapter 3, we determined thresholds for amyloid pathology and investigated the clinical relevance of grey zone amyloid burden, using dynamic [18F]florbetapir PET. Scans were visually assessed as amyloid positive/negative. Additionally, we calculated the mean binding potential (BPND) and standardized uptake value ratio (SUVr50-70) for an a priori defined composite region of interest. We determined six amyloid positivity thresholds using various data-driven methods (resulting thresholds: BPND 0.19/0.23/0.29; SUVr 1.28/1.34/1.43). Concordance with visual assessment was slightly higher for BPND thresholds than for SUVr thresholds, but overall, definitions for amyloid positivity were comparable. Analyses in subgroups showed that memory slopes gradually became steeper with higher amyloid load. Participants with a low amyloid burden benefited from a practice effect (i.e. increase in memory), whilst high amyloid burden was associated with memory decline. Memory slopes of individuals in the grey zone were intermediate. These results show that not only high, but also grey zone amyloid burden is already associated with suboptimal memory function. Multiple biomarkers have been suggested to measure neurodegeneration (N) in the ATN framework. In chapter 4, we compared five N biomarkers (CSF total (t)-tau, MTA visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL) and serum glial fibrillary acidic protein (GFAP)) and investigated their association with clinical progression and cognitive decline in individuals with SCD. N biomarkers were only modestly to moderately correlated. T-tau was strongly correlated with p-tau, although these biomarkers supposedly represent separate biomarker groups, which makes it less desirable to use as measure for N. All N biomarkers individually predicted
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