12 Chapter 1 on PET are associated with a greater risk of cognitive decline in cognitively normal individuals (12-18). Although imaging and CSF A biomarkers are not identical, they are shown to have a moderate to high agreement and relatively high correlation coefficients, implying they indeed measure the same pathological process (19, 20). However, there are difference and they could become abnormal at different time points, influencing their predictive value in different cognitive stages. Longitudinal studies with repeated biomarker measurements are needed to better understand which factors are associated with future amyloid accumulation, which would lead to a better understanding of the pathophysiology of AD. Furthermore, inherent to the ATN classification is the dichotomization of biomarkers. Often, a threshold is used to determine amyloid positivity, and additionally, PET scans can be ‘positive’ or ‘negative’ as determined by visual assessment. Although it can be useful in clinical and research settings, dichotomizing amyloid burden into a negative and positive status disregards the potential significance of early (subthreshold) amyloid pathology (21). The clinical relevance of a so-called ‘grey zone’ of amyloid burden still needs to be more thoroughly investigated. CSF p-tau is used most often as measure of T. Patients with AD dementia can be distinguished from controls by a profile with decreased concentrations of amyloidbeta and increased concentrations of p-tau (22-24). Since the emergence of tau tracers such as [18F]flortaucipir, it became possible to visualize and quantify tau load on PET, and tau PET research has expanded greatly during the past decade. Similar to A biomarkers, CSF and imaging T biomarkers are also shown to correlate fairly well (25). Neurodegeneration can have many different causes and is not specific for AD. Therefore, neurodegenerative markers are not necessary for the diagnosis, but rather have been suggested to provide pathologic staging information and predictive value. According to the framework, atrophy on MRI, hypometabolism on FDG PET or CSF t-tau can all be used to measure N. Regarding atrophy, especially atrophy of the medial temporal lobe and reduced cortical thickness in specific regions are hallmarks of (AD) dementia (26, 27). In addition to the biomarkers proposed in the framework, blood-based biomarkers are now available and have been suggested as non-invasive alternative markers for N (10, 28, 29). In contrast to biomarkers for A and T, N biomarkers are poorly correlated (20, 30-33). It still needs to be elucidated which N biomarker captures ‘neurodegeneration’ most accurately, but this proves to be difficult due to the lack of gold standard.
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