11 Introduction Figure 1. Clinical stages of AD (Histo)pathology of Alzheimer’s disease and the role of PET In general, AD pathological changes start with extracellular deposition of fibrillar amyloid-β (plaques), followed by intracellular accumulation of hyperphosphorylated tau (in neurofibrillary tangles; tau pathology), synaptic and neuronal dysfunction (among which altered cerebral blood flow (CBF)), neurodegeneration, cognitive dysfunction and, finally, dementia [7, 8]. The first pathological changes in AD develop already an estimated 15-20 year prior to symptoms onset. Formation of amyloid-β containing plaques is considered (one of the) earliest pathological events in AD, most often firstly present in the (orbito)frontal cortex and precuneus [Figure 2]. Already in early disease stages amyloid pathology spreads throughout the rest of the brain, with very limited regional specificity and little between-person variability. Other than amyloid pathology, accumulation of hyperphosporylated tau proteins does show large variability in distribution. Notwithstanding, the development generally seems to occur according to a specific topographical pattern [9, 10]. This pattern is referred to by ‘Braak stages’, describing accumulation starting in transentorhinal regions (Braak stage I), followed by hippocampal (Braak stage II) and limbic regions (Braak stage III/IV), and eventually neocortical association cortices (Braak stage V/VI) [Figure 2] [10]. Whereas tau pathology in the medial temporal lobe can be observed in cognitively unimpaired individuals, cognitively impaired individuals (almost) always show tau pathology in the neocortex [10]. 1
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