| Summary: | Cumulated scientific evidence suggests that the pathology causing Alzheimer's disease (AD) occurs many years or even decades before memory impairment and other clinical symptoms arise. Tangible and detailed knowledge about different pathological processes, their interactions, and time course is therefore of the essence both for the development of potentially successful treatments and a reliable early diagnosis of this relentless disorder. The past decade has thus seen an explosion in research on biomarkers that could provide in vivo evidence for these pathological processes, involving β-amyloid (Aβ) production and aggregation into plaques, neurofibrillary tangle formation, neuroinflammation, and eventually neurodegeneration. The rare form of dominantly-inherited early-onset familial AD (eoFAD), with almost complete mutation penetrance and defined age of disease onset, has been proposed as a model to study the very early disease mechanisms that are also supposed to underlie the common sporadic form (sAD). However, more than 200 mutations in three different genes (PSEN1 and 2, APP) have been identified as causing eoFAD, some of which have been shown to differ substantially from others. This work employed multi-tracer positron emission tomography (PET), using the tracers 2-[18F]‐fluoro-2‐deoxy‐D‐glucose (FDG), N-methyl-[11C] 2-(4'- methylaminophenyl)-6-hydroxy-benzothiazole (PIB), and [11C]-L-deuterium-deprenyl (DED) to explore the characteristics, time course and interrelationship of cerebral glucose metabolism, fibrillar Aβ burden, and astrocyte activation (astrocytosis) at different presymptomatic and symptomatic disease stages of eoFAD and sAD, in relationship to cognition, other AD biomarkers, and/or post-mortem pathology. Thalamic hypometabolism in PSEN1 eoFAD mutation carriers was demonstrated in this thesis nearly 20 years before they were expected to develop clinical symptoms. The pattern of hypometabolism studied in several mutation carriers spread subsequently to regions that are also typically affected ...
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