Imaging neurodegeneration across the Alzheimer's disease continuum:The contribution of biomarkers to understanding clinical progression

Over the past two decades, the development of biomarkers that can detect Alzheimer’s disease (AD) pathology in living individuals has transformed the field of AD research. The key pathological features of AD, namely amyloid-β (Aβ) plaques and tau neurofibrillary tangles, can be measured in vivo using PET, as well as in the cerebrospinal fluid (CSF), and using blood-based assays. Furthermore, structural MRI can provide estimates of regional neurodegeneration. In this thesis we investigated the structural brain changes of four neurodegeneration measures that occur during the progression of AD: hippocampal volume (HV), cortical thickness, grey matter (GM) networks, and cortical myelin. Furthermore, we studied their relationship with AD pathology markers and clinical progression. In chapter 2 we studied oldest-old (90+) individuals with initially intact cognition, and observed that abnormal amyloid was associated with steeper decline in memory and processing speed performance over 1.5 years. Our findings support the notion that both A pathology and brain atrophy have detrimental effects on cognitive functioning among cognitively normal individuals that are separate from normal ageing. These results suggest that A abnormality is indicative of an neurodegenerative process, that also in the oldest-old with apparent high reserve and maintenance mechanisms lead to cognitive decline. In addition, possibly A independent pathological processes might also be involved in cognitive decline in the oldest-old, as a thinner medial and lateral temporal cortex was related to subsequent decline in memory and language irrespective of A pathology. In chapter 3 we studied a sample of cognitively normal individuals with subjective cognitive decline, and observed modest to moderate correlations and low concordance among different neurodegeneration (N) biomarkers: CSF total-tau, medial temporal lobe atrophy (MTA), HV, serum NfL, serum GFAP. N biomarkers HV, NfL, and GFAP each predicted clinical progression, and had predictive value in ...