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 addition to Aβ and p-tau. Therefore, we recommend HV, NfL, or GFAP as biomarkers for N. In chapter 4 we demonstrated that higher tau-PET retention is related to greater GM network disruptions in individuals across the AD continuum. More advanced tau-related GM network abnormalities were observed with increasing disease severity. These findings suggest that tau pathology is associated with a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions indicative of a more random network topology across different AD stages. In chapter 5 we observed that T1-w/T2-w ratio values were higher in AD compared to controls, which was contrary to our expectation. These changes tended to be most pronounced in anatomical areas known to be affected in AD such as the interior parietal lobule and precuneus, and were associated with higher levels of the neuronal injury marker tau and worse cognition. Indicating that factors other than demyelination likely influence the T1w/T2w signal in AD. In chapter 6 we demonstrated that GM network measures can aid in identifying individuals with prodromal Alzheimer’s disease who are likely to progress to dementia within the next 2 years. Models combining small-world coefficient, p-tau and hippocampal volume showed the best ability to detect progression. These findings could increase power in Alzheimer’s disease trials by selecting those individuals with abnormal GM network characteristics at high risk for clinical progression within a time frame of 24 months. This thesis investigated the interplay among A deposition, tau aggregation, brain network alterations, and atrophy mechanisms underlying clinical progression. By studying early biomarker changes and their relationship to clinical progression, we are able to gain a better understanding of how these biological processes contribute to AD progression which will be essential to developing early and targeted effective treatments as well as more accurate individual-specific prognoses.