Florey Department of Neuroscience and Mental Health - Theses
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ItemProbing white matter pathology in Alzheimer's disease using advanced diffusion MRI( 2019)Alzheimer’s disease is increasingly conceptualised as a disease of network dysfunction, which is likely underpinned by substantial white matter degeneration. Indeed, white matter is known to exhibit disruption in Alzheimer’s disease, both at microstructural and macroscopic levels, and has been reported in pathological and imaging studies. However, these white matter changes across the Alzheimer’s disease spectrum have been poorly described thus far, largely due to methodological limitations. In this thesis, advanced diffusion MRI methods were applied to investigate white matter changes in Alzheimer’s disease patients, as well as in mild cognitive impairment patients, who represent an at-risk cohort for developing Alzheimer’s disease. There were three major research questions for this thesis, which formed the basis of three major studies: (1) What are the specific white matter pathways that degenerate in mild cognitive impairment and Alzheimer’s disease? (2) To what extent does the degeneration of these fibre structures relate to cognitive decline? (3) What are the in vivo microstructural characteristics of white matter lesions in Alzheimer’s disease? To address the first research question, the first study utilised a novel method known as fixel-based analysis to investigate fibre tract-specific white matter degeneration in a cohort of Alzheimer’s disease, mild cognitive impairment, and healthy elderly control participants from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) study. Using this approach, specific fibre pathways that exhibited degeneration in Alzheimer’s disease subjects compared to control subjects were identified. Of these fibre pathways, only select fibre tracts exhibited degeneration in mild cognitive impairment patients, and this degeneration did not appear to be associated with high amyloid accumulation. The findings supported a structural basis to theories of network-wide disruption in Alzheimer’s disease. In a related second study, the associations between tract-specific degeneration and decline across a number of cognitive domains were then investigated, in a similar cohort of Alzheimer’s disease, mild cognitive impairment, and healthy elderly control participants. Tract-specific degeneration was closely associated to cognitive impairment across all cognitive domains, and interestingly, certain pathways in particular (namely, the posterior cingulum and inferior fronto-occipital fasciculus) appeared to be most closely associated with all domains. This suggested that network-wide dysfunction is mediated by degeneration of specific fibre structures. Finally, the third study in this thesis aimed to investigate white matter lesions, which are commonly reported in elderly individuals, but are increased in Alzheimer’s disease. By applying novel diffusion MRI methods to characterise the diffusion profile of lesions, microstructural heterogeneity could be observed within these macroscopic lesions, which has previously been reported in post-mortem studies but has not been described in vivo. Different lesion classes were shown to exhibit distinct diffusional properties, and the findings of this work highlighted the need to account for microstructural heterogeneity when investigating the relevance of lesions to disease. The overall findings of this thesis offer disease-specific insight that highlights the crucial importance of white matter degeneration in Alzheimer’s disease. Moreover, the findings demonstrate the ability of advanced diffusion MRI to non-invasively investigate white matter changes in vivo, thus providing the potential to further our understanding of this disease in the future.