Melbourne School of Psychological Sciences - Theses
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ItemCognitively relevant networks in Alzheimer's disease: the preferential contribution of amyloid-β and hyperphosphorylated tau( 2015)Alzheimer's disease (AD) is characterised by two cardinal pathologies, namely the extracellular accumulation amyloid-related aggregates, and the intracellular formation of tau-related neurofibrillary tangles. Both of these pathologies disrupt normal neuronal function, but develop according to different anatomical trajectories. While cerebral tau-pathology first forms in mesial temporal structures, amyloid-pathology first accumulates in neocortex. The eventual distribution of these pathologies reflects their origins. The mesial temporal structures are the most heavily affected by tau-pathology while amyloid-pathology is most prominently deposited in neocortical regions. This raises the possibility that the cardinal pathologies preferentially disrupt different brain networks, resulting in differential contributions to the cognitive expression of AD. The present inquiry aimed to clarify the relationship between the cardinal pathologies and the disruption of cognitively relevant networks. It was predicted that tau-pathology would preferentially disrupt mesial temporal networks associated with fundamental memory function. In contrast, it was expected that amyloid-pathology would be preferentially associated with neocortical, particularly anterior, networks associated with the executive functions. The first study investigated the preferential association hypothesis in 191 patients with mild cognitive impairment. As expected, CSF biomarkers of tau-pathology were most strongly associated with measures of memory function. The relationship between amyloid-pathology and memory was indirect, that is, mediated by tau-pathology. Amyloid-pathology had a separate, tau-independent, relationship with information processing speed. In the second study, the hypothesis was investigated in 39 patients with dementia of the Alzheimer's type using CSF biomarkers and functional connectivity analyses obtained from resting state functional magnetic resonance imaging. Tau-pathology was preferentially associated with functional connectivity in the mesial temporal regions. Amyloid-pathology was preferentially associated with functional connectivity in the dorsal anterior cingulate cortex, a region intimately connected to anterior neocortical structures. In the third study, the hypothesis was investigated in the same cohort using CSF biomarkers, structural magnetic resonance imaging, and fluorodeoxyglucose positron emission tomography (18F-FDG-PET). Amyloid-related pathology was preferentially related to the posterior cingulate and lateral temporal cortices, while no preferential relationships were found for tau-pathology. Taken together, these findings provide early support for the preferential effects of the cardinal pathologies. The results support the link between tau-pathology, mesial temporal structures, and fundamental memory impairment in AD. Less support was found for the association between amyloid-pathology, neocortical networks, and executive function. While amyloid-pathology was preferentially associated with structurofunctional changes in a number of neocortical regions, the predicted relationship with executive function was not strongly supported. The emerging view is that abnormal tau is a destructive, intracellular pathology with a proximal relationship to cognitive impairment in AD. In contrast, abnormal amyloid is a pan-cerebral, extracellular pathology that subtly disrupts diffusely represented networks. The present findings have implications for disease-modifying therapeutic trials in AD, arguing for the need to match neurocognitive and neuroimaging endpoints with the cardinal pathology being targeted by the treatment. Overall, this thesis opens up a new, and more complex, view of the cardinal pathologies and their relationship to cognitively relevant brain networks.