Network Failure, Atrophy, and Tau Pathology in Aphasic Alzheimer Disease


Brain network organization, the emergence of cognition, and the accumulation of neurodegenerative pathology are interwoven concepts frequently studied under the umbrella of behavioral neurology, neuropsychiatry, neuropsychology, and neuropathology. One approach to studying the organization of cognitive processes is to study those with selective deficits in such networks. To understand how a system fails and deficits arise, it is critical to understand it’s structural and physiologic underpinnings. Last but not least, to study the origin and spread of disease, understanding the routes of functional and structural communication between the brain is essential. The two studies presented in this dissertation are based on such a model. Using neuroimaging in human participants, we studied differences in functional networks, atrophy, cognition, and accumulated AD pathologic burden. Study 1 examined differences between phenotypes of Alzheimer disease (AD) using network measure from resting state fMRI. Our models for studying differences in brain network integrity were, (1) participants with amnestic dementia, with primary deficits in episodic memory, and (2) participants with primary progressive aphasia (PPA), characterized by the loss of language. Both patient groups showed biomarkers consistent with or had autopsy proven AD neuropathology. We tested the hypothesis that although both groups had the same cellular neuropathology, characterized by an abnormal aggregation of amyloid-β and hyperphosphorylated tau, they would show differential network disruption, which is more closely aligned with their clinical phenotype. Namely, the amnestic dementia group would have deficits in an large-scale network for episodic memory, while the PPA group would have deficits in a left-lateralized language network. Furthermore, we hypothesized that both dementia syndromes would have lower network connectivity of a different large-scale network, the default mode network (DMN), which has previously been shown to be vulnerable across a wide range of disconnection syndromes and may not be specific for a single clinical disorder. Consistent with our hypotheses, we found (1) the PPA group had less functional connectivity of the language network compared to amnestic dementia group, (2) amnestic dementia participants had less connectivity of the episodic memory network, and (3) both syndromes showed reduce connectivity within the DMN. Study 2 focused exclusively on PPA with suspected underlying AD to study the relationship between cognition, structural atrophy, and AD tau pathologic burden measured by positron emission tomography. We tested our hypotheses with a measure of object-naming, which we hypothesized would show a more focal relationship with atrophy and more widespread relationship among connected networks for tau pathology. But in examining or predicting the future decline in naming, that tau pathology would be the leading indicator. Furthermore, we hypothesized that tau and atrophy would have a strong association throughout the brain. Consistent with prior observations from our lab and others, naming was associated with the left-lateralized language network tau and atrophy. The significant relationship between tau and naming showed a more widespread pattern than the association between naming and atrophy. Consistent with network models of naming, left anterior temporal lobe tau burden was the only predictor of future decline. We found a strong overlap with tau and atrophy, which was enhanced once we accounted for age. Overall, these studies used cutting edge methodology and materials in a unique patient population to test hypotheses related to large-scale networks, cognition, and accumulating AD pathology. Results from the studies have implications for the selective vulnerability of networks, the spatial distribution of clinicopathologic correlations, and relationships between tau pathology and neurodegeneration, further clarifying the neurobiology of neurodegenerative syndromes.

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