UCLA

Whole-brain structural and functional connectivity networks can be assessed using diffusion-weighted MRI (DW-MRI) and functional MRI (fMRI), respectively. When the brain is parcellated into its constituent subregions, specific methods quantify the relative connectivity strengths between pairs of regions. The calculation of connectivity between all pairs of regions produces a connectivity matrix. With such a matrix, mathematical methods from graph theory characterize the network for global properties of integration, segregation, and robustness. At the regional level, these methods quantify specific properties such as connection density, convergence, and isolation. In this work, we apply these methods to understand how the possession of the Apolipoprotein E ε4 allele, the primary genetic risk factor for late-onset Alzheimer's Disease (AD), contributes to global and local alterations of structural and functional connectivity. In Chapter 2, we find that DW-MRI-based fiber tractography networks in aging APOE-4 carriers exhibit accelerated negative correlations between age and clustering coefficient, a measure of local axonal connection density. This trend occurs simultaneously with reductions in global cortical thickness and decrease performance on episodic memory tests. In a highly similar population, we examined fMRI-based functional connectivity networks during performance on an episodic memory task (Chapter 3). APOE-4 carriers demonstrated reduced activation during memory encoding in the entorhinal cortex, a locus of early disease change in Alzheimer's disease. The degree of activation in this region correlated with the amount of functional brain integration, suggesting a global basis for local alterations in neuronal activity. In Chapter 4, we assessed hippocampal functional and structural connectivity during episodic memory consolidation in healthy young adults. Results indicate that elevated functional connectivity in a hippocampal-cortical network was important for the process of consolidation. The structural connections of this network all traversed the parahippocamal gyrus, an area of known structural atrophy in individuals at genetic risk for AD. In Chapter 5 we describe a web-based tool for the public sharing and analysis of brain connectivity matrices, and then apply it to reveal substantial differences in the topology of whole brain structural and functional networks. Finally, Chapter 6 contains a model of cortico-hippocampal connectivity that unifies the findings from these studies.