UC Irvine

Neuroinflammation is increasingly recognized as a key contributor to Alzheimer’s disease (AD), yet the mechanisms linking systemic immune processes to brain structure and cognition remain poorly understood. This dissertation proposes that white matter (WM) microstructure represents a critical intermediate phenotype through which neuroinflammation influences neural circuit integrity and cognitive decline. To test this framework, this work utilized advanced diffusion MRI, specifically Neurite Orientation Dispersion and Density Imaging (NODDI), to characterize biologically meaningful features of WM microstructure within medial temporal lobe pathways. This dissertation first evaluated whether NODDI, a multi-shell, multi-compartment model, provided greater sensitivity to AD-related changes compared to traditional diffusion tensor imaging (DTI). The findings established that advanced diffusion-derived metrics offer enhanced sensitivity to AD pathology and cognitive function while capturing distinct features of tissue organization inaccessible with conventional methods. Building on this foundation, the subsequent analyses reveal that the relationship between peripheral cytokine neuroinflammation and brain structure is not uniform but instead reflects differences in circuit level vulnerability. Neuroinflammatory effects on WM microstructure and cognition vary as a function of biological sex, suggesting that disease risk is shaped not only by systemic burden, but by the brain’s sensitivity to those signals. Extending this work to a genetically high-risk population, individuals with Down syndrome, this dissertation further demonstrates that chronic systemic neuroinflammation is associated with selective alterations in limbic white matter pathways, supporting a model in which neuroinflammation contributes to structural brain vulnerability. Together, these findings identify white matter microstructure as a key link between systemic biology and cognitive decline. By integrating diffusion imaging with neuroinflammatory and cognitive measures, this work provides a framework for understanding how neuroinflammation related processes shape brain structure during the earliest stages of disease. These results have important implications for the development of non-invasive biomarkers aimed at improving early detection and informing therapeutic strategies in Alzheimer's disease.