Abstract
White matter hyperintensities (WMHs) are associated with age-related cognitive impairment and increased risk of Alzheimer's disease. However, the manner by which WMHs contribute to cognitive impairment is unclear. Using a combination of predictive modeling and network neuroscience, we investigated the relationship between structural white matter connectivity and age, fluid cognition, and WMHs in 68 healthy adults (18-78 years). Consistent with previous work, WMHs were increased in older adults and exhibited a strong negative association with fluid cognition. Extending previous work, using predictive modeling, we demonstrated that age, WMHs, and fluid cognition were jointly associated with widespread alterations in structural connectivity. Subcortical-cortical connections between the thalamus/basal ganglia and frontal and parietal regions of the default mode and frontoparietal networks were most prominent. At the network level, both age and WMHs were negatively associated with network density and communicability, and positively associated with modularity. Spatially, WMHs were most prominent in arterial zones served by the middle cerebral artery and associated lenticulostriate branches that supply subcortical regions. Finally, WMHs overlapped with all major white matter tracts, most prominently in tracts that facilitate subcortical-cortical communication and are implicated in fluid cognition, including the anterior thalamic-radiations and forceps minor. Finally, results of mediation analyses suggest that whole-brain WMH load influences age-related decline in fluid cognition. Thus, across multiple levels of analysis, we showed that WMHs were increased in older adults and associated with altered structural white matter connectivity and network topology involving subcortical-cortical pathways critical for fluid cognition.