Why so hyperintense? : identifying functional networks associated with cognition and mobility in cerebral small vessel disease

White matter hyperintensities (WMH) are a prominent feature of cerebral small vessel disease and are associated with cognitive and mobility impairment. These deficits may be caused by the disruption of large-scale functional networks due to the presence of WMHs. However, knowledge regarding the relevance of these lesions on functional networks remains inconclusive. In this thesis I used lesion network mapping to: 1) investigate the functional connectivity specifically associated with WMHs; and 2) determine whether WMH-related disruption to major functional networks is associated with impairments in cognition and mobility. In addition, physical activity (PA) is a possible countermeasure to reduce both WMHs and falls risk. However, no study has yet investigated whether PA attenuates the association between WMHs, falls risk, and cognition. I conducted a secondary cross-sectional analysis to investigate whether PA moderates the association between WMH volume, falls risk, and cognition. Finally, resistance training (RT) is a promising lifestyle intervention to reduce WMH progression, improve executive functions, and reduce falls. However, the underlying neurobiological process by which RT improves executive functions and falls risk remain unclear. Thus, I conducted an exploratory analyses of a randomized controlled trial to: 1) identify whether RT is able to mitigate WMH-related network disruption; and 2) determine whether changes in network disruption are associated with changes in cognition and falls risk. My research showed that WMH-related disruption to the sensorimotor, and ventral attention network was associated with poorer global cognition and postural sway, while disruption to the dorsal attention network was associated with increased falls risk. I showed that PA moderates the association between WMHs and falls risk and that 12 months of twice-weekly RT slowed WMH-related disruption to the sensorimotor, dorsal attention, and ventral attention networks. Reduced disruption to the dorsal and ventral attention networks was associated with improved executive functions and reduced falls risk respectively. The findings from this thesis highlight the functional networks disrupted by WMHs that may underlie the cognitive impairment and increased falls risk evident in older adults with cerebral small vessel disease. Further, interventions targeting disease progression should aim to increase physical activity, with a potential emphasis on RT.