Abstract
Cerebral small vessel disease (SVD) is considered the most important vascular contributor to the development of cognitive impairment and dementia. There is increasing awareness that SVD exerts its clinical effects by disrupting white matter connections, predominantly disrupting connections between rich club nodes, a set of highly connected and interconnected regions. Here we examined the progression of disturbances in rich club organization in older adults with SVD and their associations with conventional SVD markers and cognitive decline. We additionally investigated associations of baseline network measures with dementia. In 270 participants of the RUN DMC study, we performed diffusion tensor imaging (DTI) and cognitive assessments longitudinally. Rich club organization was examined in structural networks derived from DTI followed by deterministic tractography. Global efficiency (p<0.05) and strength of rich club connections (p<0.001) declined during follow-up. Decline in strength of peripheral connections was associated with a decline in overall cognition (β=0.164; p<0.01), psychomotor speed (β=0.151; p<0.05) and executive function (β=0.117; p<0.05). Baseline network measures were reduced in participants with dementia, and the association between WMH and dementia was causally mediated by global efficiency (p = =0.037) and peripheral connection strength (p = =0.040). SVD-related disturbances in rich club organization progressed over time, predominantly in participants with severe SVD. In this study, we found no specific role of rich club connectivity disruption in causing cognitive decline or dementia. The effect of WMH on dementia was mediated by global network efficiency and the strength of peripheral connections, suggesting an important role for network disruption in causing cognitive decline and dementia in older adults with SVD.
Highlights
Cerebral small vessel disease (SVD) is considered the most important vascular contributor to the development of cognitive impairment and dementia (Banerjee et al, 2016; Gorelick et al, 2011; Prins and Scheltens, 2015), but exactly how SVD results in cognitive decline or dementia is hitherto incompletely understood (Patel and Markus, 2011; Wardlaw et al, 2013)
The strength of rich club connections declined over time, in contrast to the strength of feeder and peripheral connections
The White matter hyperintensities (WMH) group x time interaction term was not significant, meaning that the decline in rich club connections did not differ between participants with mild and severe WMH (p = =0.830)
Summary
Cerebral small vessel disease (SVD) is considered the most important vascular contributor to the development of cognitive impairment and dementia (Banerjee et al, 2016; Gorelick et al, 2011; Prins and Scheltens, 2015), but exactly how SVD results in cognitive decline or dementia is hitherto incompletely understood (Patel and Markus, 2011; Wardlaw et al, 2013). Several cross-sectional studies in patients with SVD have shown that reduced structural network integrity, reflected by decreased global efficiency, was related to increased cognitive impairment (Lawrence et al, 2014; Reijmer et al, 2015; Tuladhar et al, 2015, 2016a) and to an increased risk of future dementia (Tuladhar et al., 2016b). Reduced connectivity was predominantly observed for connections between so-called rich club nodes (Tuladhar et al, 2017) – nodes that are both highly connected to the network and highly interconnected with each other (van den Heuvel et al, 2012; van den Heuvel and Sporns, 2011). How SVD-related disturbances in rich club organization progress over time and how this relates to subsequent cognitive decline is unknown
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