White matter hyperintensities and the structural connectome: a network perspective on clinical heterogeneity

White matter hyperintensities (WMH) are common radiological findings with diverse clinical outcomes, including absence of clinical symptom, cognitive decline and dementia. One potential explanation for these differences is that WMH could differentially disrupt specific white matter tracts and lead to alterations in structural brain networks. We included participants from the UK Biobank who had available information on WMH volume and divided them into three groups: healthy controls (HC), individuals at risk for cerebral small vessel disease (RcSVD) and individuals with dementia. We assessed alterations in structural connectivity in RcSVD and dementia groups relative to the HC group, and examined whether the alteration in structural connectivity is associated with WMH volumes. To further investigate the extent to which between-group differences in structural connectivity can be explained by the location of WMH, we mapped WMH-specific disconnectivity matrices for every individual and compared them with the alterations in structural connectivity identified. We found a widespread disruption of structural brain networks, both in RcSVD and dementia group, compared to HC. We showed that these disruptions can be partially explained by individual differences in WMH's volume and location. Moreover, we found that WMH are more strongly associated with RcSVD-related structural connectivity changes (average r = -0.32) than with those implicated in dementia (average r = -0.03). This suggest that WMH may impact structural brain network through different pathways in RcSVD and dementia. Our work underscores the important role of WMH lesions in disrupting structural brain networks in RcSVD and dementia, offering insights into the varying clinical impacts of WMH.