Large-scale network dysfunction in vascular cognitive disorder supports connectional diaschisis in advanced arteriosclerosis.

BACKGROUND AND PURPOSE: The interrelation of cognitive performance, cerebrovascular damage and brain functional connectivity (FC) in advanced arteriosclerosis remains unclear. Our aim was to investigate the associations between FC, white matter damage and cognitive impairment in carotid artery disease.

METHODS: Seventy-one participants with recent cerebrovascular event and with written informed consent underwent resting-state functional MRI (fMRI) and the Addenbrooke's Cognitive Examination-Revised (ACE-R). Network and inter-hemispheric FC metrics were compared between cognitively normal and impaired subjects, and interrelated with cognition. In order to explore the nature of FC changes, we investigated their associations with microstructural damage of related white matter tracts and cognitive performance, followed by mediation analysis.

RESULTS: Participants with global cognitive impairment showed reduced FC compared to the cognitively intact subjects within the central executive network (CEN), and between hemispheres. Patients with executive dysfunction had decreased CEN FC while patients with memory loss demonstrated low FC in both CEN and default mode network (DMN). Global performance correlated with connectivity metrics of the CEN hub with DMN nodes, and between hemispheres. Cingulum mean diffusivity (MD) was negatively correlated with the ACE-R and CEN-DMN FC. The cingulum MD-cognition association was partially mediated by CEN DMN FC.

CONCLUSIONS: Long-range functional disconnection of CEN with DMN nodes is the main feature of cognitive impairment in elderly subjects with symptomatic carotid artery disease. Our findings provide further support for the connectional diaschisis concept of vascular cognitive disorder (VCD), and highlight a mediation role of functional disconnection to explain associations between microstructural white matter tract damage and cognitive impairment.