Differential effects of confluent and non-confluent white matter hyperintensities on functional connectivity in mild cognitive impairment.

Background White matter hyperintensities (WMH) indicates active small vessel disease. Emerging evidence suggests that confluent WMH (C-WMH) results in greater cognitive impairment compared to non-confluent WMH (NC-WMH) visualized as punctate lesions. However, the mechanism linking C-WMH and early cognitive impairment is not clearly understood. Aims To investigate the effects of C-WMH and NC-WMH on whole-brain functional connectivity (FC) across 138 regions-of-interest (ROI) and cognition in sixty-three subjects with Mild Cognitive Impairment (MCI). Methods MCI subjects were classified as C-WMH or NC-WMH using the Staal's criteria on the Fazekas WMH scale. Group-level ROI-to-ROI FC trends and differences based on WMH subtypes were computed using standard rs-fMRI analysis. Global cognitive performance was measured with mini-mental-state examination (MMSE). Results Subjects with C-WMH exhibited increased inter-regional FC in the fronto-parietal, fronto-occipital, parieto-occipital, and temporo-parietal regions of the salience, dorsal-attention, default-mode, and visual networks compared to NC-WMH. Increased intra-regional FC was also observed within the frontal and parietal lobes in C-WMH. In addition to widespread increased FC in C-WMH, a few regions in the fronto-temporal and intra-frontal areas demonstrated reduced FC in C-WMH compared to NC-WMH. Analyses of cognitive correlates demonstrated increased parieto-occipital FC to be negatively associated with MMSE in the C-WMH. The increased parieto-occipital FC may be related to loss of higher order inhibitory control in the parieto-occipital regions induced by C-WMH or alternatively a compensatory mechanism to FC alterations induced by C-WMH. Conclusion C-WMH in subjects with MCI is associated with widespread increase in intra- and inter-regional FC. These findings provide novel insights into divergent FC related to confluence of WMH in MCI.