Differential Effects of Confluent and Nonconfluent White Matter Hyperintensities on Functional Connectivity in Mild Cognitive Impairment

Abstract

Background: White matter hyperintensities (WMHs) indicate active small vessel disease. Emerging evidence suggests that confluent WMH (C-WMH) results in greater cognitive impairment compared with nonconfluent 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 (ROIs) and cognition in 63 subjects with mild cognitive impairment (MCI). Methods: MCI subjects were classified as C-WMH or NC-WMH using the Staals criteria on the Fazekas WMH scale. Group-level ROI-to-ROI FC trends and differences based on WMH subtypes were computed using standard resting-state functional magnetic resonance imaging 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 with 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 with 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. Impact statement White matter hyperintensities (WMHs) have been demonstrated to be a major risk factor for progressive cognitive decline. However, the relationship between structural and functional brain changes related to different types of WMH lesions as well as different stages of WMH progression remains unclear. In this study, we demonstrate that confluent WMH is significantly associated with divergent functional connectivity changes in patients with mild cognitive impairment (MCI). This finding may allow identification of MCI subjects who are adversely affected by WMH and thus provides a window of opportunity to introduce pharmacological and nonpharmacological interventional measures.