The effect of white matter hyperintensities on cognition is mediated by cortical atrophy

Abstract

White matter hyperintensities (WMH) have been linked to cognitive dysfunction and dementia, although the reasons are unclear. One possibility is that WMH promote neurodegeneration, which, in turn, affects cognition. We examined whether cortical thickness, a marker of neurodegeneration, mediates the relationship between WMH and cognition among 519 older adults. Using conditional process analysis modeling techniques, we examined the association between WMH volume and global cognition and tested whether cortical thickness mediates this relationship statistically. We also tested specific regional hypotheses to determine whether cortical thickness or volume in the medial temporal lobe mediates the relationship between WMH volume and memory. Increased total WMH volume was associated with poorer global cognition and memory. Global cortical thickness and medial temporal lobe thickness/volume mediated the relationship of WMH volume on global cognition and memory functioning. The mediating relationship was similar across racial and ethnic groups and across diagnostic groups (i.e., mild cognitive impairment/Alzheimer's disease). The findings suggest that WMH promote atrophy, which, in turn, drives cognitive decline and highlight a potential pathway in which small vessel cerebrovascular disease affects cognition by promoting neurodegenerative changes directly.

Keywords: Alzheimer's disease; Cognition; Cortical thickness; Memory; White matter hyperintensities.

Fig. 1

A single axial slice displaying distribution of WMH labeled (top panel, left) with in-house developed software and WMH unlabeled (top panel, right). A three-dimensional rendering of the labeled WMH volume (bottom panel). Abbreviation: WMH, white matter hyperintensity.

Fig. 2

Graphical illustration of direct, indirect (mediation), and moderated-mediation statistical models run in the study. Abbreviation: WMH, white matter hyperintensity.

Fig. 3

Graphical illustration of brain regions in which total WMH volume is associated with cortical thinning. Figure was generated with a general linear model performed on each cortical vertex; minimum statistical threshold set at p = 0.05 (dark blue) and minimum set at p = 0.001 (lightest blue). Abbreviation: WMH, white matter hyperintensity. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)