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.

White matter hyperintensities mediate gray matter volume and processing speed relationship in cognitively unimpaired participants

“…On the other hand, the previous results in older and/or cognitively impaired individuals indicate that in these individuals with a higher WMH burden, GMv exerts an additional effect of cognitive function that is independent of WMH burden. This may also explain why, in contrast to previous findings (Rizvi et al, ; Swardfager et al, ), we did not find a significant mediation effect with EM performance in our main model. An additional factor that could explain such a discrepancy might be the test that we used to measure EM (MBT), whose characteristics may differ from those of the other memory tests used in similar reports.…”

“…In this work, we have studied whether WMH volume mediates the relationship between GMv and cognition in cognitively unimpaired middle‐aged participants to extend previous findings in older populations with additional comorbidities (Knopman et al, ; Rizvi et al, ; Swardfager et al, ; Tuladhar et al, ), to a younger and healthier cohort both from the cognitive and cerebrovascular standpoint. Our results show that, even in such a low‐risk population, higher WMH lesion volume is significantly associated with a widespread pattern of lower GMv in frontal, occipital, and temporal regions, including the hippocampus, as well as in the thalamus and cerebellum.…”

“…Previous studies showed a relationship between WMH and global GM atrophy also in the temporal (Habes et al, ; Swardfager et al, ), and frontal cortex (Raji et al, ), and in the bilateral hippocampus (Habes et al, ). However, to the best of our knowledge, no previous research has looked at for the joint impact of both WMH and GMv on cognition using voxel‐wise approach (Rizvi et al, ; Wen et al, ). Regarding path c , we had previously established in this cohort that EM and EF rely on nonoverlapping cerebral structural networks (Cacciaglia, Molinuevo, Sánchez‐Benavides, et al, ).…”

“…Previous cross‐sectional studies in older nondemented samples (Knopman et al, ) or including MCI and AD patients (Rizvi et al, ; Swardfager et al, ) that used mediation pathway analysis selected WMH as predictor, whose association with cognition was mediated by GMv. For comparability with these previous reposts, we built an alternative mediation model with GMv as the mediator of the association between WMH load and cognitive performance (Figure ).…”

“…Prior studies have shown that high WMH burden is associated with GM atrophy (Wen, Sachdev, Chen, & Anstey, 2006) in the temporal lobe (Habes et al, 2016;Rizvi et al, 2018;Swardfager et al, 2018) and the frontal cortex (Raji et al, 2012;Rizvi et al, 2018). However, the regional patterns of brain atrophy associated with higher WMH burden are still not widely understood in cognitively unimpaired young individuals.…”