White Matter Hyperintensity Load Drives Differential Grey Matter Changes in Mild Cognitive Impairment

Abstract

Background: Small-vessel cerebrovascular disease often represented as white matter hyperintensities on magnetic resonance imaging, is considered an important risk factor for progression to dementia. Grey matter volume alterations in Alzheimer’s disease-specific regions comprising the default mode network and executive control network are also key features of early Alzheimer’s disease. However, the relationship between increasing white matter hyperintensity load and grey matter volume needs further examination in the cognitively normal and mild cognitive impairment. Here, we examined the load-dependent influence of white matter hyperintensities on grey matter volume and cognition in the cognitively normal and mild cognitive impairment stages.Methods: Magnetic resonance imaging data from 93 mild cognitive impairment and 90 cognitively normal subjects were studied and white matter hyperintensity load was categorized into low, medium and high terciles. We examined how differing loads of white matter hyperintensities related to whole-brain voxel-wise and regional grey matter volume in the default mode network and executive control network. We further investigated how regional grey matter volume moderated the relationship between white matter hyperintensities and cognition at differing white matter hyperintensity loads.Results: We found differential load-dependent effects of white matter hyperintensity burden on voxel-wise and regional grey matter atrophy in only mild cognitive impairment subjects. At low load, white matter hyperintensity load was positively related to grey matter volume in the executive control network but at high load, white matter hyperintensity load was negatively related to grey matter volume across both the executive control and default mode networks and no relationship was observed at medium white matter hyperintensity load. Additionally, negative associations between white matter hyperintensities and domains of memory and executive function were moderated by regional grey matter volume. Conclusions: Our results demonstrate dynamic relationships between white matter hyperintensity load, grey matter volume and cognition in the mild cognitive impairment stage. Interventions to slow the progression of white matter hyperintensities, instituted when white matter hyperintensity load is low could potentially prevent further cognitive decline.