REGIONAL VARIATIONS IN THE RELATIONSHIP BETWEEN BRAIN WHITE MATTER HYPERINTENSITIES BURDEN AND AGE-RELATED NEUROPATHOLOGIES

Abstract

White matter hyperintensities (WMH) are common in older adults and have been associated with increased risk of cognitive decline and dementia. Previous efforts have attempted to identify the neuropathologies associated with whole brain WMH burden. We hypothesized that the relationship between brain white matter hyperintensities burden and age-related neuropathologies is region dependent. Therefore, the purpose of this research was to investigate the association between regional WMH burden and neuropathologies, by combining ex-vivo brain MRI and neuropathology in a large community cohort of older adults. Cerebral hemispheres were obtained from 275 participants of the Rush Memory and Aging Project and Religious Orders Study, two longitudinal cohort studies of aging (Fig.1). All hemispheres were imaged ex vivo on a 3T MRI scanner. An experienced observer manually outlined WMH on ex-vivo MRI. The white matter of each hemisphere was segmented into periventricular and deep white matter, and each segment was further divided into frontal, temporal, and parieto-occipital regions, using an automated approach. The total volume of WMH in each of the six white matter segments was measured for each hemisphere. Regional WMH burden was then defined as the square root of the regional WMH volume normalized by the height of the participant. Neuropathologic assessment was performed by a board-certified neuropathologist (Fig.2). Multiple linear regression was used to investigate the link between regional WMH burden and age-related neuropathologies: amyloid plaques, PHF-tau tangles, Lewy bodies, TDP43, hippocampal sclerosis, gross and microscopic infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy (CAA), controlling for age at death, sex, education, and postmortem interval to fixation. Arteriolosclerosis was associated with WMH burden in most white matter segments: in parieto-occipital periventricular and in all deep white matter segments (p<0.05). Gross infarcts and atherosclerosis were associated with WMH burden in frontal periventricular and deep white matter (p<0.05). CAA was associated with WMH burden in parieto-occipital deep white matter (p<0.05). Tangles were associated with WMH burden in frontal periventricular and temporal deep white matter (p<0.05). The present study in a large community cohort provides robust evidence on regional variations in the relationship between WMH burden and age-related neuropathologies.