Increases in periventricular white matter hyperintensities associate with Alzheimer disease biomarkers

Abstract

AbstractBackgroundVascular dysfunction can compound white matter damage in an Alzheimer disease (AD) cohort, leading to the formation of white matter hyperintensities (WMHs). The spatial distribution of WMHs at various stages of the disease is of interest, as previous work has found that patients with late‐onset AD show the earliest changes in posterior regions. We evaluated whether volumetric and microstructural changes within WMHs and normal‐appearing white matter were associated with biomarkers for AD.MethodT2‐weighted‐Fluid‐Attenuated Inversion Recovery (T2‐FLAIR) MRI images and diffusion tensor imaging (DTI) were obtained from 199 biomarker (amyloid PET) negative in centiloid, cognitively normal; 48 biomarker positive, cognitively normal (preclinical AD); and 19 biomarker positive, cognitively impaired participants (symptomatic AD) followed by the Knight Alzheimer Disease Research Center. Cognitively normal was defined as having a clinical dementia rating (CDR) of 0. Masks demarcating periventricular (PVWMHs) or deep (DWMHs) WMHs were created based on their proximity to the lateral ventricles and quantified as singular values representing the extent of lesion burden. PVWMHs were further dichotomized as anterior or posterior based on their location relative to the mid‐slice of the corpus callosum. Each WMH map was overlaid onto the corresponding diffusivity map, and mean diffusivity (MD) was used to evaluate white matter tract integrity within WMHs. Volumetric and DTI data were compared among disease groups using a Mann‐Whitney test of medians.ResultIncreases in PVWMH but not DWMH volume were associated with AD progression in a stepwise manner – symptomatic AD participants had the largest PVWMH volume compared to preclinical AD (p=0.003) and biomarker negative participants (p<0.001). MD within PVWMHs was significantly increased for preclinical and symptomatic AD participants when compared to biomarker negative controls. Within PVWMHs, posterior but not anterior PVWMH volumes were significantly increased (p=0.029) among preclinical AD participants compared to biomarker negative controls.ConclusionPVWMH volume associated with AD biomarkers and posterior regions showed increases in PVWMHs among participants with preclinical AD. Increases in MD within WMHs were present in asymptomatic individuals, suggesting potential for measurable changes in axonal integrity prior to symptom onset. These results suggest a more direct link between AD and WMHs.