Topographic patterns of white matter hyperintensities are associated with multimodal neuroimaging biomarkers of Alzheimer's disease

Abstract

Background: White matter hyperintensities (WMH) are frequently found in Alzheimer's disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (Aβ) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with Aβ burden, glucose hypometabolism, and gray matter volume reduction.

Methods: In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical Aβ deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure.

Results: There were no significant associations between global Aβ burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater Aβ deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas.

Conclusions: This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Aß deposition and neurodegeneration.

Keywords: Alzheimer’s disease; Alzheimer’s disease pathology; Cerebrovascular disease; White matter lesion.

Fig. 1

Frequency map and results of voxel-based analyses. a WMH frequency map across the whole cohort (n = 155) thresholded at 5% used as an explicit mask in regressions analyses. b–d Relationships between AV45-SUVR (b), FDG-SUVR (c), GMV (d), and spatial WMH distribution at the voxel level (dependent variable). Topographic patterns are displayed at p < .005 uncorrected. Corresponding scatter plots visualize the respective relationships using unadjusted values for the whole cohort. Circles represent individual data points (blue = OC, green = SCD, orange = MCI, red = AD), lines indicate linear trends, gray-shaded areas indicate 95% confidence intervals. e Superposition of the three topographic patterns (b, c, and d) with blue = FDG-SUVR only, green = GMV only, orange = superposition FDG-SUVR/GMV, and red = superposition AV45-SUVR/FDG-SUVR/GMV. OC older controls, SCD participants with subjective cognitive decline, MCI patients with mild cognitive impairment, AD patients with Alzheimer’s disease, WMH white matter hyperintensities, SUVR standardized uptake value ratio, AV45 florbetapir, FDG fluorodeoxyglucose, GMV gray matter volume, TIV total intracranial volume.