Multimodal Imaging of White Matter Hyperintensities in Alzheimer’s Disease: A Pilot Study.

Abstract

Objective White matter hyperintensities (WMHs) in Alzheimer's disease (AD) are commonly linked to vascular causes, but emerging evidence suggests AD-specific pathologies may also contribute. This pilot study used multimodal imaging to comprehensively analyze WMH volume, microstructural changes, perfusion abnormalities, and their associations with amyloid and tau pathologies, offering insights into the interaction between vascular and neurodegenerative factors. Methods Thirty cognitively normal (CN), 30 mild cognitive impairment (MCI), and 10 AD participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3) underwent T1-weighted (T1w), fluid-attenuated inversion recovery (FLAIR), T2*-weighted, multi-shell diffusion MRI (dMRI), arterial spin labeling (ASL) perfusion, amyloid positron emission tomography (PET), tau PET, and vascular risk assessment. WMH volume was extracted using HyperMapp3r algorithm and Lesion Segmentation Tool (LST), and associated with amyloid and tau burden. Perfusion and diffusion metrics were also compared between WMHs and adjacent normal-appearing white matter (NAWM). Results The total WMH volume was higher in the AD cohort compared to MCI and CN, after adjusting for age, sex, and intracranial volume (F(5, 60)=11.28, p<0.001). Amyloid burden (β=0.045, p<0.001) was a predictor of WMH volume, independent of vascular risk factors, while tau was not. WMH volume was highest in amyloid positive individuals with high vascular risk, followed by amyloid positive individuals but with low vascular risk, and lowest in the amyloid-negative individuals with high vascular risk group. Across all groups, WMH showed more diffusion-related damage than normal-appearing white matter (NAWM). Conclusion This study highlights the influence of both vascular and neurodegenerative factors in WMH development in AD. Additionally, it offers critical data for powering future research aimed at differentiating WMHs driven by vascular versus AD-related neurodegenerative pathologies, which can inform targeted interventions and treatment strategies.