Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients

Abstract

Introduction: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations.

Methods: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures.

Results: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant.

Discussion: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD.

Keywords: Alzheimer's disease; biomarker; cerebral small vessel disease; diffusion tensor imaging; free water imaging; white matter.

Conflict of interest statement

Declarations of Interest

None.

© 2020 the Alzheimer's Association.

Figures

Figure 1.. Study concept and participant selection flowchart.

Samples cover the entire spectrum of AD, mixed disease, and SVD. AD, Alzheimer’s disease; DTI, diffusion tensor imaging; EYO, estimated years from symptom onset; FLAIR, fluid-attenuated inversion recovery; p-tau, phosphorylated-tau181; SVD, small vessel disease; t-tau, total tau.

Figure 2.. Simple regression analyses.

Simple linear regression analyses between diffusion measures and AD biomarkers or SVD markers. Standardized β is represented by color. AD, Alzheimer’s disease; βs, standardized beta; FAu, uncorrected fractional anisotropy; FAt, free water corrected tissue compartment of fractional anisotropy; FW, free water content; MDu, uncorrected mean diffusivity; MDt, free water corrected tissue compartment of mean diffusivity; np, not possible (all patients had the maximum score); ns, not significant; p-tau, phosphorylated- tau181; SVD, small vessel disease; SVD score, total small vessel disease score; t-tau, total tau; WMHvol, white matter hyperintensity volume.

Figure 3.. Multivariable analyses.

Random forest regression analyses for estimating the relative variable importance of AD biomarkers (grey bars), SVD markers (black bars), age and sex (white bars) with regard to conventional DTI measures (FAu, MDu) while accounting for all other variables (conditional importance). Lines indicate the 95% confidence interval for the conditional variable importance. AD, Alzheimer’s disease; FAu, uncorrected fractional anisotropy; MDu, uncorrected mean diffusivity; p-tau, phosphorylated-tau181; SVD, small vessel disease; SVD score, total small vessel disease score; T-tau, total tau; WMHvol, white matter hyperintensity volume.