Microstructural diffusion changes are independent of macrostructural volume loss in moderate to severe Alzheimer's disease

Abstract

Although it is established that Alzheimer's disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD. Seventeen patients with moderate-severe AD and 13 healthy volunteers underwent diffusion-weighted and T1-weighted MR scanning. Images were processed to obtain measures of macrostructural atrophy (gray and white matter volumes) and microstructural damage (fractional anisotropy and mean diffusivity). Microstructural diffusion changes independent of macrostructural loss were investigated using an ANCOVA where macrostructural maps were used as voxel-wise covariates. The reverse ANCOVA model was also assessed, where macrostructural loss was the dependent variable and microstructural diffusion tensor imaging maps were the imaging covariates. Diffusion differences between patients and controls were observed after controlling for volumetric differences in medial temporal, retrosplenial regions, anterior commissure, corona radiata, internal capsule, thalamus, corticopontine tracts, cerebral peduncle, striatum, and precentral gyrus. Independent volumetric differences were observed in the entorhinal cortex, inferior temporal lobe, posterior cingulate cortex, splenium and cerebellum. While it is well known that AD is associated with pronounced volumetric change, this study suggests that measures of microstructure provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD and in those thought to be spared. As such this work provides great understanding of the topography of pathological changes in AD that can be captured with imaging.

Figure 1

A Diagrammatic Representation of the Image Processing Streams. The text provides a full description of the image processing stream with Roman Numerals detailing T1-weighted processing and letters detailing Diffusion Tensor Imaging processing. Abbreviations: T1w, T1-weighted; T2w, T2-weighted; DTI, Diffusion Tensor Imaging; S0, DTI with no diffusion weighting; MNI, Montreal Neurological Institute; DARTEL, Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra; FA, Fractional Anisotropy; MD, Mean Diffusivity; VBM5, Voxel-Based Morphometry Toolbox 5.

Figure 2

Coronal slices from Y=-5 to Y=-42 showing regional decreases of GM (A) and WM (B) loss in AD compared to controls (VBM) overlaid on the GM (A) and WM (B) normalized DARTEL templates. All contrast are shown using p<0.001 uncorrected in at least 50 edge-connected voxels. Color bars denote t-values.

Figure 3

Coronal slices from Y=-5 to Y=-42 showing regions with higher MD values (‘warm’ colors) and lower FA values (‘cold’ colors) in AD compared to controls. Row A: BPM ANCOVAs using GM and WM images as covariates. Row B: ANCOVAs without imaging covariates. Darkened green indicates areas with both FA and MD changes. Contrasts are shown at p<0.001 uncorrected in at least 50 edge connected voxels. Color bars denote t-values.

Figure 4

Coronal slices from Y=-5 to Y=-42 showing areas with macrostructural volume loss only (GM or WM, red); microstructural damage only (MD and FA, blue); and the combination of macrostructural and microstructural changes (green).