Accelerated decline in white matter integrity in clinically normal individuals at risk for Alzheimer's disease

Abstract

Prior studies have identified white matter abnormalities in Alzheimer's disease (AD). Yet, cross-sectional studies in normal older individuals show little evidence for an association between markers of AD risk (APOE4 genotype and amyloid deposition), and white matter integrity. Here, 108 normal older adults (age, 66-87) with assessments of apolipoprotein e4 (APOE4) genotype and assessment of amyloid burden by positron emission tomography underwent diffusion tensor imaging scans for measuring white matter integrity at 2 time points, on average 2.6 years apart. Linear mixed-effects models showed that amyloid burden at baseline was associated with steeper decline in fractional anisotropy in the parahippocampal cingulum (p < 0.05). This association was not significant between baseline measures suggesting that longitudinal analyses can provide novel insights that are not detectable in cross-sectional designs. Amyloid-related changes in hippocampus volume did not explain the association between amyloid burden and change in fractional anisotropy. The results suggest that accumulation of cortical amyloid and white matter changes in parahippocampal cingulum are not independent processes in individuals at increased risk for AD.

Keywords: Aging; Amyloid; Diffusion tensor imaging; Longitudinal; White matter.

Figure 1. Data processing

DTI data for each subject were processed independently at each timepoint. DTI scans were pre-processed to generate fractional anisotropy (FA) maps, motion (average rotation and translation parameters) estimates were saved and included in the longitudinal analyses as a time-dependent covariate. FA images were transformed to standard space to compute mean FA in 12 atlas-based regions of interest at each timepoint: Major association fibers (red = superior longitudinal fasciculus, blue = superior frontal occipital fasciculus, green = inferior frontal occipital fasciculus), projection fibers (red = anterior, blue = superior and green = posterior corona radiate, yellow = internal capsule), corpus callosum (red = genu, blue = body and red = splenium) and limbic fibers (red = cingulum and blue = parahippocampal cingulum).

Figure 2. Aging-related changes in FA

Raw FA data is plotted in black lines for each individual for 12 regions of interest. Beta estimates for average annual longitudinal (LT) change are plotted in solid red lines from a linear mixed model. Estimates of cross-sectional (CS) associations with age, estimated in baseline data only, are plotted in blue. The plotted effects are estimated after controlling for baseline age. The only estimates that are not significant at p < 0.05 (Bonferroni-corrected) are the longitudinal estimates for splenium, genu and anterior corona radiata (bottom row).

Figure 3. Association between amyloid burden and change in FA

Within-person trajectories of change for parahippocampal cingulum FA (A) and average estimates of annual decline for individuals with and without measurable amyloid burden at baseline (B) are shown.

Figure 4. Associations between amyloid burden and parahippocampal white matter integrity are independent of hippocampus volume

Plots shows within-person trajectories of change for hippocampal volume (A) and average estimates of annual decline for individuals with (Aβ+) and without (Aβ−) measurable amyloid burden (B). The effect of amyloid burden at baseline on FA decline in the parahippocampal cingulum bundle, independent of hippocampal atrophy, is shown in C. Significant increases for Aβ+ versus Aβ− are observed for radial diffusivity (solid lines) but not axial diffusivity (dashed lines). For illustration purposes, hippocampal atrophy was re-coded as low atrophy (Hip−, i.e. larger hippocampi) and high atrophy (Hip+, i.e. smaller hippocampi) by median split. Radial and axial diffusivity were z-transformed. Beta estimates from linear mixed models are shown for graphs B-D.