Amyloid burden accelerates white matter degradation in cognitively normal elderly individuals

Abstract

Alterations in parietal and temporal white matter microstructure derived from diffusion tensor imaging occur in preclinical and clinical Alzheimer's disease. Amyloid beta (Aβ) deposition and such white matter alterations are two pathological hallmarks of Alzheimer's disease. However, the relationship between these pathologies is not yet understood, partly since conventional diffusion MRI methods cannot distinguish between cellular and extracellular processes. Thus, we studied Aβ-associated longitudinal diffusion MRI changes in Aβ-positive (N = 21) and Aβ-negative (N = 51) cognitively normal elderly obtained from the Alzheimer's Disease Neuroimaging Initiative dataset using linear mixed models. Aβ-positivity was based on Alzheimer's Disease Neuroimaging Initiative amyloid-PET recommendations using a standardized uptake value ratio cut-off of 1.11. We used free-water imaging to distinguish cellular and extracellular changes. We found that Aβ-positive subjects had increased baseline right uncinate fasciculus free-water fraction (FW), associated with worse baseline Alzheimer's disease assessment scale scores. Furthermore, Aβ-positive subjects showed faster decrease in fractional anisotropy (FW-corrected) in the right uncinate fasciculus and faster age-dependent right inferior longitudinal fasciculus FW increases over time. Right inferior longitudinal fasciculus FW increases were associated with greater memory decline. Importantly, these results remained significant after controlling for gray and white matter volume and hippocampal volume. This is the first study to illustrate the influence of Aβ burden on early longitudinal (in addition to baseline) white matter changes in cognitively normal elderly individuals at-risk of Alzheimer's disease, thus underscoring the importance of longitudinal studies in assessing microstructural alterations in individuals at risk of Alzheimer's disease prior to symptoms onset.

Keywords: Alzheimer's disease; amyloid beta; at-risk cognitively normal elderly; diffusion tensor imaging; free-water correction; longitudinal study.

Figure 1

Cognitively normal individuals show significant age and time interaction for the average white matter free water. Cognitively normal participants that were older at baseline showed greater increases in FW over time. FW, free water [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Asymptomatic elderly individuals with high amyloid burden exhibit greater longitudinal free water increase in the right inferior longitudinal fasciculus. Brain slice depicts corresponding reconstructed white matter fiber using TRACULA. The spaghetti plot on the left illustrates that cognitively normal elderly participants that were older at baseline and possessed significant Aβ burden in the brain that is, Aβ +ve (red) showed a greater longitudinal increase in the RILF FW over time compared to Aβ −ve participants (blue). The scatterplot on the right illustrates that the spatial Aβ*Age*Time effect (beta value) was higher in the temporal than occipital RILF. Abbreviations: TRACULA, TRActs Constrained by UnderLying Anatomy; FAt, tissue fractional anisotropy; Aβ, amyloid beta; RILF, right inferior longitudinal fasciculus

Figure 3

Cross‐sectional amyloid beta effect on right uncinate fasciculus free water. Brain slices depict corresponding reconstructed white matter fiber using TRACULA. The bar chart on the left illustrates that participants that were Aβ +ve (red) had higher RUNC FW at baseline. Error bars represent ± 2 standard error. The scatterplot on the right illustrates that Aβ +ve participants (red) showed a higher FW than Aβ −ve participants (blue) across all positions in the RUNC, especially in the temporal part of the RUNC. Abbreviations: TRACULA, TRActs Constrained by UnderLying Anatomy; FW, free water; Aβ, amyloid beta; RUNC, right uncinate fasciculus

Figure 4

Asymptomatic elderly individuals with high amyloid burden exhibit greater longitudinal tissue fractional anisotropy decline in the right uncinate fasciculus. Brain slice depicts corresponding reconstructed white matter fiber using TRACULA. The spaghetti plot on the left illustrates that participants that possessed significant Aβ burden in the brain that is, Aβ +ve (red) showed a greater longitudinal reduction in the RUNC FAt over time compared to Aβ −ve participants (blue). The scatterplot on the right illustrates that the spatial Aβ*Time effect (beta values) was greater in the temporal than orbitofrontal RUNC. Abbreviations: TRACULA, TRActs Constrained by UnderLying Anatomy; FAt, tissue fractional anisotropy; Aβ, amyloid beta; RUNC, right uncinate fasciculus

Figure 5

Baseline Alzheimer's disease assessment scale score is associated with baseline right uncinate fasciculus free water. With increase in baseline ADAS score there was an increase in RUNC FW at baseline. Abbreviations: RUNC, right uncinate fasciculus; FW, free water; ADAS, Alzheimer's disease assessment scale