Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation

Abstract

Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ-) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ- in all three ROIs and in Aβi compared to Aβ- in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.

Keywords: AD risk; ANCOVA, Analysis of Covariance; ANTs, Advanced Normalization Tools; APOE4, apolipoprotein E gene ε4; Alzheimer's disease; Amyloid imaging; Aβ+, amyloid positive; Aβi, amyloid indeterminate; Aβ−, amyloid negative; BET, Brain Extraction Tool; Cingulum–CC, cingulum adjacent to corpus callosum; Cingulum–HC, hippocampal cingulum (projecting to medial temporal lobe); DTI, Diffusion Tensor Imaging; DTI-TK, Diffusion Tensor Imaging Toolkit; DVR, distribution volume ratio; Da, axial diffusivity; Dr, radial diffusivity; FA, fractional anisotropy; FH, (parental) family history; FSL, FMRIB Software Library; FUGUE, FMRIB's utility for geometrically unwarping EPIs; FWE, family wise error; GM, gray matter; HARDI, high angular resolution diffusion imaging; ICBM, International Consortium for Brain Mapping; MD, mean diffusivity; PCC, posterior cingulate cortex; PIB, Pittsburgh compound B; PRELUDE, phase region expanding labeler for unwrapping discrete estimates; RAVLT, Rey Auditory Verbal Learning Test; SPM, Statistical Parametric Mapping; TMT, Trail Making Test; WASI, Wechsler Abbreviated Scale of Intelligence; WM, white matter; WRAP, Wisconsin Registry for Alzheimer's Prevention; WRAT, Wide Range Achievement Test; White matter.

Graphical abstract

Fig. 1

Regions of interest. The 3 ROIs assessed in this study are the cingulum-CC, which is the cingulum adjacent to the corpus callosum (green), the lateral fornix (blue), and the cingulum-HC, which is the part of the cingulum that extends from the posterior cingulum to the hippocampus (magenta).

Fig. 2

Fractional anisotropy group differences in ROIs. Significant group differences in fractional anisotropy within the three ROIs displayed on FSL's FMRIB58_FA template transformed to this study's population space. Regions where Aβ + had significantly higher FA than Aβ − (p(FWE) < .05, blue), Aβi had significantly higher FA than Aβ − (p(FWE) < .05, red), both Aβ + and Aβi had significantly higher FA than Aβ − (p(FWE) < .05, purple), Aβ + showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, yellow), Aβi showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, cyan), and both Aβ + and Aβi showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, light green). A.) Sagittal slices from left to right. B.) Coronal slices from posterior to anterior. Left is on the left.

Fig. 3

Fractional anisotropy whole-brain group differences. Significant group differences (p(FWE) < .05) from whole-brain analyses in FA displayed on FSL's FMRIB58_FA template transformed to this study's population space. Regions where Aβ + had higher FA than Aβ − (blue), Aβi had higher FA than Aβ − (red), and both Aβ + and Aβi had higher FA than Aβ − (purple). A.) Sagittal slices from left to right. B.) Coronal slices from posterior to anterior. Left is on the left.

Fig. 4

Mean diffusivity whole-brain group differences. Significant group differences from whole-brain analyses in MD displayed on FSL's FMRIB58_FA template transformed to this study's population space. Higher mean diffusivity was observed in Aβ − compared to Aβ + sin fronto-lateral GM, p(FWE) = 0.024. Left is on the left.

Fig. 5

Mean diffusivity and PiB DVR correlation. Moderate correlation between PiB DVR and MD from the significant MD cluster from Table 4 and Fig. 4. Spearman coefficient = − 0.392.