Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer's disease supports retrogenesis

Abstract

The retrogenesis model of Alzheimer's disease (AD) posits that white matter (WM) degeneration follows a pattern that is the reverse of myelogenesis. Using diffusion tensor imaging (DTI) to test this model, we predicted greater loss of microstructural integrity in late-myelinating WM fiber pathways in AD patients than in healthy older adults, whereas differences in early-myelinating WM fiber pathways were not expected. We compared 16 AD patients and 14 demographically-matched healthy older adults with a whole-brain approach via tract-based spatial statistics (TBSS), and a region of interest (ROI) approach targeting early-myelinating (posterior limb of internal capsule, cerebral peduncles) and late-myelinating (inferior longitudinal fasciculus [ILF], superior longitudinal fasciculus [SLF]) fiber pathways. Permutation-based voxelwise analysis supported the retrogenesis model. There was significantly lower fractional anisotropy (FA) in AD patients compared to healthy older adults in late-myelinating but not early-myelinating pathways. These group differences appeared to be driven by loss of myelin integrity based on our finding of greater radial diffusion in AD than in healthy elderly. ROI analyses were generally in agreement with whole-brain findings, with significantly lower FA and increased radial diffusion in the ILF in the AD group. Consistent with the retrogenesis model, AD patients showed demonstrable changes in late-myelinating WM fiber pathways. Given greater change in the ILF than the SLF, wallerian degeneration secondary to cortical atrophy may also be a contributing mechanism. Knowledge of the pattern of WM microstructural changes in AD and its underlying mechanisms may contribute to earlier detection and intervention in at-risk groups.

Fig. 1

Regions of interest: posterior limb of the internal capsule (in green), superior longitudinal fasciculus (in orange), cerebral peduncles (in purple), and inferior longitudinal fasciculus (in pink) overlaid on mean FA skeleton (in blue). The left hemisphere of the brain corresponds to the right side of the image.

Fig. 2

Voxelwise group differences in the uncinate fasciculus, inferior longitudinal fasciculus, fornix, splenium, cingulum, forceps major and superior longitudinal fasciculus (in red) overlaid on mean FA skeleton (in blue). In all instances, AD patients demonstrated significantly lower fractional anisotropy values in the aforementioned regions. The left hemisphere of the brain corresponds to the right side of the image.