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.

Introduction

The retrogenesis model of Alzheimer's disease (AD) and other neurodegenerative diseases posits that white matter (WM) degeneration reflects myelin breakdown that develops in a pattern that is the reverse of myelogenesis (Reisberg et al., 1999). According to this model, pathways with large diameter fibers that myelinate first in development, such as primary motor fibers, are the last to be affected by AD. In contrast, pathways with small diameter fibers that myelinate much later in normal development, such as neocortical association and allocortical fibers, are the first to be affected by the AD degenerative process (Bartzokis, 2004). Because corticocortical association pathways are the latest-myelinating fiber pathways in the brain, followed by commissural and limbic pathways (Kinney et al., 1988, Yakovlev and Lecours, 1967), they are particularly vulnerable to early degeneration in AD according to the retrogenesis model. However, many of these late-myelinating pathways also connect to medial temporal lobe structures affected early in AD (Brun and Englund, 1986), so it is possible that observed WM changes may reflect wallerian degeneration secondary to neuronal loss as well (see Coleman, 2005).

Neuropathological mechanisms underlying WM changes in AD can be investigated using diffusion tensor imaging (DTI), which allows for in vivo examination of the orientation and microstructural integrity of WM. WM microstructural integrity is reflected by the degree of intravoxel diffusion anisotropy, most commonly represented as fractional anisotropy (FA, Le Bihan et al., 2001, Pierpaoli and Basser, 1996). Preliminary studies suggest that examination of directional diffusivities (e.g., axial and radial diffusion) may yield important information about the underlying neuropathology driving differences in FA (Song et al., 2003, Song et al., 2002, Sun et al., 2005). Specifically, radial diffusion (DR) may signify loss of myelin integrity and axial diffusion (DA) may implicate axonal damage that would be expected with wallerian degeneration (Song et al., 2003, Song et al., 2002, Sun et al., 2005).

Studies not specifically testing a theoretical model of WM changes in AD have provided mixed support for both the retrogenesis model and wallerian degeneration. Many published papers have attributed WM changes in late-myelinating or corticocortical pathways in AD to retrogenesis, but these studies did not directly compare early- versus late-myelinating regions (Fellgiebel et al., 2008, Naggara et al., 2006, Taoka et al., 2006, Teipel et al., 2007). For example, Teipel et al. (2007) used a whole-brain multivariate voxel-based morphometry (VBM) approach and found a pattern of regional WM changes consistent with the retrogenesis model. Specifically, patients with AD had significantly reduced FA in intracortical projecting WM tracts and a relative preservation of extracortical projecting fiber tracts. Other groups have concluded that their results support wallerian degeneration (Duan et al., 2006, Huang and Auchus, 2007, Yoshiura et al., 2006). For example, Huang and Auchus (2007) found decreased axial diffusivity in the temporal lobe in patients with AD or mild cognitive impairment (MCI) compared to healthy elderly, suggesting axonal damage secondary to wallerian degeneration. Other investigators have reported a pattern of results that support both wallerian degeneration and retrogenesis as possible neuropathological mechanisms of WM changes in AD (Medina et al., 2006, Salat et al., 2008, Stahl et al., 2007, Xie et al., 2006).

Although studies have consistently demonstrated reduced WM integrity in AD patients compared to healthy elderly, the pattern and underlying mechanism of these changes remain unclear. One reason for this uncertainty is that few studies have tested a priori hypotheses based on a specified neuropathological mechanism. The only study to date that tested the retrogenesis model prospectively used a region of interest (ROI) approach and found support for the model in AD (Choi et al., 2005). However, unlike the present study, these investigators did not additionally employ a whole-brain approach and their analyses were therefore limited to preselected ROIs.

In the present study we utilized a novel DTI post-processing procedure, tract-based spatial statistics (TBSS, Smith et al., 2006), to test the retrogenesis model of AD using both a whole-brain exploratory approach to evaluate regional patterns of WM changes and an ROI approach to test a priori hypotheses. We predicted that there would be less WM microstructural integrity in patients with AD relative to normal healthy elderly in late-myelinating WM fiber pathways, whereas early-myelinating fiber pathways would be relatively spared. We also investigated the underlying neuropathological mechanism of WM changes by testing whether group differences remained after controlling for generalized atrophy and by evaluating group differences in axial and radial diffusion. In accordance with the retrogenesis model, we predicted that group differences would be independent of generalized atrophy and would be driven by myelin breakdown rather than wallerian degeneration.