Using Diffusion Tensor Imaging and Mixed-Effects Models to Investigate Primary and Secondary White Matter Degeneration in Alzheimer's Disease and Mild Cognitive Impairment

Abstract

White matter (WM) degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI) may be a key indicator of early damage in AD. Here, we analyzed WM diffusion tensor data using Tract-Based Spatial Statistics in conjunction with mixed-effects models. Four indices of diffusion were assessed in 61 healthy control, 19 non-amnestic MCIs, 14 amnestic MCIs, and 9 AD patients. The aim of the study was to use advanced mixed-effects models to investigate the retrogenesis hypothesis of AD, which suggests that tracts that are late to myelinate in ontogenetic development are the earliest to be affected in AD. Our results show that a number of late-myelinating pathways, including the parahippocampal region and the inferior longitudinal fasciculus, were predominantly affected by changes in WM volume. Conversely, early-myelinating pathways were found to be affected by a combination of both WM and gray matter (GM) atrophy. A model of the entire WM structure of the brain returned GM models for two indices of diffusion, suggesting that more complex regional landscapes of diffusion lie hidden beneath a global analysis of the entire brain. Our results warn against an explanation of white matter damage that points simply to one of two mechanisms: secondary degeneration or direct damage of myelin. We suggest that tracts may be affected by both mechanisms, with the balance depending on whether tracts are early or late-myelinating. A greater understanding of the pattern of WM changes in AD may prove useful for the early detection of AD.

Sexual Dimorphism in Healthy Aging and Mild Cognitive Impairment: A DTI Study

“…This is particularly true in MCI, where the structural changes are subtle. In an earlier study we also noted diffusion changes in healthy older, MCIna and MCIa subjects, in the absence of significant changes in normalised WM volume [19]. However, in the situation of AD dementia both WM volume and diffusion indices were significantly affected [19].…”

Different Patterns of White Matter Degeneration Using Multiple Diffusion Indices and Volumetric Data in Mild Cognitive Impairment and Alzheimer Patients

“…Early DTI studies have employed FA alone or in combination with MD [9]. It has also been suggested in AD and MCI patients that an increase in radial and axial diffusivities may be more reliable markers of degeneration than FA, which is a function of the ratio of these diffusivities [18], [19] and may not be able to detect subtle changes in WM [19]. Furthermore, recent reports suggest that the sensitivity of radial diffusivity to the changes that occur in WM during normal aging is higher than that of axial diffusivity, possibly because the former is more closely associated with myelin breakdown [20]; conversely, other studies indicate that axial diffusivity increases are more useful in identifying early changes (e.g., axonal damage) in AD [12].…”

Associations between T1 white matter lesion volume and regional white matter microstructure in aging

“…WMSAs, as well as reduced white matter integrity, have both been independently tied to clinical status such as dementia or mild cognitive impairment (O'Dwyer, et al In Press; Salat, et al 2009). It may be that the relationship between WMSAs and white matter integrity may have specific impacts on cognition, such that the degree of association may be tied to certain cognitive profiles.…”