Absolute diffusivities define the landscape of white matter degeneration in Alzheimer's disease

Abstract

Recent imaging evidence in Alzheimer's disease suggests that neural involvement in early-stage disease is more complex than is encapsulated in the commonly held position of predominant mesial temporal lobe degeneration-there is also early posterior cingulate cortex and diencephalic damage. These findings suggest that early clinical Alzheimer's disease is underpinned by damage to an inter-connected network. If correct, this hypothesis would predict degeneration of the white matter pathways that connect this network. This prediction can be tested in vivo by diffusion magnetic resonance imaging. Most diffusion tensor imaging studies of white matter in neurodegenerative disorders such as Alzheimer's disease have concentrated on fractional anisotropy reductions and increased 'apparent' diffusivity; however, there is a lack of empirical biological evidence to assume that fractional anisotropy changes will necessarily capture the full extent of white matter changes in Alzheimer's disease. In this study, therefore, we undertook a comprehensive investigation of diffusion behaviour in Alzheimer's disease by analysing each of the component eigenvalues of the diffusion tensor in isolation to test the hypothesis that early Alzheimer's disease is associated with degeneration of a specific neural network. Using tract-based spatial statistics, we performed voxel-wise analyses of fractional anisotropy, axial, radial and mean diffusivities in 25 Alzheimer's disease patients compared with 13 elderly controls. We found that increased absolute (axial, radial and mean) diffusivities in Alzheimer's disease were concordant in a distribution consistent with the network hypothesis, highly statistically significant and far more sensitive than fractional anisotropy reductions. The former three measures identified confluent white matter abnormalities in parahippocampal gyrus and posterior cingulum, extending laterally into adjacent temporo-parietal regions as well as splenium and fornix. The caudal occipital lobe, temporal pole, genu and prefrontal white matter were relatively preserved. This distribution is highly consistent with expected predictions of tract degeneration from grey matter lesions identified by fluorodeoxyglucose positron emission tomography and structural magnetic resonance imaging. Concordant with results from these other imaging modalities, this pattern predominantly involves degeneration of the tracts connecting the circuit of Papez. These findings also highlight that early neuropathological processes are associated with changes of the diffusion ellipsoid that are predominantly proportional along all semi-principal axes.

Individual Classification of Mild Cognitive Impairment Subtypes by Support Vector Machine Analysis of White Matter DTI

“…However, another recent TBSS study assessing the same diffusion parameters in clinically overt AD cases compared with healthy controls led to the opposite results. 74 The few available recent . Gray, mean FA value; green, average skeleton.…”

“…Suprathreshold voxels were enlarged by using TBSS fill (part of FSL) for illustrative purposes. investigations on the different diffusion parameters in normal aging, MCI, and AD 28,[74][75][76][77] provided inconsistent data with respect to the regional differences in the distribution of significant changes in FA, longitudinal diffusivity, radial diffusivity, and mean diffusivity. For example, in the above mentioned study of subjects with MCI and AD, FA was more closely related to the cognitive profile than longitudinal diffusivity or radial diffusivity.…”

“…28 In contrast, another study in AD showed stronger differences in longitudinal diffusivity, radial diffusivity, and mean diffusivity than FA. 74 It is likely that the sensitivity of the different diffusion parameters may vary substantially as a function of the disease severity. Research using these different diffusion indices is still at an early stage, as is our understanding of the relevance of longitudinal diffusivity and radial diffusivity changes in terms of myelin or axonal damage.…”

Complex regional pain syndrome: The matter of white matter?

“…However, the interpretations of the altered DTI parameters are not straightforward because the underlying cellular‐level pathophysiology is incompletely understood (for a review, see e.g., Concha, 2014). For example, increased AD combined with increased RD has been found in several neurological diseases such as multiple sclerosis (Roosendaal et al., 2009), Alzheimer's disease (Acosta‐Cabronero et al., 2010), and amyotrophic lateral sclerosis (Metwalli et al., 2010) with otherwise separate and distinctive pathophysiology.…”

“…(2008) showed FA to be lowered in the left cingulum; the subsequent region‐of‐interest analysis revealed decreased axial diffusivity (AD) and increased radial diffusivity (RD) in the same area. However, because FA is sometimes insensitive to changes in other DTI measures (Acosta‐Cabronero, Williams, Pengas, & Nestor, 2010; Hasan, 2006), it would be important to examine each of these measures in a whole‐brain manner.…”