DTI measures in crossing-fibre areas: Increased diffusion anisotropy reveals early white matter alteration in MCI and mild Alzheimer's disease

Abstract

Though mild cognitive impairment is an intermediate clinical state between healthy aging and Alzheimer's disease (AD), there are very few whole-brain voxel-wise diffusion MRI studies directly comparing changes in healthy control, mild cognitive impairment (MCI) and AD subjects. Here we report whole-brain findings from a comprehensive study of diffusion tensor indices and probabilistic tractography obtained in a very large population of healthy controls, MCI and probable AD subjects. As expected from the literature, all diffusion indices converged to show that the cingulum bundle, the uncinate fasciculus, the entire corpus callosum and the superior longitudinal fasciculus are the most affected white matter tracts in AD. Significant differences between MCI and AD were essentially confined to the corpus callosum. More importantly, we introduce for the first time in a degenerative disorder an application of a recently developed tensor index, the "mode" of anisotropy, as well as probabilistic crossing-fibre tractography. The mode of anisotropy specifies the type of anisotropy as a continuous measure reflecting differences in shape of the diffusion tensor ranging from planar (e.g., in regions of crossing fibres from two fibre populations of similar density or regions of "kissing" fibres) to linear (e.g., in regions where one fibre population orientation predominates), while probabilistic crossing-fibre tractography allows to accurately trace pathways from a crossing-fibre region. Remarkably, when looking for whole-brain diffusion differences between MCI patients and healthy subjects, the only region with significant abnormalities was a region of crossing fibres in the centrum semiovale, showing an increased mode of anisotropy. The only white matter region demonstrating a significant difference in correlations between neuropsychological scores and a diffusion measure (mode of anisotropy) across the three groups was the same region of crossing fibres. Further examination using probabilistic tractography established explicitly and quantitatively that this previously unreported increase of mode and co-localised increase of fractional anisotropy was explained by a relative preservation of motor-related projection fibres (at this early stage of the disease) crossing the association fibres of the superior longitudinal fasciculus. These findings emphasise the benefit of looking at the more complex regions in which spared and affected pathways are crossing to detect very early alterations of the white matter that could not be detected in regions consisting of one fibre population only. Finally, the methods used in this study may have general applicability for other degenerative disorders and, beyond the clinical sphere, they could contribute to a better quantification and understanding of subtle effects generated by normal processes such as visuospatial attention or motor learning.

Altered White Matter Integrity in Adolescents with Prelingual Deafness: A High-Resolution Tract-Based Spatial Statistics Imaging Study

“…Compared with other imaging techniques, DTI is more sensitive because it can detect WM microstructural changes well before a macrostructural loss of WM becomes measurable by other procedures, such as voxel-based morphometry. 19 Although the precise underlying mechanism for the changes of anisotropy is still unclear, decreased FA or increased RD may be interpreted as loss or insufficient development of myelination, loss of axons, gliosis, or tissue edema. Taking into account that our prelingually deaf adolescents did not show any pathologic changes as a result of brain injury, we can ascertain that the anisotropy changes may best be attributed to axonal loss and/or lack of myelination at an early age in life.…”

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

“…A recent study including both AD and MCI subjects [196] demonstrated a circumscribed increase in FA. These findings were aided by examining variations of a third tensor invariant, tensor mode [197] allowing to differentiate the type of anisotropy (planar, e.g.…”

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“…1). Notably, this mask did not include the superior longitudinal fasciculus, located medial to S1-adjacent U-fibres, as it is difficult to interpret fractional anisotropy in crossing-fibre areas (Douaud et al, 2011).…”