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.

Fig. 1

Left. Target mask (turquoise) and exclusion mask (red) for the association fibres (AF). Right. Target mask (green) and exclusion mask (orange) for the projections fibres (PF).

Fig. 2

Top. Significant FA differences (F-test) across the 3 groups; Plot: FA values in the significant TBSS FA regions highlighted in the figure. Bottom. Significant MD differences (F-test) across the 3 groups; Plot: MD values in the significant TBSS MD regions highlighted in the figure.

Fig. 3

Top. First row: Significant TBSS FA results showing the contrast MCI N AD; Second row: Significant TBSS FA results showing CON N AD. Bottom. First row: Significant TBSS MD results showing the contrast ADNMCI; Second row: Significant TBSS MD results showing ADNCON. No significant differences between CON and MCI were found with either FA or MD.

Fig. 4

Significant TBSS MO differences (F-test) across the 3 groups.

Fig. 5

Top. Significant TBSS MO results showing the contrast MCINAD. Bottom. Significant TBSS MO results showing CONNAD.

Fig. 6

Top. Significant TBSS MO results showing the contrast MCINCON (arrows). Middle. Significant TBSS MO results showing the contrast ADNMCI. Bottom. Significant TBSS MO results showing the contrast ADNCON.

Fig. 7

Significant voxel-wise increase of FA in AD compared with healthy controls (red–yellow) superimposed over the voxel-wise increase of MO in AD compared with controls (blue–pink).

Fig. 8

Left. Average result of the tracing of the association fibres (AF; yellow–red); boxplot shows average number of particles belonging to the association fibres (***P = 0.0002). Middle. The tracing of the projection fibres (PF: blue–pink) and average number of particles belonging to the projection fibres (NS: non-significant). Right. Seed mask region (white, dark blue contours) over both association and projection fibres results of the tracing; boxplot shows ratio of the number of particles belonging to the projection fibres over the association fibres (**P=0.002).