Assessing the effects of age on long white matter tracts using diffusion tensor tractography

Abstract

Aging is associated with significant white matter deterioration and this deterioration is assumed to be at least partly a consequence of myelin degeneration. The present study investigated specific predictions of the myelodegeneration hypothesis using diffusion tensor tractography. This technique has several advantages over other methods of assessing white matter architecture, including the possibility of isolating individual white matter tracts and measuring effects along the whole extent of each tract. The study yielded three main findings. First, age-related white matter deficits increased gradually from posterior to anterior segments within specific fiber tracts traversing frontal and parietal, but not temporal cortex. This pattern inverts the sequence of myelination during childhood and early development observed in previous studies and lends support to a "last-in-first-out" theory of the white matter health across the lifespan. Second, both the effects of aging on white matter and their impact on cognitive performance were stronger for radial diffusivity (RD) than for axial diffusivity (AD). Given that RD has previously been shown to be more sensitive to myelin integrity than AD, this second finding is also consistent with the myelodegeneration hypothesis. Finally, the effects of aging on select white matter tracts were associated with age difference in specific cognitive functions. Specifically, FA in anterior tracts was shown to be primarily associated with executive tasks and FA in posterior tracts mainly associated with visual memory tasks. Furthermore, these correlations were mirrored in RD, but not AD, suggesting that RD is more sensitive to age-related changes in cognition. Taken together, the results help to clarify how age-related white matter decline impairs cognitive performance.

Figure 1

Methodology for assessing diffusion metrics along fiber tract lengths. (A) Seed (red) and target (green) regions were drawn on the b0 image in order to identify white matter tracts; in this example an axial view of the anterior cortex depicts a seed region around the midline and left and right ROIs in frontal cortex are used to elucidate fiber tracts passing through the genu of the corpus callosum; (B) identified extracted fiber tracts with outliers removed; (C) mean fibers were constructed by averaging the spatial characteristics of all fibers within a tract. (D) Linearly adjusted mean differences were assed via ANOVA and F-statistics were transposed back onto the mean tract for visualization.

Figure 2

Age-related differences in FA, RD, and AD for tracts of interest. FA differences are shown along a tract; FA data were smoothed with a 6mm kernel and displayed upon mean tracts from a representative subject for the genu, UFs, CBs, ILFs, and splenium. RD and AD differences within these target sections are displayed in graphs corresponding to specific long association tracts. RD = radial diffusivity; AD = axial diffusivity; CB = cingulum bundle; UF = uncinate fasciculus; ILF = inferior longitudinal fasciculus. Metric dimensions: AD, RD: 10⁻³ mm²/s; * = P < 0.01; ** = P < 0.005; *** = P < 0.001.

Figure 3

Age-related differences in AD (A) and RD (B) represented upon mean tracts from a representative subject, demonstrating greater age-related effects for RD than AD. Color scales for RD have been reversed such that OA > YA differences are reflected by warmer colors. RD = radial diffusivity; AD = axial diffusivity.

Figure 4

Trend analysis of the CB and frontal UF. Trend lines for both linear (solid) and quadratic (dashed) trends are represented over the y-axis component (Talairach coordinates) of each tract using the effect size (partial eta) based on a pairwise analysis at points along a tract. F statistics for best fit for both linear and quadratic terms are displayed below the data. Linear trends are significant for the left and right CB, and the left and right (frontal) UF. The vertical dashed line approximates the border between frontal and parietal cortex, according to the anterior border precentral sulcus. CB = cingulum bundle; UF = uncinate fasciculus; YA = young adult; OA = older adult.

Figure 5

Representative correlation between diffusivity measures extracted from the right uncinate fasciculus and performance on the Intra-Extra Dimensional Set Shift (IED) task. Scatterplots show significant relationships between IED performance and FA and RD, but not AD. Metric dimensions: FA: dimensionless; AD, RD: 10⁻³ mm²/s. * = P < 0.05; *** = P < 0.005.