Quantitative DTI metrics in a canine model of Krabbe disease: comparisons versus age-matched controls across multiple ages

Abstract

Purpose The purpose of this study was to compare quantitative diffusion tensor imaging metrics in dogs affected with a model of Krabbe disease to age-matched normal controls. We hypothesized that fractional anisotropy would be decreased and radial diffusivity would be increased in the Krabbe dogs. Methods We used a highly reproducible region-of-interest interrogation technique to measure fractional anisotropy and radial diffusivity in three different white matter regions within the internal capsule and centrum semiovale in four Krabbe affected brains and three age-matched normal control brains. Results Despite all four Krabbe dogs manifesting pelvic limb paralysis at the time of death, age-dependent differences in DTI metrics were observed. In the 9, 12, and 14 week old Krabbe dogs, FA values unexpectedly increased and RD values decreased. FA values were generally higher and RD values generally lower in both regions of the internal capsule in the Krabbe brains during this period. FA values in the brain from the 16 week old Krabbe dog decreased and were lower than in control brains and RD values increased and were higher than in control brain. Conclusion Our findings suggest that FA and RD in the internal capsule and centrum semiovale are affected differently at different ages, despite disease having progressed to pelvic limb paralysis in all dogs evaluated. In 9, 12, and 14 week old Krabbe dogs, higher FA values and lower RD values are seen in the internal capsule. However, in the 16 week old Krabbe dog, lower FA and higher RD values are seen, consistent with previous observations in Krabbe dogs, as well as observations in human Krabbe patients.

Keywords: Diffusion tensor; Krabbe; canine; fractional anisotropy; lysosomal storage disease; magnetic resonance; radial diffusivity.

Figure 1.

Example of region of interest (ROI) placement in the unaffected 17-week control specimen. (a) ROIs have been placed in the posterior internal capsule. The black line indicates the dorsal boundary of the internal capsule. (b) ROIs have been placed in the centrum semiovale. The black line indicates the boundary between the centrum semiovale and the internal capsule and the white line indicates the boundary between the centrum semiovale and the corpus callosum.

Figure 2.

Depiction of fractional anisotropy (FA) in each region by specimen. Mean values and 95% confidence intervals are depicted. The 17 week normal specimen is included here as the 16 week control. Significant differences between age-matched pairs are marked with (*). No overlap in confidence intervals was otherwise seen between age-matched pairs or between specimens of the nearest age except where noted. (a) Anterior internal capsule. Confidence intervals are seen to overlap between the 9 week Krabbe and 9 week control specimens. (b) Posterior internal capsule. Confidence intervals are seen to overlap between the 9 week and 12 week control specimens, and between the 16 week Krabbe and 17 week control specimens. (c) Centrum semiovale. Confidence intervals are seen to overlap between the 12 week, 14 week and 16 week Krabbe specimens, and between the 9 week and 12 week control specimens.

Figure 3.

Radial diffusivity (RD) in each region by specimen. Mean values and 95% confidence intervals are depicted. The 17 week normal specimen is included here as the 16 week control. Significant differences between age-matched pairs are marked with (*). No overlap was otherwise seen in confidence intervals between age-matched pairs or between specimens of the nearest age except where noted. (a) Anterior internal capsule. Confidence intervals are seen to overlap between the 9 week and 12 week Krabbe specimens, and between the 9 week Krabbe and 9 week control specimens. (b) Posterior internal capsule. Confidence intervals are seen to overlap between the 12 week and 14 week Krabbe specimens. (c) Centrum semiovale. Confidence intervals are seen to overlap between the 9 week and 12 week Krabbe specimens.