Microstructural integrity of cerebral fiber tracts in hereditary spastic paraparesis with SPG11 mutation

Abstract

Background and purpose: ARHSP-TCC is characterized by progressive leg spasticity, ataxia, and cognitive dysfunction. Although mutations in the human SPG11 gene were identified as responsible for ARHSP-TCC, the cerebral fiber integrity has not been assessed systemically. The objective of this study was to assess cerebral fiber integrity and its clinical significance in patients with ARHSP-TCC.

Materials and methods: Five patients from 2 families who were clinically and genetically confirmed to have ARHSP-TCC were examined by neuropsychological evaluation and DSI of the brain. We performed voxel-based GFA analysis for global white matter evaluation, tractography-based analysis for tract-to-tract comparisons, and tract-specific analysis of the CST to evaluate microstructural integrity along the axonal direction.

Results: The neuropsychological evaluation revealed widespread cognitive decline across all domains. Voxel-based analysis showed global reduction of GFA in the cerebral white matter. Tractography-based analysis revealed a significant reduction of the microstructural integrity in all neural fiber types, while commissure and association fibers had more GFA reduction than projection fibers (P < .00001). Prefrontal and motor portions of the CC were most severely affected among all fiber tracts (P < .00001, P = .018). Tract-specific analysis of the CST validated a "dying-back" phenomenon (R(2) = 0.68, P < .00001).

Conclusions: There was a characteristic gradation in the reduction of microstructural integrity among fiber types and within the CC in patients with the SPG11 mutation. The dying-back process in CST might explain the pathogenic mechanisms for ARHSP-TCC.

Fig 1.

Examples of ROIs and reconstructed tracts. A, ROIs of orbitofrontal (green and yellow), motor (light and dark brown), and occipital (greenish blue and blue) portions of the CC. B, ROIs (blue and yellow) of the left arcuate fasciculus. C, ROIs (dark brown, light brown, and yellow) of the left cingulum bundle. D, ROIs (yellow, dark brown, and light brown) of the bilateral CSTs. The fiber tracts are pseudocolored in 3D according to the local tract orientation with respect to the image coordinates.

Fig 2.

P value map and tractography in patients and controls. A, P value map shows significant differences in microstructure integrity of white matter between patients and controls. B–D, Reconstructive tracts of the CC, arcuate fasciculus, and CST in a control subject. E–G, Corresponding tracts in patient 3.

Fig 3.

Quantitative evaluation of microstructural integrity of fiber tracts. A, Mean GFA values of commissure, association, and projection fibers in patients (white bars) and controls (gray bars) and normalized GFA values (patients/controls, black bars) in each fiber type (double asterisks indicate P < .0001; asterisk, P < .001). B, Normalized GFA value of each fiber tract of the corpus callosum (double asterisks indicate P < .0001; asterisk, P = .0178). C, Mean GFA value of controls (black line, filled circles) and patients (gray line, open circles) along the CSTs from the motor cortices (step 71, x-axis) to the pyramid (step 1, x-axis). D, Normalized GFA value of CSTs between the pyramid to the internal capsule and the linear regression values.