Cortical and Pyramidal Tract Pathology in ALS Patients as Detected by Voxel-Based Morphometry and Diffusion Tensor Imaging

Objective: We have attempted to detect brain abnormalities in ALS patients by using an unbiased approach with optimized voxel-based morphometry and diffusion tensor imaging in comparison to healthy controls. Background: In ALS patients, the presence of cerebral atrophy on conventional and scientific neuroimaging has been a matter of debate. We therefore applied voxel-based morphometry (VBM) and diffusion-tensor imaging (DTI) as powerful unbiased whole-brain methods to detect subtle regional differences in grey matter volume (GMV) and fractional anisotropy (FA). Methods: 17 ALS patients diagnosed according to the revised El-Escorial criteria and 17 age-matched control subjects were enrolled in this study. The mean revised ALS functional rating scale score (ALSFRS-R, mean±SD) was 40±5. All subjects had a 3D T₁-weighted high-resolution anatomical MRI and FA maps derived from 12 bidirectional planes on a 1.5T neuro-optimized GE scanner. Images were analyzed using an optimized protocol in SPM99. Group comparisons of regional grey matter volume (modulated data) were made using ANCOVA with the global mean voxel value as confounding factor. Relationships between significant voxels and the ALSFRS-R were modelled using regression analyses. We also performed a small volume correction (SVC, 10mm sphere) when a priori hypotheses about regional effects existed. Results: ALS patients showed a relative decrease in GMV in the precentral gyrus bilaterally, inferior parietal lobe and the middle frontal gyrus bilaterally. There was a positive correlation between ALSFRS-R and GMV in the frontal superior gyrus and the inferior parietal lobe. A significant decrease of fractional anisotropy indicating fiber damage was found in the corticospinal tract, along commissural fibers and frontal projections. Single subject blinded analysis of FA contrast maps allowed the detection of ALS pathology in 16 out of 17 patients Conclusion: Using VBM, our results consistently show atrophy in precentral, parietal and frontal regions which is in line with findings of pathology extending from the sensorimotor cortex to frontal areas in ALS. The changes seen in DTI also indicate widespread pathology in the corresponding fiber tracts. Our study supports the view that ALS is a multisystem disorder which is not restricted to the motor system. Longitudinal studies should give new insight into the spatiotemporal characteristics of cerebral abnormalities in ALS.