Widespread microstructural white matter involvement in amyotrophic lateral sclerosis: a whole-brain DTI study

Abstract

Background and purpose: The extensive application of advanced MR imaging techniques to the study of ALS has undoubtedly improved our knowledge of disease pathophysiology, even if the actual spread of the neurodegenerative process throughout the central nervous system is not fully understood. The present study aimed to detect WM patterns of microstructural abnormalities to better investigate the pathologic process in ALS, within but also beyond CSTs, in a whole-brain analysis.

Materials and methods: DTI was performed in 19 patients with ALS and 20 matched healthy controls, by using whole-brain TBSS and VOI analyses.

Results: We observed a significant decrease of FA in the body of CC of the ALS group (P < .05). At the VOI level, both FA decrease and RD increase in the body of CC significantly correlated with the UMN score (P = .003 and P = .02). Additionally, significant voxelwise positive correlations between FA and the ALSFRS-R were detected in the WM tracts underneath the left premotor cortex (P < .05).

Conclusions: The correlations between reduction of FA and increase of RD in the body of CC with the UMN score indicate that the WM degeneration in the CC is strictly related to the ALS pyramidal impairment, while the correlation between FA and ALSFRS-R in the associative tracts underneath the left premotor cortex might reflect the progressive spread of the disease from the motor toward the extramotor areas.

Fig 1.

Regional FA reductions in patients with ALS compared with controls. Blue shows the CST (B) and the uncinate (C), the inferior occipitofrontal (D) and the superior longitudinal (E) fasciculi (derived from the Johns Hopkins University WM tractography atlas^,). F−H, 3D renderings of the FA skeleton (green), in which red shows regional FA reductions in patients. Prominent involvement of the CC (A) and rostral CST (B) is revealed in patients with ALS (red-yellow scale), with caudal CST changes seen in uncorrected FA results (A, green-only scale). Reduced FA values in the ALS group are also detected in frontal (associative) tracts (C−H).

Fig 2.

VOI (top panel) and GLM (lower panel) correlation analyses of FA and RD measures with UMN score values. VOI analysis (top panel) shows significant inverse and positive correlations, respectively, of FA and RD values (expressed in mm² × s⁻¹) with the UMN score in the body of CC (P = .003, P = .02). GLM analysis (lower panel) also shows an inverse correlation between FA and the UMN score in the midbody of CC (red-yellow), while RD values correlate with the UMN score mainly within the left paracentral lobule WM (blue) but not in the CC (uncorrected level of significance).

Fig 3.

GLM correlation analyses of FA, RD, and MD measures with ALSFRS-R and disease progression-rate values. A positive correlation between FA and ALSFRS-R is revealed in the WM underneath the left premotor cortex (especially the paracentral lobule and cingulate gyrus) (P < .05, corrected) (top left), while an inverse correlation is identified between FA and the disease-progression rate within the CSTs (pons) and frontotemporal WM (middle temporal and left inferior frontal gyri) (P < .01, uncorrected) (top right). Additionally, positive correlations are identified with both RD (low left) and MD (low right) measures in the hippocampus and within the inferior longitudinal fasciculus (P < .01, uncorrected).