Whole brain-based analysis of regional white matter tract alterations in rare motor neuron diseases by diffusion tensor imaging

Abstract

Different motor neuron disorders (MNDs) are mainly defined by the clinical presentation based on the predominance of upper or lower motor neuron impairment and the course of the disease. Magnetic resonance imaging (MRI) mostly serves as a tool to exclude other pathologies, but novel approaches such as diffusion tensor imaging (DTI) have begun to add information on the underlying pathophysiological processes of these disorders in vivo. The present study was designed to investigate three different rare MNDs, i.e., primary lateral sclerosis (PLS, N = 25), hereditary spastic paraparesis (HSP, N = 24), and X-linked spinobulbar muscular atrophy (X-SBMA, N = 20), by use of whole-brain-based DTI analysis in comparison with matched controls. This analysis of white matter (WM) impairment revealed widespread and characteristic patterns of alterations within the motor system with a predominant deterioration of the corticospinal tract (CST) in HSP and PLS patients according to the clinical presentation and also in patients with X-SBMA to a lesser degree, but also WM changes in projections to the limbic system and within distinct areas of the corpus callosum (CC), the latter both for HSP and PLS. In summary, DTI was able to define a characteristic WM pathoanatomy in motor and extra-motor brain areas, such as the CC and the limbic projectional system, for different MNDs via whole brain-based FA assessment and quantitative fiber tracking. Future advanced MRI-based investigations might help to provide a fingerprint-identification of MNDs.

Figure 1

Results of the whole brain‐based analysis of the PLS patients. Local maximum of decreased FA values (thresholded at P < 0.05, corrected for multiple comparisons) in projections to the midbody of the corpus callosum (CC) in PLS patients in a sagittal, coronar and axial view (upper panel). The coronar multi‐slice view (lower panel) exhibits widespread clusters of reduced FA values within subcortical WM areas of mainly the motor system including the CST and the CC as well as the projectional fiber system of the upper brain stem and the frontal lobe. The significance level (Z‐score) is indicated by color temperature according to the scale (L = left).

Figure 2

Results of the whole brain‐based FA analysis of the HSP patients. Local maximum of decreased FA values (thresholded at P < 0.05, corrected for multiple comparisons) in projection to the dorsal part of the CC in patients with HSP (upper panel). The multi‐slice view shows significantly reduced FA values within subcortical WM areas of the motor and limbic system (lower panel).

Figure 3

Results of the whole brain‐based FA analysis of the X‐SBMA patients. Local maximum of decreased FA values (thresholded at P < 0.05, corrected for multiple comparisons) in projections to the CST in patients with X‐SBMA (upper panel). The multi‐slice view shows significantly reduced FA values within subcortical WM areas of the motor and limbic system (lower panel).

Figure 4

Results of the cojoint whole brain‐based analysis of the PLS patients and the HSP patients: Cojoint display of decreased FA values (red) and increased MD values (green) (each thresholded at P < 0.05, corrected for multiple comparisons) in PLS patients (upper row) and in HSP patients (lower row). The overlap between significantly decreased FA and significantly increased MD is color‐coded in yellow. The significance level (Z‐score) is indicated by color intensity according to the scale (red—significant FA decrease, green—significant MD increase, yellow—overlap) (L = left).

Figure 5

Results of the fiber tracking (FT) analysis of the PLS patient group (left column), the HSP patient group (center column), and the X‐SBMA patient group (right column). The 3D view of the comparison of tractography results with seed points within the areas of significantly reduced FA values in the CC (upper row) and in the posterior limb of the internal capsule (PLIC) of both hemispheres (lower row). According to color‐coding conventions, red means right‐left, green means anterior‐posterior and blue means cranio‐caudal directionality. FT was performed on averaged DTI datasets that were created by arithmetically averaging all MNI‐normalized single subject DTI datasets of one group (e.g., all PLS patients and the corresponding controls).

Figure 6

Upper row: significant FA decrease between X‐SBMA patients and HSP patients. Display focus is the splenium of the corpus callosum (MNI (x,y,z) = (0, −38, 19)). Central row: significant FA decrease between X‐SBMA patients and PLS patients. Display focus is the midbody of the corpus callosum (MNI (x,y,z) = (0, −15, 26)). Lower row: significant differences between HSP patients and PLS patients, where FA reduction (FA(HSP) > FA(PLS)) is encoded red and FA increase (FA(HSP) < FA(PLS)) is encoded blue. The display focus was chosen to display FA differences within the motor system (MNI (x,y,z) = (0, −33, 43)). All data are thresholded at P < 0.05 and FDR corrected, including a cluster threshold of 64 voxels.