Relationship between Clinical Parameters and Brain Structure in Sporadic Amyotrophic Lateral Sclerosis Patients According to Onset Type: A Voxel-Based Morphometric Study

Abstract

Background and purpose: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, phenotypically heterogeneous neurodegenerative disease affecting mainly the motor neuron system. The present voxel-based morphometry (VBM) study investigated whether patterns of brain atrophy differ among sporadic ALS subtypes.

Material and methods: Sporadic ALS patients (n = 62) with normal cognition and age-matched healthy controls (n = 57) were included in the study. ALS patients were divided into limb- and bulbar-onset groups according to clinical manifestations at symptom onset (n = 48 and 14, respectively). Clinical measures were ALS Functional Rating Scale-Revised (ALSFRS-R) score, disease duration, and forced vital capacity (FVC). Patterns of brain atrophy between ALS subgroups were compared by VBM.

Results: In limb-onset ALS patients, atrophy was largely confined to the motor cortex and adjacent pre- and postcentral regions. However, in the bulbar-onset group, affected regions were more widespread and included these same areas but also extended to the bilateral frontotemporal and left superior temporal and supramarginal gyri, and multiple regression analysis revealed that their ALSFRS-R scores were associated with extensive loss of gray matter while FVC was related to atrophy in subcortical regions of the left superior temporal gyrus. In limb-onset ALS patients, disease duration was related to the degree of atrophy in the motor and adjacent areas.

Conclusion: Sporadic ALS subtypes show different patterns of brain atrophy. Neural networks related to limb and bulbar motor functions in each ALS subtype may underlie their distinct patterns of cerebral atrophy. That is, more extensive cortical and subcortical atrophy is correlated with greater ALSFRS-R severity and shorter disease duration in the bulbar-onset subtype and may explain the poor prognosis of these patients.

Fig 1. Regional atrophy in ALS patients relative to controls.

(A, C) Limb-onset ALS showing gray matter atrophy in bilateral inferior frontal, left superior frontal, and left precentral gyri, SMA, and thalamus (A). In bulbar-onset ALS, atrophy was detected in bilateral frontal lobes, left superior temporal pole, and left inferior parietal, precentral, and postcentral gyri relative to healthy controls (C). In limb-onset ALS, white matter atrophy occurred around motor and association areas (SMA and around central lobules). (B, D) In the bulbar type, multiple areas of the white matter tract in extra-motor areas (SMA and inferior and superior frontal gyri) as well as the motor area were affected (displayed at P < 0.001, uncorrected, extended threshold = 100 voxels). The colored bar represents the T score.

Fig 2. Comparative analysis of regional gray and white matter atrophy between limb- and bulbar-onset ALS patients.

(A, B) The limb-onset subtype was characterized by decreased gray matter volume around motor areas (pre- and post-central and medial superior frontal areas) relative to the bulbar-onset subtype. (C, D) The bulbar-onset subtype exhibited atrophy in both gray and white matter in extra-motor areas—i.e., bilateral frontal, temporal, and cerebellar areas as compared to the limb type (displayed at P < 0.001, uncorrected, extended threshold = 100 voxels). The colored bar represents the T score.

Fig 3. Different atrophic patterns in bulbar- and limb-onset ALS patients according to ALSFRS-R scores.

(A, B) The bulbar-onset group showed atrophy in the bilateral frontal, left superior temporal, and supramarginal gyri (A). The limb-onset group showed atrophy in the left orbitofrontal area (B) (displayed at P < 0.001, uncorrected, extended threshold 100 voxels). The colored bar represents the T score.