Asymmetry in amyotrophic lateral sclerosis: Clinical, neuroimaging and histological observations

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor system marked by significant phenotypic heterogeneity. Motor symptoms in the limbs consistently emerge focally and asymmetrically and, whilst variable, the pattern of regional progression related to the balance of clinical upper and lower motor neuron signs, upper versus lower limb onset and hand dominance to some extent. The neurobiological mechanisms and pathological correlates for this lateralized onset and non-random progression are uncertain. Cerebral neuroimaging studies have commonly reported structural and functional asymmetries in ALS, but the limited analysis of the pre-symptomatic phase has limited their implications. Post-mortem study of spinal cord provided strong evidence for focal pathology at symptom onset in ALS. Histopathological staging of molecular pathology in post-mortem tissue lacks clinical correlation and an ordered, sequential temporal progression in life cannot be assumed. The development of integrated brain and cord MRI holds the hope of deepening understanding of the relationship between focal symptomatology and histopathological progression. This review considers the nature and implications of asymmetry in ALS across clinical, neuroimaging and post-mortem histopathology, highlighting the current gaps in knowledge and the need for a broader investigative framework.

Keywords: DTI; MRI; fMRI; handedness; neuropathology.

Figure 1

Evidence sources for pathological asymmetry in ALS. In the approximately two-thirds of cases for which the onset of symptoms is with limb weakness (A), this is strikingly focal and lateralized. Bulbar-onset of symptoms may be considered to be bilateral but this may simply be lack of clinicopathological resolution. The progression of symptoms is influenced by the predominance of upper motor neuron (UMN) versus lower motor neuron (LMN) clinical involvement (B), as well as by the dominant upper limb. However, this is less consistent in cases with lower limb symptom onset (C). Advanced structural MRI studies in amyotrophic lateral sclerosis (ALS) (D) have frequently reported lateralized volumetric and white matter tract involvement, but with very limited correlation to the anatomical site of initial weakness e.g. homuncular somatotopic representation. Functional MRI studies have tended to show more symmetrical activation, which might reflect compensatory recruitment of less affected brain regions. Post-mortem histopathological studies in the ALS cord have shown that pathology is maximal at the level and side of initial weakness (E, represented by darker stars, including the cord in the case of limb onset ALS). Within the cerebral histopathological Braak staging system, this key issue has not been considered systematically, due to the limitations of end-stage study, and so a stereotyped, sequential pattern of spread of ALS pathology during life cannot be assumed. Created in BioRender. Yoganathan, K. (2025) https://BioRender.com/u29y282.

Figure 2

PRISMA diagram of paper selection for inclusion in the systematic review.