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

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.