Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis

Abstract

Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.

Fig 1

Amyotrophic lateral sclerosis (ALS) phenotypic spectrum. PBP=progressive bulbar palsy; PLS=primary lateral sclerosis; PMA=progressive muscular atrophy. Created using BioRender.com

Fig 2

Amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD) clinical syndromes and disease mechanisms contributing to neurodegeneration. ALS=amyotrophic lateral sclerosis; ALSbi=ALS with behavioral impairment; ALScbi=ALS with combined cognitive and behavioral impairment; ALSci=ALS with cognitive impairment; bvFTD=behavioral variant FTD; CBS=corticobasal syndrome; FTD=frontotemporal dementia; LMND=lower motor neuron predominant; nfvPPA=non-fluent variant primary progressive aphasia; PBP=progressive bulbar palsy; PLS=primary lateral sclerosis; PMA=progressive muscular atrophy; PSP=progressive supranuclear palsy; svPPA=semantic variant primary progressive aphasia; UMND=upper motor neuron predominant

Fig 3

Neuroimaging changes in amyotrophic lateral sclerosis. A: motor cortex (red) atrophy. B: axial T2-FLAIR (fluid attenuated inversion recovery sequence) magnetic resonance image at level of midbrain, showing hyperintensity in cerebral peduncles corresponding to corticospinal tracts (black arrow)