Proposed Research Criteria for Mild Motor Impairment as a Prodromal Syndrome in Amyotrophic Lateral Sclerosis

BACKGROUND AND OBJECTIVES: The presymptomatic stage of amyotrophic lateral sclerosis (ALS) is typically assumed to be clinically silent. Our previous work, however, has revealed evidence of a prodromal stage, termed mild motor impairment (MMI). In this study, we propose operational criteria for MMI, describe its frequency in a genetically diverse cohort, and examine the association between MMI and time to ALS phenoconversion. METHODS: cohort. Among phenoconverters and presymptomatic carriers, cumulative probabilities of phenoconversion were estimated for those with and without MMI at baseline. Cox proportional hazard models evaluated associations between risk factors (MMI, age, genotype) and time from baseline to ALS phenoconversion. Moreover, the hazard rate of phenoconversion was 1.7 times higher for every 10-year increase in age and varied by genotype. DISCUSSION: MMI is a recognizable syndrome. Although nonspecific, it identifies presymptomatic carriers at elevated risk of ALS phenoconversion. Combining MMI with emerging biomarkers of underlying pathology may help differentiate those who are prodromal from those who are not prodromal for ALS. Characterization and study of MMI, including replication in other studies, may empower early therapeutic intervention and ALS prevention efforts.