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

Abstract

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: Pre-Symptomatic Familial ALS (Pre-fALS) study, initiated in 2007, is a longitudinal natural history and biomarker study of unaffected carriers of any ALS-associated pathogenic variant. Proposed research criteria for MMI were developed based on clinical review of case histories of ALS phenoconverters in the Pre-fALS study. These criteria were then systematically applied to the remaining Pre-fALS 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.

Results: The study cohort includes 49 controls (mean age 38.9, 61% female), 153 presymptomatic carriers (mean age 43.1, 61% female), and 31 ALS phenoconverters (mean age 54.4, 58% female). Seven criteria for MMI are proposed, each reflecting a different pattern of upper/lower motor neuron signs, without corresponding weakness, in 1 or more of 4 topographic regions. MMI, defined as meeting ≥1 of these criteria, was observed at 1 or more study visits in 17 of 31 phenoconverters (55%) before clinically manifest ALS, 66 of 153 presymptomatic carriers (43%) who had not yet phenoconverted, and 7 of 49 controls (14%). Among all mutation carriers, the 25th percentile (95% CI) of time to phenoconversion was, respectively, 3.7 (1.6-4.7) and 14.1 (8.9-∞) years for those with and without MMI at baseline, with a hazard ratio of 5.1 (95% CI 2.2-12.2, p < 0.0001). 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.

Figure 1. Temporal Course of MMI

Swimmer plots illustrating the temporal course with which MMI is observed among (A) ALS phenoconverters, (B) presymptomatic SOD1 A4V and non-A4V variant carriers, and (C) presymptomatic carriers of C9orf72 repeat expansion. Each row depicts the follow-up history of a unique participant since their baseline assessment, with red crosses (+) denoting study visits with MMI and empty blue circles (◯) denoting study visits without MMI. Row colors indicate genotypes: SOD1 A4V (blue), SOD1 non-A4V (pink), C9orf72 HRE (green), and pathogenic variants in other genes (brown). The x-axis indicates follow-up time, right-aligned at time of phenoconversion (A) or most recent follow-up (B, C). For additional protection of participant confidentiality and the blinding implemented in the study, only partial information is displayed for the presymptomatic group, with follow-up duration truncated at −9 (B) or −6.5 (C) years and data from only approximately 85% of participants shown. ALS = amyotrophic lateral sclerosis; HRE = hexanucleotide repeat expansion; MMI = mild motor impairment.

Figure 2. Cumulative Probability of Phenoconversion by MMI Status at Baseline

Cumulative probability of phenoconversion among those with MMI at baseline (red) compared with those without MMI at baseline (blue). (A) All genotypes combined (log-rank p < 0.0001). The 25th percentiles of time to phenoconversion were 3.7 and 14.1 years for those with and without MMI at baseline, respectively. The median time to phenoconversion was 4.7 years among those with MMI at baseline, and not estimable for those without MMI at baseline. (B) Carriers of a pathogenic variant in the SOD1 gene (log-rank p = 0.0005). The 25th percentiles of time to phenoconversion were 3.4 and 9.1 years for those with and without MMI at baseline, respectively. (C) Carriers of C9orf72 HRE (log-rank p = 0.0005). The 25th percentile of time to phenoconversion was 4.7 years for those with MMI at baseline, but was not estimable for those without MMI at baseline. MMI = mild motor impairment.