Mild cognitive impairment in presymptomatic amyotrophic lateral sclerosis

Background Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically and biologically related, and each may be preceded by a prodromal stage of disease. Mild cognitive and behavioural impairment (MCI/MBI) have also been observed in those with clinically manifest ALS. The primary aim of this study was to characterise MCI in presymptomatic ALS. Methods Criteria for frontotemporal-related MCI (MCI-ft), which require evidence of subthreshold cognitive performance or decline, were adapted from existing frameworks for MCI in prodromal FTD, presymptomatic ALS and clinically manifest ALS. MCI-ft was characterised in 216 Pre-fALS participants (74 C9ORF72 , 94 SOD1 , 20 other pathogenic variant carriers and 28 non-carriers) with neuropsychological data at 807 study visits. All designations were reviewed by a research neuropsychologist, with consensus discussions as needed. Results MCI-ft was observed in 15 (20%) C9ORF72 , 12 (13%) SOD1 and 3 (%) of other carriers at one or more study visits, compared to 1 (4%) non-carrier. Most visits with MCI-ft showed impairment affecting both language and executive functioning. Fluctuations in MCI-ft status between assessments were common. Conclusion The observed frequency and temporal course of MCI-ft in presymptomatic ALS, using criteria based on subthreshold cognitive performance and decline, expands understanding of this phase of disease. These findings help to inform future research examining the risk of phenoconversion to clinically manifest disease and aid the design of disease prevention trials.