Cognitive and behavioral manifestations of the C9orf72 mutation in Amyotrophic Lateral Sclerosis: an age, education, and gender-matched cohort study.

OBJECTIVES: The presence of a hexanucleotide expansion in the gene C9orf72 confers a higher risk of developing ALS and FTD with associated cognitive and behavioral change, although penetrance is incomplete, and many gene carriers never exhibit any clinical signs during their lifetime. To date, there have been few studies investigating additional factors such as age, years of education, gender, and their influence on cognition and behavior in people with ALS (pwALS), particularly those with a hexanucleotide expansion in the gene C9orf72. METHODS: We selected 104 consenting pwALS from the Irish ALS register, comprising 52 C9orf72 positive participants and 52 C9orf72 negative controls matched on age, years of education, and gender. Cognitive functioning was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), while behavioral changes were examined using the Beaumont Behavioral Inventory (BBI). RESULTS: No significant differences in ECAS performance were observed across the two groups, with the exception of visuospatial performance, which was more impaired in those carrying the C9orf72 repeat expansion (p = .001). Similarly, there was no difference in behavoural scores between the 2 groups. CONCLUSIONS: These findings suggest that the presence of the C9orf72 repeat expansion does not presage the development of significant cognitive or behavioral impairment early in the disease stage when controlled for age, years of education, and gender. When interpreting these results, it is important to consider the relatively small sample size, and the exclusion criteria of previous clinically significant comorbidities.