Theory of mind impairment related to C9orf72 repeat expansion in amyotrophic lateral sclerosis: a case-control study

Objective: To investigate cognitive and affective theory of mind (ToM) in amyotrophic lateral sclerosis (ALS) patients carrying the C9orf72 repeat expansion (C9orf72+), compared with matched non-mutated (C9orf72−) ALS patients and healthy controls (HCs). Methods: We assessed 34 C9orf72+ ALS patients, 34 C9orf72− ALS patients matched for sex, age, education, and cognitive category, and 34 HC matched for sex, age, and education. Participants underwent neuropsychological evaluation, including the Story-Based Empathy Task (SET), assessing cognitive ToM (Intention Attribution, IA), affective ToM (Emotion Attribution, EA), and Causal Inference (CI). Results: C9orf72+ patients showed lower SET-global score than C9orf72− patients (p = 0.028). Compared with HC, C9orf72+ showed lower score in SET-global score and all SET subtests (all p < 0.05). C9orf72+ cognitively normal differed from HC in SET-global score, IA, and EA (all p < 0.038), whereas C9orf72− cognitively normal did not differ from HC. Multiple linear regression analyses indicated that ALS-specific cognitive domains only explained ∼25% of ToM variance, with no association with demographic, clinical, or behavioral variables. Cluster analysis identified three cognitive profiles based on SET performance, with the most impaired cluster showing the highest proportion of C9orf72+ patients (68%). Conclusion: C9orf72-mutated ALS patients showed more pronounced impairment in cognitive and affective ToM than non-mutated ALS patients, independent of demographic, clinical, and cognitive features. These findings, although requiring confirmation on larger samples, suggest that ToM dysfunction may represent a sensitive marker of cognitive involvement in ALS-C9orf72-associated disease, particularly in its affective component.