Social Cognition Deficits in Amyotrophic Lateral Sclerosis: Cognitive, phenotypic and genetic determinants

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized not only by motor involvement but also by marked cognitive and behavioural heterogeneity, affecting up to 50% of patients. In recent years, social cognition (SC) — including facial emotion recognition (FER) and theory of mind (ToM) — has emerged as a relevant domain of dysfunction and has been incorporated into the revised diagnostic criteria for the ALS-frontotemporal spectrum disorder (ALS-FTSD). This PhD project investigated the prevalence of SC deficits in ALS, their cognitive, phenotypic, and genetic determinants, and the clinical implications of their systematic assessment. The first two studies, conducted on cohorts of 83 and 121 consecutively recruited patients at the Turin ALS Centre, documented a high prevalence of SC impairment: 31% of patients showed FER deficits, 22% ToM deficits, and 13% isolated SC impairment without deficits in other cognitive domains or behavioural symptoms. Even cognitively normal patients according to the Strong criteria performed significantly worse than healthy controls on SC measures, suggesting early and subtle involvement of this domain. Multiple linear regression and machine-learning analyses demonstrated that SC functions are largely independent from executive functions, although ToM showed partial associations with selected executive measures. SC assessment contributed to the attribution of cognitive impairment in 8–10% of patients, increasing the sensitivity of current diagnostic criteria. The third study, conducted on 1,322 patients using propensity score matching, revealed sex-specific trajectories of cognitive decline. Female patients showed better baseline FER performance but experienced a steeper decline as cognitive impairment progressed, including an approximately twofold higher risk of developing frontotemporal dementia compared with males. These findings suggest distinct biological mechanisms underlying sex-related cognitive vulnerability in ALS. The fourth study examined the ToM profile of 34 patients carrying the C9orf72 hexanucleotide repeat expansion compared with 34 matched non-carrier ALS patients and 34 healthy controls. C9orf72-positive patients performed significantly worse in both cognitive and affective ToM, independently of demographic characteristics, overall cognitive profile, and clinical phenotype, including among cognitively normal individuals. Cluster analysis identified three cognitive profiles, with the highest proportion of C9orf72 carriers concentrated in the most impaired cluster, supporting the existence of a mutation-specific neuropsychological signature. The fifth study explored the relationship between cognitive status and Advance Care Planning (ACP) in 1,219 patients from the PARALS registry. Cognitive impairment, including intermediate cognitive-behavioural profiles, was associated with a lower likelihood of completing ACP, highlighting the need for earlier and tailored interventions. In conclusion, SC deficits in ALS are frequent, often emerge early, and are partially dissociable from executive dysfunction. These deficits are associated with specific phenotypic and genetic determinants and have important clinical implications, particularly for diagnostic classification and end-of-life care planning. Overall, these findings support the clinical relevance of SC assessment in ALS and encourage further research into its neurobiological and prognostic correlates, with the aim of improving patient care throughout the disease course.