High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants

Objective: While the cognitive-behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive-behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS-related genes (wild-type [WT]-ALS) and healthy controls. Methods: All ALS patients seen at the Turin ALS expert center in the 2009-2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1-ALS) and WT-ALS (n = 829) were enrolled in the study. A series of 129 controls was also included. Results: Among the 28 SOD1-ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS-FTD. SOD1-ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1-ALS patients had similar scores in all tests compared to WT-ALS, except the Story-based Empathy Task (SET), where they performed worse. Interpretation: Cognitive-behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1-ALS. ANN NEUROL 2024