Objective:

This study aimed to assess the progression of cognitive and behavioral changes and identify early predictors of these alterations in ALS patients.

Background:

Despite advances in understanding cognitive and behavioral impairments in ALS, how these functions change over time is still uncertain. Existing longitudinal studies have yielded inconsistent results

Design/Methods:

A total of 161 ALS patients were evaluated within one month of diagnosis (T0) and re-assessed after one year (T1) using a comprehensive set of cognitive and behavioral tests. Whole genome sequencing was performed on all participants, and 26 patients with normal cognitive function (ALS-CN) underwent 18F-FDG PET imaging at T0.

Results:

Of the 161 patients, 107 completed the follow-up at T1. The remaining patients included 10 with frontotemporal dementia and 44 who were either unable to participate or had passed away. At T0, 67 patients (62.6%) were cognitively normal (ALS-CN), while 40 (38.4%) exhibited some level of cognitive or behavioral impairment. By T1, 18 ALS-CN patients (26.9%) showed cognitive decline. Those who experienced phenoconversion had lower baseline scores in Letter Fluency (FAS) (p<0.001) and ECAS Verbal Fluency (p=0.017). Both measures independently predicted phenoconversion in logistic regression models, with cut-off values of 28.75 and 14.2, providing good sensitivity and specificity. Additional predictors included older age, lower education, and specific ALS-related genetic mutations. Phenoconverting patients also exhibited hypometabolism in the left temporal lobe. Among the 40 patients with cognitive impairment at T0, 13 (32.5%) showed further deterioration by T1, with FAS (p=0.02) and ECAS Verbal Fluency (p=0.023) scores predicting their decline.

Conclusions: