The Basis of Cognitive and Behavioral Dysfunction in Amyotrophic Lateral Sclerosis

ABSTRACT Objective To summarize and evaluate evidence pertaining to the clinical, genetic, histopathological, and neuroimaging correlates of cognitive and behavioral dysfunction in amyotrophic lateral sclerosis (ALS). Methodology We comprehensively reviewed the literature on cognitive and behavioral manifestations of ALS, narrating findings from both cross‐sectional and longitudinal studies. We discussed knowledge gaps in the evidence base and key limitations affecting studies to date, before formulating a framework for future research paradigms aimed at investigating clinicopathological correlates of neuropsychological dysfunction in ALS. Results Studies have demonstrated clinical associations with cognitive dysfunction in ALS e.g., bulbar‐onset of symptoms, pathological associations (extramotor TDP‐43 deposition), and imaging associations (frontotemporal involvement). The most common behavioral deficit, apathy, is highly associated with verbal fluency, but longitudinal studies assessing behavioral dysfunction in ALS are comparatively lacking. Conclusion Longitudinal studies have been helpful in identifying several potential correlates of cognitive and behavioral dysfunction but have frequently been confounded by selection bias and inappropriate testing platforms. This review provides a framework for more robust assessment of clinicopathological associations of neuropsychological abnormalities in ALS in the future, advocating for greater utilization of pre‐symptomatic C9orf72 repeat expansion‐carrying cohorts.