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.

Keywords: C9orf72; TDP‐43; amyotrophic lateral sclerosis; behavioral; cognitive; frontotemporal dementia; motor neurone disease.

FIGURE 1

A potential pipeline for assessing the clinicopathological basis for cognitive and behavioral dysfunction in ALS. Asymptomatic recruitment of participants is essential. Clinical phenotyping should occur at regular periods from baseline to death using consistent cognitive and behavioral assessment and same‐day neuroimaging analysis to minimize temporal dissociation. Known pre‐symptomatic C9orf72 hexanucleotide repeat expansion (HRE) carriers can be utilized to elucidate the genesis of cognitive/behavioral impairment in the ALS disease process. At postmortem, pTDP‐43 immunohistochemical staining and transcriptomic analysis (e.g., bulk RNA‐seq and in situ hybridization techniques) on clinico‐anatomically relevant regions may identify pathological signatures associated with cognitive or behavioral domain‐specific impairment. ALS, amyotrophic lateral sclerosis; ECAS, Edinburgh Cognitive and Behavioural ALS Screen. Source: Created with Biorender.com.