# A Comprehensive Overview of Neurophysiological Correlates of Cognitive Impairment in Amyotrophic Lateral Sclerosis

## TL;DR

This paper reviews how cognitive impairments in ALS are linked to brain changes, suggesting they may be part of a broader disease process.

## Contribution

The paper provides a narrative review connecting cognitive deficits in ALS with neurophysiological and genetic findings.

## Key findings

- ALS and FTD are linked through shared neuropathological and genetic features.
- Cognitive deficits in motor-dominant ALS are associated with systems-level brain disruptions.
- Neuroimaging and EEG studies may reveal biomarkers for cognitive impairment in ALS.

## Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the gradual loss of motor control, typically resulting in paralysis and death within 3 to 5 years of diagnosis. ALS shares neuropathological and genetic associations with fronto-temporal dementia (FTD), a neurodegenerative condition primarily impacting cognitive functions. These two conditions are increasingly viewed as manifestations of a single molecular disease process that affects distinct brain systems, impacting motor neuronal pathways in ALS and fronto-cortical functions in FTD. However, this simple dichotomy belies the complexity of these conditions. In particular, patients with primary motor ALS can also experience significant cognitive deficits. Investigating the pathobiological and neurophysiological underpinnings of these impairments is essential for a comprehensive understanding of ALS and may open avenues for targeted therapies to alleviate these debilitating symptoms. Moreover, the biophysical correlates of cognitive deficits in ALS may serve as sensitive biomarkers for evaluating potential therapeutics. In this narrative review, we begin with an overview of the clinical features and genetics of ALS, followed by a review of the associated cognitive deficits that are adjunctive to motor decline. We then highlight neuroimaging studies from our laboratory and the broader literature, using EEG and other modalities that are beginning to uncover systems-level brain disruptions potentially underlying cognitive impairment in motor-dominant ALS.