Neuropsychological impairment in amyotrophic lateral sclerosis-frontotemporal spectrum disorder

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a rapid course, characterized by motor neuron dysfunction, leading to progressive disability and death. This Review, which is aimed at neurologists, psychologists and other health professionals who follow evidence-based practice relating to ALS and frontotemporal dementia (FTD), examines the neuropsychological evidence that has driven the reconceptualization of ALS as a spectrum disorder ranging from a pure motor phenotype to ALS-FTD. It focuses on changes in cognition and behaviour, which vary in severity across the spectrum: around 50% individuals with ALS are within the normal range, 15% meet the criteria for ALS-FTD, and the remaining 35% are in the mid-spectrum range with milder and more focal impairments. The cognitive impairments include deficits in verbal fluency, executive functions, social cognition and language, and apathy is the most prevalent behavioural change. The pattern and severity of cognitive and behavioural change predicts underlying regional cerebral dysfunction from brain imaging and post-mortem pathology. Our increased recognition of cognition and behaviour as part of the ALS phenotype has led to the development and standardization of assessment tools, which have been incorporated into research and clinical care. Measuring change over the course of the disease is vital for clinical trials, and neuropsychology is proving to be a biomarker for the earliest preclinical changes. The term amyotrophic lateral sclerosis (ALS)-frontotemporal spectrum disorder encompasses a spectrum ranging from pure motor ALS to ALS with frontotemporal dementia. This Review focuses on the cognitive and behavioural impairments that are found in the mid-range of this spectrum. Cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) is heterogeneous and represents a spectrum of changes from ALS to ALS-frontotemporal dementia, also referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD).Neuropsychology has been pivotal in identifying the mid-spectrum range of ALS-FTSD; executive, verbal fluency, social cognition and language impairments are common, and apathy is the most prevalent behavioural change.Cerebral dysfunction underlying these impairments has been shown in both grey and white matter using a range of imaging techniques, and specific cognitive deficits were shown to predict TAR DNA-binding protein 43 pathology in specific brain regions.Assessment tools including the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioural Screen (ALS-CBS) are well validated and standardized across different languages and are now incorporated into clinical trials.This Review provides recommendations for neuropsychological assessment and intervention in ALS.