Cognitive and Behavioral Manifestations in ALS: Beyond Motor System Involvement.

Rose Bruffaerts,Rik Vandenberghe,Robert Rusina

doi:10.3390/diagnostics11040624

Abstract

Amyotrophic lateral sclerosis (ALS) has long been considered to be a purely motor disorder. However, it has become apparent that many ALS patients develop cognitive and behavioral manifestations similar to frontotemporal dementia and the term amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is now used in these circumstances. This review is intended to be an overview of the cognitive and behavioral manifestations commonly encountered in ALS patients with the goal of improving case-oriented management in clinical practice. We introduce the principal ALS-FTSD subtypes and comment on their principal clinical manifestations, neuroimaging findings, neuropathological and genetic background, and summarize available therapeutic options. Diagnostic criteria for ALS-FTSD create distinct categories based on the type of neuropsychological manifestations, i.e., changes in behavior, impaired social cognition, executive dysfunction, and language or memory impairment. Cognitive impairment is found in up to 65%, while frank dementia affects about 15% of ALS patients. ALS motor and cognitive manifestations can worsen in parallel, becoming more pronounced when bulbar functions (affecting speech, swallowing, and salivation) are involved. Dementia can precede or develop after the appearance of motor symptoms. ALS-FTSD patients have a worse prognosis and shorter survival rates than patients with ALS or frontotemporal dementia alone. Important negative prognostic factors are behavioral and personality changes. From the clinician’s perspective, there are five major distinguishable ALS-FTSD subtypes: ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, fully developed frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer’s disease. Although the most consistent ALS and ALS-FTSD pathology is a disturbance in transactive response DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein metabolism have also been observed in ALS-FTSD. Early detection and careful monitoring of cognitive deficits in ALS are crucial for patient and caregiver support and enable personalized management of individual patient needs.

Highlights

Amyotrophic lateral sclerosis (ALS) has long been considered a purely motor disorder, with occasional reports of associated neuropsychiatric symptoms
Since the publication of the seminal case series in 2002, it has become apparent that many ALS patients develop cognitive and behavioral manifestations similar to frontotemporal dementia (FTD) [1] and the term amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is used in these circumstances
With disease progression, impaired planning, judgment, and task switching or set-shifting appear, and perseveration develops. These manifestations correlate with further involvement of the dorsolateral frontal cortex and the inferior frontal gyrus [18], and their prevalence is comparable to the prevalence of executive dysfunction in behavioral variant of frontotemporal dementia (bvFTD) [19]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) has long been considered a purely motor disorder, with occasional reports of associated neuropsychiatric symptoms. The recently proposed diagnostic criteria for ALS-FTSD create distinct categories based on the type of neuropsychological manifestation, i.e., changes in behavior, impaired social cognition, executive dysfunction, and language or memory impairment [2]. These manifestations result from a variable degree of frontotemporal dysfunction and atrophy in ALS (Table 1). Patients become irritable and negative, profoundly egocentric, and both their emotional perception and behavior tend to change, which results in dramatically altered social and communication skills (often confirmed by relatives, but only after targeted questioning) These manifestations are in stark contrast with the mild degree of cognitive impairment, often assessed using standard neuropsychological assessments of the classic cognitive domains.

Prevalence of ALS-FTSD

Clinical Manifestations of ALS-FTSD

Executive Dysfunction

Behavioral Manifestations

Speech and Language Impairment

Memory Impairment

Cognitive and Behavioral Screening for ALS-FTSD

Neuroimaging

Genetic Background

Neuropathology

Therapeutic Options

Findings