Cognitive and Behavioral Manifestations in ALS: Beyond Motor System Involvement

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.

Abnormal Stability of Dynamic Functional Architecture in Amyotrophic Lateral Sclerosis: A Preliminary Resting-State fMRI Study

“…The temporal pole is thought to be a node of the paralimbic cortex that plays a key role in language and memory functions ( 42 , 43 ). Abnormal functional stability in this region might lead to the deficits in semantic processing and memory, all of which are observed in ALS ( 44 ).…”

Molecular Pathology of ALS: What We Currently Know and What Important Information Is Still Missing

“…(3) ALS with combined cognitive and behavioral impairment (ALS-cbi); (4) Fully developed behavioral variant of frontotemporal dementia (bvFTD) in combination with ALS (ALS-FTD); (5) Comorbid ALS and Alzheimer's disease (AD) [55].…”

“…Considering comorbid cases and dementia in ALS, some comorbid ALS/AD cases have appeared in the literature; for example, one study reported that about 50% of ALS cases had Aβ deposits, and at least half of the cases had neuritic plaques in the neocortex [126]. Those patients with comorbid ALS/AD usually have progressive amnestic dementia, which is typical for AD and is accompanied by early distinctive impairment of episodic memory; MRIs of the hippocampus show significant atrophy [55].…”

Pre-Morbid Risk Factors for Amyotrophic Lateral Sclerosis: Prospective Cohort Study

“…There are, for example, reasons to anticipate associations between ALS and earlier measurements of cognitive function, psychological distress, and lung function, not least because these characteristics may be pre-clinical features of the disorder. 18 Although these indices have shown prognostic value in studies of patient groups -less favourable levels are associated with adverse outcomes including disability severity and reduced life expectancy 19,20 -they are untested as risk factors for disease occurrence.…”