The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update

• Published in: International journal of molecular sciences Vol. 24; no. 19; p. 14647
• Main Author: Jellinger, Kurt A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27-09-2023; MDPI
• Subjects: ALS; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Brain - pathology; Brain damage; brain hypometabolism; Cognition & reasoning; Cognition disorders; Cognition Disorders - pathology; Cognitive ability; Cognitive Dysfunction - pathology; cognitive impairment; Dementia; Development and progression; Disease; Executive function; Frontotemporal Dementia - genetics; frontotemporal lobe degeneration; functional connectivity; Humans; Language disorders; Medical prognosis; Memory; Metabolism; multimodal neuroimaging; Neurodegenerative Diseases - pathology; Neuromuscular diseases; Neurophysiology; Pathology; Pick Disease of the Brain - pathology; Proteins; Review; functional connectivity; cognitive reserve; ALS; multimodal neuroimaging; cognitive impairment; frontotemporal lobe degeneration; brain hypometabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241914647

Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies.