Mild cognitive impairment in presymptomatic amyotrophic lateral sclerosis
5 affiliations
- 1School of Psychology, Faculty of Natural Sciences, University of Stirling, 3B101 Cottrell Building, Stirling, FK9 4LQ UK
- 2Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, UK
- 3Department of Neurology and the ALS Center, University of Miami Miller School of Medicine, 1120 NW 14 Street, CRB1318, Miami, FL 33136 USA
- 4The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY USA
- 5Department of Psychology, School of Philosophy, Psychology, and Language Sciences, University of Edinburgh, Edinburgh, UK
Abstract
Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically and biologically related, and each may be preceded by a prodromal stage of disease. Mild cognitive and behavioural impairment (MCI/MBI) have also been observed in those with clinically manifest ALS. The primary aim of this study was to characterise MCI in presymptomatic ALS.
Methods: Criteria for frontotemporal-related MCI (MCI-ft), which require evidence of subthreshold cognitive performance or decline, were adapted from existing frameworks for MCI in prodromal FTD, presymptomatic ALS and clinically manifest ALS. MCI-ft was characterised in 216 Pre-fALS participants (74 C9ORF72, 94 SOD1, 20 other pathogenic variant carriers and 28 non-carriers) with neuropsychological data at 807 study visits. All designations were reviewed by a research neuropsychologist, with consensus discussions as needed.
Results: MCI-ft was observed in 15 (20%) C9ORF72, 12 (13%) SOD1 and 3 (%) of other carriers at one or more study visits, compared to 1 (4%) non-carrier. Most visits with MCI-ft showed impairment affecting both language and executive functioning. Fluctuations in MCI-ft status between assessments were common.
Conclusion: The observed frequency and temporal course of MCI-ft in presymptomatic ALS, using criteria based on subthreshold cognitive performance and decline, expands understanding of this phase of disease. These findings help to inform future research examining the risk of phenoconversion to clinically manifest disease and aid the design of disease prevention trials.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00415-026-14206-0.
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BibTeX
@article{mchutchison2026mild,
title = {{Mild cognitive impairment in presymptomatic amyotrophic lateral sclerosis}},
author = {Caroline McHutchison and Joanne Wuu and Stephanie Cosentino and Regla Saldana and Enjolie Vadella and Ana Benacerraf and Katja McBane and Alexa S. Gonzalez and Jessica H. Stark and Yindi Li and Sharon Abrahams and Michael Benatar},
journal = {Journal of Neurology},
year = {2026},
month = oct,
doi = {10.1007/s00415-026-14206-0},
url = {https://doi.org/10.1007/s00415-026-14206-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mild cognitive impairment in presymptomatic amyotrophic lateral sclerosis
AU - Caroline McHutchison
AU - Joanne Wuu
AU - Stephanie Cosentino
AU - Regla Saldana
AU - Enjolie Vadella
AU - Ana Benacerraf
AU - Katja McBane
AU - Alexa S. Gonzalez
AU - Jessica H. Stark
AU - Yindi Li
AU - Sharon Abrahams
AU - Michael Benatar
PY - 2026
DA - 2026/10/25
JO - Journal of Neurology
DO - 10.1007/s00415-026-14206-0
UR - https://doi.org/10.1007/s00415-026-14206-0
AB - Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically and biologically related, and each may be preceded by a prodromal stage of disease. Mild cognitive and behavioural impairment (MCI/MBI) have also been observed in those with clinically manifest ALS. The primary aim of this study was to characterise MCI in presymptomatic ALS. Methods: Criteria for frontotemporal-related MCI (MCI-ft), which require evidence of subthreshold cognitive performance or decline, were adapted from existing frameworks for MCI in prodromal FTD, presymptomatic ALS and clinically manifest ALS. MCI-ft was characterised in 216 Pre-fALS participants (74 C9ORF72, 94 SOD1, 20 other pathogenic variant carriers and 28 non-carriers) with neuropsychological data at 807 study visits. All designations were reviewed by a research neuropsychologist, with consensus discussions as needed. Results: MCI-ft was observed in 15 (20%) C9ORF72, 12 (13%) SOD1 and 3 (%) of other carriers at one or more study visits, compared to 1 (4%) non-carrier. Most visits with MCI-ft showed impairment affecting both language and executive functioning. Fluctuations in MCI-ft status between assessments were common. Conclusion: The observed frequency and temporal course of MCI-ft in presymptomatic ALS, using criteria based on subthreshold cognitive performance and decline, expands understanding of this phase of disease. These findings help to inform future research examining the risk of phenoconversion to clinically manifest disease and aid the design of disease prevention trials. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00415-026-14206-0.
SN - 0340-5354
SN - 1432-1459
ER -