Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis

Harold H.G. Tan; Abram D. Nitert; Kevin van Veenhuijzen; Stefan Dukic; Martine J.E. van Zandvoort; Jeroen Hendrikse; Michael A. van Es; Jan H. Veldink; Henk Jan Westeneng; Leonard H. van den Berg

doi:10.1016/j.nicl.2025.103749

Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis

Harold H.G. Tan
, Abram D. Nitert
, Kevin van Veenhuijzen
, Stefan Dukic
, Martine J.E. van Zandvoort
, Jeroen Hendrikse
, Michael A. van Es
, Jan H. Veldink
, Henk Jan Westeneng
, Leonard H. van den Berg^*

^*Corresponding author for this work

University Medical Center Utrecht

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI.

Methods: We performed multimodal brain MRI and Edinburgh cognitive and behavioral ALS screen (ECAS) in 293 patients and 237 controls. Follow-up data were acquired from 171 patients with a median duration of 7.9 months. Domain-level cognitive scores from the ECAS were compared with grey and white matter MRI parameters. Interaction analyses between patients and controls were performed to explore whether correlates were specific to ALS, rather than related to normal aging. Follow-up data were used to assess changes of domain-associated brain structures over time.

Results: Language impairment was significantly associated with (left predominant) frontal, temporal, parietal and subcortical grey matter neurodegeneration. Letter fluency with widespread cortical and subcortical grey matter involvement. Memory dysfunction with hippocampal and medial-temporal atrophy. Executive impairment was exclusively correlated with widespread white matter impairment. Visuospatial scores did not correlate with MRI parameters. Interaction analyses between patients and controls showed that most ECAS-MRI correlations were stronger in ALS than in controls (75.7% significant in grey matter, 52.7% in white matter). Longitudinal analyses showed that all grey matter structures associated with cognitive domains worsened over time while, for this study population, ECAS domain scores did not decline significantly.

Conclusions: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.

Original language	English
Article number	103749
Number of pages	10
Journal	NeuroImage: Clinical
Volume	45
DOIs	https://doi.org/10.1016/j.nicl.2025.103749
Publication status	Published - Jan 2025

Bibliographical note

Publisher Copyright:
© 2025

Funding

This work was supported by the ALS Foundation Netherlands (grant ALS-023). M.A. van Es received funding from the Netherlands Organization for Health Research and Development (VENI and VIDI scheme), Joint Program Neurodegeneration (JPND), The Thierry Latran Foundation, Motor Neuron Disease Association (MNDA), FIGHT-MND and the Netherlands ALS Foundation. J.H. Veldink received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no 772376-EScORIAL). L.H. van den Berg received funding from the Netherlands Organization for Scientific Research (VICI scheme) and the Netherlands Organization for Health Research and Development, funded through the EU Joint Program Neurodegenerative Disease Research (JPND).

Funders	Funder number
Stichting ALS Nederland	ALS-023
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
EU Joint Programme – Neurodegenerative Disease Research
Thierry Latran Foundation
Motor Neurone Disease Association
FIGHT-MND
European Research Council
Horizon 2020 Framework Programme	772376-EScORIAL

Keywords

Amyotrophic lateral sclerosis
Brain imaging
Cognitive impairment
Frontal temporal dementia
Motor neuron disease
MRI
Neuropsychological assessment

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1-s2.0-S2213158225000191-mainFinal published version, 6.06 MBLicence: CC BY-NC-ND

Cite this

@article{f925876632dd42cd9b1d1873a0aa80fb,

title = "Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis",

abstract = "Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI.Methods: We performed multimodal brain MRI and Edinburgh cognitive and behavioral ALS screen (ECAS) in 293 patients and 237 controls. Follow-up data were acquired from 171 patients with a median duration of 7.9 months. Domain-level cognitive scores from the ECAS were compared with grey and white matter MRI parameters. Interaction analyses between patients and controls were performed to explore whether correlates were specific to ALS, rather than related to normal aging. Follow-up data were used to assess changes of domain-associated brain structures over time.Results: Language impairment was significantly associated with (left predominant) frontal, temporal, parietal and subcortical grey matter neurodegeneration. Letter fluency with widespread cortical and subcortical grey matter involvement. Memory dysfunction with hippocampal and medial-temporal atrophy. Executive impairment was exclusively correlated with widespread white matter impairment. Visuospatial scores did not correlate with MRI parameters. Interaction analyses between patients and controls showed that most ECAS-MRI correlations were stronger in ALS than in controls (75.7\% significant in grey matter, 52.7\% in white matter). Longitudinal analyses showed that all grey matter structures associated with cognitive domains worsened over time while, for this study population, ECAS domain scores did not decline significantly. Conclusions: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.",

keywords = "Amyotrophic lateral sclerosis, Brain imaging, Cognitive impairment, Frontal temporal dementia, Motor neuron disease, MRI, Neuropsychological assessment",

author = "Tan, \{Harold H.G.\} and Nitert, \{Abram D.\} and \{van Veenhuijzen\}, Kevin and Stefan Dukic and \{van Zandvoort\}, \{Martine J.E.\} and Jeroen Hendrikse and \{van Es\}, \{Michael A.\} and Veldink, \{Jan H.\} and Westeneng, \{Henk Jan\} and \{van den Berg\}, \{Leonard H.\}",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = jan,

doi = "10.1016/j.nicl.2025.103749",

language = "English",

volume = "45",

journal = "NeuroImage: Clinical",

issn = "2213-1582",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis

AU - Tan, Harold H.G.

AU - Nitert, Abram D.

AU - van Veenhuijzen, Kevin

AU - Dukic, Stefan

AU - van Zandvoort, Martine J.E.

AU - Hendrikse, Jeroen

AU - van Es, Michael A.

AU - Veldink, Jan H.

AU - Westeneng, Henk Jan

AU - van den Berg, Leonard H.

PY - 2025/1

Y1 - 2025/1

N2 - Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI.Methods: We performed multimodal brain MRI and Edinburgh cognitive and behavioral ALS screen (ECAS) in 293 patients and 237 controls. Follow-up data were acquired from 171 patients with a median duration of 7.9 months. Domain-level cognitive scores from the ECAS were compared with grey and white matter MRI parameters. Interaction analyses between patients and controls were performed to explore whether correlates were specific to ALS, rather than related to normal aging. Follow-up data were used to assess changes of domain-associated brain structures over time.Results: Language impairment was significantly associated with (left predominant) frontal, temporal, parietal and subcortical grey matter neurodegeneration. Letter fluency with widespread cortical and subcortical grey matter involvement. Memory dysfunction with hippocampal and medial-temporal atrophy. Executive impairment was exclusively correlated with widespread white matter impairment. Visuospatial scores did not correlate with MRI parameters. Interaction analyses between patients and controls showed that most ECAS-MRI correlations were stronger in ALS than in controls (75.7% significant in grey matter, 52.7% in white matter). Longitudinal analyses showed that all grey matter structures associated with cognitive domains worsened over time while, for this study population, ECAS domain scores did not decline significantly. Conclusions: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.

AB - Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI.Methods: We performed multimodal brain MRI and Edinburgh cognitive and behavioral ALS screen (ECAS) in 293 patients and 237 controls. Follow-up data were acquired from 171 patients with a median duration of 7.9 months. Domain-level cognitive scores from the ECAS were compared with grey and white matter MRI parameters. Interaction analyses between patients and controls were performed to explore whether correlates were specific to ALS, rather than related to normal aging. Follow-up data were used to assess changes of domain-associated brain structures over time.Results: Language impairment was significantly associated with (left predominant) frontal, temporal, parietal and subcortical grey matter neurodegeneration. Letter fluency with widespread cortical and subcortical grey matter involvement. Memory dysfunction with hippocampal and medial-temporal atrophy. Executive impairment was exclusively correlated with widespread white matter impairment. Visuospatial scores did not correlate with MRI parameters. Interaction analyses between patients and controls showed that most ECAS-MRI correlations were stronger in ALS than in controls (75.7% significant in grey matter, 52.7% in white matter). Longitudinal analyses showed that all grey matter structures associated with cognitive domains worsened over time while, for this study population, ECAS domain scores did not decline significantly. Conclusions: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.

KW - Amyotrophic lateral sclerosis

KW - Brain imaging

KW - Cognitive impairment

KW - Frontal temporal dementia

KW - Motor neuron disease

KW - MRI

KW - Neuropsychological assessment

UR - https://www.scopus.com/pages/publications/85217400670

U2 - 10.1016/j.nicl.2025.103749

DO - 10.1016/j.nicl.2025.103749

M3 - Article

C2 - 39947099

AN - SCOPUS:85217400670

SN - 2213-1582

VL - 45

JO - NeuroImage: Clinical

JF - NeuroImage: Clinical

M1 - 103749

ER -

Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis

Abstract

Bibliographical note

Funding

Keywords

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