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Journal of Neurology
Published in: Journal of Neurology 7/2023

Open Access 06-04-2023 | Amyotrophic Lateral Sclerosis | Original Communication

Brainstem–cortex disconnection in amyotrophic lateral sclerosis: bulbar impairment, genotype associations, asymptomatic changes and biomarker opportunities

Authors: Marlene Tahedl, Ee Ling Tan, Rangariroyashe H. Chipika, Jennifer C. Hengeveld, Alice Vajda, Mark A. Doherty, Russell L. McLaughlin, We Fong Siah, Orla Hardiman, Peter Bede

Published in: Journal of Neurology | Issue 7/2023

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Abstract

Background

Bulbar dysfunction is a cardinal feature of ALS with important quality of life and management implications. The objective of this study is the longitudinal evaluation of a large panel imaging metrics pertaining to bulbar dysfunction, encompassing cortical measures, structural and functional cortico-medullary connectivity indices and brainstem metrics.

Methods

A standardised, multimodal imaging protocol was implemented with clinical and genetic profiling to systematically appraise the biomarker potential of specific metrics. A total of 198 patients with ALS and 108 healthy controls were included.

Results

Longitudinal analyses revealed progressive structural and functional disconnection between the motor cortex and the brainstem over time. Cortical thickness reduction was an early feature on cross-sectional analyses with limited further progression on longitudinal follow-up. Receiver operating characteristic analyses of the panel of MR metrics confirmed the discriminatory potential of bulbar imaging measures between patients and controls and area-under-the-curve values increased significantly on longitudinal follow-up. C9orf72 carriers exhibited lower brainstem volumes, lower cortico-medullary structural connectivity and faster cortical thinning. Sporadic patients without bulbar symptoms, already exhibit significant brainstem and cortico-medullary connectivity alterations.

Discussion

Our results indicate that ALS is associated with multi-level integrity change from cortex to brainstem. The demonstration of significant corticobulbar alterations in patients without bulbar symptoms confirms considerable presymptomatic disease burden in sporadic ALS. The systematic assessment of radiological measures in a single-centre academic study helps to appraise the diagnostic and monitoring utility of specific measures for future clinical and clinical trial applications.
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Metadata
Title
Brainstem–cortex disconnection in amyotrophic lateral sclerosis: bulbar impairment, genotype associations, asymptomatic changes and biomarker opportunities
Authors
Marlene Tahedl
Ee Ling Tan
Rangariroyashe H. Chipika
Jennifer C. Hengeveld
Alice Vajda
Mark A. Doherty
Russell L. McLaughlin
We Fong Siah
Orla Hardiman
Peter Bede
Publication date
06-04-2023
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 7/2023
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-023-11682-6

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