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Lookup NU author(s): Dr Jacopo Pasquini, Dr Hilmar SigurdssonORCiD, Dr Michael FirbankORCiD, Dr Laura Best, Victoria Foster, Debra Galley, Dr Ross Maxwell, Dr George Petrides, Emeritus Professor David Brooks, Professor Nicola PaveseORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025. The Author(s). BACKGROUND: Cognitive dysfunction is increasingly recognized in multiple system atrophy (MSA). Locus coeruleus (LC) integrity is associated with cognitive performance both in healthy controls (HC) and neurodegenerative conditions such as Parkinson's disease (PD). Furthermore, cortical glucose hypometabolism is associated with impaired cognitive performance in MSA. However, knowledge about LC sub-regional degeneration and its association with cognitive dysfunction and cortical glucose metabolism is lacking. OBJECTIVE: To investigate LC sub-regional involvement and its association with cognitive impairment and brain metabolism in MSA. METHODS: Eleven MSA, eighteen PD, and eighteen HC participants were included in the study. Neuromelanin-sensitive MRI was used to determine rostral, middle and caudal LC neuromelanin signals. Brain glucose metabolism was investigated with [18F]Fluorodeoxyglucose PET (FDG-PET). The Montreal Cognitive Assessment (MoCA) was used as a measure of global cognition. RESULTS: Middle LC neuromelanin signal was significantly reduced in MSA [t(43) = 3.70, corrected-p = 0.004] and PD [t(43) = 2.63, corrected-p = 0.041] compared to HC, while caudal LC was only reduced in MSA [t(43) = 2.82, corrected-p = 0.030]. In MSA, decreased rostral LC neuromelanin was associated with lower MoCA scores (ρ = 0.760, p = 0.006) which, in turn, were associated with lower frontal cortex glucose metabolism. An association between rostral LC neuromelanin signal and frontal cortex glucose metabolism was found in exploratory analyses. CONCLUSION: Loss of LC neuromelanin signal was found in MSA, the middle and caudal parts being targeted. Rostral LC neuromelanin signal loss was associated with both frontal cortex hypometabolism and lower MoCA scores. This pathophysiological link should be further investigated as the noradrenergic system transmission is amenable to pharmacological manipulation.
Author(s): Pasquini J, Sigurdsson HP, Firbank M, Best L, Foster V, Galley D, Maxwell R, Silani V, Ceravolo R, Petrides G, Brooks DJ, Pavese N
Publication type: Article
Publication status: Published
Journal: Journal of Neurology
Year: 2025
Volume: 272
Issue: 3
Online publication date: 11/02/2025
Acceptance date: 20/01/2025
Date deposited: 10/03/2025
ISSN (print): 0340-5354
ISSN (electronic): 1432-1459
Publisher: Springer Nature
URL: https://doi.org/10.1007/s00415-025-12932-5
DOI: 10.1007/s00415-025-12932-5
PubMed id: 39932591
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