Locus coeruleus neuromelanin, cognitive dysfunction, and brain metabolism in multiple system atrophy

Jacopo Pasquini, Hilmar P Sigurdsson, Michael Firbank, Laura Best, Victoria Foster, Debra Galley, Ross Maxwell, Vincenzo Silani, Roberto Ceravolo, George Petrides, David J Brooks, Nicola Pavese

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number195
Book seriesJournal of Neurology
Volume272
Issue3
Pages (from-to)195
Number of pages1
ISSN0939-1517
DOIs
Publication statusPublished - Mar 2025

Keywords

  • Aged
  • Brain/metabolism
  • Cognitive Dysfunction/metabolism
  • Female
  • Fluorodeoxyglucose F18
  • Glucose/metabolism
  • Humans
  • Locus Coeruleus/metabolism
  • Magnetic Resonance Imaging
  • Male
  • Melanins/metabolism
  • Middle Aged
  • Multiple System Atrophy/metabolism
  • Parkinson Disease/metabolism
  • Positron-Emission Tomography
  • FDG-PET
  • Cognitive decline
  • Multiple system atrophy
  • Locus coeruleus

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