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. 2025 Feb 11;272(3):195.
doi: 10.1007/s00415-025-12932-5.

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

Jacopo Pasquini  1   2 , Hilmar P Sigurdsson  1 , Michael Firbank  1 , Laura Best  3 , Victoria Foster  1 , Debra Galley  1 , Ross Maxwell  1 , Vincenzo Silani  4   5 , Roberto Ceravolo  2   6 , George Petrides  7 , David J Brooks  1   8 , Nicola Pavese  9   10
Affiliations

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

Jacopo Pasquini et al. J Neurol. .

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.

Keywords: Cognitive decline; FDG-PET; Locus coeruleus; Multiple system atrophy.

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Conflict of interest statement

Declarations. Conflicts of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethical standard: Ethical approval was granted by the London-Surrey Research Ethics Committee Research Ethics Committee (18/LO/2123). All participants involved in the study provided written informed consent according to the Declaration of Helsinki.

Figures

Fig. 1
Fig. 1
Line plots showing mean and 95% confidence intervals for locus coeruleus (LC) rostral, middle and caudal average (Av.) neuromelanin contrast in healthy controls (HC), multiple system atrophy (MSA) and Parkinson’s disease (PD). Individual values are also shown. Asterisks (*) indicate significant differences (after family-wise error rate correction) between single subgroups in post hoc tests that followed significant omnibus ANCOVA models
Fig. 2
Fig. 2
Anatomical localization of significant (voxel-wise thresholding at p < 0.001 uncorrected followed by family-wise error FWE cluster correction) direct associations between brain metabolism as measured by FDG-PET and Montreal Cognitive Assessment (MoCA) scores projected onto sections of a standard template in MNI space. The exact anatomical coordinates are referenced in the text and in Table 2. Top panel: sagittal view, lower panel: axial view. Numbers indicate MNI coordinates. R right, L left
Fig. 3
Fig. 3
Anatomical localization of significant (exploratory voxel-wise thresholding at p < 0.01 uncorrected, followed by family-wise error FWE cluster correction) direct associations between brain metabolism as measured by FDG-PET and rostral locus coeruleus neuromelanin contrast scores projected onto sections of a standard template in MNI space. The exact anatomical coordinates are referenced in the Table 3. Top panel: sagittal view, middle panel: axial view, bottom panel: coronal view. Numbers indicate MNI coordinates
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