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

doi:10.1007/s00415-025-12932-5

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

Department of Clinical Medicine - Nuclear Medicine and PET

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-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 language	English
Article number	195
Book series	Journal of Neurology
Volume	272
Issue	3
Pages (from-to)	195
Number of pages	1
ISSN	0939-1517
DOIs	https://doi.org/10.1007/s00415-025-12932-5
Publication status	Published - 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

Access to Document

10.1007/s00415-025-12932-5

Cite this

@article{ec735104274348dcb38d656fe6b6b6d9,

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

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 = "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",

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

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = mar,

doi = "10.1007/s00415-025-12932-5",

language = "English",

volume = "272",

pages = "195",

journal = "Journal of Neurology",

issn = "0939-1517",

publisher = "Springer",

number = "3",

}

Locus coeruleus neuromelanin, cognitive dysfunction, and brain metabolism in multiple system atrophy. / Pasquini, Jacopo; Sigurdsson, Hilmar P; Firbank, Michael et al.
In: Journal of Neurology, Vol. 272, No. 3, 195, 03.2025, p. 195.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Locus coeruleus neuromelanin, cognitive dysfunction, and brain metabolism in multiple system atrophy

AU - Pasquini, Jacopo

AU - Sigurdsson, Hilmar P

AU - Firbank, Michael

AU - Best, Laura

AU - Foster, Victoria

AU - Galley, Debra

AU - Maxwell, Ross

AU - Silani, Vincenzo

AU - Ceravolo, Roberto

AU - Petrides, George

AU - Brooks, David J

AU - Pavese, Nicola

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

KW - Aged

KW - Brain/metabolism

KW - Cognitive Dysfunction/metabolism

KW - Female

KW - Fluorodeoxyglucose F18

KW - Glucose/metabolism

KW - Humans

KW - Locus Coeruleus/metabolism

KW - Magnetic Resonance Imaging

KW - Male

KW - Melanins/metabolism

KW - Middle Aged

KW - Multiple System Atrophy/metabolism

KW - Parkinson Disease/metabolism

KW - Positron-Emission Tomography

KW - FDG-PET

KW - Cognitive decline

KW - Multiple system atrophy

KW - Locus coeruleus

UR - http://www.scopus.com/inward/record.url?scp=85218438310&partnerID=8YFLogxK

U2 - 10.1007/s00415-025-12932-5

DO - 10.1007/s00415-025-12932-5

M3 - Journal article

C2 - 39932591

SN - 0939-1517

VL - 272

SP - 195

JO - Journal of Neurology

JF - Journal of Neurology

IS - 3

M1 - 195

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this