Toggle Main Menu Toggle Search

Open Access padlockePrints

Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson’s disease

Lookup NU author(s): Professor David BrooksORCiD



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press, 2021.

For re-use rights please refer to the publisher's terms and conditions.


Previous studies have reported substantial involvement of the noradrenergic system in Parkinson’s disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters, respectively. Combining these methods, we investigated the relationship of neurodegeneration in these distinct compartments in Parkinson’s disease. To this end, we examined 93 subjects (40 healthy controls and 53 Parkinson’s disease patients) with neuromelanin-sensitive turbo spin-echo MRI and calculated locus coeruleus-to-pons signal contrasts. We extracted voxels with the highest intensities from published locus coeruleus coordinates transformed to individual MRI. To also investigate a potential spatial pattern of locus coeruleus degeneration, we extracted the highest signal intensities from the rostral, middle, and caudal third of the locus coeruleus. Additionally, a study-specific probabilistic map of the locus coeruleus was created and used to extract mean MRI contrast from the entire locus coeruleus and each rostro-caudal subdivision. Manual segmentations were used to measure locus coeruleus volumes. A subset of 73 subjects had 11C-MeNER PET to determine noradrenaline transporter density, and distribution volume ratios of noradrenaline transporter rich regions were computed. Parkinson’s disease patients showed reduced locus coeruleus MRI contrast independently of the selected method (voxel approach: p < 0.0001, probabilistic map: p < 0.05) and reduced locus coeruleus volume (p < 0.0001) compared to controls, specifically on the clinically-defined most affected side (p < 0.05). Reduced locus coeruleus MRI contrast was confined to the middle and caudal locus coeruleus (voxel approach – rostral: p = 0.25, middle and caudal: p < 0.05, probabilistic map – rostral: p = 0.80, middle and caudal: p < 0.01). The noradrenaline transporter density was lower in Parkinson’s disease patients in all examined regions (group effect p < 0.0001). No significant correlation was observed between locus coeruleus MRI contrast and noradrenaline transporter density. In contrast, the individual ratios of noradrenaline transporter density and locus coeruleus MRI contrast were lower in Parkinson’s disease patients in all examined regions (group effect p < 0.001). Our multimodal imaging approach revealed pronounced noradrenergic terminal loss relative to cellular locus coeruleus degeneration in Parkinson’s disease; the latter followed a distinct spatial pattern with the middle-caudal portion being more affected than the rostral part. The data shed first light on the interaction between the axonal and cell body compartments and their differential susceptibility to neurodegeneration in Parkinson’s disease, which may eventually direct research toward potential novel treatment approaches.

Publication metadata

Author(s): Doppler CEJ, Kinnerup MB, Brune C, Farrher E, Betts M, Fedorova TD, Schaldemose JL, Knudsen K, Ismail R, Seger AD, Hansen AK, Stær K, Fink GR, Brooks DJ, Nahimi A, Borghammer P, Sommerauer M

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2021

Volume: 144

Issue: 9

Pages: 2732-2744

Print publication date: 01/09/2021

Online publication date: 01/07/2021

Acceptance date: 06/06/2021

Date deposited: 12/06/2021

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/awab236


Altmetrics provided by Altmetric