Relationship between neuromelanin and dopamine terminals within the parkinson’s nigrostriatal system
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Accepted version
Author(s)
Type
Journal Article
Abstract
Parkinson’s disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterising its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we utilised neuromelanin-sensitive magnetic resonance imaging and the highly specific dopamine transporter positron emission tomography radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson’s disease. Fifteen healthy controls also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal/ventral tiers and striatal nuclei into pre/post-commissural sub-regions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson’s disease subjects displayed reduced neuromelanin levels in the ventral (-30±28%) and dorsal tiers (-21±24%) as compared to the control group (F1,43 = 11.95, P = 0.001). Within the Parkinson’s disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier (F1,29 = 36.19, P < 0.001) and lower in the clinically-defined most affected side (F1,29 = 4.85, P = 0.036). Similarly, lower dopamine transporter density was observed in the ventral tier (F1,29 = 76.39, P < 0.001) and clinically-defined most affected side (F1,29 = 4.21, P = 0.049). Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal sub-regions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson’s disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine-hydroxylase positive nigral cells.
Date Issued
2019-07-01
Online Publication Date
2020-05-05T06:00:20Z
Date Acceptance
2019-03-05
ISSN
1460-2156
Publisher
Oxford University Press (OUP)
Start Page
2023
End Page
2036
Journal / Book Title
Brain
Volume
142
Issue
7
Copyright Statement
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This is a pre-copy-editing, author-produced version of an article accepted for publication in Brain following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: https://academic.oup.com/brain/article/142/7/2023/5485828
Source Database
manual-entry
Subjects
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
Parkinson's disease
magnetic resonance imaging
positron emission tomography
neuromelanin
dopamine transporter
HUMAN SUBSTANTIA-NIGRA
AGE-RELATED DECLINE
HUMAN BRAIN
AXONAL DEGENERATION
TRANSPORTER LOSS
HIGH-AFFINITY
DISEASE
PROGRESSION
PET
SPECT
Parkinson’s disease
dopamine transporter
magnetic resonance imaging
neuromelanin
positron emission tomography
11 Medical and Health Sciences
17 Psychology and Cognitive Sciences
Neurology & Neurosurgery
Publication Status
Published
Date Publish Online
2019-05-05