Abstract
Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function and disease. However, their roles in aging and neurodegenerative disease mechanisms have remained unclear due to a lack of tools to study them in vivo. Preclinical and post-mortem human investigations indicate that the relationship between tissue neuromelanin content and neurodegeneration is complex. Neuromelanin exhibits both neuroprotective and cytotoxic characteristics, and tissue neuromelanin content varies across the lifespan, exhibiting an inverted U-shaped relationship with age. Neuromelanin-sensitive MRI (NM-MRI) is an emerging modality that allows measurement of neuromelanin-associated contrast in SNc and LC in humans. NM-MRI robustly detects disease effects in these structures in neurodegenerative and psychiatric conditions, including Parkinson’s disease (PD). Previous NM-MRI studies of PD have largely focused on detecting disease group effects, but few studies have reported NM-MRI correlations with phenotype. Because neuromelanin dynamics are complex, we hypothesize that they are best interpreted in the context of both disease stage and aging, with neuromelanin loss correlating with symptoms most clearly in advanced stages where neuromelanin loss and neurodegeneration are coupled. We tested this hypothesis using NM-MRI to measure SNc and LC volumes in healthy older adult control individuals and in PD patients with and without freezing of gait (FOG), a severe and disabling PD symptom. We assessed for group differences and correlations between NM-MRI measures and aging, cognition and motor deficits. SNc volume was significantly decreased in PD with FOG compared to controls. SNc volume correlated significantly with motor symptoms and cognitive measures in PD with FOG, but not in PD without FOG. SNc volume correlated significantly with aging in PD. When PD patients were stratified by disease duration, SNc volume correlated with aging, cognition, and motor deficits only in PD with disease duration >5 years. We conclude that in severe or advanced PD, identified by either FOG or disease duration >5 years, the observed correlations between SNc volume and aging, cognition, and motor function may reflect the coupling of neuromelanin loss with neurodegeneration and the associated emergence of a linear relationship between NM-MRI measures and phenotype.
Competing Interest Statement
Daniel Huddleston is inventor on an issued patent (U.S. patent # 9600881, 3/21/17) which covers aspects of the neuromelanin-sensitive MRI methods discussed here, as well as a patent application (US-2021/0007603-A1) which covers aspects of the analysis method presented here. Stewart Factor has the following disclosures: Honoraria: Lundbeck, Sunovion, Biogen, Acorda, Alterity, Takeda. Grants: Medtronics, Boston Scientific, Sun Pharmaceuticals Advanced Research Company, Biohaven, Impax, Sunovion Therapeutics, Neurocrine, Vaccinex, Voyager, Addex Pharma S.A., Prilenia Therapeutics CHDI Foundation, Michael J. Fox Foundation, Parkinson Foundation. Royalties: Demos, Blackwell Futura, Springer for textbooks, Uptodate Other Signant Health (Bracket Global LLC) Lucas McKay performs technical consulting for Biocircuit Technologies. Richa Tripathi has following disclosures: Honoraria: UpToDate.
Funding Statement
Daniel Huddleston and Xiaoping Hu receive funding from the Michael J. Fox Foundation (MJFF 10854 and MJFF 010556). Daniel Huddleston and Lucas McKay are supported by the American Parkinson Disease Association (APDA) Center for Advanced Research at Emory. Lucas McKay is also supported by the McCamish Parkinson Disease Innovation Program at Georgia Tech. Stewart Factor and Daniel Huddleston are supported by the Curtis Family and the Sartain Lanier Family Foundation. Dr. Factor is also supported by NIH grant funding (U10 NS077366). Daniel Huddleston is also supported by NIH grant funding (NIH-NINDS 1K23NS105944-01A1; NIH-NINDS 1U19AG071754), the Emory Lewy Body Dementia Association (LBDA) Research Center of Excellence, and the McMahon Family. The Emory MRI facility used in this study is supported in part by funding from a Shared Instrumentation Grant (S10) grant 1S10OD016413-01 to the Emory University Center for Systems Imaging Core. Recruitment of control individuals for this research was facilitated by the Emory Alzheimer Disease Research Center (NIH-NINDS P50-AG025688).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The Institutional Review Board of Emory University gave ethical approval for this work.
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Data Availability
All data produced in the present study are available upon reasonable request to the authors.
