Neuromelanin-sensitive MRI correlates of cognitive and motor function in Parkinson's disease with freezing of gait

Front Dement. 2023 Aug 11:2:1215505. doi: 10.3389/frdem.2023.1215505. eCollection 2023.

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 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.

Keywords: Parkinson's disease (PD); aging; cognition; cognitive reserve; freezing of gait (FOG); neuromelanin (NM); neuromelanin-sensitive MRI (NM-MRI); substantia nigra (SN).

Grants and funding

DH and XH receive funding from the Michael J. Fox Foundation for Parkinson's Research (MJFF 10854 and MJFF 010556). DH and JM were supported by the American Parkinson's Disease Association (APDA) Center for Advanced Research at Emory. JM was also supported by the McCamish Parkinson's Disease Innovation Program at Georgia Tech. SF and DH were supported by the Curtis Family and the Sartain Lanier Family Foundation. SF was also supported by NIH grant funding (U10 NS077366). DH was also supported by NIH grant funding (NIH-NINDS 1K23NS105944-01A1 and 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 was 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's Disease Research Center (NIH-NINDS P50-AG025688).