Principal Component Analysis of Striatal and Extrastriatal D2 Dopamine Receptor Positron Emission Tomography in Manganese-Exposed Workers

Authors

Susan R. Criswell, Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Susan Searles Nielsen, Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Wendy W. Dlamini, Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Mark N. Warden, Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Joel S. Perlmutter, Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Lianne Sheppard, Department of Environmental and Occupational Health Sciences, University of Washington, School of Public Health, Seattle, Washington 98195, USA.
Stephen M. Moerlein, Department of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Jason Lenox-Krug, Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Harvey Checkoway, Department of Family Medicine and Public Health, University of California, San Diego, School of Medicine, La Jolla, California 92093, USA.
Brad A. Racette, Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Document Type

Article

Abstract

The relationships between the neurotoxicant manganese (Mn), dopaminergic pathology, and parkinsonism remain unclear. Therefore, we used [11C](N-methyl)benperidol (NMB) positron emission tomography to investigate the associations between Mn exposure, striatal and extrastriatal D2 dopamine receptors (D2R), and motor function in 54 workers with a range of Mn exposure. Cumulative Mn exposure was estimated from work histories, and all workers were examined by a movement specialist and completed a Grooved Pegboard test (GPT). NMB D2R nondisplaceable binding potentials (BPND) were calculated for brain regions of interest. We identified 2 principal components (PCs) in a PC analysis which explained 66.8% of the regional NMB BPND variance (PC1 = 55.4%; PC2 = 11.4%). PC1 was positively correlated with NMB binding in all regions and inversely correlated with age. PC2 was driven by NMB binding in 7 brain regions (all p < .05), positively in the substantia nigra, thalamus, amygdala, and medial orbital frontal gyrus and negatively in the nucleus accumbens, anterior putamen, and caudate. PC2 was associated with both Mn exposure status and exposure duration (years). In addition, PC2 was associated with higher Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) scores and slower GPT performance. We conclude Mn exposure is associated with both striatal and extrastriatal D2R binding. Multifocal alterations in D2R expression are also associated with motor dysfunction as measured by both the GPT and UPDRS3, demonstrating a link between Mn exposure, striatal and extrastriatal D2R expression, and clinical neurotoxicity.

Medical Subject Headings

Brain (diagnostic imaging); Corpus Striatum (diagnostic imaging); Humans; Manganese (toxicity); Positron-Emission Tomography; Principal Component Analysis

Publication Date

7-16-2021

Publication Title

Toxicological sciences : an official journal of the Society of Toxicology

E-ISSN

1096-0929

Volume

182

Issue

1

First Page

132

Last Page

141

PubMed ID

33881537

Digital Object Identifier (DOI)

10.1093/toxsci/kfab045

Recommended Citation

Criswell, Susan R.; Searles Nielsen, Susan; Dlamini, Wendy W.; Warden, Mark N.; Perlmutter, Joel S.; Sheppard, Lianne; Moerlein, Stephen M.; Lenox-Krug, Jason; Checkoway, Harvey; and Racette, Brad A., "Principal Component Analysis of Striatal and Extrastriatal D2 Dopamine Receptor Positron Emission Tomography in Manganese-Exposed Workers" (2021). Neurology. 1256.
https://scholar.barrowneuro.org/neurology/1256