Cholinergic dysfunction in occupational manganese exposure

T Noah Hutson, Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, USA. Electronic address: timothy.hutson@commonspirit.org.
Susan Searles Nielsen, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA. Electronic address: snielsen@wustl.edu.
Natalie Senini, Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, USA. Electronic address: natalie.c.senini@gmail.com.
John O'Donnell, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA. Electronic address: jodonn@wustl.edu.
Hubert P. Flores, Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, USA. Electronic address: hugh.flores@barrowneuro.org.
Tamara Hershey, Department of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA. Electronic address: tammy@wustl.edu.
Joel S. Perlmutter, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA; Department of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA; Program in Physical Therapy, Washington University in St. Louis, St. Louis, MO, USA; Program in Occupational Therapy, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA; Program in Physical Therapy, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA. Electronic address: perlmutterjoel@wustl.edu.
Anil Kumar Soda, Department of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA. Electronic address: soda@wustl.edu.
Stephen M. Moerlein, Department of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA. Electronic address: moerleins@wustl.edu.
Zhude Tu, Department of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA. Electronic address: zhudetu@wustl.edu.
Michael Kasper, Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, USA. Electronic address: michael.kasper44@gmail.com.
Lianne Sheppard, Department of Environmental and Occupational Health Sciences, University of Washington, School of Public Health, 3980 15th Ave NE, Seattle, WA 98195, USA; Department of Biostatistics, School of Public Health, University of Washington, 3980 15th Ave NE, Seattle, WA 98195, USA. Electronic address: sheppard@uw.edu.
Brad A. Racette, Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, USA; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand 27 St. Andrews Rd, Parktown 2193, South Africa. Electronic address: brad.racette@barrowneuro.org.
Susan R. Criswell, Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, USA; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA. Electronic address: susan.criswell@barrowneuro.org.

Document Type

Article

Abstract

BACKGROUND AND OBJECTIVE: Excessive exposure to manganese (Mn) produces a clinical syndrome of parkinsonism and cognitive impairment. However, our understanding of the mechanisms of Mn neurotoxicity remains limited. This study aimed to evaluate the relationships between Mn exposure, cholinergic function, and cognitive impairment in exposed workers. METHODS: We assessed brain cholinergic function using vesicular acetylcholine transporter (VAChT) radiotracer (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone (VAT) with positron emission tomography (PET) in 21 Mn-exposed workers. We estimated occupational Mn exposure from work histories and the MRI pallidal index. A cognitive control battery consisting of the Verbal Fluency (VF), Letter Number Sequencing (LNS), Two-Back Letter Task (2B), Go-No-Go (GnG), and Simon Task assessed cognitive function. We applied generalized linear models to Mn exposure, voxel-based cholinergic PET, and cognitive control measures, estimating coefficients for cholinergic-mediated associations between Mn and cognitive function. We utilized bootstrapping techniques to validate the mediation coefficients. RESULTS: Both Mn exposure metrics were associated with low cholinergic VAT binding in the caudate and cortical regions including the precuneus, pars triangularis, pars opercularis, middle temporal lobe, and entorhinal cortex. Regional cholinergic function mediated the relationship between Mn exposure and both the composite cognitive control score (mean of the 5 cognitive tests) [β = -0.661, 90 % confidence interval (CI) -2.130, -0.032] and the individual VF assessment (β = -0.944, 90 % CI -2.157, -0.065). DISCUSSION: Higher Mn exposure is associated with lower cholinergic activity in multiple brain regions. Cholinergic function also mediates a portion of the relationship between Mn exposure and cognitive control performance. Caudate and cortical cholinergic activity may be a biomarker of early Mn neurotoxicity and represent an important mechanism of cognitive dysfunction in parkinsonian syndromes.

Medical Subject Headings

Humans; Male; Occupational Exposure (adverse effects); Manganese (toxicity, adverse effects); Adult; Middle Aged; Positron-Emission Tomography; Female; Manganese Poisoning (diagnostic imaging, psychology, metabolism); Vesicular Acetylcholine Transport Proteins (metabolism); Cognitive Dysfunction (chemically induced, diagnostic imaging, metabolism); Neuropsychological Tests; Brain (diagnostic imaging, metabolism, drug effects)

Publication Date

12-1-2025

Publication Title

Neurotoxicology

E-ISSN

1872-9711

Volume

111

First Page

103313

PubMed ID

40912474

Digital Object Identifier (DOI)

10.1016/j.neuro.2025.103313

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