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. 2025 Sep 3:111:103313.
doi: 10.1016/j.neuro.2025.103313. Online ahead of print.

Cholinergic dysfunction in occupational manganese exposure

T Noah Hutson  1 , Susan Searles Nielsen  2 , Natalie Senini  3 , John O'Donnell  4 , Hubert P Flores  5 , Tamara Hershey  6 , Joel S Perlmutter  7 , Anil Kumar Soda  8 , Stephen M Moerlein  9 , Zhude Tu  10 , Michael Kasper  11 , Lianne Sheppard  12 , Brad A Racette  13 , Susan R Criswell  14
Affiliations

Cholinergic dysfunction in occupational manganese exposure

T Noah Hutson et al. Neurotoxicology. .

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.

Keywords: Biomarkers; Cholinergic; Manganese; Neurotoxicology; PET.

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Conflict of interest statement

Declaration of Competing Interest T. Noah Hutson reports no disclosures relevant to the manuscript; S. Searles Nielsen receives support from the following government and non-governmental organizations: R01ES029524NIEHS R01ES029524, R01ES026891, R01ES026891-S1, R01ES025991, R01ES025991-S1, K01ES028295, the US Department of Defense PD190057, and MJFF 000939, 020718; N. Senini reports no disclosures relevant to the manuscript; J. O'Donnell reports no disclosures relevant to the manuscript; H.P. Flores reports no disclosures relevant to the manuscript; T. Hershey receives support from the following government organizations: NIEHS R01ES021488, R01ES029524, R01ES013743; J. S. Perlmutter receives support from the following government and non-governmental organizations: NIA/NINDS RF1NS075321, the American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, the Missouri Chapter of the APDA, the Riney Fund, and the Barnes-Jewish Hospital Foundation; A. K. Soda reports no disclosures relevant to the manuscript; S. M. Moerlein reports no disclosures relevant to the manuscript; Z. Tu receives support from the following government organizations: NIA/NINDS R01NS075527; M. Kasper reports no disclosures relevant to the manuscript; L. Sheppard receives research support from the following government organizations: R01ES029524; B.A. Racette receives research support from the following government and non-governmental organizations: MJFF 000939, 020718, NIEHS R01ES025991, R01ES025991–02S1, R01ES030937-S1,R01ES029524, NIOSH R01OH011661, Department of Defense PD190057, Hope Center for Neurologic Disorders (Washington University), and the Kemper and Ethel Marley Foundation. B.A. Racette has received honoraria (personal compensation) for service on the National Advisory Environmental Health Sciences Council for NIEHS; S.R. Criswell receives research support from the following government and nongovernmental organizations: NIEHS R01ES029524, R01OH011661, R01ES021488.

Figures

Fig. 1.
Fig. 1.
Mediation model from Mn exposure to cognitive control performance through cholinergic VAT BPND while adjusting for age. Direct pathways of influence from Mn exposure and age on cognitive control function are shown in red (see Eq. (2)), while indirect (VAT BPND mediated) pathways are represented by the products of the blue and black arrows (also see Eq. (1)). Mn = manganese; VAT = (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone; BPND = non-displaceable binding potentials.
Fig. 2.
Fig. 2.
GLM parameter maps (estimated between mg-Mn/m3-year and cholinergic VAT BPND with age adjustment) per voxel on a selected slice depicting values for the three criteria for voxel selection: A. magnitude of the negative beta coefficients; B. r2 values; and C. p-values. Voxels selected for final cluster would exhibit high (red or yellow) values for panels A and B while exhibiting low (green or blue) p-values for panel C. GLM = generalized linear models; Mn = manganese; VAT = (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone; BPND = non-displaceable binding potentials.
Fig. 3.
Fig. 3.
A. Representative slice of a VOI cluster (in red) superimposed on the T1 MPRAGE MR atlas, and B. The association between cumulative Mn exposure (mg-Mn/m3-year) and cholinergic VAT BPND for the full VOI represented in A in red. VOI = volume of interest; MPRAGE = magnetization-prepared rapid gradient echo; Mn = manganese; VAT = (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone; BPND = non-displaceable binding potentials.
Fig. 4.
Fig. 4.
Representative slice of VOI clusters for mg-Mn/m3-year/cholinergic VAT BPND (in red) and PI/VAT BPND (in yellow) associations superimposed on 711–2B atlas. Areas of overlap are represented in orange. VOI = volume of interest; Mn = manganese; VAT = (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone; BPND = non-displaceable binding potentials; PI = pallidal index.
See this image and copyright information in PMC

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