Cholinergic dysfunction in occupational manganese exposure

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.