Downloaded from http://journals.lww.com/joem by BhDMf5ePHKbH4TTImqenVBZZxeh5YHRL3OIOk14Fov2sRZC5AMYxzANUvAvXK3iLkEduPXULBZw= on 10/23/2020 Copyright © 2020 American College of Occupational and Environmental Medicine. Unauthorized reproduction of this article is prohibited [ 11 C]dihydrotetrabenazine Positron Emission Tomography in Manganese-Exposed Workers Susan R. Criswell, MD, MSCI, Susan Searles Nielsen, PhD, Mark N. Warden, MS, Joel S. Perlmutter, MD, Stephen M. Moerlein, PharmD, PhD, Lianne Sheppard, PhD, Jason Lenox-Krug, MS, Harvey Checkoway, PhD, and Brad A. Racette, MD Objective: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [ 11 C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2). Methods: Basal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkin- sonism were examined by mixed linear regression. Results: Thalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m 3 -yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2mg Mn/m 3 -yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P ¼ 0.003). Conclusion: Mn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on mono- aminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity. Keywords: manganese, positron emission tomography, parkinsonism, vesicular monoamine transporter 2 I n excess, manganese (Mn) is a neurotoxicant that targets basal ganglia, 1 which makes Mn a candidate neurotoxin risk factor for parkinsonism and idiopathic Parkinson disease (PD). While the classic Mn-associated phenotype is quite distinct from PD, 2 exposures in these historic cases were orders of magnitude higher than modern exposures. Expert phenotyping of welders with lower level, contemporary Mn exposures demonstrates a clinical phenotype and associated impair- ments much more closely resembling those seen in PD. 3 Investigating the relationship between parkinsonism and in vivo neuronal integrity informs our understanding of the effects of Mn exposure on brain pathways relevant to human neurodegenerative disease. PET-based approaches, utilizing radiotracers to assess dopa- minergic neurons, have been used to investigate the role of Mn as a nigrostriatal toxin. The three presynaptic targets of PET radio- ligands include dopamine synthesis, dopamine reuptake, and the vesicular transport of monoamines. However, human studies of Mn toxicity using radioligands for the dopamine transporter (DAT), which is responsible for the reuptake of dopamine into dopaminer- gic nerve terminals, have been limited and provided inconsistent results. 4–6 We previously used the presynaptic dopaminergic radio- ligand 6-[ 18 F]fluoro-L-DOPA (FDOPA), which reflects neuronal aromatic L-amino acid decarboxylase activity, 7 to investigate Mn- exposed in occupationally exposed welders and found lower caudate FDOPA uptake in comparison to non-exposed subjects. 8 Although FDOPA uptake did not relate to Mn-dose, we hypothesized that this may be due to upregulation of dopa-decarboxylase in response to Learning Objectives  Discuss previous knowledge of manganese (Mn) as a neurotoxin associated with parkinsonism, including the limitations of radioligands used in previous studies of Mn as a nigrostriatal toxin.  Summarize the findings of the new study using [11C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) in Mn-exposed workers.  Identify exposure-related associations with DTBZ binding in selected brain areas and their implications for clinical Mn neurotoxicity. From the Department of Neurology (Dr Criswell, Dr Nielsen, Mr Warden, Dr Perlmutter, Mr Lenox-Krug, Dr Racette); Department of Radiology (Dr Perlmut- ter, Dr Moerlein); Department of Neuroscience (Dr Perlmutter); Program in Physical Therapy (Dr Perlmutter); Program in Occupational Therapy (Dr Perl- mutter); Department of Biochemistry and Molecular Biophysics (Dr Moerlein), Washington University School of Medicine, St. Louis, Missouri ; Department of Environmental and Occupational Health Sciences (Dr Sheppard); Department of Biostatistics (Dr Sheppard), School of Public Health, University of Washington, Seattle, Washington; Department of Family Medicine and Public Health (Dr Checkoway); Department of Neurosciences (Dr Checkoway), School of Medi- cine, University of California, San Diego, La Jolla, California; Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, Parktown, South Africa (Dr Racette). Clinical significance: We found Mn-dose-dependent associations with thalamic and pallidal DTBZ binding in Mn-exposed welders and non-welders. Tha- lamic DTBZ binding was also associated with parkinsonism, suggesting that the thalamic monoaminergic system may be an early biomarker of Mn neurotoxicity and that the extrastriatal dopaminergic system may be critical to clinical Mn neurotoxicity. Funding Sources: This work was supported by NIH Grants [R01ES021488, K23ES021444, K24ES017765, R01ES013743, R01ES021488-02S1, P42ES004696, R01ES029524]; and the American Parkinson’s Disease Asso- ciation. Financial Disclosures of all Authors: Dr Criswell reports grant funding from the NIH including K23ES021444, R01ES029524, and R01ES013743. Dr Searles Nielsen reports grant funding from the NIH including K24ES017765 and R01ES021488 and grants from Michael J. Fox Foundation and American Parkinson Disease Association. Dr Perlmutter reports grant funding from NIH including R01ES021488, R01ES029524, and R01ES013743. Dr Moerlein reports grant funding from the NIH including R01ES021488, R01ES029524. Dr. Sheppard reports grant funding from NIH including R01ES029524, R01ES026187, and R01ES021488. Mr Lenox-Krug reports funding from R01ES029524. Dr Checkoway reports grant funding from the NIH including R01ES021488, R21ES026084, R01ES025991, and R01ES025792. Dr Racette receives research support from NIH including K24ES017765, R01ES026891, R01ES026891-S1, R01ES021488, R01ES025991, R01ES025991-S1, and R01ES029524, Grant #10289-01 from the Michael J. Fox Foundation, and the American Parkinson Disease Association. Dr Racette has received honoraria (personal compensation) for lectures from Harvard University and the American Academy of Neurology. He has received personal compensation for peer review from the Parkinson Study Group and for service on the National Advisory Environmental Health Sciences Council for NIEHS. Mr Warden has nothing to report. Criswell, Nielsen, Warden, Perlmutter, Moerlein, Sheppard, Lenox-Krug, Checkoway, and Racette have no relationships/conditions/circumstances that present potential conflict of interest. The JOEM editorial board and planners have no financial interest related to this research. Supplemental digital contents are available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.joem.org). Address correspondence to: Susan R. Criswell, MD, MSCI, Department of Neurology, Washington University School of Medicine, 660 South Euclid Ave., Box 8111, St. Louis, MO 63110 (criswells@wustl.edu). Copyright ß 2020 American College of Occupational and Environmental Medicine DOI: 10.1097/JOM.0000000000001915 788 JOEM  Volume 62, Number 10, October 2020 CME A VAILABLE FOR THIS ARTICLE AT ACOEM.ORG