Criswell Laboratory

Contributions to Science – We have utilized structural and molecular in-vivo imaging techniques in occupationally exposed welders to better understand the pathophysiology and temporal progression of Mn-associated neurotoxicity. Imaging a cohort of previously unexposed apprentice welders, we demonstrated T1-weighted MR changes can be detected even at very low levels of Mn exposure. Using diffusion weighted MRI, we identified restricted diffusion in the putamen and globus pallidus in a cohort of asymptomatic welders with chronic, long term Mn exposure when compared to non-welder reference subjects. In an expanded cohort that included asymptomatic and symptomatic Mn-exposed workers, molecular positron emission tomography (PET) imaging showed that Mn-exposed welders have Mn-dose-dependent associations with thalamic and pallidal [11C]dihydrotetrabenazine (DTBZ) binding, indicating direct effects on monoaminergic vesicular monoamine transporter 2. Mn-exposed welders also demonstrate upregulation of the D2 receptor radioligand [11C](N-methyl)benperidol (NMB) in the substantia nigra. We identified a Mn dose-dependent positive linear relation between the duration of Mn exposure and nigral NMB binding (p = 0.01) as well as a positive association between nigral NMB binding and degree of parkinsonism (p = 0.05). These studies demonstrate that Mn exposure is associated with presynaptic thalamic, pallidal, and nigral dopaminergic dysfunction that can be identified in asymptomatic workers and that persists with continued exposure.

Active Research Project – R01 ES029524 (PI-Criswell)

Novel PET Markers of Cognitive Impairment in Manganese Neurotoxicity

Manganese is a widespread neurotoxicant that results in clinical parkinsonism and cognitive impairment. This study employs state-of-the-art molecular imaging methods combined with an innovative statistical approach to understand the dual roles of the cholinergic and dopaminergic systems in Mn-induced cognitive impairment.

Active Research Project – R01ES021488 (PI-Racette)

Imaging Biomarkers of Neurotoxicity in Welders

This renewal builds on our previous studies by exploring the role of neuroinflammation in Mn-induced dopaminergic neurotoxicity utilizing PET imaging of neuroinflammation and dopaminergic degeneration.

Related Publications

1. Criswell SR, Nielsen SS, Warden MN, Perlmutter JS, Moerlein SM, Sheppard L, Lenox-Krug J, Checkoway H, Racette BA. [11C]dihydrotetrabenazine Positron Emission Tomography in Manganese-Exposed Workers. J Occup Environ Med. 2020 Oct;62(10):788-794. PubMed PMID: 32472844; Central PMCID: PMC7786890.
2. Baker MG, Criswell SR, Racette BA, Simpson CD, Sheppard L, Checkoway H, Seixas NS. Neurological outcomes associated with low-level manganese exposure in an inception cohort of asymptomatic welding trainees. Scand J Work Environ Health. 2015 Jan;41(1):94-101. PubMed PMID: 25380186; PubMed Central PMCID: PMC4354936.
3. Criswell SR, Perlmutter JS, Huang JL, Golchin N, Flores HP, Hobson A, Aschner M, Erikson KM, Checkoway H, Racette BA. Basal ganglia intensity indices and diffusion weighted imaging in manganese-exposed welders. Occup Environ Med. 2012 Jun;69(6):437-43. PubMed PMID: 22447645; PubMed Central PMCID: PMC3651997.
4. Criswell SR, Warden MN, Searles Nielsen S, Perlmutter JS, Moerlein SM, Sheppard L, Lenox-Krug J, Checkoway H, Racette BA. Selective D2 receptor PET in manganese-exposed workers. Neurology. 2018 Sep 11;91(11):e1022-e1030. PubMed PMID: 30097475; PubMed Central PMCID: PMC6140373.

Contributions to Science – We have contributed to the development of an autopsy research program with South African Mn mineworkers through a collaboration with the University of the Witwatersrand in Johannesburg, South Africa. We performed ex-vivo MRI, including a neuromelanin-sensitive sequence, along with neuropathological examination of the basal ganglia, of age-, race-, and sex-matched mine workers. We demonstrated that the T1 MRI basal ganglia signal from the neuromelanin-sensitive sequence correlated with cumulative exposure, and that Mn mine workers had 52% and 38% more microglia per high powered field in the external and internal segments of the globus pallidus than non-Mn-mine workers. There was also significant correlation between microglial density in the internal segment of the globus pallidus and years worked in the mines. These studies suggest Mn may promote neurotoxicity by inducing a pro-inflammatory state with microglial activation in the basal ganglia that leads to neuronal injury.

Related Publications

1. Nelson G, Criswell SR, Zhang J, Murray J, Racette BA. Research capacity development in South African manganese mines to bridge exposure and neuropathologic outcomes. Neurotoxicology. 2012 Aug;33(4):683-6. PubMed PMID: 22313906; PubMed Central PMCID: PMC3411927.
2. Gonzalez-Cuyar LF, Nelson G, Criswell SR, Ho P, Lonzanida JA, Checkoway H, Seixas N, Gelman BB, Evanoff BA, Murray J, Zhang J, Racette BA. Quantitative neuropathology associated with chronic manganese exposure in South African mine workers. Neurotoxicology. 2014 Dec;45:260-6. PubMed PMID: 24374477; PubMed Central PMCID: PMC4072755.
3. Criswell SR, Nelson G, Gonzalez-Cuyar LF, Huang J, Shimony JS, Checkoway H, Simpson CD, Dills R, Seixas NS, Racette BA. Ex vivo magnetic resonance imaging in South African manganese mine workers. Neurotoxicology. 2015 Jul;49:8-14. PubMed PMID: 25912463; PubMed Central PMCID: PMC4523412.

Contributions to Science – We have assisted in the development of exposure reconstruction and clinical research methodologies to study the epidemiology of parkinsonism and cognitive impairment in manganese (Mn)-exposure. In a cohort of nearly 1,000 welding-exposed workers, we have demonstrated that Mn-exposed workers demonstrate a high prevalence of parkinsonism, poorer working memory performance, and reductions in quality of life in comparison to non-exposed reference subjects. More recently, we demonstrated that welding- exposed workers in this cohort have a Mn dose-dependent progression of parkinsonism. These studies demonstrate a high clinical burden associated with Mn exposures.

Active Research Project – R01 OH011661 (PI-Checkoway)

Manganese-Related Motor and Cognitive System Toxicity Among Professional Welders

The primary goal of this study is to test the hypothesis that the underlying mechanisms of Mn- induced motor system neurotoxicity share features similar to those involved in the pathogenesis of Parkinson disease, which is the most common neurodegenerative cause of parkinsonism.

Active Research Project – U19 AG071754 (PIs-Ju, Boeve, Postuma)

Related Publications

1. Al-Lozi A, Nielsen SS, Hershey T, Birke A, Checkoway H, Criswell SR, Racette BA. Cognitive control dysfunction in workers exposed to manganese-containing welding fume. Am J Ind Med. 2017 Feb;60(2):181-188. PubMed PMID: 27862095.
2. Racette BA, Searles Nielsen S, Criswell SR, Sheppard L, Seixas N, Warden MN, Checkoway H. Dose-dependent progression of parkinsonism in manganese-exposed welders. Neurology. 2017 Jan 24;88(4):344-351. PubMed PMID: 28031394; PubMed Central PMCID: PMC5272970.
3. Racette BA, Criswell SR, Lundin JI, Hobson A, Seixas N, Kotzbauer PT, Evanoff BA, Perlmutter JS, Zhang J, Sheppard L, Checkoway H. Increased risk of parkinsonism associated with welding exposure. Neurotoxicology. 2012 Oct;33(5):1356-61. PubMed PMID: 22975422; PubMed Central PMCID: PMC3651999.
4. Harris RC, Lundin JI, Criswell SR, Hobson A, Swisher LM, Evanoff BA, Checkoway H, Racette BA. Effects of parkinsonism on health status in welding exposed workers. Parkinsonism Relat Disord. 2011 Nov;17(9):672-6. PubMed PMID: 21724446; PubMed Central PMCID: PMC3200492.

The North American Prodromal Synucleinopathy Consortium for RBD, Stage 2 (NAPS2) program builds on previous efforts by NAPS1 with the overarching goals of establishing infrastructure to support long-term research in prodromal synucleinopathies (αSN). These include dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and multiple system atrophy (MSA); expanding a rapid eye movement (REM) sleep behavior disorder (RBD) cohort; collecting and analyzing a comprehensive array of longitudinal data and bio samples to develop biomarkers of αSN burden and phenoconversion as well as a prodromal synucleinopathy rating scale (PSRS); and ultimately, preparing for disease-modifying interventional clinical trials.

Active Research Project – U19 AG071754 (PIs-Ju, Boeve, Postuma)

Related Publications

1. Elliott JE, Lim MM, Keil AT, Postuma RB, Pelletier A, Gagnon JF, St Louis EK, Forsberg LK, Fields JA, Huddleston DE, Bliwise DL, Avidan AY, Howell MJ, Schenck CH, McLeland J, Criswell SR, Videnovic A, During EH, Miglis MG, Shprecher DR, Lee-Iannotti JK, Boeve BF, Ju YS; North American Prodromal Synucleinopathy (NAPS) Consortium.  Baseline characteristics of the North American Prodromal Synucleinopathy cohort.  Ann Clin Transl Neurol. 2023 Feb 8. doi: 10.1002/acn3.51738. Online ahead of print.  PMID: 36751940.

The focus of this project is to characterize the neurologic effects of long Covid including the clinical phenotype, neuroimaging, and biomarker profile to understand if long Covid might represent a risk factor for Alzheimer’s disease.

Active Research Project – GR-ARPA-BNF-010123-01, State of Arizona (PI-Racette, Sattler, Sabbagh)

Related Publications

Pending Research Project – R01 ES036296-01 (PI-Criswell)

We are examining the relationships between persistent environmental neurotoxicants, the internal environment (metabolomics and genomics), and the clinical progression of prodromal synucleinopathies. Our goal is to understand the role of environmental neurotoxicants in the progression of synucleinopathies and to identify important new targets for intervention before the onset of disabling motor impairment and dementia.

Pending Research Project – R01 ES036296-01 (PI-Criswell)