Our Contributions to Science

Our Contributions to Science

Epidemiology of Parkinsonism in Mn-exposed Workers

Our team has developed the clinical research methodologies to reconstruct exposure history in Mn-exposed welders and has demonstrated that welders have a high prevalence of parkinsonian clinical signs. We have also shown that these clinical signs overlap with the clinical phenotype seen in idiopathic PD patients, including reductions on PD related quality of life measures. More recently, our team has demonstrated that inflammation, mediated by NOS2 gene expression, may underlie the pathophysiology of parkinsonism in Mn-exposed welders. These studies provide a clinical and pathophysiologic link between Mn neurotoxicity and idiopathic PD.

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Dr. Racette and his team conducting field assessments in the shipyard welder study

 

 

 

 

 

 

 

 

 

Related Publications

Hobson A, Seixas N, Sterling D, Racette BA. Estimation of particulate mass and manganese exposure levels among welders. Ann Occup Hyg. 2011 Jan;55(1):113-25. PubMed PMID: 20870928; PubMed Central PMCID: PMC3020674.

Hobson AJ, Sterling DA, Emo B, Evanoff BA, Sterling CS, Good L, Seixas N, Checkoway H, Racette BA. Validity and Reliability of an Occupational Exposure Questionnaire for Parkinsonism in Welders. J Occup Environ Hyg 2009;6(6):324-331. PubMed PMID: 19288335; PubMed Central PMCID: PMC2879629.

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.

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.

Racette BA, Aschner M, Guilarte TR, Dydak U, Criswell SR, Zheng W. Pathophysiology of manganese-associated neurotoxicity. Neurotoxicology. 2012 Aug;33(4):881-6. PubMed PMID: 22202748; PubMed Central PMCID: PMC3350837.

Racette BA. Manganism in the 21st century: the Hanninen lecture. Neurotoxicology. 2014 Dec;45:201-7. PubMed PMID: 24148923; PubMed Central PMCID: PMC3992192.

Lundin JI, Checkoway H, Criswell SR, Hobson A, Harris RC, Swisher LM, Evanoff BA, Racette BA. Screening for early detection of parkinsonism using a self-administered questionnaire: a cross-sectional epidemiologic study
Neurotoxicology 2014;45:232-7. PubMed PMID: 24035927; PubMed Central PMCID: PMC3954448.

Andruska KM, Racette AB. Neuromythology of Manganism. Curr Epidemiol Rep. 2015 Jun;2(2):143-148. PubMed PMID: 26046010; PubMed Central PMCID: PMC4450773.

Searles Nielsen S, Checkoway H, Criswell SR, Farin FM, Stapleton PL, Sheppard L, Racette BA. Inducible nitric oxide synthase gene methylation and parkinsonism in manganese-exposed welders. Parkinsonism Relat Disord. 2015 Apr;21(4):355-60. PubMed PMID: 25634431; PubMed Central PMCID: PMC4512640.

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;41(1):94-101. PubMed PMID: 25380186; PubMed Central PMCID: PMC4354936.

Structural and Molecular Imaging of Mn Neurotoxicity

We have used structural (MRI) and molecular imaging in Mn-exposed welders to understand the pathophysiology of Mn-associated neurotoxicity. We have found that asymptomatic Mn-exposed welders have lower uptake of the radioligand FDOPA, than non-welder reference subjects, in the caudate nucleus. Mn-exposed patients with liver failure and with symptomatic parkinsonism have lower FDOPA uptake in the caudate and putamen. Using diffusion weighted brain MRI, we found that Mn-exposed welders have restricted diffusion in the globus pallidus and putamen as compared to non-welder reference subjects. These studies demonstrate that Mn exposure is associated with pre-synaptic dopaminergic dysfunction and neurotoxic injury to the striatum.

Racette BA, Antenor JA, McGee-Minnich L, Moerlein SM, Videen TO, Kotagal V, Perlmutter JS. [18F]FDOPA PET and clinical features in parkinsonism due to manganism. Mov Disord. 2005 Apr;20(4):492-6. PubMed PMID: 15648057.

Criswell SR, Perlmutter JS, Videen TO, Moerlein SM, Flores HP, Birke AM, Racette BA. Reduced uptake of [¹⁸F]FDOPA PET in asymptomatic welders with occupational manganese exposure. Neurology. 2011 Apr 12;76(15):1296-301. PubMed PMID: 21471467; PubMed Central PMCID: PMC3090062.

 

FDOPA PET scans showing reduced FDOPA uptake in the caudate nucleus in a welder compared to reduced uptake in the posterior putamen>caudate in a PD patient

FDOPA PET scans showing reduced FDOPA uptake in the caudate nucleus in a welder compared to reduced uptake in the posterior putamen>caudate in a PD patient

 

 

 

 

 

 

 

TI MRI of the brain in an Mn-exposed subject showing bright signal in the globus pallidum

TI MRI of the brain in an Mn-exposed subject showing bright signal in the globus pallidum

 

 

 

 Related Publications:

Criswell SR, Perlmutter JS, Crippin JS, Videen TO, Moerlein SM, Flores HP, Birke AM, Racette BA. Reduced uptake of FDOPA PET in end-stage liver disease with elevated manganese levels. Arch Neurol. 2012 Mar;69(3):394-7. PubMed PMID: 22410448; PubMed Central PMCID: PMC3644556.

 

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.

 

Neuropathology of Chronic Mn Exposure

 

Mn Mine Region in the Northern Cape Province in South Africa

Mn Mine Region in the Northern Cape Province in South Africa

Wall of an underground Mn mine

Wall of an underground Mn mine in the Norther Cape Province in South Africa

In a collaboration with the University of the Witwatersrand in Johannesburg, South Africa, we have developed a neuropathology autopsy research program in South African Mn mineworkers. Our initial results suggest that Mn mineworkers have lower neuron and astrocyte density and higher microglial density in the striatum. This suggests that Mn may induce a proinflammatory balance in the corpus striatum that ultimately leads to neuronal injury. Although these workers have typical high signal in their basal ganglia on MRI, the Mn concentration is the same in Mn miners as compared to non-Mn miners.

 

 

Selected publications from these studies:

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.

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.

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.

MRI imaging of an ex-vivo Mn miner brain and resultant image

MRI imaging of an ex-vivo Mn miner brain and resultant image

 

Standardized incidence of PD in the U.S. demonstrating significant clustering of cases in Midwest and Northeast

Standardized incidence of PD in the U.S. demonstrating significant clustering of cases in Midwest and Northeast

Environmental Exposures and PD Risk

Using Medicare to identify all patients with PD over age 65 in the U.S., we demonstrated a highly significant geographic clustering of prevalent and incident PD in the Midwestern and Eastern U.S. Using EPA reported industrial emissions data, we also demonstrated that those living in counties with high industrial Mn emissions had a higher incidence of PD than those living in counties with low Mn emissions, after adjusting for covariates. We also found that survival in PD patients living in counties with high Mn emissions was lower than those living in counties with low Mn emissions. These studies suggest that environmental Mn exposure is associated with a higher risk of PD and reduced survival, possibly due to a more treatment resistant clinical phenotype.

Selected publications from these studies:

Wright Willis A, Evanoff BA, Lian M, Criswell SR, Racette BA. Geographic and ethnic variation in Parkinson disease: a population-based study of U.S. Medicare beneficiaries. Neuroepidemiology. 2010;34(3):143-51. PubMed PMID: 20090375; PubMed Central PMCID: PMC2865395.

Willis AW, Evanoff BA, Lian M, Galarza A, Wegrzyn A, Schootman M, Racette BA. Metal emissions and urban incident Parkinson disease: a community health study of Medicare beneficiaries by using geographic information systems. Am J Epidemiol. 2010 Dec 15;172(12):1357-63. PubMed PMID: 20959505; PubMed Central PMCID: PMC2998201.

Willis AW, Schootman M, Kung N, Evanoff BA, Perlmutter JS, Racette BA. Predictors of survival in patients with Parkinson disease. Arch Neurol. 2012 May;69(5):601-7. PubMed PMID: 22213411; PubMed Central PMCID: PMC3599783.

Willis AW, Schootman M, Kung N, Racette BA. Epidemiology and neuropsychiatric manifestations of Young Onset Parkinson’s Disease in the United States. Parkinsonism Relat Disord. 2013;19(2):202-6. PubMed PMID: 23083512; PubMed Central PMCID: PMC3562561.

Health Services Utilization in Patients with PD

We have published several high impact studies investigating the use of neurologic specialty services in patients with PD using Medicare data. In these studies we have found that over 50% of patients with PD do not see a neurologist and that neurologist care is associated with improved survival and reduced risk of PD related co-morbidities. We have also demonstrated that minorities, women, and those from low socioeconomic neighborhoods access specialty care less frequently and are less likely to be treated with advanced surgical therapies.

Selected publications from these studies:

Willis AW, Schootman M, Evanoff BA, Perlmutter JS, Racette BA. Neurologist care in Parkinson disease: a utilization, outcomes, and survival study. Neurology. 2011 Aug 30;77(9):851-7. PubMed PMID: 21832214; PubMed Central PMCID: PMC3162639.

Willis AW, Schootman M, Tran R, Kung N, Evanoff BA, Perlmutter JS, Racette BA. Neurologist-associated reduction in PD-related hospitalizations and health care expenditures. Neurology. 2012 Oct 23;79(17):1774-80. PubMed PMID: 23054239; PubMed Central PMCID: PMC3475618.

Willis AW, Schootman M, Kung N, Wang XY, Perlmutter JS, Racette BA. Disparities in deep brain stimulation surgery among insured elders with Parkinson disease. Neurology. 2014 Jan 14;82(2):163-71. PubMed PMID: 24336138; PubMed Central PMCID: PMC3897433.

Harris-Hayes M, Willis AW, Klein SE, Czuppon S, Crowner B, Racette BA. Relative mortality in U.S. Medicare beneficiaries with Parkinson disease and hip and pelvic fractures. J Bone Joint Surg Am. 2014 Feb 19;96(4):e27. PubMed PMID: 24553896; PubMed Central PMCID: PMC3918936.

Safarpour D, Dylan P, Thibault DP, DeSanto CL, Boyd CM, Ray Dorsey ER, Racette BA, Willis AW. Nursing Home and End-of-Life Care in Parkinson Disease. Neurology 2015; 85(5):413-419. PubMed PMID: 26138947; PubMed Central PMCID: PMC4534080.

Tobacco and PD

Dr. Searles Nielsen has conducted several studies to understand the inverse association between tobacco smoking and PD. This association is strong and consistent throughout the literature, but it remains unclear whether this association is causal, and if so, the relevant constituents of tobacco. These studies included investigations into the relation between other sources of nicotine and risk of PD, the relevance of genotype on this association, and a number of other exposure-related hypotheses and gene-environment interactions with PD.

Searles Nielsen S, Gallagher LG, Lundin JI, Zabetian CP, Farin FM, Longstreth Jr WT, Smith-Weller T, Franklin GM, Swanson PD, Checkoway H. D1 dopamine receptor polymorphism and smoking: Differential effect in Parkinson’s disease. World Federation of Neurology – Neuroepidemiology; 2010 April; Toronto, Canada. 34:270: Neuroepidemiology; c2010.

Searles Nielsen S, Gallagher LG, Lundin JI, Longstreth WT Jr, Smith-Weller T, Franklin GM, Swanson PD, Checkoway H. Environmental tobacco smoke and Parkinson’s disease. Mov Disord. 2012 Feb;27(2):293-6. PubMed PMID: 22095755; PubMed Central PMCID: PMC3289937.

Nielsen SS, Franklin GM, Longstreth WT, Swanson PD, Checkoway H. Nicotine from edible Solanaceae and risk of Parkinson disease. Ann Neurol. 2013 Sep;74(3):472-7. PubMed PMID: 23661325.

Genetics of PD

Dr. Searles Nielsen and Racette have published extensively in genetics of PD, including numerous large family genetic studies and genetic association studies.

Ahmed I, Lee PC, Lill CM, Searles Nielsen S, Artaud F, Gallagher LG, Loriot MA, Mulot C, Nacfer M, Liu T, Biernacka JM, Armasu S, Anderson K, Farin FM, Lassen CF, Hansen J, Olsen JH, Bertram L, Maraganore DM, Checkoway H, Ritz B, Elbaz A. Lack of replication of the GRIN2A-by-coffee interaction in Parkinson disease. PLoS Genet. 2014 Nov;10(11):e1004788. PubMed PMID: 25412286; PubMed Central PMCID: PMC4238979.

Parsian A, Racette B, Goldsmith LJ, Perlmutter JS. Parkinson’s disease and apolipoprotein E: Possible association with dementia but not age of onset. Genomics. 2002;79(3):458_61. PubMed PMID: 11863377.

Racette BA, Rundle M, Parsian A, Perlmutter JS. Evaluation of a Screening Questionnaire for Genetic Linkage Studies of Parkinson’s Disease. American Journal of Medical Genetics (Neuropsychiatric section) 1999;88:539-543. PubMed PMID: 10490713.

Racette BA, Rundle M, Wang JC, Goate A, Saccone NL, Farrer M, Lincoln S, Hussey J, Lin J, Suarez B, Parsian A, Perlmutter JS. A Multi-incident, Old-Order Amish family with PD. Neurology 2002; 58: 568-574. PubMed PMID: 11865134.

Parsian A, Racette B, Zhang ZH, Rundle MR, Perlmutter JS. Association of variations in monoamine oxidases A and B with Parkinson’s disease subgroups. Genomics 2004; 83(3):454-60. PubMed PMID: 14962671.

Sinha R, Racette B, Perlmutter JS, Parsian A. Prevalence of parkin gene mutations and variations in IPD. Parkinsonism Relat Disord 2005;11(6):341-347. PubMed PMID: 16019250.

Karamohamed S, Latourelle JC, Racette BA, Perlmutter JS, Wooten GF, Lew MF, Klein C, Shill H, Golbe LI, Mark MH, Guttman M, Nicholson G, Wilk JB, Saint-Hilaire MH, DeStefano AL, Prakash R, Williamson S, Tobin J, Suchowersky O, Labelle N, Growdon JH, Singer C, Watts RL, Goldwurm S, Pezzoli G, Baker KB, Giroux ML, Pramstaller PP, Burn DJ, Chinnery PF, Sherman S, Vieregge P, Litvan I, Gusella JF, Myers RH, Parsian A. BDNF genetic variants are associated with onset-age of familial Parkinson’s disease: GenePD study. Neurology 2005;65(11):1823-1825. PubMed PMID: 16344533.

Racette BA, Good LM, Antenor J, McGee-Minnich L, Moerlein SM, Videen TO, Perlmutter JS. [18F]FDOPA PET as an Endophenotype for Parkinson’s Disease Linkage Studies. American Journal of Medical Genetics (Neuropsychiatric section) 2006; 141(3):245-9. PubMed PMID: 16528749; PubMed Central PMCID: PMC2646004.

Racette BA, Good LM, Kissel AM, Criswell SR, Perlmutter JS. A Population Based Study of Parkinsonism in an Amish Community. Neuroepidemiology 2009; 33(3):225-230. PubMed PMID: 19641327; PubMed Central PMCID: PMC2826445.