Our Current Grant Funding

K24 ES017765-07, NIEHS Racette (PI) 05/01/2009 – 08/31/2019

Epidemiology and Biomarkers of Parkinsonism in Welders

This renewal of K24ES017765 builds on substantial scientific and mentoring progress made in the last five years. Scientifically, the investigators have conducted impactful human clinical epidemiological, imaging, and pathology studies investigating the neurotoxic effects of manganese (Mn) exposure. Manganese (Mn) is a metal with complex pharmacology due to its role as both an essential trace element and an established neurotoxicant. The scientific aims of this renewal provide a critical link between Mn deposition in tissue and biomarkers in Mn-exposed workers, consistent with the theme of this application. A better understanding of these relationships and the biology of the MRI signal intensity in humans will provide essential information to inform future studies on the health effects of Mn. The investigators propose to leverage a long-standing relationship with our colleagues in South Africa to collect neuropathologic (brain) and other tissue from deceased Mn miners to investigate the inter-relationship between Mn exposure, state-of-the-art quantitative MRI metal sequences, and tissue Mn/Fe concentrations. This study will inform their currently funded research in Mn-exposed welders and future studies in South African Mn miners. In addition, it will provide a rare opportunity to investigate metal deposition in brain and other tissues in Mn-exposed subjects in order to develop and validate biomarkers for Mn exposure.

R01 ES021488-04, NIEHS Racette (PI) 12/06/2012 – 10/31/2017

Imaging Biomarkers of Neurotoxicity in Welders

Manganese (Mn) is a neurotoxicant that is present in soil, air, and water. Investigations of occupationally-exposed groups, such as welders, provide an ideal opportunity to characterize dose-related dopaminergic system damage associated with Mn. Recent studies from our collaborating institutions demonstrate a high prevalence of Parkinsonism in workers with chronic exposure to Mn containing welding fumes and dopaminergic dysfunction on [18F] fluorodopa (FDOPA) PET. This study utilizes an established, well characterized cohort of welders with detailed exposure and clinical assessments, developed through NIEHS funded research projects. For this proposal, a cohort of 40 career welders with baseline FDOPA PET scans will undergo repeat PET imaging of the nigrostriatal dopamine system using FDOPA and first time imaging with the pre-synaptic dopaminergic radioligand [11C]dihydrotetrabenazine (DTBZ) and the post-synaptic dopamine D2 receptor selective radioligand [11C]N-methylbenperidol (NMB). These workers will be compared to a second group of non-welder reference subjects who will be imaged at baseline and four years. The specific goals of this project are 1) to investigate progression of dopaminergic dysfunction in welding exposed workers as evidence of progressive neurotoxicity, 2) to use the radioligand DTBZ to investigate the dose-response relationship with welding fume exposure as an indicator of the underlying etiologic relationship between Mn and damage to the pre-synaptic dopaminergic system, and 3) to use the radioligand NMB to investigate the dose-response relationship with welding fume exposure as an indicator of the underlying etiologic relationship between Mn and damage to the postsynaptic dopamine system. This proposal uses state-of-the-art imaging methods to investigate the health effects of a common environmental and occupational health hazard. The results of this study will have broad implications for public and worker health worldwide and will inform future community based studies of metal neurotoxicity. In addition, this study, in conjunction with our previously published data, will provide converging evidence of the role of Mn as a nigrostriatal neurotoxin. The methods described in this application represent cutting edge molecular and MRI techniques, and the institutions and investigators are ideally suited for this unique epidemiology and imaging proposal.

R01 ES021488-02S1, NIEHS Racette (PI) 12/06/2012 – 10/31/2017

Imaging Biomarkers of Neurotoxicity in Welders

The purpose of this supplement is to perform metabolomic analysis in Mn-exposed welders to investigate associations with imaging and exposure biomarkers.

R21 ES024120-02, NIEHS Racette (PI) 08/25/2014 – 07/31/2016

Risk of Parkinson Disease Associated with Solvent Exposures in Finland

PD is a common disease of the elderly associated with substantial morbidity and early mortality. The causes of PD are largely unknown, but recent studies in small cohorts have implicated occupational exposure to neurotoxic solvents. Demonstrating a relation in a larger study would provide an opportunity to reduce exposures and hence disease risk. This is particularly important given the lack of any definitive pharmacotherapy to slow disease progression. Moreover, prevention would not be limited to workers with high exposures such as painters, mechanics, metal workers, and plastic workers, since solvents are common environmental air and water pollutants in urban areas of the U.S. This proposal investigates the relation between occupational solvent exposure and incident PD in a large and efficiently-constructed, population-based study using existing data in Finland. Finland is an ideal country in which to conduct the studies described below due to low migration/immigration, universal health care, PD diagnoses made by neurologists, and high patient compliance with treatment plans. For this study, we will link the Finnish national population registry to the national comprehensive health care database to identify incident PD cases and a highly suitable comparison group, along with a wealth of covariate data for all subjects. We will further link these data with individual-level occupational data from the Finnish census and national pension database, and then estimate occupational solvent exposure, using the validated Finnish Job-Exposure Matrix (FINJEM). These Finnish databases have been used extensively to investigate occupational risk factors for many other diseases, including cancer and coronary heart disease, but remain to be used to investigate occupational risks associated with PD or other neurodegenerative diseases. The investigators and institutions in this proposal are ideally suited to perform the proposed study, representing the leading occupational health experts from the Finnish Institute of Occupational Health (FIOH) and well-established occupational epidemiology research collaboration between Washington University and the University of Washington.

R01 ES025991-01, NIEHS Racette (PI) 08/01/2015 – 04/30/2020

Motor and Cognitive Health Outcomes in an Mn-Exposed African Community

Manganese (Mn) is an established neurotoxicant with complex pharmacology, due to its role as an essential trace element. This proposal builds on a large body of research generated by our investigative team over the last decade. In these studies, we have demonstrated that Mn-exposed welders have a high prevalence of parkinsonism compared to a reference population; the phenotype of parkinsonism in Mn-exposed workers overlaps substantially with the phenotype seen in (PD; Mn-exposed workers have pre-synaptic dopaminergic dysfunction, thereby linking Mn exposure to the same pathways involved in PD; and there is an increased risk of PD in regions of the U.S. with high industrial Mn emissions. In this proposal, we will perform a population-based epidemiology study of Mn-exposed adults living near a large Mn smelter in Meyerton, South Africa, and of a non-exposed reference community in Kroonstad, South Africa, in which we will compare the prevalence and severity of motor, cognitive control, and mood dysfunction between the two communities. Within the Mn-exposed Meyerton community, we will also investigate the dose-response relationship between environmental Mn exposure and these health outcomes. Our preliminary data clearly support the hypotheses we propose to test and demonstrate that the proposed work is feasible. Our research team is ideally suited to conduct these studies and includes world experts in clinical assessment of Mn neurotoxicity, environmental pollution modeling, and epidemiology. The mixed-race (black and white) South African community to be studied will provide a unique opportunity to investigate racial differences to sensitivity to Mn. Demonstrating motor and cognitive health effects from ambient Mn at exposure levels below the current Environmental Protection Agency lowest observed adverse effect level will have a substantial public health impact by informing environmental regulatory policy in the United States and worldwide.

Grant # 10289, MJFF Racette (PI) 07/01/2015 – 06/30/2016

Identifying Pre-symptomatic PD Using Medicare Data

A variety of non-motor symptoms, such as anxiety, sleep disorders, and constipation often occur in the years before diagnosis of PPD. There are likely other medical problems that precede the diagnosis of PD. A systematic examination of medical records from the general population may permit identification of PD patients earlier in the disease course, before motor symptoms such as tremor or bradykinesia begin, by using medical diagnoses or patterns of health care use. Medicare is an ideal source of data to identify people prior to diagnosis of PD, since nearly all Americans over the age of 65 receive medical insurance coverage through Medicare, making this a comprehensive source of data to study PD in older Americans who are at highest risk of developing PD. Medical conditions and health care utilization patterns not previously known to precede PD diagnosis remain to be identified. Using these and known predictors of PD, Medicare beneficiaries with a new diagnosis of PD can be identified from their Medicare claims data in the five years preceding diagnosis. We will identify all PD patients newly diagnosed in 2009 in Medicare claims data and randomly select additional Medicare beneficiaries from the same year but without PD. We will compare these two groups according to other diagnoses and patterns of health care utilization in the five years prior. Accordingly, while accounting for known predictors of PD such as age, sex, race, ethnicity, and indicators of smoking, we will develop a method to predict PD diagnoses earlier. This project promises to build new insights about the pre-motor phase of PD and to allow earlier identification of PD before symptom onset. This will permit earlier treatment of PD symptoms to reduce disability.

K23 ES021444-01 Criswell, Susan (PI) 09/01/2012 – 07/31/2017

Resting State Functional Connectivity MRI in Manganese Exposed Welders

There are over one million workers in the United States exposed to welding fumes as part of their job duties. The process of welding produces concentrated particulate fumes and gases including manganese. Concerns have arisen about exposure to manganese and the subsequent development of Parkinsonism and cognitive impairment. Positron emission tomography studies demonstrate asymptomatic welders have reduced 6-[18F]fluoro-L-DOPA uptake implying pre-clinical dysfunction of nigrostriatal pathways. Unfortunately, large scale use of this modality would be challenging and costly. In this set of experiments the investigators will investigate resting state functional connectivity MRI (rs-fcMRI) as a functional marker of manganese neurotoxicity in exposed welders. The specific aims will test the following hypotheses 1) welding with manganese exposure will cause abnormal functional connections on rs-fcMRI between basal ganglia and cognitive control networks; 2) welders with clinical manganese neurotoxicity will have greater abnormalities in functional connectivity within basal ganglia and executive control networks than exposed but asymptomatic welders; 3) rs-fcMRI can identify functional connectivity abnormalities that are potential antecedent biomarkers for the subsequent development of clinical neurotoxicity including cognitive impairment and parkinsonism. These studies will have implications for our understanding of mechanisms of manganese neurotoxicity and its relationship to Parkinsonism and cognitive dysfunction. Furthermore, study results and the techniques employed will be useful for future development of functional biomarkers of both neurotoxins and neurodegenerative processes.