Brad A. Racette, M.D. - US grants

The applicant is a neurologist and movement disorders specialist with three years of post-fellowship, faculty experience involving clinical care, clinical trials, and clinical research into etiologic risk factors for PD including genetic factors. The goal of this career development award is to provide the applicant with comprehensive training in genetic epidemiology through course work, individual tutorials, and practical application of gene mapping techniques to a multi-incident Amish family with Parkinson Disease (PD). PD is a neurodegenerative disorder that produces substantial disability for nearly 1 million people in North America. There is no known cause of the disease in the majority of patients; however, a genetic etiology has been found in a few rare multi-incidence families. Identification of such genes and subsequent determination of the cell biological effects of these mutations will provide important clues to the pathophysiology. Each new mutation discovered adds critical converging evidence about pathophysiological mechanisms common to all to those affected with PD. We have identified 27 members of a large Amish family with clinically typical PD and have excluded known PD genetic mutations. However, we still need to prove that PD is inherited in this pedigree. We will use two different methods to prove that PD in this kindred has a genetic basis. The first approach will assume an autosomal recessive model of inheritance and use genetic marker data provided by CIDR on our subjects to perform homozygosity mapping. A second approach will be to calculate a kinship coefficient to determine if the affected members of the pedigree are "more related" than randomly selected age-matched individuals from the same population. Finally, we will test whether [18]FDOPA PET permits the conversion of some people identified clinically as possible or probable PD in to PET-confirmed PD and thereby functioning as an endophenotype for disease state. This family provides a unique opportunity for the candidate to become a productive independent investigator in genetics of Parkinson Disease and other movements disorders and to develop skills needed for interpretation of [18]FDOPA PET.

[unreadable] DESCRIPTION (provided by applicant): The goal of this application is to collaborate with a coordination center, a biostatistics center, the NINDS program oversite group and 41 study sites throughout the United States for the implementation of a large, multi-center controlled clinical trial. In this trial we propose to recruit, enroll, and evaluate 84 subjects during the conduct of a neuroprotective trial in Parkinson's disease. The Movement Disorders Center (MDC) at Washington University School of Medicine has participated in over 20 clinical trials in Parkinson's disease; nine of these trials were with untreated subjects. As the only academic movement disorder program within a 200 mile radius, the MDC has an extensive primary care referral base necessary to recruit a large number of de novo patients. Initial study recruitment will occur from within the MDC clinical practice. In addition, we will utilize the Greater St. Louis Chapter of the American Parkinson Disease Association (APDA) and the APDA information and referral service to identify newly diagnosed subjects. Other recruitment strategies will include local TV, radio, and print media, web-based advertisements, and free Parkinson's Disease screenings. We propose that the study pilot phase include investigation of the validity and accuracy of electronic data entry using either a web-based or local system. The MDC has pioneered the development of an electronic medical record directly applicable to clinical practice and research studies in movement disorders. In addition, we propose that during the pilot phase of the study, a biomarker such as [18F]FDOPA PET undergo necessary validation to determine if the study medication interferes with uptake of the biomarker. If a biomarker proves to be unaffected by the study medication and meets other criteria proposed in this application, the biomarker could be used to assess disease progression in a sub-set of study subjects. The MDC at Washington University School of Medicine provides the breadth of clinical and basic research experience required to be a productive site in this large, multi-center neuroprotective trial in PD.

[unreadable] DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder affecting one million people in North America. There is no known cause for most cases of PD although environmental factors have been implicated in the majority of cases. We have preliminary evidence that parkinsonism is three to ten times more common in career welders than the general population. This application consists of a cohort study to test the hypothesis that the prevalence of parkinsonism is increased in a dose-dependent manner relative to non-exposed persons of similar age and gender. For our first specific aim we will perform a population based epidemiological study of the prevalence of parkinsonism in career welders and non-exposed referents. We will assemble a population based cohort of 875 workers and retirees (members of the International Brotherhood of Boilermakers) and 200 same-sex, nearest-age sibling referents with no prior welding history. Movement disorders specialists will perform all evaluations and ratings will be verified by a movement disorders specialist who will review a videotaped examination. Prevalence of parkinsonism will be compared between welders and the non-welder reference cohort. For the second specific aim of this study, an industrial hygienist will reconstruct subject welding exposure from a detailed exposure questionnaire in all exposed subjects. Subjects will be grouped into tertiles of exposure using a Job Exposure Matrix to determine if there is a dose-response relationship between welding exposure and parkinsonism. The research team represents a collaboration of movement disorders specialists, epidemiologists, industrial hygienists, and industry leaders. Demonstrating a definitive relationship between welding and parkinsonism will have substantial public health impact since the majority of these cases should be preventable through worksite modifications. The cohort assembled will provide unique opportunities for future research projects into gene-environment interactions and exposure related neuroimaging changes. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The goal of this application is to collaborate with a coordination center, a biostatistics center, the NINDS program oversite group and 41 study sites throughout the United States for the implementation of a large, multi-center controlled clinical trial. In this trial we propose to recruit, enroll, and evaluate 84 subjects during the conduct of a neuroprotective trial in Parkinson's disease. The Movement Disorders Center (MDC) at Washington University School of Medicine has participated in over 20 clinical trials in Parkinson's disease; nine of these trials were with untreated subjects. As the only academic movement disorder program within a 200 mile radius, the MDC has an extensive primary care referral base necessary to recruit a large number of de novo patients. Initial study recruitment will occur from within the MDC clinical practice. In addition, we will utilize the Greater St. Louis Chapter of the American Parkinson Disease Association (APDA) and the APDA information and referral service to identify newly diagnosed subjects. Other recruitment strategies will include local TV, radio, and print media, web-based advertisements, and free Parkinson's Disease screenings. We propose that the study pilot phase include investigation of the validity and accuracy of electronic data entry using either a web-based or local system. The MDC has pioneered the development of an electronic medical record directly applicable to clinical practice and research studies in movement disorders. In addition, we propose that during the pilot phase of the study, a biomarker such as [18F]FDOPA PET undergo necessary validation to determine if the study medication interferes with uptake of the biomarker. If a biomarker proves to be unaffected by the study medication and meets other criteria proposed in this application, the biomarker could be used to assess disease progression in a sub-set of study subjects. The MDC at Washington University School of Medicine provides the breadth of clinical and basic research experience required to be a productive site in this large, multi-center neuroprotective trial in PD.

Parkinson's disease (PD) is a neurodegenerative disorder affecting one million people in North America. There is no known cause for most cases of PD although environmental factors have been implicated in the majority of cases. We have preliminary evidence that parkinsonism is three to ten times more common in career welders than the general population. This proposal consists of a cohort study to test the hypothesis that the prevalence of parkinsonism is increased in a dose-dependent manner relative to non-exposed persons of similar age and gender. For our first specific aim we will perform a population based epidemiological study of the prevalence of parkinsonism in career welders and non-exposed referents. We will assemble a a population based cohort of 875 workers and retirees (members of the International Brotherhood of Boilermakers) and 200 same-sex, nearest-age sibling referents with no prior welding history. Movement disorders specialists will perform all evaluations and ratings will be verified by a movement disorders specialist who will review a videotaped examination. Prevalence of parkinsonism will be compared between welders and the non-welder reference cohort For the second specific aim of this study, an industrial hygienist will reconstruct subject welding exposure from a detailed exposure questionnaire in all exposed subjects. Subjects will be grouped into tertiles of exposure using a Job Exposure Matrix to determine if there is a dose-response relationship between welding exposure and parkinsonism. The research team represents a collaboration of movement disorders specialists, epidemiologists, industrial hygienists, and industry leaders. Demonstrating a definitive relationship between welding and parkinsonism will have substantial public health impact since the majority of these cases should be preventable through worksite modifications. The cohort assembled will provide unique opportunities for future research projects into gene-environment interactions and exposure related neuroimaging changes.

DESCRIPTION (provided by applicant): PROJECT SUMMARY: Parkinson's disease (PD) is a neurodegenerative disorder affecting one million people in North America. There is no known cause for most cases of PD although environmental factors have been implicated in the majority of cases. We have preliminary evidence that parkinsonism is three to ten times more common in career welders than the general population. We have an NIEHS and Michael J. Fox Foundation funded research program to investigate welding as a risk-factor for parkinsonism. For the funded research, we will perform a population based, epidemiology study of the prevalence of parkinsonism in career welders and controls. We will assemble a cohort of 875 active shipyard workers (and retirees) and 200 same-sex, nearest age, sibling controls. Movement disorders specialists will examine all subjects for parkinsonism. Prevalence of parkinsonism will be compared between shipyard welders, non-welder shipyard workers and the non-welder, same-sex, sibling controls. An industrial hygienist will reconstruct subject welding exposure from a detailed exposure questionnaire in all exposed subjects and subjects will be grouped into tertiles of exposure using a Job Exposure Matrix (JEM) to determine if there is a dose-response relationship between welding exposure and parkinsonism. New research to be supported by this proposal includes assessment of the relationship between blood manganese levels and increased Tl-weighted signal changes in globus pallidum. In addition, we will determine if lifetime welding exposure reconstructed from a validated questionnaire and categorized by a JEM is associated with a dose dependent decrease in [18FJFDOPA striatal uptake using PET and with greater severity of parkinsonism as measured by clinical examination and timed motor tasks. The team conducting this research represents a unique collaboration of movement disorders specialists, epidemiologists, occupational medicine specialists, industrial hygienists, and industry leaders. Demonstrating a definitive relationship between welding and parkinsonism will have substantial public health impact since the majority of these cases should be preventable through worksite modifications. This multi-institution and multi-discipline research program, in addition to the numerous educational (institutional K12, extensive lectures/seminar series) and collaborative resources in the Department of Neurology (P30), makes this research proposal an ideal environment to mentor trainees in patient-oriented neurological research. RELEVANCE: None provided.

DESCRIPTION (provided by applicant): Parkinson disease (PD) is a common neurodegenerative disorder affecting more than 1 million people in North America. The cause of PD is unknown in most cases but environmental metal exposure may be a risk factor. The primary goal of this grant is to compare brains of South African manganese (Mn) miners to the brains of South African gold (Au) miners to investigate the hypothesis that workers with chronic exposure to Mn will have neuropathologic findings typical of early PD, to further clarify the role of environmental metal exposure in the pathogenesis of PD. To accomplish this goal, we will perform neuropathologic examinations of brains obtained from South African Mn miners and reference brains from South African Au miners. Neurons, astrocytes and microglia will be counted with stereology, following immunohistochemical staining with antibodies against NeuN, GFAP and CD68, in the following fixed brain regions: globus pallidus interna, substantia nigra pars compacta, locus ceruleus, and olfactory bulb. We will also attempt to correlate sterologic cell count with tissue Mn deposition in each region of interest. Distribution of Lewy bodies, Lewy neurites and alpha-synuclein aggregates, if any, will also be evaluated after tissues are stained with an antibody against alpha-synuclein. In addition, the number of neurons and the extent of gliosis or other markers of injury in miners exposed to Mn will be correlated with the reconstructed occupational Mn exposure as well as with clinical signs of parkinsonism from past neurological exams available through employment health files. The amount of alpha-synuclein and its aggregates will be quantified with Western blot in these same brain regions. Additionally, residual tyrosine hydroxylase (TH) will be determined in the striatum of miners. We will attempt to correlate alpha-synuclein aggregation and residual striatal TH in Mn miners with reconstructed occupational Mn exposure as well as clinical signs of parkinsonism from available employment health files. This project involves a unique international collaboration of American PD and Mn researchers and the South African National Institute of Occupational Health in the world's leading Mn producing country. PUBLIC HEALTH RELEVANCE: The results of this study will provide a better understanding of the relationship between metal exposure, specifically, manganese and Parkinson disease. Findings from this study may be translated into preventative measures to reduce the frequency of Parkinson disease.

DESCRIPTION (provided by applicant): The goal of this application is to collaborate with a coordination center, a biostatistics center, the NINDS program oversite group and 41 study sites throughout the United States for the implementation of a large, multi-center controlled clinical trial. In this trial we propose to recruit, enroll, and evaluate 84 subjects during the conduct of a neuroprotective trial in Parkinson's disease. The Movement Disorders Center (MDC) at Washington University School of Medicine has participated in over 20 clinical trials in Parkinson's disease;nine of these trials were with untreated subjects. As the only academic movement disorder program within a 200 mile radius, the MDC has an extensive primary care referral base necessary to recruit a large number of de novo patients. Initial study recruitment will occur from within the MDC clinical practice. In addition, we will utilize the Greater St. Louis Chapter of the American Parkinson Disease Association (APDA) and the APDA information and referral service to identify newly diagnosed subjects. Other recruitment strategies will include local TV, radio, and print media, web-based advertisements, and free Parkinson's Disease screenings. We propose that the study pilot phase include investigation of the validity and accuracy of electronic data entry using either a web-based or local system. The MDC has pioneered the development of an electronic medical record directly applicable to clinical practice and research studies in movement disorders. In addition, we propose that during the pilot phase of the study, a biomarker such as [18F]FDOPA PET undergo necessary validation to determine if the study medication interferes with uptake of the biomarker. If a biomarker proves to be unaffected by the study medication and meets other criteria proposed in this application, the biomarker could be used to assess disease progression in a sub-set of study subjects. The MDC at Washington University School of Medicine provides the breadth of clinical and basic research experience required to be a productive site in this large, multi-center neuroprotective trial in PD.

DESCRIPTION (provided by applicant): 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 presynaptic 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 presynaptic 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.

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is one of the most common adult neurodegenerative disorders, affecting over one million people in North America. Although effective symptomatic treatments are available for PD, there are no medications available to forestall the inexorable clinical decline. As a first step in identifying such therapies, the NINDS Exploratory Trials in Parkinson's disease (NET-PD) network successfully completed futility studies, identifying creatine as a potential agent to slow clinical decline in PD. The NET-PD network is now conducting a large, long-term. Phase 3 trial (known as LS1) comparing creatine to placebo using a novel design and statistical approach. The aims of this competitive renewal are to complete follow-up and retention of enrolled subjects in the LS-1 study and to assess the efficacy of creatine using a novel primary composite clinical decline outcome. Secondary analyses include individual components of the primary outcome measure, use of health services, levodopa-dose equivalents, safety, and tolerability. The Washington University School of Medicine site has demonstrated outstanding retention in the NET-PD studies (97-100%) and 99% query resolution. The Washington University School of Medicine site has extensive experience with clinical trials and management of PD, making this an ideal site for this exploratory PD trials network.

DESCRIPTION (provided by applicant): Parkinson disease (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 US. 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.

? DESCRIPTION (provided by applicant): 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 Parkinson disease (PD); Mn-exposed workers have presynaptic 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.

Abstract Manganese (Mn) is an established neurotoxicant that affects motor and cognitive brain pathways. This proposal builds on a growing body of Mn neurotoxicity research generated by our investigative team and others. Despite these important contributions to studying the health effects of Mn exposure in vivo, defining the associated neuropathology is essential to understand mechanisms of injury and to characterize dose- response relations that will inform regulatory policy. These types of studies are extremely challenging due to the difficulty in acquiring human brain tissue and quantifying lifetime exposure to Mn in the same subjects. Over the last seven years, we have developed a collaboration with the University of the Witwatersrand in Johannesburg, South Africa using the only population-wide, occupational autopsy program in the world. Through this collaboration we have conducted novel preliminary Mn neuropathology studies that support the aims in this proposal. Our data suggest that chronic, low-level Mn exposure in these mines is associated with lower neuronal density and higher microglial/astrocyte ratios in the caudate and putamen, indicating that Mn exposure may cause astrocytic dysfunction which in turn induces a pro-inflammatory neurotoxic state in the corpus striatum (caudate, putamen, globus pallidus), driven by the activation of microglia. Astrocytic dysfunction is likely attributable, in part, to dysregulation of several key mitochondrial proteins induced by Mn exposure. However, our preliminary studies also suggest that Mn mineworkers, with high MRI signal intensity on T1 MRI, have similar corpus striatal tissue Mn concentrations, but possibly lower Fe concentrations, than non-Mn mineworkers. In this proposal, we will follow-up on these preliminary data by collecting brains from deceased Mn mineworkers with contemporaneous Mn exposures and appropriately matched non-Mn mineworkers. We will use unbiased stereologic methods to quantify neurons, astrocytes, and microglia in the caudate, putamen, globus pallidus, substantia nigra pars compacta (SNpc), and olfactory bulbs in both groups of workers and investigate the overall and dose-response associations between these counts and cumulative Mn exposure. We will also use immunofluorescence microscopy to quantify targeted astrocytic mitochondrial proteins and inductively coupled plasma-mass spectrometry to compare corpus striatal Mn and Fe concentrations between groups. This highly innovative study will provide a rare opportunity to advance the field of Mn neurotoxicity by investigating the neuropathologic effects of chronic Mn exposure.