Along with a number of associated genetic factors, a large body of data indicates that environmental agents, especially neurotoxic metals, may play a role in the etiology of neurobehavioral disorders. Exposure to manganese (Mn), a well-known neurotoxicant, is widespread in the general population from gasoline additives, fossil fuel combustion, and accumulates at high levels in workers exposed to welding fumes. Overt Mn neurotoxicity (manganism or Mn-induced parkinsonism) causes symptoms that are similar to Parkinson's disease, and studies with "asymptomatic" welders suggest an association between exposure to Mn-containing metal fumes and subclinical neurobehavioral deficits. A link between low levels of Mn and neurological disorders is suspected, but weakened by both the lack of an in vivo objective marker of Mn dose to the human brain, and from insufficient data on how this correlates with functional impairment. Divalent Mn (Mn2+) is paramagnetic and causes a reduction in T1 relaxation time that is significantly greater than for all other metals, particularly the metals contained in welding fumes. Thus, magnetic resonance imaging (MRI) T1 relaxation time and T1 contrast changes of magnetic resonance imaging (MRI) may reflect Mn accumulation in the brain tissue of welders with adequate specificity. Historically, the pallidal index has served as an MRI measure for overt Mn poisoning. Its utility has been questioned because regions other than the globus pallidus (GP) have been neglected for study, and the pallidal index may not be sensitive to low levels of exposure. Supported by preliminary data in human subjects, we propose to test the central hypothesis that, relative to matched controls, "asymptomatic" welders will have significantly higher Mn accumulation in specific brain regions [e.g., olfactory bulbs (OB), basal ganglia (BG: i.e., caudate, putamen &GP), frontal lobe (FL: i.e., frontal gray (FGM) and white matter (FWM) &prefrontal cortex (including the orbital frontal cortex)] that correlate with airborne Mn exposure and region-specific neurobehavioral changes. We propose a study of 40 welders (boilermakers/pipefitters) and 40 matched controls (electricians/sprinkler fitters) with both retrospective and prospective environmental exposure measurements, neuropsychological tests, blood metal (Fe and Mn) assessment, and state-of-the-art MRI estimates of both Mn (with rapid T1 mapping) and Fe [with Susceptibility Weighted Images (SWI)]. Via this study, we shall develop an important clinical tool to bridge the gap between basic and applied research in this area that will lead to a better understanding of the role that neurotoxic metals play in the development of neurobehavioral disorders. This will be accomplished through the following specific aims:
Aim 1 will validate that the MRI T1 measurements provide a reliable biomarker of Mn exposure in specific brain regions [e.g., OB, BG and FL, etc.] in humans.
Aim 2 will delineate the functional consequences of region-specific Mn accumulation in the brain.
Aim 3 will explore Fe-Mn interactions in brain and their functional consequences.

Public Health Relevance

Manganese (Mn), a well-known neurotoxicant that is ubiquitous in the environment from gasoline additives, the combustion of fossil fuels, as well as being particularly concentrated in welding fumes, may play a role in neurodegenerative processes. The basic and epidemiological studies in this area, however, are marred by the lack of an objective marker(s) of metal deposition in the human brain and how this correlates directly with neurobehavioral impairment. The proposed study will use the improved, state-of-the-art MRI techniques to reflect regional brain Mn deposition in response to environmental exposure, delineate its functional correlations, and will lead to a better understanding of the role of environmental neurotoxicants in the development of neurobehavioral disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01ES019672-04
Application #
8663697
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Hollander, Jonathan
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Hershey
State
PA
Country
United States
Zip Code
17033
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