$3.7 million aimed at studying effect of manganese exposure on cognitive skills

Researchers at Washington University School of Medicine in St. Louis have received a $3.7 million grant to investigate the link between manganese and cognitive problems. Understanding how the metal harms the brain could lead to better ways to prevent or treat some forms of cognitive impairment, including in Parkinson’s disease.

The grant, from the National Institute of Environmental Health Sciences of the National Institutes of Health (NIH), will focus on welders, many of whom have high levels of manganese exposure.

Manganese is an essential mineral, but too much of it can lead to parkinsonism, or movement difficulties similar to Parkinson’s disease: tremor, stiffness, slow movement, and problems with balance and walking. Overexposure to the metal also is linked to cognitive issues such as memory and attention lapses, slow thinking, irritability, aggression and confusion.

The connection between the metal and movement problems is well understood: Excess manganese collects in an area of the brain devoted to movement and damages a kind of neuron there. But the cognitive effects are more puzzling.

“People think of Parkinson’s disease as a movement disorder, and it is, but cognitive problems are also very common among people with Parkinson’s disease,” said principal investigator Susan Criswell, MD, an associate professor of neurology. “The cognitive issues you see in people exposed to manganese are very similar to mild cognitive impairment and dementia in Parkinson’s disease. Understanding the causes of these cognitive issues is going to be very helpful in ultimately finding better treatments for people exposed to manganese and people with dementia linked to Parkinson’s.”

Criswell’s focus is on welders, who breathe in manganese found in welding fumes. Health regulations limit the amount of the metal in such fumes, but in previous research, Criswell and colleagues found that welders exposed to higher levels of manganese have more movement and cognitive problems, even when their exposure levels are below the guidelines set by the Occupational Safety and Health Administration.

The metal injures so-called dopaminergic neurons – named for their ability to produce the chemical dopamine ­– and causes a shortage of dopamine in the brain. Degeneration of dopaminergic neurons is also a hallmark of Parkinson’s disease. Both Parkinson’s disease and parkinsonism are commonly treated by supplementing with a form of dopamine.

But researchers have found that people with cognitive impairment often have problems with a different kind of neuron: cholinergic neurons, which release the chemical acetylcholine. The two kinds of neurons sit side by side in the brain. Criswell suspects that manganese also injures cholinergic neurons, and that the degeneration of cholinergic neurons accounts for the cognitive effects of manganese exposure.

To find out, she is studying 60 welders who work at plants in the Midwest. Study participants visit the School of Medicine for a day, during which each undergoes a double positron emission tomography (PET) brain scan to detect signs of degeneration in dopaminergic and cholinergic neurons. In addition, the workers undergo a battery of assessments of their memory, thinking speed, ability to focus and plan, and other cognitive skills. The goal is to identify the relationship between manganese exposure, cognitive impairment, and degeneration of each kind of neuron. Criswell and colleagues have worked for a decade with welders at the same plants to study the effects of manganese exposure on the nervous system.

“The welders have been great research partners,” Criswell said. “Welding is their source of income so they want to continue doing the work, but they want to do it safely. They have been really committed to this project, and I can’t say how much I appreciate all the time and effort they put into participating.”

An estimated 1 million people are living with Parkinson’s disease in the U.S. Scientists know little about the early stages of the disease, before people’s symptoms become severe enough to warrant a trip to the doctor’s office. But workers exposed to manganese can be identified through their workplaces, and studying them could shine light on the neurological changes that take place in the earliest stages of parkinsonism and Parkinson’s disease — and potentially lead to interventions that halt the disease process before it seriously undermines their quality of life.

“When we do screenings with welders, we always find some with very mild symptoms that only a trained neurologist would detect,” Criswell said. “But their symptoms can worsen over time, and that progression does seem to be related to the amount of manganese exposure. The welders present an opportunity to find people with early, early symptoms and follow them to see what happens. It could yield real insight into how the disease develops and how we can stop it.”

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