June 6, 2006 - New Hope for Manganese Toxicity

 From:  Science Now

NewHope for Manganese Toxicity

by Greg Miller on 9 June 2006, 12:00 AM

Off target.
In a still from a video shot in 1987, the manganism patient misses the tip of her nose.

Credit: Wei Zheng

A chemical cousin of aspirin may help treat neurological problems caused by exposure to high levels of manganese metal, according to a dramatic case study in this month's Journal of Occupational and Environmental Medicine. If the results hold up in larger trials, the drug could provide the first effective treatment for thousands of workers exposed to high levels of manganese through mining, steel production, and other occupations.

Neurological problems associated with high-level manganese exposure have been noted since the 1800s. Exposed workers often exhibit tremors, rigidity, and coordination problems strikingly similar to those observed in Parkinson's disease. (A debate simmers about whether long-term exposure to low manganese levels can cause similar problems--see Science, 21 May 2003). Yet Parkinson's drugs such as levodopa have little effect in people with manganism; the same goes for compounds that help the body rid itself of manganese.

That's why the new findings are so promising, says Wei Zheng of Purdue University in West Lafayette, Indiana. He and colleagues in Italy and China have followed the case of a Chinese woman who worked for 19 years at a manganese milling facility. She was hospitalized several times in the 1980s. In videos taken in 1987, her movements are unsteady and halting, and she struggles to touch a finger to the tip of her nose and perform other simple tasks. Then, over 3 months, she received an experimental treatment of 15 intravenous infusions of para-aminosalicylic acid (PAS), a relative of aspirin that is used to treat tuberculosis. Nearly all of her symptoms disappeared and she has remained healthy ever since, Zheng and colleagues report. "The video speaks for itself," Zheng says. He adds that he and colleagues have tried PAS in 85 additional patients in China. The drug seems to help about two-thirds of them, he says, but so far those results have only appeared in Chinese-language journals.

It's not clear how PAS works, Zheng says, but one possibility is that it sops up manganese and clears the metal from the brain more effectively than the drugs that have been tried previously. Or it may have anti-inflammatory properties that protect neurons.

"The results are very impressive," says Michael Aschner, a neurotoxicologist at Vanderbilt University in Nashville, Tennessee. Even so, Aschner cautions that large-scale trials will be needed to determine whether PAS is an effective treatment for manganism.

Related sites

·         Zheng's Web site, with videos of the patient WEBSITE INACTIVE

·         Information about Parkinson's disease from NINDS

Nov. 29, 2011 - NIH grant to help MRI scientist seek answers about manganese toxicity, Parkinson's disease

From:  Purdue University News Service 

NIH grant to help MRI scientist seek answers about manganese toxicity, Parkinson's disease

November 29, 2011

Ulrike Dydak, a Purdue assistant professor of health sciences who specializes in medical imaging of neurodegenerative diseases, received more than $2 million through an Outstanding New Environmental Scientist Award (ONES) from the National Institute of Environmental Health Sciences. The five-year grant will help fund noninvasive neuroimaging techniques using magnetic resonance imaging to study manganese toxicity and lead to a better understanding of the neural system and the mechanism of this condition, which has similarities to Parkinson's disease. (Purdue University photo/Andrew Hancock)

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WEST LAFAYETTE, Ind. - People exposed to manganese in occupational settings such as welding may not see signs for years that the element is toxic to their nervous systems, but new medical imaging techniques being developed and tested by a Purdue University professor could help reveal toxicity before symptoms appear that indicate irreversible brain damage.
Ulrike Dydak, an assistant professor of health sciences who specializes in medical imaging of neurodegenerative diseases, received more than $2 million through an Outstanding New Environmental Scientist Award (ONES) from the National Institute of Environmental Health Sciences, which is part of the National Institutes of Health.

This career award is meant to provide a foundation for outstanding scientists who are in the early, formative stages of their careers in environmental health research. It was given to seven scientists nationally this year to help them launch research programs that focus on human disease and the influence of the environment.
The five-year grant will help fund Dydak's noninvasive neuroimaging techniques using magnetic resonance imaging, known as MRI, to study manganese toxicity. The work could lead to a better understanding of the neural system and the mechanism of manganese toxicity, which has similarities to Parkinson's disease.

"Patients with manganese intoxication - also known as manganism and manganese-induced Parkinsonism - as well as patients with idiopathic Parkinson's disease, have motor control issues, tremors and problems walking," Dydak said. "However, the patients with manganism don't respond to the medication used to manage Parkinson's disease symptoms because the two conditions have a different mechanism. Early diagnosis is crucial for prevention, and our goal is to see if we can identify pre-symptomatic biomarkers through new imaging techniques to create a diagnostic tool and also learn more about the disease so patients can better manage it."

Those who are mostly affected by manganese intoxication work in welding or smelting in the steel industry. There also is low-level exposure from gasoline as well as the environment of steel plants. Manganese is an element that is essential to neurological function, but too much is toxic and can cause irreversible brain damage. It also has been found recently that low amounts of manganese exposure can affect cognitive functions, such as short-term memory or reaction time.

"So far, most studies on the toxicity of manganese and other metals are performed in animal models," she said. "If we can improve medical imaging to observe specific changes in living human brain chemistry and observe these changes over the long run, it will help create a better understanding of this neurodegenerative disease and help people by improving diagnostic and therapeutic tools."

Imaging techniques that can better reveal the levels and interactions of amino acids, neurotransmitters and other physiological aspects of the brain also would be of interest to those researching other neurodegenerative diseases and in fields such as psychiatry and speech, language and hearing sciences.

Dydak has studied welders in China, where until recently the amount of manganese exposure was less regulated. Dydak will use the grant to continue developing imaging software and to observe study participants for the long term. She also will be able to study U.S. welders.

"Since it is not known at what levels of exposure manganese starts to have adverse effects, it also is important to study our local welders, even if they work under well-regulated exposure conditions," Dydak said.

Dydak has shown in previous studies that manganese exposure is related to an increase of the brain's main inhibitory neurotransmitter, gamma-aminobutyric acid, known as GABA. The increase occurs in a region of the brain responsible for movement. She also found that young, healthy workers exposed to manganese daily in the workplace had double the levels of GABA than control subjects. The increase in GABA was accompanied by a decrease in levels of N-acetylaspartate, which indicates decreased neural function. Her findings were published in the February 2011 Environmental Health Perspectives journal.
In the upcoming study, the brain chemistry and health of 48 workers with high and low exposure levels will be compared to 24 people who aren't exposed, 15 manganism patients, and 24 patients with Parkinson's disease not related to manganese exposure.

While the study's human component focuses on noninvasive diagnostic tools by MRI, the animal component will focus on new imaging options in positron emission tomography (PET) scans to learn more about brain chemistry. In this part of the study, Dydak will focus on changes of dopamine, which helps the brain regulate movement.

"In Parkinson's disease, it is known that the dopamine system is compromised," she said. "Using PET imaging and novel MRI techniques at the same time allows us to pick up and analyze changes between dopamine and GABA."

Dydak is working with the Guangxi Medical University in Nanning, China, and Indiana University School of Medicine. She is based in Purdue's School of Health Sciences, and her imaging lab is at the Indiana Institute for Biomedical Imaging Sciences at IU's School of Medicine, where she has a joint appointment.

Her interdisciplinary collaborators on this project are Wei Zheng, professor of toxicology and head of Purdue's School of Health Sciences; Frank Rosenthal, Purdue associate professor of occupational and environmental health sciences; Yueming Jiang, professor of toxicology at Guangxi Medical University; S. Elizabeth Zauber, assistant professor of neurology at Indiana University School of Medicine; Karmen Yoder, assistant professor of radiology and imaging sciences at Indiana University School of Medicine.

Writer: Amy Patterson Neubert, 765-494-9723, apatterson@purdue.edu

Source: Ulrike Dydak, 765-494-0550, udydak@purdue.edu
Note to Journalists: Ulrike Dydak is pronounced Ul-REEK-a DYE-deck. Journalists interested in a copy of the related February 2011 article from Environmental Health Perspectives can contact Amy Patterson Neubert at 765-494-9723, apattereson@purdue.edu.