ARRA IMPACT REPORT:
Environmental Risk Factors in Neurodegenerative Disease


Public Health Burden
Neurodegenerative diseases, including movement disorders and Alzheimer’s Disease, affect millions of people in the United States and cost billions of dollars per year. Approximately 1.5 million people in the United States have essential tremor, the most common movement disorder, in which shaking of body parts or the voice often increases to the point that it prevents daily activities. Approximately 1 million people in the United States have Parkinson’s Disease, which impairs balance and coordination and causes rigidity as well as tremor. An estimated 5.4 million people in the United States have Alzheimer’s Disease, characterized by progressive decline in cognitive skills and memory as well as behavior changes. It is estimated that as the population ages, Alzheimer’s prevalence will at least double by 2050.1

Mechanisms of Environmental Exposures and Disease
Via studies in animals as well as in humans, ARRA-funded researchers are revealing how environmental chemicals contribute to the pathogenesis that leads to common neurodegenerative disorders.

  • Lead and Alzheimer’s Disease: Increased production or decreased clearance of the peptide beta amyloid in the brain is thought to result in formation of the amyloid plaques found in Alzheimer’s Disease. In a mouse model, researchers at Purdue University found that exposure to lead may disrupt a particular protein that helps move beta amyloid out of the brain, and thus may be a contributor to Alzheimer’s.2
  • Harmane and Essential Tremor: Researchers at Purdue University found that people with essential tremor had levels of a compound called harmane that were twice as high as those in people without the disorder. These elevated harmane levels persisted in a repeated measurement taken an average of six years later. Harmane is produced by the body but also found in common foods such as wheat and rice. The study suggests that people with the disorder are exposed to higher harmane levels in their diets, metabolize harmane differently, or produce more of it in their bodies.3
  • The Herbicide Paraquat and Parkinson’s Disease: Many epidemiological studies have linked the herbicide paraquat to Parkinson’s Disease risk, and studies have shown that people with a gene variant of a particular type of molecular transporter for the neurotransmitter dopamine have a higher risk of Parkinson’s than others when exposed to paraquat. An outstanding question that is still debated is whether paraquat can act on dopamine producing neurons. Researchers at the University of Rochester revealed that they can, and provided details about the mechanism involved.4

Early Detection – Manganese Toxicity
Occupational exposure to manganese is a common source of a severe movement disorder known as manganism. An urgent need exists for early detection of this and other neurodegenerative disorders. Researchers at Purdue University for the first time used a noninvasive magnetic resonance imaging/magnetic resonance spectroscopy technique to quantify the concentrations of a brain metabolite called gamma-aminobutyric acid (GABA) in the brains of living people exposed to airborne manganese in a work environment. This ARRA-funded study showed that using magnetic resonance spectroscopy to measure levels of GABA and another brain metabolite (N-acetylaspartate or NAA) may be a powerful tool for detecting manganese toxicity before symptoms begin.5

Treatment
Several ARRA-funded researchers have conducted early studies in animal models or cultured cells that reveal potential therapies for neurodegenerative diseases to be pursued through further research.

  • Transcranial Laser Therapy: In a mouse model of Alzheimer’s, researchers at the Medical University of South Carolina(MUSC) showed that transcranial laser therapy reduced amyloid plaques and inflammation and reduced behavioral effects, highlighting the treatment as a potential therapy for Alzheimer’s.6
  • Vitamin D: Researchers at MUSC have found that vitamin D therapy may be helpful for Alzheimer’s patients. In mice, those who ate a vitamin-D3-supplemented diet showed a decrease in beta amyloid plaques and a decrease in inflammation compared to mice that ate D3-deficient diets or control diets.7
  • Novel Therapeutic Target for Inherited Parkinson’s: In cells in culture, scientists at the University of Rochester defined the role played by proteins PINK1 and Parkin in inherited Parkinson’s Disease, and they used a small molecule that inhibits mitochondrial division to reverse the disruptions in cell functions caused by a mutation in PINK1. This work suggests a novel therapeutic target for inherited Parkinson’s.9

Contributing NIH Institutes & Centers

  • National Institute of Environmental Health Sciences (NIEHS)

  1. http://www.ncbi.nlm.nih.gov/pubmed/22404854
  2. 3R21ES017055-01S1, http://www.ncbi.nlm.nih.gov/pubmed/21167913 - ZHENG, WEI - PURDUE UNIVERSITY WEST LAFAYETTE - WEST LAFAYETTE - IN
  3. 3R01ES012231-04S1 - FACTOR-LITVAK, PAM R. - COLUMBIA UNIVERSITY HEALTH SCIENCES - NEW YORK - NY
    5R01ES017024-02 - FACTOR-LITVAK, PAM R. - COLUMBIA UNIVERSITY HEALTH SCIENCES - NEW YORK - NY
    5R21ES017055-02 - ZHENG, WEI - PURDUE UNIVERSITY WEST LAFAYETTE - WEST LAFAYETTE - IN
    http://www.ncbi.nlm.nih.gov/pubmed/22757671
  4. 1R21ES017470-01, http://www.ncbi.nlm.nih.gov/pubmed/22143804 - TIEU, KIM - UNIVERSITY OF ROCHESTER - ROCHESTER - NY
  5. 5R21ES017498-02, http://www.ncbi.nlm.nih.gov/pubmed/20876035 - DYDAK, ULRIKE - PURDUE UNIVERSITY WEST LAFAYETTE - WEST LAFAYETTE - IN
  6. 5R01ES016774-02, http://www.ncbi.nlm.nih.gov/pubmed/21116053 - KINDY, MARK S - MEDICAL UNIVERSITY OF SOUTH CAROLINA - CHARLESTON - SC
  7. 5R01ES016774-02, http://www.ncbi.nlm.nih.gov/pubmed/21422528 - KINDY, MARK S - MEDICAL UNIVERSITY OF SOUTH CAROLINA - CHARLESTON - SC
  8. 1R21ES017470-01, http://www.ncbi.nlm.nih.gov/pubmed/19966284 - TIEU, KIM - UNIVERSITY OF ROCHESTER - ROCHESTER - NY
  9. 1R21ES017470-01, http://www.ncbi.nlm.nih.gov/pubmed/20164189 - TIEU, KIM - UNIVERSITY OF ROCHESTER - ROCHESTER - NY