25 Apr 2011

No one knows exactly what causes sporadic Parkinson’s disease, but scientists know that both genetic and environmental risk factors contribute. One suspected environmental culprit is manganese, a metal often alloyed with steel to increase its hardness. High levels of manganese are known to be neurotoxic; data on the effects of low levels of environmental manganese exposure are limited, but suggest a link to parkinsonism or PD. A paper in the April 12 Neurology provides compelling new evidence that chronic exposure to manganese correlates with damage to the brain’s dopaminergic system. Researchers led by Brad Racette at Washington University, St. Louis, Missouri, found that relatively young, healthy welders, whose work often subjects them to manganese-laden fumes, have abnormalities in dopamine uptake in the caudate nucleus, one of the regions of the brain affected in PD patients. They also had very subtle motor deficits. The long-term medical significance of this finding is unclear, but the data are troubling and point to the need for further investigation of manganese’s health risks. The study reflects the field’s current push to study preclinical stages of parkinsonism.

“I think this study will potentially have a high impact on the way we view this type of neurotoxicity and its links to PD,” said Ole Isacson at McLean Hospital, Belmont, Massachusetts, who was not involved in the study. “The evidence in these welders shows there is clearly dysfunction in the dopaminergic system that would be consistent with the beginnings of PD. The question now is whether these people will develop the disease in the next 20 to 30 years.” Epidemiological studies have not found an increased incidence of PD in welders (see, e.g., Stampfer, 2009; Tanner et al., 2009), but the significance remains controversial.

Acute manganese toxicity has long been known to cause parkinsonism (see, e.g., Bleecker, 1988), but whether chronic exposure to low levels of manganese can increase the risk of parkinsonism or PD is an open question. In other words, researchers do not yet know what the threshold for neurotoxicity is. However, converging lines of evidence suggest that even low levels of occupational exposure are a serious concern, Isacson said. For example, in non-human primates, chronic low-level exposure to the metal leads to a steep drop in dopamine release in the brain, as seen by positron emission tomography (PET), and the animals have abnormal movements (see Guilarte et al., 2006; Guilarte et al., 2008). The level of manganese exposure in these studies is on a par with the high end of environmental and occupational exposures seen in people. Manganese inhalation can produce a Parkinson’s-like phenotype in rodents as well (see, e.g., Ordoñoz-Librado et al., 2010), although exactly how the metal damages the dopaminergic system is still unknown. In humans, epidemiological studies have shown an increased risk of PD in people living in areas with high levels of the metal (see Willis et al., 2010).

In addition, several studies have demonstrated an interaction between manganese and genes that are risk factors for PD, such as parkin and DJ1 (see Sriram et al., 2010), as well as ATP13A2 (ARF related news story on Gitler et al., 2009). Mutations in LRRK2, a prevalent PD risk factor currently in the number three spot on PDGene Top Results, also interact with manganese (see Lovitt et al., 2010; Covy et al., 2011).

Welders comprise one of the groups at highest risk for manganese exposure, since welding rods and the fumes they generate contain the metal. Manganese accumulates in the blood and body tissues of these workers. Though this is a significant health concern for the almost half a million full-time welders and solderers in the U.S., only a handful of studies have looked at dopamine function in the brains of people exposed to manganese. The largest previous study examined only four people (see Wolters et al., 1989; Racette et al., 2001; Racette et al., 2005). Although some of the participants had abnormal dopamine readings, the studies were confounded by the fact that the participants already showed symptoms of parkinsonism and could have had coincident PD.

To rectify these limitations, first author Susan Criswell at WashU compared brain scans of 20 healthy, asymptomatic welders with 20 normal controls and 20 people with idiopathic PD. The average age of the welders was 45, with the other groups skewing slightly older. Criswell and colleagues used PET imaging with [18F] fluoro-L-dopa to measure the integrity of presynaptic dopaminergic nerve terminals in the basal ganglia. The researchers found that welders had significantly less FDOPA uptake in the caudate nucleus than controls did, with the welders’ levels comparable to those in PD patients. This indicates that the welders’ dopaminergic system has already sustained some damage only halfway through their working life.

In an accompanying editorial, W.R. Wayne Martin at Glenrose Rehabilitation Hospital in Edmonton, Alberta, Canada, notes, “As an exploratory study of a potential risk factor for PD, this study provides valuable new information. Longitudinal motor, neuropsychological, and neuroimaging data are required, however, to clarify the significance, if any, of the reported abnormalities.”

One interesting finding was that the pattern of dysfunction was different from that seen in people with manifest PD: The PD patients had lower levels of FDOPA uptake in the putamen than in the caudate, while putamen uptake was normal in the welders. The significance of this difference is unknown, but the authors point out a couple of hypotheses. One is that manganese preferentially targets dopamine neurons that project to the caudate, rather than the putamen. Caudate damage typically comes with cognitive and psychiatric problems, while lesions in the putamen are more closely linked to motor symptoms. Manganese toxicity is marked by cognitive deficits, hallucinations, and depression (see Rodier, 1955), and manganese-exposed welders show problems with attention (see Bowler et al., 2007), lending support to this hypothesis.

The other possibility is that the caudate degenerates first in preclinical parkinsonism, with the damage spreading to the putamen as the disease progresses. In other words, this pattern might be typical in early, pre-symptomatic PD but go undetected. No single study will distinguish between these hypotheses, Racette said, but a combination of studies might help solve the puzzle. For example, by doing follow-up scans on the welders in this study, the researchers can see whether the pattern of dysfunction changes over time to become predominant in the putamen. Racette said it would also be informative to look at people with PD who have high lifetime exposures to metals, and see if they show a different pattern of PD than other patients.

A movement disorders specialist examined all study participants and scored them on the Unified Parkinson’s Disease Rating Scale, motor subsection 3 (UPDRS3). The welders showed subtle deficits compared to controls, scoring about half as high as PD patients. Although mild effects showed up in testing, the welders were not aware of any movement problems, Racette said. As with the other findings, the data are suggestive of manganese toxicity, but not conclusive. Racette told ARF they plan to follow the participants to see if their clinical condition changes, and are also applying for funding to do follow-up PET scans to see if the dopamine system deteriorates further. Although people who get acute manganese toxicity show progressive neurodegeneration, it is unknown if these lower levels of chronic exposure lead to progressive disease, Racette noted. The answer to that “will help us understand the repercussions for workers’ health in terms of long-term prognosis,” Racette said. His group will also watch for differences in progression in welders who leave the profession versus those who continue to work, to see if avoiding further manganese exposure makes a difference in long-term health outcomes.

Racette said he hopes this work will eventually provide a way to detect the earliest symptoms of neurotoxicity in workers, with an eye to preventing or intervening in the disorder. PET imaging will probably not be practical for large-scale screening, Racette said, but he believes MRI scans may one day provide a cost-effective way to screen for early effects of manganese. Racette noted that the crucial question is to determine the threshold beyond which manganese exposure becomes neurotoxic. “We are not there quite, yet, but that is where we are hoping to go with these studies over the next five years,” he said. That information could lead to improved safety regulations for industrial workers.

In his editorial, Martin noted that this study provides an excellent example of the use of FDOPA PET to assess the health of the dopamine system in asymptomatic, at-risk populations. This kind of screening is the trend of the future, scientists in the field agree. In an editorial in the April 20 Science Translational Medicine, Todd Sherer at the Michael J. Fox Foundation for Parkinson’s Research in New York City wrote, “Identification of patients with PD in the earliest stages of the disease is a top research priority.” Sherer notes that neuroimaging of the dopamine system is currently the gold-standard biomarker for PD, and is being used in conjunction with other biomarkers to identify the pre-motor phase of the disease. The hope is that, eventually, early diagnosis could allow physicians to intervene before the dopamine system sustains irreversible damage.—Madolyn Bowman Rogers

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References

News Citations

1. Yeast Screen Implicates PARK9 in Synuclein Toxicity 7 Feb 2009

Paper Citations

1. Stampfer MJ. Welding occupations and mortality from Parkinson's disease and other neurodegenerative diseases among United States men, 1985-1999. J Occup Environ Hyg. 2009 May;6(5):267-72. PubMed.
2. Tanner CM, Ross GW, Jewell SA, Hauser RA, Jankovic J, Factor SA, Bressman S, Deligtisch A, Marras C, Lyons KE, Bhudhikanok GS, Roucoux DF, Meng C, Abbott RD, Langston JW. Occupation and risk of parkinsonism: a multicenter case-control study. Arch Neurol. 2009 Sep;66(9):1106-13. PubMed.
3. Bleecker ML. Parkinsonism: a clinical marker of exposure to neurotoxins. Neurotoxicol Teratol. 1988 Sep-Oct;10(5):475-8. PubMed. RETRACTED
4. Guilarte TR, Chen MK, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS. Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol. 2006 Dec;202(2):381-90. PubMed.
5. Guilarte TR, Burton NC, McGlothan JL, Verina T, Zhou Y, Alexander M, Pham L, Griswold M, Wong DF, Syversen T, Schneider JS. Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): implications to manganese-induced parkinsonism. J Neurochem. 2008 Dec;107(5):1236-47. PubMed.
6. Ordoñez-Librado JL, Anaya-Martínez V, Gutierrez-Valdez AL, Colín-Barenque L, Montiel-Flores E, Avila-Costa MR. Manganese inhalation as a Parkinson disease model. Parkinsons Dis. 2010;2011:612989. PubMed.
8. Sriram K, Lin GX, Jefferson AM, Roberts JR, Wirth O, Hayashi Y, Krajnak KM, Soukup JM, Ghio AJ, Reynolds SH, Castranova V, Munson AE, Antonini JM. Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes. FASEB J. 2010 Dec;24(12):4989-5002. PubMed.
9. Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet JC, Lindquist S. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet. 2009 Mar;41(3):308-15. PubMed.
10. Lovitt B, Vanderporten EC, Sheng Z, Zhu H, Drummond J, Liu Y. Differential effects of divalent manganese and magnesium on the kinase activity of leucine-rich repeat kinase 2 (LRRK2). Biochemistry. 2010 Apr 13;49(14):3092-100. PubMed.
11. Covy JP, Giasson BI. α-Synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of parkinson disease. Neurotoxicology. 2011 Oct;32(5):622-9. PubMed.
12. Wolters EC, Huang CC, Clark C, Peppard RF, Okada J, Chu NS, Adam MJ, Ruth TJ, Li D, Calne DB. Positron emission tomography in manganese intoxication. Ann Neurol. 1989 Nov;26(5):647-51. PubMed.
13. Racette BA, McGee-Minnich L, Moerlein SM, Mink JW, Videen TO, Perlmutter JS. Welding-related parkinsonism: clinical features, treatment, and pathophysiology. Neurology. 2001 Jan 9;56(1):8-13. PubMed.
14. Racette BA, Antenor JA, McGee-Minnich L, Moerlein SM, Videen TO, Kotagal V, Perlmutter JS. [18F]FDOPA PET and clinical features in parkinsonism due to manganism. Mov Disord. 2005 Apr;20(4):492-6. PubMed.
15. RODIER J. Manganese poisoning in Moroccan miners. Br J Ind Med. 1955 Jan;12(1):21-35. PubMed.
16. Bowler RM, Nakagawa S, Drezgic M, Roels HA, Park RM, Diamond E, Mergler D, Bouchard M, Bowler RP, Koller W. Sequelae of fume exposure in confined space welding: a neurological and neuropsychological case series. Neurotoxicology. 2007 Mar;28(2):298-311. PubMed.

External Citations

1. parkin
2. DJ1
3. ATP13A2
4. LRRK2
5. PDGene Top Results

Further Reading

News

1. Barcelona: Taking Parkinson’s Research From Movement to Mind 28 Mar 2011
2. Barcelona: Stocking Biomarker Arsenal for Lewy Body Dementia 30 Mar 2011
3. PPMI: Brain Imaging To Reveal Preclinical Parkinson’s Signature? 20 Oct 2010
4. Yeast Screen Implicates PARK9 in Synuclein Toxicity 7 Feb 2009