Should Age at Onset of Parkinsonism be the End Point of Interest in Investigations of the Link Between Exosomal α-Synuclein and Manganese Exposure in Welders?

To the Editor:

Parkinsonism (PDism) is a neurologic disorder which, when it occurs in the context of a well-documented occupational history of exposure to neurotoxicants, is also a biological marker of neurotoxic effects.^1,2 The parkinsonism seen among miners exposed to manganese (Mn) is perhaps the most well-recognized example of such an association.³ Not too surprisingly the response to Mn is dose dependent. Because some studies have not found an increased risk for PDism,⁴ the link between chronic low level exposure to Mn such as occurs among welders and PDism has remained somewhat more controversial.

Blood and urine Mn levels can be used to document ongoing and recent exposures.^5–7 Ongoing and recent exposure to Mn can also be documented with a conventional magnetic resonance imaging (MRI) based on the presence of bilateral hyperintensities in T1 weighted images of the globus pallidus.^8–10 Whenever possible, such biological markers of exposure should be obtained and interpreted in relationship to all biological markers of effect.² Unfortunately, many workers with a history of occupational exposure to chemicals, including welders exposed to Mn who develop PDism, do not seek medical attention until after cessation of exposure making the process of relating such objective biomarkers of Mn exposure to biomarkers of effect impossible. As a result, the diagnosis of PDism due to Mn exposure is often a clinical one based on the occupational history combined with ruling out other known factors that cause PDism including family history.

It has recently been demonstrated that welders exposed to Mn have increased levels of misfolded α-synuclein in their serum exosomes but the use of this novel biomarker as a tool for predicting risk for PDism has not been established.¹¹ The aforementioned observation that welders exposed to Mn have increased misfolded α-synuclein in their serum exosomes is perhaps one of the most important observations to date with respect to the reported increased risk for PDism among some welders. These same authors also demonstrated that Mn promotes cell to cell exosomal transmission of α-synuclein between neurons and microglia, which in turn induces inflammation and neuronal cell death.¹¹ Increased misfolded α-synuclein seen in plasma/serum of subjects with idiopathic PD and Mn exposed welders respectfully provides a putative point of interaction or “link” between Mn neurotoxicity and PDism.¹² Because a significant correlation is also observed between plasma exosomal α-synuclein and idiopathic PD symptom severity, the reported observations in welders are extremely important to anticipating the clinical manifestations of Mn exposure.¹³ In short, these observations predict that Mn exposure will alter the both subclinical and clinical courses of idiopathic PDism. Previous genome wide studies have revealed that α-synuclein mechanisms of PD pathogenesis influence age at onset.¹⁴ An interaction between Mn exposure and α-synuclein mechanisms of PD pathogenesis would there be expected a priori to also influence age at onset and, to be manifested clinically by a younger age at onset of PDism.

To determine if the above stated a priori hypothesis is correct, we asked if age at onset of PDism is younger in a group of welders and welders helpers exposed to Mn. We specifically looked at PDism among 283 welders and welder's helpers with mean hours during of occupational exposure to welding fumes of 8 to 29 years; mean hours of occupational exposure to welding fumes was determine to be 39,894.6 ± 21,414.7. These workers ranged in age from 22 to 73 with an average age at the time of evaluation of 53.8 ± 8.8. Thirteen percent (37/283) of these subjects were found to have symptoms of PDism. Seven of these subjects were subsequently excluded based on the presence of other identifiable risk factors including: (1) family history (4/37); (2) history of exposure to carbon monoxide (2/37); (3) and liver disease (1/37). The remaining 30 subjects had no other identifiable risk factors for PDism other than their history of occupational exposure to Mn (Tables 1 and 2). The average age of onset of PDism among these subjects was 48.9 ± 9.03 (range 39 to 72). Racette et al^15,16 have also observed a younger age at onset of PDism among welders exposed to Mn. Gamache et al¹⁷ have also shown that welders have a younger age at onset of Parkinson disease.

TABLE 1: Clinical Characteristics of Welders and Welder's Helpers

TABLE 2: Age-Stratified Prevalence Rates in North American Welders from Washington State and California

CONCLUSIONS

The data reviewed and presented here support the hypothesis that exposure to Mn via welding fumes acts as a disease modifying factor in PD. The effect of Mn on PD can therefore be anticipated a priori to unmask latent disease and thereby contribute to a younger age at onset of PD in susceptible individuals. Thus, it is our opinion based on our review of the literature and our own observations in welders and welders helpers that future studies employing serum exosomal α-synuclein as a biomarker of Mn effect should be designed to assess for the interactions between age at onset of PD and exposure to Mn.