The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

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Manganese (Mn) was first recognized as a neurotoxin in the 19th century with the report of four manganese ore crushers, developing a syndrome of a lower extremity predominant "muscular weakness," festination, postural instability, facial masking, hypophonia, and sialorrhea (40). The syndrome was more clearly delineated by Rodier (35) in 1955 when he described a group of Moroccan manganese miners with a neurologic illness, characterized by parkinsonism, gait disorder, dystonia, psychosis, and emotional lability. All of these individuals worked underground, and the majority mined manganese ore. The latency to symptom onset from work exposure was one month to over 10 years. Rodier divided the syndrome into three phases: the prodromal period, the intermediate phase, and the established phase. The first phase was characterized by akinesia and apathy, followed by "manganese psychosis." During this phase, the gait was described as "staggering," and patients became aggressive. Early characteristics of the intermediate phase were hypophonia with vocal "freezing", facial masking, and emotional lability. In the final phase, the patients developed rigidity, bradykinesia, tremor, flexed posture, shuffling gait, and postural instability. Some patients developed a dystonic, wide-based gait described as a "cock gait." The disease progressed to total disability in most, despite discontinuing exposure (35). There are numerous other clinical reports of atypical parkin-sonism in manganese-exposed workers (34,41).

Exposure to manganese at much lower levels may also be associated with parkinsonism. The Occupational Safety and Health Administration has a permissible exposure limit ceiling for manganese of 5mg/m3 (42). A cross-sectional epi-demiologic study of workers in a manganese oxide and salt producing plant found that workers exposed to low levels of manganese (approximately 1mg/m3) had slowed simple reaction times on a standardized reaction time test and increased hand tremor, as measured by a standardized hand steadiness assessment (43). Manganese-exposed foundry workers in Sweden (mean Mn exposure 0.18-0.41 mg/m3) demonstrated slower reaction time, reduced finger-tapping speed, reduced tapping endurance, and diadochokinesis (44-46). A larger, population-based study of workers in a manganese alloy facility found that exposed subjects had slower computerized finger-tapping scores and less hand steadiness (47). Lucchini et al. found an exposure-dependent increase in blood and urine manganese levels, and slowing of finger-tapping in workers in a ferroalloy plant exposed to low-level, chronic manganese. Even nonoccupational blood elevations in manganese are associated with an exposure-related slowing of motor tasks and difficulty with pointing tasks consistent with tremor (48).

Although high-level, acute exposures are clearly associated with parkinsonism and lower-level exposures are associated with parkinsonian motor abnormalities, evidence implicating manganese in the etiology of PD is contradictory. In a population-based case-control study using blinded industrial hygiene exposure assessment, Gorell et al. (49) found that occupational exposure to copper [odds ratio (OR) = 2.49] and manganese (OR = 10.61) for more than 20 years was associated with the diagnosis of PD. However, their study only had three cases and one control with long-duration manganese exposure (50). Zayed et al. (25) found an increased risk of PD in subjects exposed to a combination of manganese, iron, and aluminum for greater than 30 years. This study did not analyze the effects of individual metals nor was there a dose-response relationship (the association was only significant with the longest duration of exposure). In addition, the study sample was small and occupational categories were broad. In a population-based German cohort, Seidler et al. (51)

found no association between PD and occupational heavy-metal exposure, categorized in a job-exposure matrix. Another population-based study using self-reported occupational exposures found no association between PD and manganese (52). Differences in study design, populations studied, and exposures likely account for the discrepant findings in these studies.

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