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Background: Excessive exposure to manganese (Mn) may cause parkinsonian-like motor and tremor symptoms and adverse cognitive effects, including problems with executive functioning (EF), resembling those found in later-stage Parkinson's disease (PD). Studies seeking to differentiate PD patients into subgroups with associated cognitive and functional outcomes using motor and tremor symptoms identified tremor-dominant (TD) and non-tremor dominant (NTD) subtypes. It is unclear whether differing patterns of pathophysiology and symptoms exist in Mn neurotoxicity, as they do in PD., Methods: Residents of East Liverpool (n=83) and Marietta, OH (n=99) exposed to chronic (>10years) environmental Mn through industrial pollution were administered neuropsychological measures and a physician-rated scale of movement-disorder symptoms. Two-step cluster analysis was used to group residents based on tremor symptoms, bradykinesia/rigidity symptoms, gait disturbance, and executive function. Cluster membership was validated using modeled air-Mn exposure and a computerized tremor measure., Results: Elevated tremor and motor symptoms and executive dysfunction were observed, and TD and NTD symptom clusters were identified. Two additional clusters were also identified: Executive Dysfunction and Normal Functioning. The NTD residents, with elevated levels of gait disturbance and other movement disorder symptoms, did not evidence EF impairment, as predicted. Instead, residents with EF impairment formed their own cluster, and were relatively free of movement disorder symptoms., Conclusions: Results resemble reports in the PD literature with TD and NTD clusters identified, but executive dysfunction did not cluster with NTD symptoms. PD and Mn exposure likely have differing pathophysiology and developmental courses, and therefore different symptom patterns, even when similar symptoms are present., (Published by Elsevier B.V.)

Introduction: Neurologist-assessed parkinsonism signs are prevalent among workers exposed to manganese (Mn)-containing welding fume. Neuroinflammation may possibly play a role. Inducible nitric oxide synthase, coded by NOS2, is involved in inflammation, and particulate exposure increases the gene's expression through methylation of CpG sites in the 5' region., Methods: We assessed DNA methylation at three CpG sites in the NOS2 exon 1 from blood from 201 welders. All were non-Hispanic Caucasian men 25-65 years old who were examined by a neurologist specializing in movement disorders. We categorized the workers according to their Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3) scores as parkinsonism cases (UPDRS3 ≥ 15; n = 49), controls (UPDRS3 < 6; n = 103), or intermediate (UPDRS3 ≥ 6 to < 15; n = 49)., Results: While accounting for age, examiner and experimental plate, parkinsonism cases had lower mean NOS2 methylation than controls (p-value for trend = 0.04), specifically at CpG site 8329 located in an exonic splicing enhancer of NOS2 (p-value for trend = 0.07). These associations were not observed for the intermediate UPDRS3 group (both p-value for trend ≥ 0.59)., Conclusions: Inflammation mediated by inducible nitric oxide synthase may possibly contribute to the association between welding fume and parkinsonism, but requires verification in a longitudinal study., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Methcathinone abuse is a significant cause of parkinsonism among young patients in the Eastern European countries. The drug is synthesized from over-the-counter cold remedies containing ephedrine or pseudoephedrine. The final mixture contains a high concentration of manganese if potassium permanganate is used as the oxidant agent. Though manganese is an essential trace element and its homeostasis is well maintained, exposure to a high level of manganese is neurotoxic. The use of manganese-contaminated methcathinone may cause permanent neurological damage and severe disability. Drug users develop a distinctive extrapyramidal syndrome that resembles classic manganese intoxication. Methcathinone could have additive neurotoxic effect to the progression of parkinsonism. The most prevalent symptoms are symmetrical bradykinesia, dystonias, and early postural, gait, and speech impairment. After cessation of exposure, the syndrome is generally irreversible and can even progress., (© 2015 Elsevier Inc. All rights reserved.)

Introduction: A higher prevalence of individuals affected by Parkinsonism was found in Valcamonica, Italy. This may be related to ferro-alloy smelters in the area, releasing manganese (Mn) in the air, soil and water for about a century. There exists individual susceptibility for Mn neurotoxicity., Aim: To analyse how polymorphism in genes regulating Mn metabolism and toxicity can modify neurophysiological effects of Mn exposure., Materials and Methods: Elderly (N=255) and adolescents (N=311) from Northern Italy were examined for neuromotor and olfactory functions. Exposure to Mn was assessed in blood and urine by atomic absorption spectroscopy and in soil by a portable instrument based on X-Ray fluorescence technology. Polymorphisms in the Parkinson-related gene ATPase type 13A2 (ATP13A2, also called PARK9: rs3738815, rs2076602, rs4920608, rs2871776 and rs2076600), and in the secretory pathway Ca(2+)/Mn(2+) ATPase isoform 1 gene (SPCA1: rs218498, rs3773814 and rs2669858) were analysed by TaqMan probes., Results: For both adolescents and elderly, negative correlations between Mn in soil and motor coordination (R(s)=-0.20, p<0.001; R(s)=-0.13, p=0.05, respectively) were demonstrated. Also among adolescents, negative correlations were seen between Mn in soil with odor identification (R(s)=-0.17, p<0.01). No associations were seen for Mn in blood or urine. ATP13A2 polymorphisms rs4920608 and rs2871776 significantly modified the effects of Mn exposure on impaired motor coordination in elderly (p for interaction=0.029, p=0.041, respectively), also after adjustments for age and gender. The rs2871776 altered a binding site for transcription factor insulinoma-associated 1., Conclusions: ATP13A2 variation may be a risk marker for neurotoxic effects of Mn in humans., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Manganese (Mn) is a well established neurotoxin associated with specific damage to the basal ganglia in humans. The phenotype associated with Mn neurotoxicity was first described in two workers with occupational exposure to Mn oxide (Couper, 1837). Although the description did not use modern clinical terminology, a parkinsonian illness characterized by slowness of movement (bradykinesia), masked facies, and gait impairment (postural instability) appears to have predominated. Nearly 100 years later an outbreak of an atypical parkinsonian illness in a Chilean Mn mine provided a phenotypic description of a fulminant neurologic disorder with parkinsonism, dystonia, and neuropsychiatric symptoms (Rodier, 1955). Exposures associated with this syndrome were massive and an order of magnitude greater than modern exposures (Rodier, 1955; Hobson et al., 2011). The clinical syndrome associated with Mn neurotoxicity has been called manganism. Modern exposures to Mn occur primarily through occupations in the steel industry and welding. These exposures are often chronic and varied, occurring over decades in the healthy workforce. Although the severe neurologic disorder described by Rodier and Couper are no longer seen, several reports have suggested a possible increased risk of neurotoxicity in these workers (Racette et al., 2005b; Bowler et al., 2007; Harris et al., 2011). Based upon limited prior imaging and pathologic investigations into the pathophysiology of neurotoxicity in Mn exposed workers (Huang et al., 2003), many investigators have concluded that the syndrome spares the dopamine system distinguishing manganism from Parkinson disease (PD), the most common cause of parkinsonism in the general population, and a disease with characteristic degenerative changes in the dopaminergic system (Jankovic, 2005). The purpose of this symposium was to highlight recent advances in the understanding of the pathophysiology of Mn associated neurotoxicity from Caenorhabditis elegans to humans. Dr. Aschner's presentation discussed mechanisms of dopaminergic neuronal toxicity in C. elegans and demonstrates a compelling potential role of Mn in dopaminergic degeneration. Dr. Guilarte's experimental, non-human primate model of Mn neurotoxicity suggests that Mn decreases dopamine release in the brain without loss of neuronal integrity markers, including dopamine. Dr. Racette's presentation demonstrates a unique pattern of dopaminergic dysfunction in active welders with chronic exposure to Mn containing welding fumes. Finally, Dr. Dydak presented novel magnetic resonance (MR) spectroscopy data in Mn exposed smelter workers and demonstrated abnormalities in the thalamus and frontal cortex for those workers. This symposium provided some converging evidence of the potential neurotoxic impact of Mn on the dopaminergic system and challenged existing paradigms on the pathophysiology of Mn in the central nervous system., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We report a rare case of manganese (Mn)-induced parkinsonism in a patient on maintenance hemodialysis therapy who complained of gait disturbance and dysarthria. His symptoms and abnormal magnetic resonance imaging (MRI) findings of the brain were thought to be caused, at least in part, by long-term ingestion of a health supplement (Chlorella extract) that contained 1.7 mg of Mn in the usual daily dose. Elevated serum and cerebrospinal fluid Mn levels were detected, and brain MRI showed areas of abnormal intensity in the bilateral basal ganglia (low intensity on T1-weighted images and high intensity on T2-weighted images). Edetic acid infusion therapy dramatically improved the MRI abnormalities, after which his symptoms gradually improved 4 months later.

Chronic exposure to manganese may induce parkinsonism similar to idiopathic Parkinson's disease (PD). However, clinical manifestations of manganism also have some features different from PD. The mechanisms of manganese-induced parkinsonism remain not fully understood. (99m)Tc-TRODAT-1 is a cocaine analogue that can bind to the dopamine transporter (DAT) site reflecting the function of presynaptic dopaminergic terminals. The purpose of this study was to evaluate DAT function using (99m)Tc-TRODAT-1 to investigate the integrity of the presynaptic dopaminergic terminals in manganese-induced parkinsonism. Brain (99m)Tc-TRODAT-1 single photon emission computed tomography was performed in 4 patients with chronic manganese intoxication in a ferromanganese smelting plant in Taiwan. Twelve PD patients and 12 healthy volunteers served as abnormal and normal controls, respectively. Clinically, all manganism patients had a bradykinetic-rigid syndrome. The scores of the Unified Parkinson's Disease Rating Scale ranged between 19 and 64. The uptake values of the (99m)Tc-TRODAT-1 were 0.868+/-0.136 in the right corpus striatum and 0.865+/-0.118 in the left, as compared with 0.951+/-0.059 and 0.956+/-0.058, respectively for the normal controls. The data were significantly higher than 0.250+/-0.070 and 0.317+/-0.066 respectively for the PD patients. Interestingly, there was a mild decrease in the uptake of (99m)Tc-TRODAT-1 in the putamen and the ratio of putamen and caudate when compared with the normal controls. Although the DAT shows a slight decrease in the putamen of manganism patients as compared with that of the normal controls, the data indicate that the presynaptic dopaminergic terminals are not the main target of chronic manganese intoxication. In addition (99m)Tc-TRODAT-1 SPECT can provide a useful, convenient and inexpensive tool for differentiation between chronic manganism and PD.

Manganese (Mn) exposure can cause parkinsonism. Pathological changes occur mostly in the pallidum and striatum. Two patients with a long history of occupational Mn exposure presented with Mn-induced parkinsonism. In one patient, magnetic resonance imaging (MRI) showed findings consistent with Mn exposure, and Mn concentration was increased in the blood and urine. However, this patient's clinical features were typical of idiopathic Parkinson disease (PD). Previous pathological and positron emission tomography studies indicate that striatal dopamine transporter density is normal in Mn-induced parkinsonism, whereas it is decreased in PD. Therefore, we performed [(123)I]-(1r)-2 beta-carboxymethoxy-3beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) single-photon emission computed tomography. Severe reduction of striatal beta-CIT binding was indicated, which is consistent with PD. We propose three interpretations: (1) the patients have PD, and Mn exposure is incidental; (2) Mn induces selective degeneration of presynaptic dopaminergic nerve terminals, thereby causing parkinsonism; or (3) Mn exposure acts as a risk of PD in these patients. Our results and careful review of previous studies indicate that the axiom that Mn causes parkinsonism by pallidal lesion may be over-simplified; Mn exposure and parkinsonism may be more complex than previously thought. Further studies are required to elucidate the relationship between Mn and various forms of parkinsonism., (Copyright 2002 Movement Disorder Society)

A 56-year-old welder working for 30 years developed postural instability and writing clumsiness since October, 1998. Neurologic findings revealed dystonia of the bilateral shoulders and distal four limbs as well as parkinsonism such as masked face, bradykinesia, rigidity, and retropulsion. Brain MRI showed hyperintensity lesions on T1-weighted images in the bilateral globus pallidus, midbrain, pontine tegmentum, dentate nucleus and cerebral white matter, which reduced in size and density after ten months. The diagnosis of manganese poisoning was made by the high manganese levels of both serum and urine, and by the marked elevated urinary manganese level after administration of the cheleting agent. We pointed out the diagnostic significance of brain MRI in patients with chronic manganese exposure.

Recent studies have implicated chronic elevated exposures to environmental agents, such as metals (e.g., manganese, Mn) and pesticides, as contributors to neurological disease. In particular, there is a concern that sensitive subpopulations such as the aged may be at increased risk for the onset of neurologic disorders because elevated exposures to Mn is associated with increased incidence of parkinsonism. Here, we utilized a rat model of pre-parkinsonism to investigate the effects of Mn exposure on neurotoxicity and the exacerbation of parkinsonism. A pre-parkinsonism state was induced using a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), followed 4 weeks later by Mn exposure (4.8 mg Mn/kgx3 intraperitoneal injections/week) for 5 weeks. Female Sprague-Dawley rats (n=44) were divided among the following treatments: (A) control, saline/vehicle; (B) Mn only; (C) 6-OHDA only; and (D) 6-OHDA+Mn. Brain Mn levels were measured by ICP-MS. Neurobehavioral function was assessed following Mn exposure using a functional observational battery (FOB) consisting of 10 neurobehavioral tests. Unilateral 6-OHDA lesions produced significant ipsilateral vs. contralateral striatal dopamine depletions (60-70%), but no measurable impairment of neurobehavioral function, thereby substantiating this pre-parkinsonism (i.e., subthreshold) model. In contrast, Mn exposure resulted in significant impairment of neurobehavioral function for eight of the 10 FOB tests. No effects of Mn exposure on striatal dopamine depletion were detected, despite the 3.4-fold increase in brain Mn levels over controls. Notably, Mn exposure in the presence of a pre-parkinsonism state significantly exacerbated the neurobehavioral impairment in the reactivity to handling (P<.049) and hopping contralateral rear limb (P<.033) FOB tests. While the persistence and Mn dose-response relationship of these neurobehavioral effects were not evaluated here, these results nonetheless suggest that chronic Mn exposure may increase the risk of neurobehavioral impairment in subpopulations that are in a pre-parkinsonism state.

Neurologic syndromes attributed to conditioning or medications have been reported in BMT recipients. A patient is presented who developed extrapyramidal symptoms on day +56 after allogeneic BMT. Brain magnetic resonance images of this patient demonstrated hyperintense basal ganglia, which has been associated with manganese (Mn) toxicity. The patient had received total parenteral nutrition (TPN) with standard trace element supplementation and had been cholestatic. Serum Mn was elevated, and continued to be so 5 months after BMT, long after discontinuation of TPN. Cholestatic patients and those on long-term TPN have been found to have high blood or serum levels of Mn, but generally are asymptomatic. When other cholestatic BMT patients were reviewed, all had elevated serum Mn. Manganese supplementation in TPN requires evaluation for BMT recipients.

To elucidate the possible role of manganese in the risk of developing Parkinson's disease (PD), we compared serum levels of manganese, and 24-h manganese excretion by urine in 29 PD patients and in 27 matched controls. We also measured chromium and cobalt in the same samples. All these values did not differ significantly between the groups, they were not influenced by antiparkinsonian drugs, and they did not correlate with age, age at onset and duration of the PD, scores of the Unified PD Rating Scale or the Hoehn & Yahr staging in the PD group. These results might suggest that serum levels and urinary excretion of manganese are apparently unrelated to the risk of developing PD.

Permanent parkinsonism was observed in a man with chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate). Symptoms developed at 37 years of age, two years after exposure had ceased. To our knowledge, this is the second report on parkinsonism associated with exposure to maneb. Manganese is a well-known parkinsonigen toxin in humans. More recently, it has been shown that dithiocarbamates can also induce extrapyramidal syndromes. The biochemical effects of manganese and dithiocarbamates are reviewed and their possible neurotoxic mechanisms are discussed. Both of these components may have played a role in this case.

We report a longitudinal follow-up study on six patients with chronic manganese-induced parkinsonism following cessation of manganese exposure. Compared with the 1987 study, their parkinsonian symptoms showed a slow progression, particularly in gait disturbances such as freezing during turning and walking backward with retropulsion. The mean disability scores on the King's College Hospital Rating Scale were 15.0 +/- 4.2 in 1987 and 28.3 +/- 6.7 in 1991 (p = 0.003, paired t test). Review of the video records also confirmed a worsening of parkinsonism, especially in difficulty turning. Three of six patients receiving levodopa treatment had an initial improvement. The response decreased after 2 to 3 years. During the therapy, they did not develop on-off fluctuation or dyskinesia. We conclude that patients with manganese-induced parkinsonism may develop increasing neurologic dysfunction long after cessation of exposure and that their responses to levodopa are different from those of patients with Parkinson's disease.

To study the effects from low level exposure to manganese, 30 men at steel smelting works and 60 nonexposed reference subjects, were neurophysiologically examined using: (i) Electroencephalogram (EEG), Event related auditory evoked potential (AEP/P300), Brain stem auditory evoked potential (BAEP) and diadochokinesometry. No group differences concerning EEG or BAEP were found. Diadochokinesis was slower and there was a tendency towards prolonged P300 latency in the exposed group as compared to the referents. These effects may be interpreted as early (subclinical) signs of disturbances of the same type as parkinsonism.

Several cases of parkinsonism were found in a ferromanganese smelter after the ventilation system had broken down and had not been repaired for eight months in 1985. To determine the aetiology and prevalence of parkinsonism, 132 workers were submitted to thorough medical examination and estimated air concentrations of carbon monoxide and manganese at different worksites. Only six of eight workers performing electrode fixation or welding during 1985 developed parkinsonism. They were exposed for 30 minutes each day, seven days a week, to high concentrations of air manganese (greater than 28.8 mg/m3). There was a consistent trend between the index of exposure to manganese and signs and symptoms exhibited by extrapyramidal systems. After repair of the ventilation system, the air concentration of manganese during electrode fixation and welding decreased to less than 4.4 mg/m3; furthermore, no new cases of parkinsonism have been observed. Workers with parkinsonism recovered partially after removal from original worksites and treatment with levodopa. It is concluded that the outbreak resulted from exposure to high concentrations of manganese fumes through the breakdown of the ventilation system.