Nigral MRI features of asymptomatic welders.

INTRODUCTION: Manganese (Mn)-induced parkinsonism involves motor symptoms similar to those observed in Parkinson's disease (PD). Previous literature suggests that chronic Mn- exposure may increase PD risk, although Mn-induced clinical syndromes are considered atypical for PD. This study investigated whether asymptomatic welders display differences in the substantia nigra (SN), the key pathological locus of PD. METHOD: Brain MRI data and occupational exposure history were obtained in welders (N = 43) and matched controls (N = 31). Diffusion tensor imaging fractional anisotropy (FA; estimate of microstructural integrity) and R2* (estimate of iron and other PD-related brain differences) values in the SN pars compacta (SNc), SN reticulata (SNr), and globus pallidus (GP) were compared between the two groups. The MRI markers of the SN and GP within welders were related to exposure estimates. RESULTS: Compared to controls, welders who had chronic, but low-level, Mn-exposure had similar FA and R2* values in both SN regions (p's > 0.082), but significantly lower FA (p = 0.0013), although not R2* (p = 0.553), in the GP. In welders, FA values in the SN and GP showed a second-order polynomial relationship with cumulative lifetime welding exposure (p's < 0.03). CONCLUSION: Neurotoxic processes associated with Mn-exposure may be different from those in PD when the exposure-level is relatively low. Greater welding duration and level, however, were associated with FA differences in the GP and SN, indicating that welding exposures above a certain level may induce neurotoxicity in the SN, a finding that should be explored further in future studies.

Hypermanganesemia Induced Chorea and Cognitive Decline in a Tea Seller.

Background: Manganese associated neurotoxicity and neurodegeneration is quite rare yet established neurological disorder. This neurotoxic element has predilection for depositing in basal ganglia structures, manifesting mainly as parkinsonian and dystonic movement disorders with behavioral abnormalities. Case report: We report a 40-year-old man who presented with a subacute onset bilateral, asymmetric hyperkinetic movement disorder (predominantly left sided chorea) with multi-domain cognitive impairment, dysarthria, and generalized rigidity. Clinical history and examination yielded multiple differential diagnoses including deposition and metabolic disorders, autoimmune and paraneoplastic encephalitis involving basal ganglia, and neurodegenerative disorders with chorea and cognitive impairment. However, magnetic resonance imaging was suggestive of paramagnetic substance deposition, which came out to be manganese after laboratory investigations. History, clinical examinations, and investigation results pointed towards a diagnosis of acquired hypermanganesemia due to over-ingestion of manganese containing substance (i.e., black tea). He was treated symptomatically and with chelation therapy (calcium disodium edetate). At the sixth month of follow-up, complete resolution of chorea, dysarthria and partial amelioration of rigidity were observed. His cognitive decline and behavioral abnormalities improved. Discussion: This is probably the first reported case of acquired hypermanganesemia that presented as a combination of asymmetric chorea and cognitive dysfunction with atypical imaging characteristics. The clinical picture mimicked that of Huntington's disease. We highlight the potential deleterious effects of an apparently "benign" non-alcoholic beverage (i.e., black tea) on cerebral metabolism.

MRI Signal Intensity and Parkinsonism in Manganese-Exposed Workers.

OBJECTIVE: T1-weighted brain magnetic resonance imaging (MRI) of the basal ganglia provides a noninvasive measure of manganese (Mn) exposure, and may also represent a biomarker for clinical neurotoxicity. METHODS: We acquired T1-weighted MRI scans in 27 Mn-exposed welders, 12 other Mn-exposed workers, and 29 nonexposed participants. T1-weighted intensity indices were calculated for four basal ganglia regions. Cumulative Mn exposure was estimated from work history data. Participants were examined using the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3). RESULTS: We observed a positive dose-response association between cumulative Mn exposure and the pallidal index (PI) (ß = 2.33; 95% confidence interval [CI], 0.93 to 3.74). There was a positive relationship between the PI and UPDRS3 (ß = 0.15; 95% CI, 0.03 to 0.27). CONCLUSION: The T1-weighted pallidal signal is associated with occupational Mn exposure and severity of parkinsonism.

Selective D2 receptor PET in manganese-exposed workers.

OBJECTIVE: To investigate the associations between manganese (Mn) exposure, D2 dopamine receptors (D2Rs), and parkinsonism using [11C](N-methyl)benperidol (NMB) PET. METHODS: We used NMB PET to evaluate 50 workers with a range of Mn exposure: 22 Mn-exposed welders, 15 Mn-exposed workers, and 13 nonexposed workers. Cumulative Mn exposure was estimated from work histories, and movement disorder specialists examined all workers. We calculated NMB D2R nondisplaceable binding potential (BPND) for the striatum, globus pallidus, thalamus, and substantia nigra (SN). Multivariate analysis of covariance with post hoc descriptive discriminate analysis identified regional differences by exposure group. We used linear regression to examine the association among Mn exposure, Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) score, and regional D2R BPND. RESULTS: D2R BPND in the SN had the greatest discriminant power among exposure groups (p < 0.01). Age-adjusted SN D2R BPND was 0.073 (95% confidence interval [CI] 0.022-0.124) greater in Mn-exposed welders and 0.068 (95% CI 0.013-0.124) greater in Mn-exposed workers compared to nonexposed workers. After adjustment for age, SN D2R BPND was 0.0021 (95% CI 0.0005-0.0042) higher for each year of Mn exposure. Each 0.10 increase in SN D2R BPND was associated with a 2.65 (95% CI 0.56-4.75) increase in UPDRS3 score. CONCLUSIONS AND RELEVANCE: Nigral D2R BPND increased with Mn exposure and clinical parkinsonism, indicating dose-dependent dopaminergic dysfunction of the SN in Mn neurotoxicity.

Association of exposure to manganese and iron with relaxation rates R1 and R2*- magnetic resonance imaging results from the WELDOX II study.

OBJECTIVE: Magnetic resonance imaging is a non-invasive method that allows the indirect quantification of manganese (Mn) and iron (Fe) accumulation in the brain due to their paramagnetic features. The WELDOX II study aimed to explore the influence of airborne and systemic exposure to Mn and Fe on the brain deposition using the relaxation rates R1 and R2* as biomarkers of metal accumulation in regions of interest in 161 men, including active and former welders. MATERIAL AND METHODS: We obtained data on the relaxation rates R1 and R2* in regions that included structures within the globus pallidus (GP), substantia nigra (SN), and white matter of the frontal lobe (FL) of both hemispheres, as well as Mn in whole blood (MnB), and serum ferritin (SF). The study subjects, all male, included 48 active and 20 former welders, 41 patients with Parkinson's disease (PD), 13 patients with hemochromatosis (HC), and 39 controls. Respirable Mn and Fe were measured during a working shift for welders. Mixed regression models were applied to estimate the effects of MnB and SF on R1 and R2*. Furthermore, we estimated the influence of airborne Mn and Fe on the relaxation rates in active welders. RESULTS: MnB and SF were significant predictors of R1 but not of R2* in the GP, and were marginally associated with R1 in the SN (SF) and FL (MnB). Being a welder or suffering from PD or HC elicited no additional group effect on R1 or R2* beyond the effects of MnB and SF. In active welders, shift concentrations of respirable Mn>100µg/m3 were associated with stronger R1 signals in the GP. In addition to the effects of MnB and SF, the welding technique had no further influence on R1. CONCLUSIONS: MnB and SF were significant predictors of R1 but not of R2*, indicative of metal accumulation, especially in the GP. Also, high airborne Mn concentration was associated with higher R1 signals in this brain region. The negative results obtained for being a welder or for the techniques with higher exposure to ultrafine particles when the blood-borne concentration was included into the models indicate that airborne exposure to Mn may act mainly through MnB.

Thalamic GABA levels and occupational manganese neurotoxicity: Association with exposure levels and brain MRI.

Excessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson's disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure γ-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N=39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N=26; mean air Mn=0.13±0.1mg/m3; High: N=13; mean air Mn=0.23±0.18mg/m3), as well as unexposed control workers (N=22, mean air Mn=0.002±0.001mg/m3) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p<0.01, F(1,33)=9.55), as well as significantly worse performance in general motor function (p<0.01, F(1,33)=11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect.

[18F]FDOPA positron emission tomography in manganese-exposed workers.

Occupational manganese (Mn) exposure is associated with the development of parkinsonism; however, the mechanism of neurotoxicity is unknown. Brain positron emission tomography (PET) imaging provides a non-invasive method of assessing dopamineric neuronal function. 6-[18F]fluoro-L-DOPA (FDOPA) PET reflects in-vivo nigrostriatal function, but results in Mn exposure are conflicting. The objective of this study was to investigate the association between Mn exposure secondary to occupational welding, FDOPA striatal uptake, and clinical parkinsonism as measured by Unified Parkinson Disease Rating Scale motor subscore 3 (UPDRS3) scores. FDOPA PET scans were acquired on 72 subjects (27 Mn-exposed welders, 14 other Mn-exposed workers, and 31 non-exposed subjects). We estimated cumulative welding exposure from detailed work histories, and a movement disorders specialist examined all subjects. Striatal volumes of interest were identified on aligned magnetic resonance imaging (MRI) for each subject. Specific striatal FDOPA uptake was calculated with a graphical analysis method. We used linear regression while adjusting for age to assess the association between welding exposure and FDOPA uptake in the caudate, anterior putamen, and posterior putamen. Compared to the non-exposed subjects, mean caudate FDOPA uptake was 0.0014min-1 (95% confidence interval [CI] 0.0008, 0.0020) lower in Mn-exposed welders and 0.0012min-1 (95% CI 0.0005, 0.0019) lower in other Mn-exposed workers (both p≤0.001). There was no clear dose-response association between caudate FDOPA uptake and Mn exposure or UPDRS3 scores. Mn-exposed welders and workers demonstrated lower caudate FDOPA uptake, indicating pre-synaptic dopaminergic dysfunction in Mn-exposed subjects that was not associated with clinical parkinsonism.

Chronic manganism: A long-term follow-up study with a new dopamine terminal biomarker of 18F-FP-(+)-DTBZ (18F-AV-133) brain PET scan.

Recent experimental studies revealed that dopamine neuron dysfunction in chronic manganism may be due to a reduced capacity of dopamine release in the striatum. The findings imposed further difficulty in the differential diagnosis between manganism and IPD. We conducted a long-term clinical follow-up study of 4 manganism patients, applying a new tracer (18)F-9-fluoropropyl-(+)-dihydrotetrabenazine ((18)F-AV-133) with positron emission tomography (PET). Twenty age-matched subjects including 4 manganism patients, 8 idiopathic Parkinson's disease (IPD) patients, and 8 healthy controls were enrolled for comparison. Volumes of interest of the bilateral putamen, caudate nuclei and occipital cortex as the reference region were delineated from individual magnetic resonance images. The clinical features of the manganism patients still progressed, with increased scores on the Unified Parkinson Disease Rating Scale. The (18)F-AV-133 uptake in the IPD patients decreased at the bilateral striatum, compared with the healthy controls. In the manganism patients, there was no decreased uptake of radioactivity involving the bilateral striatum, except Patient 4, who had a stroke with decreased uptake in the right posterior putamen. The (18)F-AV-133 PET finding reveals that nigrostriatum neurons are not degenerated in chronic manganism and can provide a useful neuroimage biomarker in the differential diagnosis.

Reduced uptake of [¹8F]FDOPA PET in asymptomatic welders with occupational manganese exposure.

BACKGROUND: Welding exposes workers to manganese (Mn) fumes, but it is unclear if this exposure damages dopaminergic neurons in the basal ganglia and predisposes individuals to develop parkinsonism. PET imaging with 6-[(18)F]fluoro-l-dopa (FDOPA) is a noninvasive measure of nigrostriatal dopaminergic neuron integrity. The purpose of this study is to determine whether welding exposure is associated with damage to nigrostriatal neurons in asymptomatic workers. METHODS: We imaged 20 asymptomatic welders exposed to Mn fumes, 20 subjects with idiopathic Parkinson disease (IPD), and 20 normal controls using FDOPA PET. All subjects were examined by a movement disorders specialist. Basal ganglia volumes of interest were identified for each subject. The specific uptake of FDOPA, K(i), was generated for each region using graphical analysis method. RESULTS: Repeated measures general linear model (GLM) analysis demonstrated a strong interaction between diagnostic group and region (F(4,112) = 15.36, p < 0.001). Caudate K(i)s were lower in asymptomatic welders (0.0098 + 0.0013 minutes(-1)) compared to control subjects (0.0111 + 0.0012 minutes(-1), p = 0.002). The regional pattern of uptake in welders was most affected in the caudate > anterior putamen > posterior putamen. This uptake pattern was anatomically reversed from the pattern found in subjects with IPD. CONCLUSIONS: Active, asymptomatic welders with Mn exposure demonstrate reduced FDOPA PET uptake indicating dysfunction in the nigrostriatal dopamine system. The caudate K(i) reduction in welders may represent an early (asymptomatic) marker of Mn neurotoxicity and appears to be distinct from the pattern of dysfunction found in symptomatic IPD.

Secondary progressive chronic manganism associated with markedly decreased striatal D2 receptor density.

We describe a patient with chronic manganism due to intoxication 40 years ago. Whereas previous reports on acute or subacute intoxication have shown no or only small reductions in striatal D2 receptor density, we found markedly decreased D2 receptor density using (18)F-methylspiperone PET in this very late stage of chronic manganism, supporting the hypothesis that manganese intoxication may trigger a neurodegenerative disease process.