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The relationships between the neurotoxicant manganese (Mn), dopaminergic pathology, and parkinsonism remain unclear. Therefore, we used [11C](N-methyl)benperidol (NMB) positron emission tomography to investigate the associations between Mn exposure, striatal and extrastriatal D2 dopamine receptors (D2R), and motor function in 54 workers with a range of Mn exposure. Cumulative Mn exposure was estimated from work histories, and all workers were examined by a movement specialist and completed a Grooved Pegboard test (GPT). NMB D2R nondisplaceable binding potentials (BPND) were calculated for brain regions of interest. We identified 2 principal components (PCs) in a PC analysis which explained 66.8% of the regional NMB BPND variance (PC1 = 55.4%; PC2 = 11.4%). PC1 was positively correlated with NMB binding in all regions and inversely correlated with age. PC2 was driven by NMB binding in 7 brain regions (all p

Background The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. Methods We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. Results There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. Conclusion A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society.

IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

OBJECTIVE: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [(11)C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2). METHODS: Basal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkinsonism were examined by mixed linear regression. RESULTS: Thalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m(3)-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m(3)-yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P = 0.003). CONCLUSION: Mn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on monoaminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity.

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 0.0014 min−1 (95% confidence interval [CI] 0.0008, 0.0020) lower in Mn-exposed welders and 0.0012 min−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.

Objective:To determine whether the parkinsonian phenotype prevalent in welders is progressive, and whether progression is related to degree of exposure to manganese (Mn)-containing welding fume.Methods:This was a trade union–based longitudinal cohort study of 886 American welding-exposed workers with 1,492 examinations by a movement disorders specialist, including 398 workers with 606 follow-up examinations up to 9.9 years after baseline. We performed linear mixed model regression with cumulative Mn exposure as the independent variable and annual change in Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) as the primary outcome, and subcategories of the UPDRS3 as secondary outcomes. The primary exposure metric was cumulative Mn exposure in mg Mn/m3-year estimated from detailed work histories.Results:Progression of parkinsonism increased with cumulative Mn exposure. Specifically, we observed an annual change in UPDRS3 of 0.24 (95% confidence interval 0.10–0.38) for each mg Mn/m3-year of exposure. Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression. The association between welding exposure and progression appeared particularly marked in welders who did flux core arc welding in a confined space or workers whose baseline examination was within 5 years of first welding exposure.Conclusions:Exposure to Mn-containing welding fume may cause a dose-dependent progression of parkinsonism, especially upper limb bradykinesia, limb rigidity, and impairment of speech and facial expression.

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) (β = 2.33; 95% confidence interval [CI], 0.93 to 3.74). There was a positive relationship between the PI and UPDRS3 (β = 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.

Background Chronic exposure to manganese (Mn) is a health concern in occupations such as welding because of well-established motor effects due to basal ganglia dysfunction. We hypothesized that cognitive control (the ability to monitor, manipulate, and regulate ongoing cognitive demands) would also be affected by chronic Mn exposure. Methods We examined the relationship between Mn exposure and cognitive control performance in 95 workers with varying intensity and duration (median 15.5 years) of exposure to welding fume. We performed linear regression to assess the association between exposure to Mn-containing welding fume and cognitive control tasks. Results Overall performance was inversely related to intensity of welding exposure (P = 0.009) and was driven by the Two-Back and Letter Number Sequencing tests that assess working memory (both P = 0.02). Conclusions Occupational exposure to Mn-containing welding fume may be associated with poorer working memory performance, and workers may benefit from practices that reduce exposure intensity. Am. J. Ind. Med. 60:181–188, 2017. © 2016 Wiley Periodicals, Inc.

Background Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson’s disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day. Objective In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials. Patients and Methods The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled. Results At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was − 17.7 (standard error [SE] 1.3) vs. − 7.6 (1.3) points, respectively (− 10.1 points, 95% confidence interval [CI] − 13.8, − 6.5; p

Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson’s disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day. In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials. The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled. At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was − 17.7 (standard error [SE] 1.3) vs. − 7.6 (1.3) points, respectively (− 10.1 points, 95% confidence interval [CI] − 13.8, − 6.5; p

ObjectiveTo investigate the associations between manganese (Mn) exposure, D2 dopamine receptors (D2Rs), and parkinsonism using [11C](N-methyl)benperidol (NMB) PET.MethodsWe 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.ResultsD2R 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 relevanceNigral D2R BPND increased with Mn exposure and clinical parkinsonism, indicating dose-dependent dopaminergic dysfunction of the SN in Mn neurotoxicity.

Manganese (Mn) is a common neurotoxicant associated with a clinical syndrome that includes signs and symptoms referable to the basal ganglia. Despite many advances in understanding the pathophysiology of Mn neurotoxicity in humans, with molecular and structural imaging techniques, only a few case reports describe the associated pathological findings, and all are in symptomatic subjects exposed to relatively high-level Mn. We performed an exploratory, neurohistopathological study to investigate the changes in the corpus striatum (caudate nucleus, putamen, and globus pallidus) associated with chronic low-level Mn exposure in South African Mn mine workers. Immunohistochemical techniques were used to quantify cell density of neuronal and glial components of the corpus striatum in eight South African Mn mine workers without clinical evidence of a movement disorder and eight age-race-gender matched, non-Mn mine workers. There was higher mean microglia density in Mn mine workers than non-Mn mine workers in the globus pallidus external and internal segments [GPe: 1.33 and 0.87 cells per HPF, respectively (p=0.064); GPi: 1.37 and 0.99 cells per HPF, respectively (p=0.250)]. The number of years worked in the Mn mines was significantly correlated with microglial density in the GPi (Spearman's rho 0.886; p=0.019). The ratio of astrocytes to microglia in each brain region was lower in the Mn mine workers than the non-Mn mine workers in the caudate (7.80 and 14.68; p=0.025), putamen (7.35 and 11.11; p=0.117), GPe (10.60 and 16.10; p=0.091) and GPi (9.56 and 12.42; p=0.376). Future studies incorporating more detailed occupational exposures in a larger sample of Mn mine workers will be needed to demonstrate an etiologic relationship between Mn exposure and these pathological findings.

Manganese (Mn) is a common component of welding fume. Exposure to Mn fume has been associated with parkinsonism. A simple and reliable screening tool to evaluate Mn exposed workers for neurotoxic injury would have broad occupational health application.This study investigated 490 occupational welders recruited from a trade union list. Subjects were examined by a movement disorders specialist using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Parkinsonism, intermediate, and normal groups were defined as UPDRS3 score ≥ 15, 6-15, and6, respectively. Workers completed a health status questionnaire (PDQ39) and a Parkinson disease (PD) Symptoms Questionnaire. Areas under receiver operator curve (AUC) were analyzed based on these scores, adjusted for age, smoking, race, gender, and neurologist, using normal as the reference.The AUC was 0.79 (95% confidence interval [CI]=0.73-0.84) for PDQ39 and 0.78 (95% CI=0.72-0.85) for PD Symptoms Questionnaire score. At 70% sensitivity, the specificity for PDQ39 score and PD Symptoms Questionnaire score for the prediction of parkinsonism was 73.1% and 80.1%, respectively.These results suggest the questionnaires have reasonably good sensitivity and specificity to predict parkinsonism in Mn exposed workers. These questionnaires could be a valuable first step in a tiered screening approach for Mn exposed workers.

Manganese (Mn) over-exposure in occupational settings is associated with basal ganglia toxicity and a movement disorder characterized by parkinsonism (i.e., the signs and symptoms of Parkinson disease). A simple test to help non-neurologists identify workers with clinical Mn neurotoxicity represents an unmet need. In a cohort of Mn-exposed workers from welding worksites, with extensive clinical data, we developed a linear regression model to predict the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) score. We primarily considered factors easily obtained in a primary care or occupational medicine clinic, specifically easily assessed signs of parkinsonism and factors likely to be associated with UPDRS3 such as age, timed motor task results, and selected symptoms/conditions. Secondarily we considered other demographic variables and welding exposure. We based the model on 596 examined workers age ≤ 65 years and with timed motor task data. We selected the model based on simplicity for clinical application, biologic plausibility, and statistical significance and magnitude of regression coefficients. The model contained age, timed motor task scores for each hand, and indicators of action tremor, speech difficulty, anxiety, depression, loneliness, pain and current cigarette smoking. When we examined how well the model identified workers with clinically significant parkinsonism (UPDRS3 ≥ 15) the Receiver Operating Characteristic Area Under the Curve (AUC) was 0.72 (95% confidence interval 0.67, 0.77). With a cut point that provided 80% sensitivity, specificity was 52.0%, the positive predictive value in our cohort was 29%, and the negative predictive value was 92%. Using the same cut point for predicted UPDRS3, the AUC was nearly identical for UPDRS3 ≥ 10, and 0.83 (95% CI 0.76, 0.90) for UPDRS3 ≥ 20. Since welding exposure data was not required after including its putative effects, this model may help identify workers with clinically significant Mn neurotoxicity in a variety of settings as a first step in a tiered occupational screening program.

OBJECTIVE: Long-term, high-level exposure to manganese (Mn) is associated with impaired central nervous system (CNS) function. We quantitatively explored relations between low-level Mn exposure and selected neurological outcomes in a longitudinal inception cohort of asymptomatic welder trainees. METHODS: Welders with no previous occupational Mn exposure were observed approximately every three months over the course of the five-quarter traineeship. Fifty-six welders were assessed for motor function using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) and Grooved Pegboard tests. A subset of 17 also had MRI scans to assess T1-weighted indices. Personal exposure to Mn in welding fume was quantitatively assessed during the study period using a mixed model to obtain estimates of subject-specific exposure level by welding type. These estimates were summed to estimate cumulative exposure at the time of each neurological outcome test. RESULTS: When adjusting for possible learning effects, there were no associations between cumulative exposure and UPDRS3 score or Grooved Pegboard time. T1-weighted indices of the basal ganglia (caudate, anterior putamen, posterior putamen, and combined basal ganglia, but not the pallidal index) exhibited statistically significant increases in signal intensity in relation to increased cumulative Mn exposure. CONCLUSIONS: This study demonstrates that T1-weighted changes can be detected in the brain even at very low levels of exposure among humans before any clinically evident deficits. This suggests that with continued follow-up we could identify a T1 threshold of toxicity at which clinical symptoms begin to manifest.

Chronic exposure to manganese (Mn) is a health concern in occupations such as welding because of well-established motor effects due to basal ganglia dysfunction. We hypothesized that cognitive control (the ability to monitor, manipulate, and regulate ongoing cognitive demands) would also be affected by chronic Mn exposure.We examined the relationship between Mn exposure and cognitive control performance in 95 workers with varying intensity and duration (median 15.5 years) of exposure to welding fume. We performed linear regression to assess the association between exposure to Mn-containing welding fume and cognitive control tasks.Overall performance was inversely related to intensity of welding exposure (P = 0.009) and was driven by the Two-Back and Letter Number Sequencing tests that assess working memory (both P = 0.02).Occupational exposure to Mn-containing welding fume may be associated with poorer working memory performance, and workers may benefit from practices that reduce exposure intensity. Am. J. Ind. Med. 60:181-188, 2017. © 2016 Wiley Periodicals, Inc.

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 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.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder with unknown cause. Genetic mutations account for a minority of cases but the role of environmental factors is unclear. Methods: We performed a population-based screening for PD in subjects in an Amish community over age 60. PD was diagnosed using standard clinical criteria and the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Community prevalence was calculated. We constructed a community pedigree and calculated kinship coefficients, a measure of relatedness between 2 subjects, for every pair of subjects in diagnostic categories: clinically definite PD, UPDRS3 score >9, Mini-Mental State Exam (MMSE) score Results: Of 262 eligible subjects, 213 agreed to participate, 15 had PD, 43 had MMSE 9. The prevalence of PD was 5,703/100,000 with increasing prevalence in every decade of age. Excluding first-degree relatives, normal subjects were more related to each other (0.0102, SD = 0.0266) than subjects with clinically definite PD (0.0054, SD = 0.0100; p = 0.00003), subjects with UPDRS >9 (0.0076, SD = 0.0155; p = 0.00001), and subjects with MMSE Conclusions: PD and parkinsonian signs are common in this population and the prevalence increases with age. The finding that subjects with PD were not more related than normal subjects suggests that environmental factors may contribute to the parkinsonian phenotype in this community.

Rapidly advancing imaging technology has been essential to the study of manganese (Mn) toxicity in vivo. Over the past few decades, imaging techniques have been effectively utilized as markers of Mn exposure and to investigate the biological effects of Mn neurotoxicity. This chapter will review several of the imaging modalities that have made an impact in Mn neurotoxicity research. The scope of this chapter will include discussions of magnetic resonance imaging (MRI), including magnetic resonance spectroscopy (MRS), diffusion weighted imaging (DWI), and functional MRI (fMRI), as well as positron emission tomography (PET), single photon emission computed tomography (SPECT), and X-ray fluorescence imaging. For each modality, the basic principle of the imaging technique will be briefly described to facilitate proper data interpretation and understanding of limitations. This will be followed by a discussion on the main research findings using that modality, and how they have shaped our understanding of Mn toxicity.

Background: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. Methods: In this 26-week, randomised, double-blind, placebo-controlled trial, adults ( ≥ 25 years old ) with early-stage to mid-stage Huntington's disease were randomly assigned ( 1:1:1 ) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests ( Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test ) and scores on eight individual cognitive tests ( the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test ). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with [http://clinicaltrials.gov/] ClinicalTrials.gov, [http://clinicaltrials.gov/show/NCT01590888] NCT01590888. Findings: Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg ( n=36 ), PBT2 100 mg ( n=38 ), or placebo ( n=35 ) at 19 research centres in Australia and the USA. 32 ( 89% ) individuals on PBT2 250 mg, 38 ( 100% ) on PBT2 100 mg, and 34 ( 97% ) on placebo completed the study. Six serious adverse events ( acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease ) occurred in five participants in the PBT2 250 mg group, three ( fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease ) occurred in two participants in the PBT2 100 mg group, and one ( increasing aggression ) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 ( 89% ) participants on PBT2 250 mg, 30 ( 79% ) on PBT2 100 mg, and 28 ( 80% ) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg ( least-squares mean 0·02, 95% CI −0·10 to 0·14; p=0·772 ) nor PBT2 250 mg ( 0·07, −0·05 to 0·20; p=0·240 ) significantly improved the main composite cognition Zscore between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group ( 17·65 s, 0·65–34·65; p=0·042 ) but not in the 100 mg group ( 0·79 s improvement, −15·75 to 17·32; p=0·925 ); neither dose significantly improved cognition on the other tests. Interpretation: PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. Funding: Prana Biotechnology Limited.

Background Manganese (Mn) exposure is associated with increased T1-weighted magnetic resonance imaging (MRI) signal in the basal ganglia. T1 signal intensity has been correlated with occupational Mn exposure but not with clinical symptomatology or neuropathology. Objectives This study investigated predictors of ex vivo T1 MRI basal ganglia signal intensity in neuropathologic tissue obtained from deceased South African mine workers. Methods A 3.0 T MRI was performed on ex vivo brain tissue obtained from 19 Mn mine workers and 10 race- and sex-matched mine workers of other commodities. Basal ganglia regions of interest were identified for each subject with T1-weighted intensity indices generated for each region. In a pathology subset, regional T1 indices were compared to neuronal and glial cell density and tissue metal concentrations. Results Intensity indices were higher in Mn mine workers than non-Mn mine workers for the globus pallidus, caudate, anterior putamen, and posterior putamen with the highest values in subjects with the longest cumulative Mn exposure. Intensity indices were inversely correlated with the neuronal cell density in the caudate ( p = 0.040) and putamen ( p = 0.050). Tissue Mn concentrations were similar in Mn and non-Mn mine workers. Tissue iron (Fe) concentration trended lower across all regions in Mn mine workers. Conclusions Mn mine workers demonstrated elevated basal ganglia T1 indices when compared to non-Mn mine workers. Predictors of ex vivo T1 MRI signal intensity in Mn mine workers include duration of Mn exposure and neuronal density.

Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) ( P P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group ( P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) ( P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. Trial Registration clinicaltrials.gov Identifier:NCT01795859

Classical accounts of the pathophysiology of Parkinson’s disease have emphasized degeneration of dopaminergic nigrostriatal neurons with consequent dysfunction of cortico–striatal–thalamic loops. In contrast, post-mortem studies indicate that pathological changes in Parkinson’s disease (Lewy neurites and Lewy bodies) first appear primarily in the lower brainstem with subsequent progression to more rostral parts of the neuraxis. The nigrostriatal and histological perspectives are not incompatible, but they do emphasize different anatomical structures. To address the question of which brain structures are functionally most affected by Parkinson’s disease, we performed a resting-state functional magnetic resonance imaging study focused on striatal functional connectivity. We contrasted 13 patients with advanced Parkinson’s disease versus 19 age-matched control subjects, using methodology incorporating scrupulous attention to minimizing the effects of head motion during scanning. The principal finding in the Parkinson’s disease group was markedly lower striatal correlations with thalamus, midbrain, pons and cerebellum. This result reinforces the importance of the brainstem in the pathophysiology of Parkinson’s disease. Focally altered functional connectivity also was observed in sensori-motor and visual areas of the cerebral cortex, as well the supramarginal gyrus. Striatal functional connectivity with the brainstem was graded (posterior putamen > anterior putamen > caudate), in both patients with Parkinson’s disease and control subjects, in a manner that corresponds to well-documented gradient of striatal dopaminergic function loss in Parkinson’s disease. We hypothesize that this gradient provides a clue to the pathogenesis of Parkinson’s disease.

Manganese (Mn), an established neurotoxicant, is a common component of welding fume. The neurological phenotype associated with welding exposures has not been well described. Prior epidemiologic evidence linking occupational welding to parkinsonism is mixed, and remains controversial.This was a cross-sectional and nested case-control study to investigate the prevalence and phenotype of parkinsonism among 811 shipyard and fabrication welders recruited from trade unions. Two reference groups included 59 non-welder trade workers and 118 newly diagnosed, untreated idiopathic PD patients. Study subjects were examined by a movement disorders specialist using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Parkinsonism cases were defined as welders with UPDRS3 score ≥15. Normal was defined as UPDRS36. Exposure was classified as intensity adjusted, cumulative years of welding. Adjusted prevalence ratios for parkinsonism were calculated in relation to quartiles of welding years.The overall prevalence estimate of parkinsonism was 15.6% in welding exposed workers compared to 0% in the reference group. Among welders, we observed a U-shaped dose-response relation between weighted welding exposure-years and parkinsonism. UPDRS3 scores for most domains were similar between welders and newly diagnosed idiopathic Parkinson disease (PD) patients, except for greater frequency of rest tremor and asymmetry in PD patients.This work-site based study among welders demonstrates a high prevalence of parkinsonism compared to nonwelding-exposed workers and a clinical phenotype that overlaps substantially with PD.

Objectives Manganese exposure leads to diffuse cerebral metal deposition with the highest concentration in the globus pallidus associated with increased T1-weighted MRI signal. T1 signal intensity in extra-pallidal basal ganglia (caudate and putamen) has not been studied in occupationally exposed workers. Diffusion weighted imaging is a non-invasive measure of neuronal damage and may provide a quantification of neurotoxicity associated with welding and manganese exposure. This study investigated extra-pallidal T1 basal ganglia signal intensity as a marker of manganese exposure and basal ganglia diffusion weighted imaging abnormalities as a potential marker of neurotoxicity. Methods A 3T MR case:control imaging study was performed on 18 welders and 18 age- and gender-matched controls. Basal ganglia regions of interest were identified for each subject. T1-weighted intensity indices and apparent diffusion coefficients were generated for each region. Results All regional indices were higher in welders than controls (p≤0.05). Combined basal ganglia (ρ=0.610), caudate (ρ=0.645), anterior (ρ=0.595) and posterior putamen (ρ=0.511) indices were more correlated with exposure than pallidal (ρ=0.484) index. Welder apparent diffusion coefficient values were lower than controls for globus pallidus (p=0.03) and anterior putamen (p=0.004). Conclusions Welders demonstrated elevated T1 indices throughout the basal ganglia. Combined basal ganglia, caudate and putamen indices were more correlated with exposure than pallidal index suggesting more inclusive basal ganglia sampling results in better exposure markers. Elevated indices were associated with diffusion weighted abnormalities in the pallidum and anterior putamen suggesting neurotoxicity in these regions.

Objective To investigate whether manganese toxicity secondary to end-state liver disease is associated with nigrastriatal dysfunction as measured by 6-[18F]fluoro-L-DOPA (FDOPA) positron emission tomographic (PET) imaging. Design Observational case report. Setting The Movement Disorder Center at Washington University, St Louis, Missouri. Patient An individual with manganese toxicity secondary to end-stage liver disease. His FDOPA PET was compared with those of 10 idiopathic Parkinson disease patients and 10 age- and sex-matched healthy controls. Main Outcome Measure The average estimated net FDOPA uptake by Patlak graphical analysis for caudate, anterior putamen, and posterior putamen. Results The FDOPA uptake for the patient with secondary manganese toxicity was reduced across all regions by more than 2 SDs compared with healthy controls: caudate (reduced 24.7%), anterior putamen (28.0%), and posterior putamen (29.3%). The ratio of uptake between the caudate/posterior putamen was 0.99 and was different from that of idiopathic Parkinson disease patients, in whom the greatest reduction of FDOPA was in the posterior putamen (mean [SD] ratio, 1.65 [0.41]). Conclusions Reduce striatal uptake of FDOPA uptake indicates dysfunction of the nigrostriatal pathways in manganese toxicity secondary to end-stage liver disease. The pattern of striatal involvement with equal reduction of FDOPA uptake in the caudate compared with posterior putamen appears different from those previously reported in individuals with occupational manganese toxicity and idiopathic Parkinson disease and may be specific to manganese toxicity secondary to end-stage liver disease.

Manganese (Mn) is a common occupational exposure worldwide. Recent studies indicate clinical and imaging evidence of neurotoxicity in chronically exposed workers. The pathologic significance of these findings is unclear. South Africa produces over 80% of the world's Mn from mines from a desert region in the Northern Cape Province. An autopsy program at the National Institute for Occupational Health (NIOH) in South Africa has provided compensation to families for mining-related lung diseases for almost 100 years. Building on this, we implemented a brain autopsy program to investigate the feasibility of obtaining brains from South African Mn miners and non-exposed reference miners to investigate neuropathologic consequences of chronic Mn exposure. Employing an experienced occupational health nurse, we identified deceased miners within 100 square km of the Mn mines. The nurse was notified of any Mn (case) or other (reference) miner or ex-miner death by local medical practitioners, occupational health and mine physicians, and community members, and families were approached for consent to remove the brains in addition to the cardio-respiratory organs. Families of deceased miners who had an autopsy at the NIOH in Johannesburg were also approached. To confirm exposure in Mn miners, mean pallidal indices were compared between Mn miners and non-exposed reference miners. Sixty-eight potential brain donors were identified; we obtained consent from the families to remove 51 (75%). The mean autopsy interval was seven days. With optimized fixation methods, the tissue quality of the brains for gross and regular microscopic examination was excellent. Ex vivo MRI demonstrated increased pallidal index in Mn miners compared to reference miners. We conclude that obtaining brain tissue from deceased miners in South Africa is highly successful with only a modest investment in local infrastructure. Tissue quality was excellent and should be ideal to investigate the neuropathologic consequences of chronic occupational Mn exposure.

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.

Previous studies suggest that welders frequently display parkinsonian signs, such as bradykinesia and tremor. Demonstrating that these parkinsonian findings are associated with reductions in quality of life (QoL) or health status could have important repercussions for worker safety and performance.Subjects included 394 active workers exposed to welding fumes and evaluated for parkinsonism by movement disorders experts in a worksite-based epidemiology study. Subjects were diagnosed with parkinsonism if the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) score was ≥15. All subjects completed a Parkinson's disease (PD) symptom questionnaire and the PDQ39, a widely used QoL and health status measure for PD.Total PDQ39 score and all subscores were greater in welders with parkinsonism than welders without parkinsonism, with the most significant differences observed for mobility, emotional well-being, and activities of daily living (ADL's). The PDQ39 scores for welding exposed workers with parkinsonism were similar to scores seen in a group of early PD patients.Parkinsonism in active, welding exposed workers is associated with reductions in health status and QoL affecting a broad range of categories and within the range seen in early PD.

Psychogenic movement disorders (PMD) represent a diagnostically challenging group of patients in movement disorders. Finger tapping tests (FTT) have been used in neuropsychiatric evaluations to identify psychogenic conditions, but their use in movement disorders has been limited to the quantification of upper extremity disability in idiopathic Parkinson disease (IPD). We evaluated the ability of the FTT to objectively identify PMD by screening 195 individuals from a movement disorder clinic with IPD, dystonia, essential tremor, or PMD and compared them to 130 normal adults. All subjects performed six-30 second trials using alternate hands. We compared mean FTT score and the coefficient of variation between diagnostic groups. FTT scores in IPD were inversely correlated with Hoehn and Yahr stage (p < .001) and the United Parkinson Disease Rating Scale III (motor) subscale (p < .001). FTT scores were significantly lower in PMD (mean = 41.72) when compared to the other diagnostic groups after controlling for age. The coefficient of variation was not significantly different between diagnostic groups. ROC analysis identified a cutoff FTT ratio of 0.670 or less was 89.1% specific and 76.9% sensitive for the diagnosis of PMD. We conclude the FTT can provide supportive evidence for the diagnosis of PMD.

Background: Parkinson disease is a common neurodegenerative disease. The racial, sex, age, and geographic distributions of Parkinson disease in the US are unknown. Methods: We performed a serial cross-sectional study of US Medicare beneficiaries aged 65 and older from the years 1995, and 2000–2005. Using over 450,000 Parkinson disease cases per year, we calculated Parkinson disease prevalence and annual incidence by race, age, sex, and county. Spatial analysis investigated the geographic distribution of Parkinson disease. Results: Age-standardized Parkinson disease prevalence (per 100,000) was 2,168.18 (±95.64) in White men, but 1,036.41 (±86.01) in Blacks, and 1,138.56 (±46.47) in Asians. The incidence ratio in Blacks as compared to Whites (0.74; 95% CI = 0.732–0.748) was higher than the prevalence ratio (0.58; 95% CI = 0.575–0.581), whereas the incidence ratio for Asians (0.69; 95% CI = 0.657–0.723) was similar to the prevalence ratio (0.62; 95% CI = 0.617–0.631). Bayesian mapping of Parkinson disease revealed a concentration in the Midwest and Northeast regions. Mean county incidence by quartile ranged from 279 to 3,111, and prevalence from 1,175 to 13,800 (per 100,000). Prevalence and incidence in urban counties were greater than in rural ones (p < 0.01). Cluster analysis supported a nonrandom distribution of both incident and prevalent Parkinson disease cases (p < 0.001). Conclusions: Parkinson disease is substantially more common in Whites, and is nonrandomly distributed in the Midwest and Northeastern US.

✓ Hypertonicity is a leading cause of disability for children with cerebral palsy (CP). Botulinum toxin A (BTA) chemically denervates muscle tissue and is commonly used in the management of lower-extremity hypertonicity in children with CP because of its focal effects and wide safety margin. Randomized controlled trials have demonstrated that BTA injections in the ankle flexors, hamstrings, and adductors reduce spasticity and result in improved passive and active range of motion. In other studies, improvements in gait and measurements of functional outcome were found in appropriately selected children who had been injected with BTA. A multidisciplinary treatment approach that includes physical therapists, occupational therapists, orthotists, neurologists, physicians with expertise in performing botulinum toxin injections, orthopedic surgeons, and neurosurgeons is critical to optimize care in children with lower-extremity tone due to CP. In this paper, the authors propose treatment algorithms based on clinical presentation, detailed dosing, and technical information to optimize the treatment of these children. With a multidisciplinary approach, children with lower-extremity hypertonicity due to CP can experience improvements in muscle tone and function.

Objectives To assess whether parkinsonism in manganese (Mn)-exposed welders is associated with methylation of NOS2, a methylation-regulated gene that codes for inducible nitric oxide synthase (iNOS). We hypothesised that parkinsonian welders would have lower NOS2 methylation than other welders, consistent with greater iNOS activity and an inflammatory pathogenesis. Method In a cohort of U. S. shipyard welders we conducted a nested case-control study of parkinsonism and DNA methylation of a NOS2 region previously suggested to be altered with welding exposure. A movement disorders specialist examined each subject using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). We included 50 parkinsonian welders as cases (UPDRS3≥15), 105 welders with normal exams (UPDRS3 Results CpG sites were highly methylated (90.8–98.5% mean methylation) among all subjects. Welders with parkinsonism had significantly lower NOS2 methylation than normal welders (odds ratio [OR]=0.69, 95% confidence interval [CI] 0.49–0.97 per 1% absolute increase in methylation). The welders with intermediate UPDRS3 scores also had lower methylation compared to normal welders (OR=0.88, 95% CI 0.65–1.20) (p trend = 0.03). Adjustment for smoking did not alter the results. Conclusions This study suggests that inflammation mediated by NOS2 gene expression may underlie the pathophysiology of parkinsonism in Mn-exposed welders.

Objectives Manganese, an established neurotoxicant, is a common component of welding fumes. Symptoms of manganese poisoning include parkinsonism (PS). Prior epidemiologic evidence regarding occupational welding and PS is mixed, and remains highly controversial. Methods This study investigated the prevalence of PS among 581 active male shipyard welders recruited from a trade union. Study subjects were examined by a movement disorders specialist using the Unified Parkinson9s disease Rating Scale motor subsection 3 (UPDRS3) without knowledge of exposure. PS cases were defined as welders with UPDRS3 score ≥15; this threshold corresponds to the degree of motor impairment found in early, symptomatic Parkinson9s disease. An intermediate group was defined as UPDRS3 score 6–15. Normal was defined as UPDRS3 Results The overall prevalence estimate of PS was 13.1%. We observed a monotonic exposure-response gradient comparing PS cases with normal subjects (UPDRS3 Conclusions Results from our ongoing epidemiological study of welders support an etiologic relation of welding exposure and PS. Further work will include a non-welding reference group, and will quantify exposure to manganese.