Adherence to practice parameters in Medicare beneficiaries with amyotrophic lateral sclerosis.

OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence. METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age ≥20 with ≥1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider specialty (neurologist vs. non-neurologist). Outcomes were use of practice parameters, which included feeding tubes, non-invasive ventilation (NIV), riluzole, and receiving care from a neurologist. RESULTS: Overall, 42.9% of patients with ALS received neurologist care. Black beneficiaries (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.67), older beneficiaries (OR 0.964, 95% CI 0.961-0.968 per year), and those living in disadvantaged areas (OR 0.70, 95% CI 0.61-0.80) received less care from neurologists. Overall, only 26.7% of beneficiaries received a feeding tube, 19.2% NIV, and 15.3% riluzole. Neurologist-treated patients were more likely to receive interventions than other ALS patients: feeding tube (OR 2.80, 95% CI 2.52-3.11); NIV (OR 10.8, 95% CI 9.28-12.6); and riluzole (OR 7.67, 95% CI 6.13-9.58), after adjusting for sociodemographics. These associations remained marked and significant when we excluded ALS patients who subsequently received a code for other diseases that mimic ALS. CONCLUSIONS: ALS patients treated by neurologists received care consistent with practice parameters more often than those not treated by a neurologist. Black, older, and disadvantaged beneficiaries received less care consistent with the practice parameters.

Olfactory tract/bulb metal concentration in Manganese-exposed mineworkers.

BACKGROUND: Manganese (Mn) is an essential micronutrient as well as a well-established neurotoxicant. Occupational and environmental exposures may bypass homeostatic regulation and lead to increased systemic Mn levels. Translocation of ultrafine ambient airborne particles via nasal neuronal pathway to olfactory bulb and tract may be an important pathway by which Mn enters the central nervous system. OBJECTIVE: To measure olfactory tract/bulb tissue metal concentrations in Mn-exposed and non-exposed mineworkers. METHODS: Using inductively coupled plasma-mass spectrometry (ICP-MS), we measured and compared tissue metal concentrations in unilateral olfactory tracts/bulbs of 24 Mn-exposed and 17 non-exposed South African mineworkers. We used linear regression to investigate the association between cumulative Mn exposures and olfactory tract/bulb Mn concentration. RESULTS: The difference in mean olfactory tract/bulb Mn concentrations between Mn-exposed and non-Mn exposed mineworkers was 0.16 µg/g (95% CI -0.11, 0.42); but decreased to 0.09 µg/g (95% CI 0.004, 0.18) after exclusion of one influential observation. Olfactory tract/bulb metal concentration and cumulative Mn exposure suggested there may be a positive association; for each mg Mn/m3-year there was a 0.05 µg/g (95% CI 0.01, 0.08) greater olfactory tract/bulb Mn concentration overall, but -0.003 (95% CI -0.02, 0.02) when excluding the three influential observations. Recency of Mn exposure was not associated with olfactory tract/bulb Mn concentration. CONCLUSIONS: Our findings suggest that Mn-exposed mineworkers might have higher olfactory tract/bulb tissue Mn concentrations than non-Mn exposed mineworkers, and that concentrations might depend more on cumulative dose than recency of exposure.

Fine Particulate Matter and Parkinson Disease Risk Among Medicare Beneficiaries.

BACKGROUND AND OBJECTIVES: Numerous studies suggest that environmental exposures play a critical role in Parkinson disease (PD) pathogenesis, and large, population-based studies have the potential to advance substantially the identification of novel PD risk factors. We sought to study the nationwide geographic relationship between PD and air pollution, specifically PM2.5 (particulate matter with a diameter <2.5 micrometers), using population-based US Medicare data. METHODS: We conducted a population-based geographic study of Medicare beneficiaries aged 66-90 years geocoded to US counties and zip+4. We used integrated nested Laplace approximation to create age, sex, race, smoking, and health care utilization-adjusted relative risk (RR) at the county level for geographic analyses with PM2.5 as the primary exposure of interest. We also performed an individual-level analysis using logistic regression with cases and controls with zip+4 centroid PM2.5. We adjusted a priori for the same covariates and verified no confounding by indicators of socioeconomic status or neurologist density. RESULTS: Among 21,639,190 Medicare beneficiaries, 89,390 had incident PD in 2009. There was a nationwide association between average annual PM2.5 and PD risk whereby the RR of PD was 56% (95% CI 47%-66%) greater for those exposed to the median level of PM2.5 compared with those with the lowest level of PM2.5. This association was linear up to 13 µg/m3 corresponding to a 4.2% (95% CI 3.7%-4.8%) greater risk of PD for each additional µg/m3 of PM2.5 (p trend < 0.0001). We identified a region with high PD risk in the Mississippi-Ohio River Valley, where the risk of PD was 19% greater compared with the rest of the nation. The strongest association between PM2.5 and PD was found in a region with low PD risk in the Rocky Mountains. PM2.5 was also associated with PD in the Mississippi-Ohio River Valley where the association was relatively weaker, due to a possible ceiling effect at average annual PM2.5 levels of ∼13 µg/m3. DISCUSSION: State-of-the-art geographic analytic techniques revealed an association between PM2.5 and PD that varied in strength by region. A deeper investigation into the specific subfractions of PM2.5 may provide additional insight into regional variability in the PM2.5-PD association.

Neuroinflammation and white matter alterations in occupational manganese exposure assessed by diffusion basis spectrum imaging.

OBJECTIVE: To evaluate in-vivo neuroinflammation and white matter (WM) microstructural integrity in occupational manganese (Mn) exposure. METHODS: We assessed brain inflammation using Diffusion Basis Spectrum Imaging (DBSI) in 26 Mn-exposed welders, 17 Mn-exposed workers, and 26 non-exposed participants. Cumulative Mn exposure was estimated from work histories and the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) scores were completed by a movement specialist. Tract-based Spatial Statistics allowed for whole-brain voxel-wise WM analyses to compare WM DBSI-derived measures between the Mn-exposed and non-exposed groups. Exploratory grey matter region of interest (ROI) analyses examined the presence of similar alterations in the basal ganglia. We used voxelwise general linear modeling and linear regression to evaluate the association between cumulative Mn exposure, WM or basal ganglia DBSI metrics, and UPDRS3 scores, while adjusting for age. RESULTS: Mn-exposed welders had higher DBSI-derived restricted fraction (DBSI-RF), higher DBSI-derived nonrestricted fraction (DBSI-NRF), and lower DBSI-derived fiber fraction (DBSI-FF) in multiple WM tracts (all p < 0.05) in comparison to less-exposed workers and non-exposed participants. Basal ganglia ROI analyses revealed higher average caudate DBSI-NRF and DBSI-derived radial diffusion (DBSI-RD) values in Mn-exposed welders relative to non-exposed participants (p < 0.05). Caudate DBSI-NRF was also associated with greater cumulative Mn exposure and higher UPRDS3 scores. CONCLUSIONS: Mn-exposed welders demonstrate greater DBSI-derived indicators of neuroinflammation-related cellularity (DBSI-RF), greater extracellular edema (DBSI-NRF), and lower apparent axonal density (DBSI-FF) in multiple WM tracts suggesting a neuroinflammatory component in the pathophysiology of Mn neurotoxicity. Caudate DBSI-NRF was positively associated with both cumulative Mn exposure and clinical parkinsonism, indicating a possible dose-dependent effect on extracellular edema with associated motor effects.

A predictive algorithm to identify ever smoking in medical claims-based epidemiologic studies.

PURPOSE: To develop and validate an algorithm to estimate probability of ever smoking using administrative claims. METHODS: Using population-based samples of Medicare-aged individuals (121,278 Behavioral Risk Factor Surveillance System survey respondents and 207,885 Medicare beneficiaries), we developed a logistic regression model to predict probability of ever smoking from demographic and claims data. We applied the model in 1,657,266 additional Medicare beneficiaries and calculated area under the receiver operating characteristic curve (AUC) using presence or absence of a tobacco-specific diagnosis or procedure code as our "gold standard." We used these "gold standard" and lung/laryngeal cancer codes to over-ride predicted probability as 100%. We calculated Spearman's rho between probability from this full algorithm and smoking assessed in prior Parkinson disease studies, by substituting our observed and prior ("true") smoking-Parkinson disease odds ratios into the attenuation equation. RESULTS: The predictive model contained 23 variables, including basic demographics, high alcohol consumption, asthma, cardiovascular disease and associated risk factors, selected cancers, and indicators of routine medical usage. The AUC was 67.6% (95% confidence interval 67.5%-67.7%) comparing smoking probability to tobacco-specific diagnosis or procedure codes. Spearman's rho for the full algorithm was 0.82. CONCLUSIONS: Ever smoking might be approximated in administrative data for use as a continuous, probabilistic variable in epidemiologic analyses.

Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries.

OBJECTIVE: To identify prescription medications associated with a lower risk of three neurodegenerative diseases: Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. METHODS: We conducted a population-based, case-control study of U.S. Medicare beneficiaries in 2009 (42,885 incident neurodegenerative disease cases, 334,387 randomly selected controls). Using medication data from 2006-2007, we categorized all filled medications according to their biological targets and mechanisms of action on those targets. We used multinomial logistic regression models, while accounting for demographics, indicators of smoking, and health care utilization, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 141 target-action pairs and each neurodegenerative disease. For target-action pairs inversely associated with all three diseases, we attempted replication in a cohort study that included an active comparator group. We constructed the cohort by following controls forward for incident neurodegenerative disease from the beginning of 2010 until death or end of 2014, i.e., up to five years after the two-year exposure lag. We used Cox proportional hazards regression while accounting for the same covariates. RESULTS: The most consistent inverse association across both studies and all three neurodegenerative diseases was for xanthine dehydrogenase/oxidase blockers, represented by the gout medication, allopurinol. Allopurinol was associated with a 13-34% lower risk for each neurodegenerative disease group in multinomial regression, and a mean reduction of 23% overall, as compared to individuals who did not use allopurinol. In the replication cohort we observed a significant 23% reduction for neurodegenerative disease in the fifth year of follow-up, when comparing allopurinol users to non-users, and more marked associations with an active comparator group. We observed parallel associations for a related target-action pair unique to carvedilol. DISCUSSION/CONCLUSION: Xanthine dehydrogenase/oxidase blockade might reduce risk of neurodegenerative disease. However, further research will be necessary to confirm that the associations related to this pathway are causal or to examine whether this mechanism slows progression.

Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model.

OBJECTIVE: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. METHODS: We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. RESULTS: We observed previously established medical associations for MND and an inverse dose-response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. INTERPRETATION: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881-892.

Neocortical Lewy Body Pathology Parallels Parkinson's Dementia, but Not Always.

OBJECTIVE: The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD. METHODS: We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019. All patients with a diagnosis of PD based on neuropathology were included. We used logistic regression and multivariate analysis of covariance (MANCOVA) to investigate the relationship between neuropathology and dementia. RESULTS: A total of 165 patients with PD met inclusion criteria. Among these, 128 had clinical dementia. Those with dementia had greater mean ages of motor onset and death but equivalent mean disease duration. The delay between motor symptom onset and dementia was 1 year or less in 14 individuals, meeting research diagnostic criteria for possible or probable dementia with Lewy bodies (DLB). Braak Lewy body stage was associated with diagnosis of dementia, whereas severities of Alzheimer's disease neuropathologic change (ADNC) and small vessel pathology did not. Pathology of individuals diagnosed with DLB did not differ significantly from that of other patients with PD with dementia. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies; and 68% of the individuals with PD but without dementia did have neocortical Lewy bodies. INTERPRETATION: Neocortical Lewy bodies almost always accompany dementia in PD; however, they also appear in most PD patients without dementia. In some cases, dementia may occur in patients with PD without neocortical Lewy bodies, ADNC, or small vessel disease. Thus, other factors not directly related to these classic neuropathologic features may contribute to PD dementia. ANN NEUROL 2023;93:184-195.

Incidence of amyotrophic lateral sclerosis in older adults.

INTRODUCTION/AIMS: We investigated the age- and sex-specific incidence and survival of Medicare beneficiaries with amyotrophic lateral sclerosis (ALS) in patients 66 to 90 years of age. METHODS: We identified all incident ALS cases within a population-based sample of Medicare beneficiaries in 2009 (total: 22 000 177 person-years at risk for ALS). We calculated age- and sex-specific incidence in 2009 according to multiple, progressively more stringent case definitions. Our most inclusive definition required one ALS code, whereas the most restrictive definition required at least one additional ALS code more than 6 months after the first code, including one from a neurologist. We identified associated imaging studies and electrodiagnostic testing and followed all cases through the end of 2014 to determine survival. RESULTS: The overall incidence for our most inclusive definition was 22.84 per 100 000 person-years for men and 16.05 per 100 000 person-years for women. The overall incidence was 5.72 per 100 000 person-years for men and 3.99 per 100 000 person-years for women for our most restrictive definition. For our most inclusive definition, fewer than 39.7% of cases ever had an ALS diagnosis from a neurologist, more than 50% had an electrodiagnostic test or imaging study, and 40.1% survived less than 1 year after diagnosis, with 25.5% of these cases surviving no more than 6 months. Cases not meeting the most restrictive definition were more likely than those who did meet the restrictive definition to be older, black, or Asian. DISCUSSION: The oldest and marginalized Medicare beneficiaries diagnosed with ALS are less likely to be included in epidemiological studies with restrictive definitions, but future studies will need to assess the accuracy of diagnosis.

Environmental manganese exposure and cognitive control in a South African population.

OBJECTIVE: To characterize the association between environmental (residential air) manganese (Mn) exposure and cognitive performance, focusing on cognitive control, in a Black African population. METHODS: We administered the Go-No-Go, Digit Span, and Matrix Reasoning tests to population-based samples age ≥40 from a high Mn (smelter) exposed community, Meyerton (N = 629), and a demographically comparable low (background levels) non-exposed community, Ethembalethu, (N = 96) in Gauteng province, South Africa. We investigated the associations between community and performance on the cognitive tests, using linear regression. We adjusted a priori for age and sex, and examined the effect of adjustment for education, nonverbal IQ, smoking, and alcohol consumption. We measured airborne PM2.5-Mn to confirm community exposure differences. RESULTS: Compared to Ethembalethu residents, Meyerton residents' test scores were lower (poorer) for all tests: 0.55 (95 % confidence interval [CI] 0.08, 1.03) lower scores for Matrix Reasoning, 0.34 (95 % CI -0.07, 0.75) lower for Digit Span, and 0.15 (95 % CI 0.09, 0.21) lower for Go-No-Go (high frequency discriminability index [probability]). The latter represented the most marked difference in terms of z-scores (0.50, 95 % CI 0.30, 0.71 standard deviations lower). The mean of the z-score of each of the three tests was also lower (0.34, 95 % CI 0.18, 0.50 standard deviations lower). These associations were similar in men and women, but attenuated with adjustment for education. Differences for Matrix Reasoning and Digit Span between the two communities were observed only among those who had lived in Meyerton ≥10 years, whereas for Go-No-Go, differences were also apparent among those who had lived in Meyerton <10 years. Mean PM2.5-Mn at a long-term fixed site in Meyerton was 203 ng/m3 and 10 ng/m3 in Ethembalethu. CONCLUSION: Residence in a community near a high Mn emission source is associated with cognitive dysfunction, including aspects of cognitive control as assessed by the Go-No-Go test.

Efficacy and safety of onabotulinumtoxinA with standardized physiotherapy for the treatment of pediatric lower limb spasticity: A randomized, placebo-controlled, phase III clinical trial.

BACKGROUND: Spasticity is common in cerebral palsy and can result in pain and diminished health-related quality of life. OBJECTIVE: To evaluate the safety and efficacy of onabotulinumtoxinA for lower limb spasticity treatment in children with cerebral palsy. METHODS: In this registrational phase 3, multinational, randomized, double-blind, placebo-controlled trial (NCT01603628), children (2-< 17 years) with cerebral palsy and ankle spasticity (Modified Ashworth Scale-Bohannon [MAS] score≥2) were randomized 1 : 1 : 1 to standardized physical therapy and onabotulinumtoxinA (4 or 8 U/kg), or placebo. Primary endpoint was average change from baseline at weeks 4 and 6 in MAS ankle score. Secondary endpoints included the Modified Tardieu Scale (MTS) and Global Attainment Scale (GAS). RESULTS: 381 participants were randomized. MAS scores averaged at weeks 4 and 6 were significantly reduced with both onabotulinumtoxinA doses (8 U/kg: -1.06, p = 0.010; 4 U/kg: -1.01, p = 0.033) versus placebo (-0.8). Significant improvements in average dynamic component of spasticity, measured by MTS, and in function, measured by GAS, were observed at several time points with both onabotulinumtoxinA doses versus placebo. Most adverse events were mild or moderate. CONCLUSIONS: OnabotulinumtoxinA was well tolerated and effective in reducing lower limb spasticity and improving functional outcomes versus placebo in children.

A comparison of prediction approaches for identifying prodromal Parkinson disease.

Identifying people with Parkinson disease during the prodromal period, including via algorithms in administrative claims data, is an important research and clinical priority. We sought to improve upon an existing penalized logistic regression model, based on diagnosis and procedure codes, by adding prescription medication data or using machine learning. Using Medicare Part D beneficiaries age 66-90 from a population-based case-control study of incident Parkinson disease, we fit a penalized logistic regression both with and without Part D data. We also built a predictive algorithm using a random forest classifier for comparison. In a combined approach, we introduced the probability of Parkinson disease from the random forest, as a predictor in the penalized regression model. We calculated the receiver operator characteristic area under the curve (AUC) for each model. All models performed well, with AUCs ranging from 0.824 (simplest model) to 0.835 (combined approach). We conclude that medication data and random forests improve Parkinson disease prediction, but are not essential.

Solvent exposed occupations and risk of Parkinson disease in Finland.

INTRODUCTION: Epidemiologic and toxicology studies suggest that exposure to various solvents, especially chlorinated hydrocarbon solvents, might increase Parkinson disease (PD) risk. METHODS: In a population-based case-control study in Finland, we examined whether occupations with potential for solvent exposures were associated with PD. We identified newly diagnosed cases age 45-84 from a nationwide medication reimbursement register in 1995-2014. From the population register, we randomly selected non-PD controls matched on sex, along with birth and diagnosis years (age). We included 11,757 cases and 23,236 controls with an occupation in the 1990 census, corresponding to age 40-60. We focused on 28 occupations with ≥ 5% probability of solvent exposure according to the Finnish Job Exposure Matrix. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression modeling, adjusting for age, sex, socioeconomic status, and smoking probability. RESULTS: Similar proportions of cases (5.5%) and controls (5.6%) had an occupation with potential exposure to any solvents. However, all occupations with a point estimate above one, and all significantly or marginally significantly associated with PD (electronic/telecommunications worker [OR = 1.63, 95% CI 1.05-2.50], laboratory assistant [OR = 1.40, 95% CI 0.98-1.99], and machine/engine mechanic [OR = 1.23, 95% CI 0.99-1.52]) entailed potential for exposure to chlorinated hydrocarbon solvents, specifically. Secondary analyses indicated exposure to polycyclic aromatic hydrocarbons and some metals might contribute to the association for mechanics. CONCLUSION: PD risk might be slightly increased in occupations with potential exposure to chlorinated hydrocarbon solvents. Confirmation is required in additional studies that adjust for other occupational exposures and smoking.

Depression and anxiety in a manganese-exposed community.

OBJECTIVE: To characterize the association between residential environmental manganese (Mn) exposure and depression and anxiety, given prior associations among occupationally-exposed workers. METHODS: We administered the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) to 697 study participants in their preferred languages. These participants represented a population-based sample of residents aged ≥40 from two predominantly Black African communities in Gauteng province, South Africa: 605 in Meyerton, adjacent to a large Mn smelter, and 92 in Ethembalethu, a comparable non-exposed community. We investigated the associations between community (Meyerton vs. Ethembalethu) and severity of depression and anxiety, using linear regression, adjusting for age and sex. To document community-level differences in Mn exposure, we measured airborne PM2.5-Mn. RESULTS: Meyerton residents had BDI scores 5.63 points (95 % CI 3.07, 8.20) higher than Ethembalethu residents, with all questions contributing to this significant difference. STAI-state scores were marginally higher in Meyerton than Ethembalethu residents [2.12 (95 % CI -0.17, 4.41)], whereas STAI-trait scores were more similar between the communities [1.26 (95 % CI -0.82, 3.35)]. Mean PM2.5-Mn concentration was 203 ng/m3 at a long-term fixed site in Meyerton and 10 ng/m3 in Ethembalethu. CONCLUSION: Residence near Mn emission sources may be associated with greater depression symptomatology, and possibly current, but not lifetime, anxiety.

A Rapid Motor Task-Based Screening Tool for Parkinsonism in Community-Based Studies.

Background: The prevalence of parkinsonism in developing countries is largely unknown due to difficulty in ascertainment because access to neurologists is often limited. Objective: Develop and validate a parkinsonism screening tool using objective motor task-based tests that can be administered by non-clinicians. Methods: In a cross-sectional population-based sample from South Africa, we evaluated 315 adults, age >40, from an Mn-exposed (smelter) community, using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3), Purdue grooved pegboard, and kinematic-UPDRS3-based motor tasks. In 275 participants (training dataset), we constructed a linear regression model to predict UPDRS3. We selected motor task summary measures independently associated with UPDRS3 (p < 0.05). We validated the model internally in the remaining 40 participants from the manganese-exposed community (test dataset) using the area under the receiver operating characteristic curve (AUC), and externally in another population-based sample of 90 participants from another South African community with only background levels of environmental Mn exposure. Results: The mean UPDRS3 score in participants from the Mn-exposed community was 9.1 in both the training and test datasets (standard deviation = 6.4 and 6.1, respectively). Together, 57 (18.1%) participants in this community had a UPDRS3 ≥ 15, including three with Parkinson's disease. In the non-exposed community, the mean UPDRS3 was 3.9 (standard deviation = 4.3). Three (3.3%) had a UPDRS3 ≥ 15. Grooved pegboard time and mean velocity for hand rotation and finger tapping tasks were strongly associated with UPDRS3. Using these motor task summary measures and age, the UPDRS3 predictive model performed very well. In the test dataset, AUCs were 0.81 (95% CI 0.68, 0.94) and 0.91 (95% CI 0.81, 1.00) for cut points for neurologist-assessed UPDRS3 ≥ 10 and UPDRS3 ≥ 15, respectively. In the external validation dataset, the AUC was 0.85 (95% CI 0.73, 0.97) for UPDRS3 ≥ 10. AUCs were 0.76-0.82 when excluding age. Conclusion: A predictive model based on a series of objective motor tasks performs very well in assessing severity of parkinsonism in both Mn-exposed and non-exposed population-based cohorts.

Principal Component Analysis of Striatal and Extrastriatal D2 Dopamine Receptor Positron Emission Tomography in Manganese-Exposed Workers.

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 < .05), positively in the substantia nigra, thalamus, amygdala, and medial orbital frontal gyrus and negatively in the nucleus accumbens, anterior putamen, and caudate. PC2 was associated with both Mn exposure status and exposure duration (years). In addition, PC2 was associated with higher Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) scores and slower GPT performance. We conclude Mn exposure is associated with both striatal and extrastriatal D2R binding. Multifocal alterations in D2R expression are also associated with motor dysfunction as measured by both the GPT and UPDRS3, demonstrating a link between Mn exposure, striatal and extrastriatal D2R expression, and clinical neurotoxicity.

Severity of parkinsonism associated with environmental manganese exposure.

BACKGROUND: Exposure to occupational manganese (Mn) is associated with neurotoxic brain injury, manifesting primarily as parkinsonism. The association between environmental Mn exposure and parkinsonism is unclear. To characterize the association between environmental Mn exposure and parkinsonism, we performed population-based sampling of residents older than 40 in Meyerton, South Africa (N = 621) in residential settlements adjacent to a large Mn smelter and in a comparable non-exposed settlement in Ethembalethu, South Africa (N = 95) in 2016-2020. METHODS: A movement disorders specialist examined all participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3). Participants also completed an accelerometry-based kinematic test and a grooved pegboard test. We compared performance on the UPDRS3, grooved pegboard, and the accelerometry-based kinematic test between the settlements using linear regression, adjusting for covariates. We also measured airborne PM2.5-Mn in the study settlements. RESULTS: Mean PM2.5-Mn concentration at a long-term fixed site in Meyerton was 203 ng/m3 in 2016-2017 - approximately double that measured at two other neighborhoods in Meyerton. The mean Mn concentration in Ethembalethu was ~ 20 times lower than that of the long-term Meyerton site. UPDRS3 scores were 6.6 (CI 5.2, 7.9) points higher in Meyerton than Ethembalethu residents. Mean angular velocity for finger-tapping on the accelerometry-based kinematic test was slower in Meyerton than Ethembalethu residents [dominant hand 74.9 (CI 48.7, 101.2) and non-dominant hand 82.6 (CI 55.2, 110.1) degrees/second slower]. Similarly, Meyerton residents took longer to complete the grooved pegboard, especially for the non-dominant hand (6.9, CI -2.6, 16.3 s longer). CONCLUSIONS: Environmental airborne Mn exposures at levels substantially lower than current occupational exposure thresholds in the United States may be associated with clinical parkinsonism.

Is Levodopa Response a Valid Indicator of Parkinson's Disease?

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.

Validation of Parkinson's Disease-Related Questionnaires in South Africa.

BACKGROUND: There are very few epidemiological studies investigating Parkinson's disease (PD) in Africa. The hundreds of local languages and dialects make traditional screening and clinical evaluation tools difficult to use. OBJECTIVE: The objective of the study was to validate two commonly used PD questionnaires in an African population. METHODS: The PD Screening Questionnaire (PDSQ) and Parkinson's Disease Questionnaire (PDQ-39) were modified and translated into Afrikaans, Setswana, and isiZulu and administered to a sample of healthy local residents. We assessed the internal consistencies and cluster characteristics of the questionnaires, using a Cronbach's alpha test and exploratory factor analysis. The questionnaires were then administered to a population-based sample of 416 research participants. We evaluated the correlations between the questionnaires and both a timed motor task and the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3), using locally weighted scatterplot smoothing (LOWESS) regression analysis and Spearman's rank correlation. RESULTS: Both questionnaires had high overall internal consistency (Cronbach's alpha = 0.86 and 0.95, respectively). The modified PDQ-39 had evidence of five subscales, with Factor 1 explaining 57% and Factor 2 explaining 14%, of the variance in responses. The PDSQ and PDQ-39 scores were correlated with the UPDRS3 score (ρ = 0.35, P < 0.001; and ρ = 0.28, P < 0.001, respectively). CONCLUSION: The translated PDSQ and PDQ-39 questionnaires demonstrated high internal consistency and correlations with clinical severity of parkinsonism and a timed motor task, suggesting that they are valid tools for field-based epidemiological studies.

[11C]dihydrotetrabenazine Positron Emission Tomography in Manganese-Exposed Workers.

OBJECTIVE: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [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-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m-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.