Death Anxiety in Huntington Disease: Longitudinal Heath-Related Quality-of-Life Outcomes.

Objective: Death anxiety, represented by the HDQLIFE™ Concern with Death and Dying (CwDD) patient-reported outcome (PRO) questionnaire, captures a person's worry about the death and dying process. Previous work suggests that death anxiety remains an unremitting burden throughout all stages of Huntington disease (HD). Although palliative interventions have lessened death anxiety among people with advanced cancer, none has yet to undergo testing in the HD population. An account of how death anxiety is associated with longitudinal changes to aspects of health-related quality of life (HRQoL) would help optimize neuropalliative interventions for people with HD. Methods: HDQLIFE collected PROs concerning physical, mental, social, and cognitive HRQoL domains and clinician-rated assessments from people with HD at baseline and 12 and 24 months. Linear mixed-effects models were created to determine how baseline death anxiety was associated with follow-up changes in HRQoL PROs after controlling for baseline death anxiety and other disease and sociodemographic covariates. Results: Higher baseline HDQLIFE CwDD is associated with 12- and 24-month declines in HDQLIFE Speech Difficulties, neurology quality of life (NeuroQoL) Depression, Suicidality, HDQLIFE Meaning and Purpose, and NeuroQoL Positive Affect and Well-being. Interpretation: Death anxiety may be a risk factor for worsening mental health and speech difficulty. A further prospective study is required to evaluate whether interventions on death anxiety or mental health generally can reduce declines in HRQoL for people with HD over time.

Radiolabeled 6-(2, 3-Dichlorophenyl)-N4-methylpyrimidine-2, 4-diamine (TH287): A Potential Radiotracer for Measuring and Imaging MTH1.

MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of [3H]TH287 to MTH1 was evaluated in live glioblastoma cells (U251MG) through saturation and competitive binding assays, together with in vitro enzymatic assays. Furthermore, TH287 was radiolabeled with carbon-11 for in vivo microPET studies. Saturation binding assays show that [3H]TH287 has a dissociation constant (Kd) of 1.97 ± 0.18 nM, Bmax of 2676 ± 122 fmol/mg protein for U251MG cells, and nH of 0.98 ± 0.02. Competitive binding assays show that TH287 (Ki: 3.04 ± 0.14 nM) has a higher affinity for MTH1 in U251MG cells compared to another well studied MTH1 inhibitor: (S)-crizotinib (Ki: 153.90 ± 20.48 nM). In vitro enzymatic assays show that TH287 has an IC50 of 2.2 nM in inhibiting MTH1 hydrolase activity and a Ki of 1.3 nM from kinetics assays, these results are consistent with our radioligand binding assays. Furthermore, MicroPET imaging shows that [11C]TH287 gets into the brain with rapid clearance from the brain, kidney, and heart. The results presented here indicate that radiolabeled TH287 has favorable properties to be a useful tool for measuring MTH1 in vitro and for further evaluation for in vivo PET imaging MTH1 of brain tumors and other central nervous system disorders.

Microglia Implicated in Tauopathy in the Striatum of Neurodegenerative Disease Patients from Genotype to Phenotype.

We found interactions between dopamine and oxidative damage in the striatum involved in advanced neurodegeneration, which probably change the microglial phenotype. We observed possible microglia dystrophy in the striatum of neurodegenerative brains. To investigate the interactions between oxidative damage and microglial phenotype, we quantified myeloperoxidase (MPO), poly (ADP-Ribose) (PAR), and triggering receptors expressed on myeloid cell 2 (TREM2) using enzyme-linked immunosorbent assay (ELISA). To test the correlations of microglia dystrophy and tauopathy, we quantified translocator protein (TSPO) and tau fibrils using autoradiography. We chose the caudate and putamen of Lewy body diseases (LBDs) (Parkinson's disease, Parkinson's disease dementia, and Dementia with Lewy body), Alzheimer's disease (AD), and control brains and genotyped for TSPO, TREM2, and bridging integrator 1 (BIN1) genes using single nucleotide polymorphisms (SNP) assays. TREM2 gene variants were absent across all samples. However, associations between TSPO and BIN1 gene polymorphisms and TSPO, MPO, TREM2, and PAR level variations were found. PAR levels reduced significantly in the caudate of LBDs. TSPO density and tau fibrils decreased remarkably in the striatum of LBDs but increased in AD. Oxidative damage, induced by misfolded tau proteins and dopamine metabolism, causes microglia dystrophy or senescence during the late stage of LBDs. Consequently, microglia dysfunction conversely reduces tau propagation. The G allele of the BIN1 gene is a potential risk factor for tauopathy.

Consensus-Based Attributes for Identifying Patients With Spasmodic Dysphonia and Other Voice Disorders.

Importance: A roadblock for research on adductor spasmodic dysphonia (ADSD), abductor SD (ABSD), voice tremor (VT), and muscular tension dysphonia (MTD) is the lack of criteria for selecting patients with these disorders. Objective: To determine the agreement among experts not using standard guidelines to classify patients with ABSD, ADSD, VT, and MTD, and develop expert consensus attributes for classifying patients for research. Design, Setting and Participants: From 2011 to 2016, a multicenter observational study examined agreement among blinded experts when classifying patients with ADSD, ABSD, VT or MTD (first study). Subsequently, a 4-stage Delphi method study used reiterative stages of review by an expert panel and 46 community experts to develop consensus on attributes to be used for classifying patients with the 4 disorders (second study). The study used a convenience sample of 178 patients clinically diagnosed with ADSD, ABSD, VT MTD, vocal fold paresis/paralysis, psychogenic voice disorders, or hypophonia secondary to Parkinson disease. Participants were aged 18 years or older, without laryngeal structural disease or surgery for ADSD and underwent speech and nasolaryngoscopy video recordings following a standard protocol. Exposures: Speech and nasolaryngoscopy video recordings following a standard protocol. Main Outcomes and Measures: Specialists at 4 sites classified 178 patients into 11 categories. Four international experts independently classified 75 patients using the same categories without guidelines after viewing speech and nasolaryngoscopy video recordings. Each member from the 4 sites also classified 50 patients from other sites after viewing video clips of voice/laryngeal tasks. Interrater κ less than 0.40 indicated poor classification agreement among rater pairs and across recruiting sites. Consequently, a Delphi panel of 13 experts identified and ranked speech and laryngeal movement attributes for classifying ADSD, ABSD, VT, and MTD, which were reviewed by 46 community specialists. Based on the median attribute rankings, a final attribute list was created for each disorder. Results: When classifying patients without guidelines, raters differed in their classification distributions (likelihood ratio, χ2 = 107.66), had poor interrater agreement, and poor agreement with site categories. For 11 categories, the highest agreement was 34%, with no κ values greater than 0.26. In external rater pairs, the highest κ was 0.23 and the highest agreement was 38.5%. Using 6 categories, the highest percent agreement was 73.3% and the highest κ was 0.40. The Delphi method yielded 18 attributes for classifying disorders from speech and nasolaryngoscopic examinations. Conclusions and Relevance: Specialists without guidelines had poor agreement when classifying patients for research, leading to a Delphi-based development of the Spasmodic Dysphonia Attributes Inventory for classifying patients with ADSD, ABSD, VT, and MTD for research.

Physical therapy and deep brain stimulation in Parkinson's Disease: protocol for a pilot randomized controlled trial.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) reduces tremor, muscle stiffness, and bradykinesia in people with Parkinson's Disease (PD). Walking speed, known to be reduced in PD, typically improves after surgery; however, other important aspects of gait may not improve. Furthermore, balance may worsen and falls may increase after STN-DBS. Thus, interventions to improve balance and gait could reduce morbidity and improve quality of life following STN-DBS. Physical therapy (PT) effectively improves balance and gait in people with PD, but studies on the effects of PT have not been extended to those treated with STN-DBS. As such, the efficacy, safety, and feasibility of PT in this population remain to be determined. The purpose of this pilot study is to address these unmet needs. We hypothesize that PT designed to target balance and gait impairment will be effective, safe, and feasible in this population. METHODS/DESIGN: Participants with PD treated with STN-DBS will be randomly assigned to either a PT or control group. Participants assigned to PT will complete an 8-week, twice-weekly PT program consisting of exercises designed to improve balance and gait. Control group participants will receive the current standard of care following STN-DBS, which does not include prescription of PT. The primary aim is to assess preliminary efficacy of PT on balance (Balance Evaluation Systems Test). A secondary aim is to assess efficacy of PT on gait (GAITRite instrumented walkway). Participants will be assessed OFF medication/OFF stimulation and ON medication/ON stimulation at baseline and at 8 and 12 weeks after baseline. Adverse events will be measured over the duration of the study, and adherence to PT will be measured to determine feasibility. DISCUSSION: To our knowledge, this will be the first study to explore the preliminary efficacy, safety, and feasibility of PT for individuals with PD with STN-DBS. If the study suggests potential efficacy, then this would justify larger trials to test effectiveness and safety of PT for those with PD with STN-DBS. TRIAL REGISTRATION: NCT03181282 (clinicaltrials.gov). Registered on 7 June 2017.

ACR Appropriateness Criteria® Cranial Neuropathy.

Evaluation of cranial neuropathy can be complex given the different pathway of each cranial nerve as well as the associated anatomic landmarks. Radiological evaluation requires imaging of the entire course of the nerve from its nucleus to the end organ. MRI is the modality of choice with CT playing a complementary role, particularly in the evaluation of the bone anatomy. Since neoplastic and inflammatory lesions are prevalent on the differential diagnosis, contrast enhanced studies are preferred when possible. The American College of Radiology Appropriateness Criteria are evidencebased guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate.

The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing cholinergic dysfunction associated with dementia. We recently reported three new potent and selective carbon-11 labeled VAChT radiotracers. Herein, we report the resolution with a Chiralcel OD column of three additional fluorine containing VAChT ligands in which a fluoroethoxy or fluoroethylamino moiety was substituted for the methoxy group. An in vitro competitive binding assay showed that (-)-7 had high potency for VAChT (Ki-VAChT = 0.31 ± 0.03 nM) and excellent selectivity for VAChT versus σ receptors (Ki-σ1 = 1870 ± 250 nM, Ki-σ2 = 5480 ± 140 nM). Three different radiolabeling approaches were explored; the radiosynthesis of (-)-[18F]7 was successfully accomplished via a stepwise two-pot, three-step method with moderate yield (11 ± 2%) and high radiochemical purity (>98%). PET imaging studies in a nonhuman primate indicated that (-)-[18F]7 rapidly entered the brain and accumulated in the VAChT-enriched striatum. The uptake of (-)-[18F]7 in the target striatal area peaked at 10 min and displayed improved clearance kinetics compared to the VAChT tracer [18F]VAT, which has been approved by the Food and Drug Administration (FDA) for first-in-man studies. These studies justify further investigation of (-)-[18F]7 and exploration of the structure-activity relationships of these fluoroethoxy and fluoroethylamino analogs.

ACR Appropriateness Criteria Low Back Pain.

Most patients presenting with uncomplicated acute low back pain (LBP) and/or radiculopathy do not require imaging. Imaging is considered in those patients who have had up to 6 weeks of medical management and physical therapy that resulted in little or no improvement in their back pain. It is also considered for those patients presenting with red flags raising suspicion for serious underlying conditions, such as cauda equina syndrome, malignancy, fracture, and infection. Many imaging modalities are available to clinicians and radiologists for evaluating LBP. Application of these modalities depends largely on the working diagnosis, the urgency of the clinical problem, and comorbidities of the patient. When there is concern for fracture of the lumbar spine, multidetector CT is recommended. Those deemed to be interventional candidates, with LBP lasting for > 6 weeks having completed conservative management with persistent radiculopathic symptoms, may seek MRI. Patients with severe or progressive neurologic deficit on presentation and red flags should be evaluated with MRI. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Absorbed radiation dosimetry of the D3-specific PET radioligand [18F]FluorTriopride estimated using rodent and nonhuman primate.

[18F]FluorTriopride ([18F]FTP) is a dopamine D3-receptor preferring radioligand with potential for investigation of neuropsychiatric disorders including Parkinson disease, dystonia and schizophrenia. Here we estimate human radiation dosimetry for [18F]FTP based on the ex-vivo biodistribution in rodents and in vivo distribution in nonhuman primates. Biodistribution data were generated using male and female Sprague-Dawley rats injected with ~370 KBq of [18F]FTP and euthanized at 5, 30, 60, 120, and 240 min. Organs of interest were dissected, weighed and assayed for radioactivity content. PET imaging studies were performed in two male and one female macaque fascicularis administered 143-190 MBq of [18F]FTP and scanned whole-body in sequential sections. Organ residence times were calculated based on organ time activity curves (TAC) created from regions of Interest. OLINDA/EXM 1.1 was used to estimate human radiation dosimetry based on scaled organ residence times. In the rodent, the highest absorbed radiation dose was the upper large intestines (0.32-0.49 mGy/MBq), with an effective dose of 0.07 mSv/MBq in males and 0.1 mSv/MBq in females. For the nonhuman primate, however, the gallbladder wall was the critical organ (1.81 mGy/MBq), and the effective dose was 0.02 mSv/MBq. The species discrepancy in dosimetry estimates for [18F]FTP based on rat and primate data can be attributed to the slower transit of tracer through the hepatobiliary track of the primate compared to the rat, which lacks a gallbladder. Out findings demonstrate that the nonhuman primate model is more appropriate model for estimating human absorbed radiation dosimetry when hepatobiliary excretion plays a major role in radiotracer elimination.

Radiation dosimetry of [(18)F]VAT in nonhuman primates.

BACKGROUND: The objective of this study is to determine the radiation dosimetry of a novel radiotracer for vesicular acetylcholine transporter (-)-(1-((2R,3R)-8-(2-[(18)F]fluoro-ethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone ([(18)F]VAT) based on PET imaging in nonhuman primates. [(18)F]VAT has potential for investigation of neurological disorders including Alzheimer's disease, Parkinson's disease, and dystonia. METHODS: Three macaque fascicularis (two males, one female) received 185.4-198.3 MBq [(18)F]VAT prior to whole-body imaging in a MicroPET-F220 scanner. Time activity curves (TACs) were created from regions of interest (ROIs) that encompassed the entire small organs or samples with the highest activity within large organs. Organ residence times were calculated based on the TACs. We then used OLINDA/EXM 1.1 to calculate human radiation dose estimates based on scaled organ residence times. RESULTS: Measurements from directly sampled arterial blood yielded a residence time of 0.30 h in agreement with the residence time of 0.39 h calculated from a PET-generated time activity curve measured in the left ventricle. Organ dosimetry revealed the liver as the critical organ (51.1 and 65.4 µGy/MBq) and an effective dose of 16 and 19 µSv/MBq for male and female, respectively. CONCLUSIONS: The macaque biodistribution data showed high retention of [(18)F]VAT in the liver consistent with hepatobiliary clearance. These dosimetry data support that relatively safe doses of [(18)F]VAT can be administered to obtain imaging in humans.

In vitro and ex vivo characterization of (-)-TZ659 as a ligand for imaging the vesicular acetylcholine transporter.

The loss of cholinergic neurons and synapses relates to the severity of dementia in several neurodegenerative pathologies; and the vesicular acetylcholine transporter (VAChT) provides a reliable biomarker of cholinergic function. We recently characterized and (11)C-labeled a new VAChT inhibitor, (-)-TZ659. Here we report the in vitro and ex vivo characterization of (-)-TZ659. A stably transfected PC12(A123.7) cell line which expresses human VAChT (hVAChT) was used for the in vitro binding characterization of (-)-[(3)H]TZ659. A saturated binding curve was obtained with Kd=1.97±0.30nM and Bmax=3240±145.9fmol/mg protein. In comparison, a PC12(A123.7) cell line that expresses mutant hVAChT showed decreased binding affinity (Kd=15.94±0.28nM). Competitive binding assays using a panel of other CNS ligands showed no inhibition of (-)-[(3)H]TZ659 binding. On the other hand, binding inhibitions were observed only using VAChT inhibitors (Ki=0.20-31.35nM). An in vitro assay using rat brain homogenates showed that (-)-[(3)H]TZ659 had higher binding in striatum than in cerebellum, with a target: non-target ratio>3.46. Even higher ex vivo striatum-to-cerebellum ratios (9.56±1.11) were observed using filtered homogenates of brain tissue after rats were injected intravenously with (-)-[(11)C]TZ659. Ex vivo autoradiography of (-)-[(11)C]TZ659 confirmed high striatal uptake, with a consistently high striatum-to-cerebellum ratio (2.99±0.44). In conclusion, (-)-TZ659 demonstrated high potency and good specificity for VAChT in vitro and in vivo. These data suggest that (-)-[(11)C]TZ659 may be a promising PET tracer to image VAChT in the brain.

Levodopa-responsive hemiparkinsonism secondary to cystic expansion from a coiled cerebral aneurysm.

An 80-year-old woman with longstanding hemifacial spasm had a 1 cm × 1.5 cm internal carotid artery terminus aneurysm treated with endovascularly delivered bare metal coils. Follow-up imaging revealed an expansile perianeurysmal cyst that coincided with development of contralateral dopa-responsive hemiparkinsonism. This is the first report of perianeurysmal cyst expansion causing levodopa-responsive hemiparkinsonism.

Disparities in deep brain stimulation surgery among insured elders with Parkinson disease.

OBJECTIVE: To identify sociodemographic, clinical, and physician/practice factors associated with deep brain stimulation (DBS). DBS is a proven surgical therapy for Parkinson disease (PD), but is recommended only for patients with excellent health, results in significant out-of-pocket costs, and requires substantial physician involvement. METHODS: Retrospective cohort study of more than 657,000 Medicare beneficiaries with PD. Multivariable logistic regression models examined the association between demographic, clinical, socioeconomic status (SES), and physician/practice factors, and DBS therapy. RESULTS: There were significant disparities in the use of DBS therapy among Medicare beneficiaries with PD. The greatest disparities were associated with race: black (adjusted odds ratio [AOR] 0.20, 95% confidence interval [CI] 0.16-0.25) and Asian (AOR 0.55, 95% CI 0.44-0.70) beneficiaries were considerably less likely to receive DBS than white beneficiaries. Women (AOR 0.79, 95% CI 0.75-0.83) also had lower odds of receiving DBS compared with men. Eighteen percent of procedures were performed on patients with PD who had cognitive impairment/dementia, a reported contraindication to DBS. Beneficiaries treated in minority-serving PD practices were less likely to receive DBS, regardless of individual race (AOR 0.76, 95% CI 0.66-0.87). Even after adjustment for demographic and clinical covariates, high neighborhood SES was associated with 1.4-fold higher odds of receiving DBS (AOR 1.42, 95% CI 1.33-1.53). CONCLUSIONS: Among elderly Medicare beneficiaries with PD, race, sex, and neighborhood SES are strong independent predictors of DBS receipt. Racial disparities are amplified when adjusting for physician/clinic characteristics. Future investigations of the demographic differences in clinical need/usefulness of DBS, ease of DBS attainment, and actual/opportunity DBS costs are needed to inform policies to reduce DBS disparities and improve PD quality of care.

Research priorities in spasmodic dysphonia.

OBJECTIVE: To identify research priorities to increase understanding of the pathogenesis, diagnosis, and improved treatment of spasmodic dysphonia. STUDY DESIGN AND SETTING: A multidisciplinary working group was formed that included both scientists and clinicians from multiple disciplines (otolaryngology, neurology, speech pathology, genetics, and neuroscience) to review currently available information on spasmodic dysphonia and to identify research priorities. RESULTS: Operational definitions for spasmodic dysphonia at different levels of certainty were recommended for diagnosis and recommendations made for a multicenter multidisciplinary validation study. CONCLUSIONS: The highest priority is to characterize the disorder and identify risk factors that may contribute to its onset. Future research should compare and contrast spasmodic dysphonia with other forms of focal dystonia. Development of animal models is recommended to explore hypotheses related to pathogenesis. Improved understanding of the pathophysiology of spasmodic dysphonia should provide the basis for developing new treatment options and exploratory clinical trials. SIGNIFICANCE: This document should foster future research to improve the care of patients with this chronic debilitating voice and speech disorder by otolaryngology, neurology, and speech pathology.

Replication of association between ELAVL4 and Parkinson disease: the GenePD study.

Genetic variants in embryonic lethal, abnormal vision, Drosophila-like 4 (ELAVL4) have been reported to be associated with onset age of Parkinson disease (PD) or risk for PD affection in Caucasian populations. In the current study we genotyped three single nucleotide polymorphisms in ELAVL4 in a Caucasian study sample consisting of 712 PD patients and 312 unrelated controls from the GenePD study. The minor allele of rs967582 was associated with increased risk of PD (odds ratio = 1.46, nominal P value = 0.011) in the GenePD population. The minor allele of rs967582 was also the risk allele for PD affection or earlier onset age in the previously studied populations. This replication of association with rs967582 in a third cohort further implicates ELAVL4 as a PD susceptibility gene.

Radiation dosimetry of N-([11C]methyl)benperidol as determined by whole-body PET imaging of primates.

PURPOSE: N-([(11)C]methyl)benperidol ([(11)C]NMB) can be used for positron emission tomography (PET) measurements of D(2)-like dopamine receptor binding in vivo. We report the absorbed radiation dosimetry of i.v.-administered (11)C-NMB, a critical step before applying this radioligand to imaging studies in humans. MATERIALS AND METHODS: Whole-body PET imaging with a CTI/Siemens ECAT 953B scanner was done in a male and a female baboon. After i.v. injection of 444-1221 MBq of (11)C-NMB, sequential images taken from the head to the pelvis were collected for 3 h. Volumes of interest (VOIs) were identified that entirely encompassed small organs (whole brain, striatum, eyes, and myocardium). Large organs (liver, lungs, kidneys, lower large intestine, and urinary bladder) were sampled by drawing representative regions within the organ volume. Time-activity curves for each VOI were extracted from the PET, and organ residence times were calculated by analytical integration of a multi-exponential fit of the time-activity curves. Human radiation doses were estimated using OLINDA/EXM 1.0 and the standard human model. RESULTS: Highest retention was observed in the blood and liver, each with total residence times of 1.5 min. The highest absorbed radiation doses were to the heart (10.5 µGy/MBq) [DOSAGE ERROR CORRECTED] and kidney (9.19 µGy/MBq), [DOSAGE ERROR CORRECTED] making these the critical organs for [(11)C]NMB. A heart absorption of 50 mGy would result from an injected dose of 4,762 MBq [(11)C]NMB. CONCLUSIONS: Thus, this study suggests that up to 4,762 MBq of [(11)C]NMB can be safely administered to human subjects for PET studies. Total body dose and effective dose for [(11)C]NMB are 2.82 µGy/MBq [DOSAGE ERROR CORRECTED] and 3.7 mSv/kBq, respectively.

A rapid method for mass screening for parkinsonism.

Epidemiology studies of parkinsonism employ a variety of techniques for unbiased sampling of populations. No current method permits mass screening of all subjects in a population for parkinsonism by movement disorders specialists. We developed and piloted a new approach to facilitate accurate and efficient screening of large populations for diagnosis of parkinsonism and provide data on sensitivity and specificity. We evaluated 2081 welders referred for medical-legal screening. Subjects were video taped using a standardized protocol, and videos were rated on the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3). A "video rater" viewed video tapes and entered ratings through a web-based database. An "in-person" examiner performed a UPDRS3 examination in a randomly selected subgroup of 48 workers drawn from the 2081. We developed quantitative diagnostic criteria for parkinsonism that established minimum diagnostic thresholds based upon UPDRS3 scores and compared these criteria with diagnosis by an in-person examiner. Specificity of these criteria compared to in-person examination was 91-100% but sensitivity was 56%. A threshold UPDRS3 score greater than nine provided 100% sensitivity and 81% specificity. Liberal criteria identified 266 (13.1%) subjects with probable parkinsonism and 220 (10.8%) subjects with definite parkinsonism. Conservative criteria identified 260 (12.8%) with probable parkinsonism and 122 (6%) with definite parkinsonism. Our screening method permits rapid assessment of parkinsonian signs. An absolute UPDRS3 score greater than nine provided the best combination of sensitivity and specificity for the diagnosis of parkinsonism, while quantitative exam-based criteria for cardinal parkinsonian signs maximized specificity. Parkinsonism as diagnosed by our criteria was common in this group of welders.