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ObjectiveTo assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson’s disease (PD).BackgroundEvidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation, and whether pro-inflammatory signals are associated with clinical features and/or predict more rapid progression.MethodsWe enrolled subjects with de novo PD (n=58) and age-matched controls (n=62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson’s Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment (MCI) testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with 18F-DPA-714, a translocator protein 18kd (TSPO) ligand, and lumbar puncture if eligible and consented.ResultsBaseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. PET imaging showed increased 18F-DPA-714 signal in PD subjects. 18F-DPA-714 signal correlated with several cognitive measures and some chemokines.Conclusions18F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline.

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 (

Many advances in prevention, diagnosis, and treatment of neurologic disease have emerged in the last few decades, resulting in reduced mortality and decreased disability. However, these advances have not benefitted all populations equally. A growing body of evidence indicates that barriers to care fall along racial and ethnic lines, with persons from minority groups frequently having lower rates of evaluation, diagnosis, and intervention, and consequently experiencing worse neurologic outcomes than their white counterparts. The American Academy of Neurology (AAN) challenged its 2017 Diversity Leadership Program cohort to determine what the AAN can do to improve quality of care for racially and ethnically diverse patients with neurologic disorders. Developing a fuller understanding of the effect of disparities in neurologic care (neurodisparity) on patients is an important prerequisite for creating meaningful change. Clear insight into how bias and trust affect the doctor–patient relationship is also crucial to grasp the complexity of this issue. We propose that the AAN take a vital step toward achieving equity in neurologic care by enhancing health literacy, patient education, and shared decision-making with a focus on internet and social media. Moreover, by further strengthening its focus on health disparities research and training, the AAN can continue to inform the field and aid in the development of current and future leaders who will address neurodisparity. Ultimately, the goal of tackling neurodisparity is perfectly aligned with the mission of the AAN: to promote the highest-quality patient-centered neurologic care and enhance member career satisfaction.

ObjectiveTo assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia.MethodsClinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition.ResultsMethodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics.ConclusionThe large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.

BACKGROUND Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. OBJECTIVE To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. METHODS The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. RESULTS 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SE = 0.002, p = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p

Importance There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD). Objectives To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. Design, Setting, and Participants This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure). Interventions Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. Main Outcomes and Measures The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson’s Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers. Results At baseline, mean (SD) participants’ age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P Conclusions and Relevance While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD. Trial Registration ClinicalTrials.gov Identifier:NCT03205488

Objectives To investigate hypothesized sources of error when quantifying the effect of the sensory trick in cervical dystonia (CD) with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-2), test strategies to mitigate them, and provide guidance for future research on the sensory trick. Methods Previous analyses suggested the sensory trick (or “alleviating maneuver”, AM) item be removed from the TWSTRS-2 because of its poor clinimetric properties. We hypothesized three sources of clinimetric weakness for rating the AM: 1) whether patients were given sufficient time to demonstrate their AM; 2) whether patients' CD was sufficiently severe for detecting AM efficacy; and 3) whether raters were inadvertently rating the item in reverse of scale instructions. We tested these hypotheses with video recordings and TWSTRS-2 ratings by one “site rater” and a panel of five “video raters” for each of 185 Dystonia Coalition patients with isolated CD. Results Of 185 patients, 23 (12%) were not permitted sufficient testing time to exhibit an AM, 23 (12%) had baseline CD too mild to allow confident rating of AM effect, and 1 site- and 1 video-rater each rated the AM item with a reverse scoring convention. When these confounds were eliminated in step-wise fashion, the item's clinimetric properties improved. Conclusions The AM's efficacy can contribute to measuring CD motor severity by addressing identified sources of error during its assessment and rating. Given the AM's sensitive diagnostic and potential pathophysiologic significance, we also provide guidance on modifications to how AMs can be assessed in future CD research.

Objectives This study was undertaken to compare efficacy, tolerability, and pharmacokinetics of DM-1992, an extended-release formulation of carbidopa/levodopa (CD/l-dopa) with immediate-release (IR) CD/l-dopa in patients with advanced Parkinson's disease. Methods This randomized, open-label, crossover study included a 3-d baseline and two 10-d treatment periods. Patients with daily OFF time of 2.5 h or more taking 400 mg or more l-dopa/d in four or more divided doses were titrated to stable regimens of DM-1992 2 times per day or CD/l-dopa IR 3 times to 8 times per day. Patients were allowed to take rescue CD/l-dopa as needed. Using home diaries, patients recorded OFF time and ON time with or without troublesome dyskinesia during baseline and treatment days 7 through 9. During 12-h clinic visits on day 10, plasma samples were collected for pharmacokinetics, and motor performance was assessed hourly. Results Thirty-four patients were enrolled; mean baseline l-dopa dosage was 968 mg/d. After titration, CD/l-dopa IR was dosed 4.8 times per day and DM-1992, 2 times per day. Rescue CD/l-dopa IR was given 1.3 times during the DM-1992 arm and 0.2 times during the CD/l-dopa IR arm. The reduction from baseline in % OFF time was greater for DM-1992 compared with CD/l-dopa IR (−5.52% vs. +1.33%; P = 0.0471). At steady-state, compared with CD/l-dopa IR, DM-1992 exhibited a smoother plasma l-dopa concentration profile mostly because of a significantly higher (day 10) predose l-dopa concentration, associated with enhanced motor performance. Although more patients taking DM-1992 had one or more adverse events (AEs) than CD/l-dopa IR patients (35% vs. 15%), no pattern to the AEs was seen, nor any resulting discontinuations. Conclusions DM-1992 was associated with a reduction in %OFF time compared with CD/l-dopa IR despite a reduced dosing frequency. Although the open-label study design and the greater number of rescue doses during the DM-1992 arm call for caution in interpreting the results, the elevated predose plasma l-dopa concentration (12 h after DM-1992 administration) lends objective support to our findings, suggesting that phase 3 studies are warranted. © 2015 International Parkinson and Movement Disorder Society

Little is currently known about the higher order functional skills of patients with Parkinson disease and cognitive impairment. Medical decision-making capacity (MDC) was assessed in patients with Parkinson's disease (PD) with cognitive impairment and dementia. Participants were 16 patients with PD and cognitive impairment without dementia (PD-CIND), 16 patients with PD dementia (PDD), and 22 healthy older adults. All participants were administered the Capacity to Consent to Treatment Instrument (CCTI), a standardized capacity instrument assessing MDC under five different consent standards. Parametric and non-parametric statistical analyses were utilized to examine capacity performance on the consent standards. In addition, capacity outcomes (capable, marginally capable, or incapable outcomes) on the standards were identified for the two patient groups. Relative to controls, PD-CIND patients demonstrated significant impairment on the understanding treatment consent standard, clinically the most stringent CCTI standard. Relative to controls and PD-CIND patients, patients with PDD patients were impaired on the three clinical standards of understanding, reasoning, and appreciation. The findings suggest that impairment in decisional capacity is already present in cognitively impaired PD patients without dementia, and increases as these patients develop dementia. Clinicians and researchers should carefully assess decisional capacity in all PD patients with cognitive impairment.

Objective To report an 18-month follow-up on creatine and minocycline futility study, the Neuroprotective Exploratory Trials in Parkinson Disease, Futility Study 1 (NET-PD FS-1). Background The NET-PD FS-1 futility study on creatine and minocycline found neither agent futile in slowing down the progression of disability in Parkinson disease (PD) at 12 months using the prespecified futility threshold. An additional 6 months of follow-up aimed to assess safety and potential interactions of the study interventions with antiparkinsonian therapy. Methods Additional 6 months of follow-up in randomized, blinded phase II trial of creatine (dosage, 10 g/d) and minocycline (dosage, 200 mg/d) in subjects with early PD. Results By 18 months, symptomatic treatment of PD symptoms was required in 61% of creatine, 62% of minocycline, and 60% of placebo-treated subjects. Study treatment was prematurely discontinued in 9%, 23%, and 6% of subjects in the creatine, minocycline, and placebo arms, respectively. Creatine and minocycline did not seem to adversely influence the response to symptomatic therapy nor increase adverse events. Conclusions Data from this small, 18-month phase II trial of creatine and minocycline do not demonstrate safety concerns that would preclude a large, phase III efficacy trial, although the decreased tolerability of minocycline is a concern.

The objective of this study was to determine the reliability of a new scale for the clinical assessment of essential tremor. The Essential Tremor Rating Assessment Scale contains 9 performance items that rate action tremor in the head, face, voice, limbs, and trunk from 0 to 4 in half-point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters.Videos of 44 patients and 6 controls were rated by 10 specialists on 2 occasions 1-2 months apart. Inter- and intrarater reliability was assessed with a 2-way random-effects intraclass correlation, using an absolute agreement definition.Inter- and intrarater intraclass correlations for head and upper-limb tremor ranged from 0.86 to 0.96, and intraclass correlations for total score were 0.94 and 0.96. The intraclass correlations for voice, face, trunk, and leg were less robust.This scale is an exceptionally reliable tool for the clinical assessment of essential tremor.

Weight gain following bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson disease (PD) has been characterized previously, but little is known about changes in weight following unilateral STN DBS. Weight gain of approximately 10 kg at one year after bilateral STN DBS for PD has been noted in previous studies, and PD in the absence of DBS has been associated with weight loss. A case-control comparison evaluated the change in weight following unilateral STN DBS in PD. In 39 patients who underwent unilateral STN DBS for PD, we measured the weight change over 1 year versus both preoperative weight change and the weight change in 40 age- and disease severity-matched PD controls without DBS. Regression analyses incorporating age, gender, baseline weight in case or control were conducted to assess weight changes. At 12 months following surgery, the mean weight of unilateral STN DBS patients increased by 4.3+/-7.2 kg versus the preoperative baseline weight (p0.001) and this increase was 4.8 kg compared with the controls (p=0.015). Over a 1 year time interval, weight gain occurred in 41% of the preoperative unilateral STN DBS patients and 45% of the PD controls, while 85% of the unilateral STN DBS patients had gained weight at 12 months after surgery (p0.0001, respectively, chi square test). We conclude that unilateral STN DBS in PD is associated with weight gain, which offsets weight loss associated with advanced PD.

Purpose Financial capacity (FC) is an instrumental activity of daily living (IADL) critical to independent functioning and sensitive to cognitive impairment in dementia. Little is known about FC in cognitively impaired patients with Parkinson's disease (PD). The present study investigated FC in PD patients with prodromal and clinical dementia. Methods Participants were 20 older controls and 35 PD patients who met consensus criteria for either mild cognitive impairment (PD-MCI, n = 18) or PD dementia (PDD, n = 17). FC was assessed using a standardized performance based measure consisting of 9 domain and two global scores (Financial Capacity Instrument; FCI) (1). FCI domain and global performance scores were compared across groups. Capacity impairment ratings (no impairment, mild/moderate impairment, severe impairment) were calculated for each PD patient's domain and global scores. Results Relative to controls, PD-MCI patients were impaired on both FCI global scores and domains of basic monetary skills, financial concepts, and investment decision-making. Relative to both controls and PD-MCI patients, PDD patients were impaired on virtually all FCI variables. With respect to impairment ratings, greater than 50% of PD-MCI patients and greater than 90% of PDD patients were classified as either mild/moderate or severely impaired on the two FCI global scores. Conclusions Impairment of financial capacity is already present in PD-MCI and is advanced in PDD. Complex cognitively-mediated IADLs such as financial capacity appear to be impaired early in the course of PD dementia.

Objective: To characterize the clinical and genetic features of cervical dystonia (CD). Methods: Participants enrolled in the Dystonia Coalition biorepository (NCT01373424) with initial manifestation as CD were included in this study (n = 1,000). Data intake included demographics, family history, and the Global Dystonia Rating Scale. Participants were screened for sequence variants (SVs) in GNAL, THAP1, and Exon 5 of TOR1A. Results: The majority of participants were Caucasian (95%) and female (75%). The mean age at onset and disease duration were 45.5 ± 13.6 and 14.6 ± 11.8 years, respectively. At the time of assessment, 68.5% had involvement limited to the neck, shoulder(s), and proximal arm(s), whereas 47.4% had dystonia limited to the neck. The remaining 31.5% of the individuals exhibited more extensive anatomical spread. A head tremor was noted in 62% of the patients. Head tremor and laryngeal dystonia were more common in females. Psychiatric comorbidities, mainly depression and anxiety, were reported by 32% of the participants and were more common in females. Family histories of dystonia, parkinsonian disorder, and tremor were present in 14%, 11%, and 29% of the patients, respectively. Pathogenic or likely pathogenic SVs in THAP1, TOR1A, and GNAL were identified in 8 participants (0.8%). Two individuals harbored novel missense SVs in Exon 5 of TOR1A. Synonymous and noncoding SVs in THAP1 and GNAL were identified in 4% of the cohort. Conclusions: Head tremor, laryngeal dystonia, and psychiatric comorbidities are more common in female participants with CD. Coding and noncoding variants in GNAL, THAP1, and TOR1A make small contributions to the pathogenesis of CD.

Deficits in learning, memory, and executive functions are common cognitive sequelae of Parkinson's disease with dementia (PDD) and Alzheimer's disease (AD); however, the pattern of deficits within these populations is distinct. Hierarchical regression was used to investigate the contribution of two measures with executive function properties (Verbal Fluency and CLOX) on list-learning performance (CVLT-II total words learned) in a sample of 25 PDD patients and 25 matched AD patients. Executive measures were predictive of list learning in the PDD group after the contribution of overall cognition and contextual verbal learning was accounted for, whereas in the AD group the addition of executive measures did not add to prediction of variance in CVLT-II learning. These findings suggest that deficits in executive functions play a vital role in learning impairments in patients with PDD; however, for AD patients, learning difficulties appear relatively independent of executive dysfunction.

Spheramine (Bayer Schering Pharma AG, Berlin, Germany) is currently being tested as a new approach for the treatment of Parkinson's disease (PD). It consists of an active component of cultured human retinal pigment epithelial (hRPE) cells, attached to an excipient part of cross-linked porcine gelatin microcarrriers. Spheramine is administered by stereotactic implantation into the striatum of PD patients and the use of immunosuppression is not required. Current pharmacologic therapies of PD are oriented to the administration of dopaminergic medications. Human RPE cells produce levodopa, and this constitutes the rationale to use Spheramine for the treatment of PD. The preclinical development of Spheramine included extensive biologic, pharmacologic, and toxicologic studies in vitro and in animal models of PD. The first clinical trial in humans evaluated the safety and efficacy of Spheramine implanted in the postcommissural putamen contralateral to the most affected side in six patients with advanced PD. This open-label study demonstrated good tolerability and showed sustained motor clinical improvement. A phase II double-blind, randomized, multicenter, placebo-controlled (sham surgery) study is underway to evaluate safety, tolerability, and efficacy of Spheramine implanted bilaterally into the postcommissural putamen of patients with advanced PD. Spheramine represents a treatment approach with the potential of supplying a more continuous delivery of levodopa to the striatum in advanced PD than can be achieved with oral therapy alone.

Background Human retinal pigment epithelial (RPE) cells produce levodopa and can be isolated from postmortem human eye tissue, grown in culture, and implanted into the brain attached to microcarriers. These implants ameliorated the motor deficits in rodent and nonhuman primate models of Parkinson disease. Objective To evaluate the safety and efficacy of unilateral implantation of human RPE cells attached to gelatin microcarriers into the putamen contralateral to the more symptomatic side of patients with Parkinson disease. Design Open-label pilot study. Setting A tertiary referral center for movement disorders. Patients Six patients with advanced Parkinson disease. Interventions We performed stereotactic intrastriatal implantation of approximately 325 000 RPE cells on microcarriers. Main Outcome Measure Change from baseline to 12 months in the Unified Parkinson’s Disease Rating Scale motor subscore with the patients in the practically defined off state (not taking antiparkinsonian medications for at least 12 hours overnight). Results The implants were well tolerated. We observed an average improvement of 48% at 12 months after implantation in the Unified Parkinson’s Disease Rating Scale motor subscore with the patient in the off state, which was sustained through 24 months. Improvement was also observed in activities of daily living, quality of life, and motor fluctuations. No off-state dyskinesias were observed. Conclusions Implants of human RPE cells attached to gelatin microcarriers appear to be safe and well tolerated, and they improved motor symptoms in patients with Parkinson disease. On the basis of these results, a randomized, double-blind, placebo-controlled study has been initiated.

Background The preferred surgical target for the treatment of Parkinson disease (PD) is either the internal globus pallidus or the subthalamic nucleus (STN); the target for treatment of essential tremor (ET) is the thalamic subnucleus ventralis intermedius (Vim). Some patients with PD have coexistent ET, and the identification of a single surgical target to treat both parkinsonian motor symptoms and ET would be of practical importance. Objective To describe the use of the STN target in deep brain stimulator (DBS) surgery to treat PD motor symptoms and the action-postural tremor of ET. Design Case report. Patient A 62-year-old man had a greater than 30-year history of action-postural tremor in both hands, well controlled with β-blockers for more than 20 years. He developed resting tremor, bradykinesia, and rigidity on his right side that progressed to his left side during the past 10 years. Dopaminergic medication improved his rigid-ity and bradykinesia, with only mild improvement of his resting tremor and no effect on his action-postural tremor. Interventions Left pallidotomy followed by placement of a left DBS in the Vim and subsequent placement of a right STN DBS. Main Outcome Measures Control of symptoms of PD and ET. Results The left pallidotomy controlled the patient’s parkinsonian motor symptoms on the right side of his body, but did not affect the action-postural component of his tremor. The symptoms on the left side of the body, including both an action-postural and a resting tremor (as well as the rigidity and bradykinesia), improved after placement of a single right STN DBS. Conclusion Placement of an STN DBS should be considered as the procedure of choice for surgical treatment of patients with a combination of PD and ET.

Importance Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. Objective To examine whether CoQ10 could slow disease progression in early PD. Design, Setting, and Participants A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson’s Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. Interventions The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. Main Outcomes and Measures Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. Results The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). Conclusions and Relevance Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. Trial Registration clinicaltrials.gov Identifier:NCT00740714