Publications by authors named "James T Boyd"

22 Publications

  • Page 1 of 1

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

JAMA 2021 09;326(10):926-939

University of Cincinnati, Cincinnati, Ohio.

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 (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.

Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.

Main Outcomes And Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.

Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).

Conclusions And Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.
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http://dx.doi.org/10.1001/jama.2021.10207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441591PMC
September 2021

Prevalence and Relationship of Rest Tremor and Action Tremor in Parkinson's Disease.

Tremor Other Hyperkinet Mov (N Y) 2020 12 23;10:58. Epub 2020 Dec 23.

Department of Neurology, Columbia University, New York City, New York, US.

Background: Despite the significance of tremor in Parkinson's disease (PD) diagnosis, classification, and patient's quality of life, there is a relative lack of data on prevalence and relationship of different tremor types in PD.

Methods: The presence of rest tremor (RT) and action tremor (AT; defined as combination of both postural and kinetic tremor) was determined and RT severity was defined using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) at baseline in the Progression Marker Initiative (PPMI, n = 423), the Fox Investigation for New Discovery of Biomarkers (BioFIND, n = 118) and the Parkinson's Disease Biomarkers Program (PDBP, n = 873) cohorts.

Results: Across baseline data of all three cohorts, RT prevalence (58.2%) was higher than AT prevalence (39.0%). Patients with RT had significantly higher (Chi-square test, p < 0.05) prevalence of AT compared to patients without RT in the PPMI (40.0% versus 30.1%), BioFIND (48.0% versus 40.0%) and PDBP (49.9% versus 21.0%) cohorts. Furthermore, patients with AT had significantly (Student t-test, p < 0.05) higher RT severity that those without AT in PPMI (5.7 ± 5.4 versus 3.9 ± 3.3), BioFIND, 6.4 ± 6.3 versus 3.8 ± 4.4) and PDBP (6.4 ± 6.6 versus 3.7 ± 4.4) cohorts. In the BioFIND cohort, the prevalence of all types of tremor and their combinations significantly decreased from the off-state to on-state.

Discussion: The RT is the most frequent tremor type and present in more than half of the PD patients. However, AT is also present in nearly one-third of the PD patients. Our results also indicate that RT and AT may have cross-interactions in PD, and that dopaminergic treatment influences both RT and AT.
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http://dx.doi.org/10.5334/tohm.552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757606PMC
December 2020

Safety of Levodopa-Carbidopa Intestinal Gel Treatment in Patients with Advanced Parkinson's Disease Receiving ≥2000 mg Daily Dose of Levodopa.

Parkinsons Dis 2020 13;2020:9716317. Epub 2020 Feb 13.

Department of Neurosciences, Padua University, Padua, Italy.

Background: Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa administration and clinical benefits to patients with advanced Parkinson's disease (PD). This report evaluates long-term safety and efficacy of high-dose LCIG in PD patients.

Methods: Data were collected from several prospective, phase III clinical studies and an observational registry. The phase III program ( = 412) included four multicenter studies: a 12-week, randomized, double-blind study and three open-label studies extending ≥12 months. GLORIA ( = 412) included four multicenter studies: a 12-week, randomized, double-blind study and three open-label studies extending ≥12 months. GLORIA (.

Results: A total of 72 of 412 (17.5%) patients required dosages ≥2000 mg/day LCIG in the phase III program and 47 of 375 (12.5%) patients in GLORIA. Baseline demographics and disease severity were similar between dosage groups with more men in the high-dosage group. Compared with the <2000 mg/day dosage group, patients requiring ≥2000 mg/day LCIG had higher rates of AEs/ADRs including polyneuropathy; improvements in "Off" time and discontinuations due to AEs were similar between dosage groups and lower for discontinuations due to ADRs reported in GLORIA.

Conclusions: Patients who require ≥2000 mg/day LCIG exhibited a safety profile comparable to the established safety/tolerability of LCIG with similar clinical improvements. Higher AEs were noted but within what is accepted for LCIG. Continuous administration of LCIG is beneficial to advanced PD patients who require very high doses of levodopa.
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http://dx.doi.org/10.1155/2020/9716317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040420PMC
February 2020

A post hoc comparison of levodopa-carbidopa intestinal gel daytime monotherapy vs polytherapy safety and efficacy in patients with advanced Parkinson's disease: Results from 6 phase 3/3b open-label studies.

Clin Park Relat Disord 2020 11;2:25-34. Epub 2019 Dec 11.

Department of Neurology, Wake Forest School of Medicine, 475 Vine Street, Winston-Salem, NC 27101, USA.

Introduction: As Parkinson's disease (PD) progresses, the number/frequency of PD medications tend to increase, which is correlated with decreased patient compliance and suboptimal control of PD symptoms. We investigated efficacy and safety of levodopa-carbidopa intestinal gel (LCIG) daytime monotherapy (with or without nighttime oral levodopa-carbidopa) compared with polytherapy (LCIG with ≥1 adjunctive PD therapy) in advanced PD patients.

Methods: This post hoc descriptive study compared LCIG stable daytime monotherapy with LCIG stable polytherapy in all six phase 3/3b open-label studies from both US and international sites; because of study design variability, pooling data for comparison was not appropriate. Efficacy assessments included PD diary data (mean change from baseline in "Off" time and "On" time with or without troublesome dyskinesia), mean Unified PD Rating Scale scores (Parts II and III), and 39-item Parkinson's Disease Questionnaire (PDQ-39) summary index. Adverse events were also assessed.

Results: Overall, LCIG daytime monotherapy and polytherapy demonstrated similar efficacy/safety profiles in advanced PD patients, regardless of treatment duration or population. LCIG monotherapy vs. polytherapy groups experienced similar mean decreases in "Off" time (4.6 vs. 4.1 h/day) and similar increases in "On" time without troublesome dyskinesia (4.6 vs. 4.1 h/day). In most studies, PDQ-39 summary index scores were reduced from baseline by ≥5 points, regardless of patient population or study duration. Adverse events not related to the procedure/device were similar in both groups.

Conclusion: Our data suggest that, for appropriate patients, LCIG monotherapy can provide a more simplified treatment option with similar efficacy and safety.
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http://dx.doi.org/10.1016/j.prdoa.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302193PMC
December 2019

Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders.

Nicotine Tob Res 2019 02;21(3):357-369

Center for Health Sciences, SRI International, Menlo Park, CA.

Emerging studies indicate that striatal cholinergic interneurons play an important role in synaptic plasticity and motor control under normal physiological conditions, while their disruption may lead to movement disorders. Here we discuss the involvement of the cholinergic system in motor dysfunction, with a focus on the role of the nicotinic cholinergic system in Parkinson's disease and drug-induced dyskinesias. Evidence for a role for the striatal nicotinic cholinergic system stems from studies showing that administration of nicotine or nicotinic receptor drugs protects against nigrostriatal degeneration and decreases L-dopa-induced dyskinesias. In addition, nicotinic receptor drugs may ameliorate tardive dyskinesia, Tourette's syndrome and ataxia, although further study is required to understand their full potential in the treatment of these disorders. A role for the striatal muscarinic cholinergic system in movement disorders stems from studies showing that muscarinic receptor drugs acutely improve Parkinson's disease motor symptoms, and may reduce dyskinesias and dystonia. Selective stimulation or lesioning of striatal cholinergic interneurons suggests they are primary players in this regulation, although multiple central nervous systems appear to be involved.

Implications: Accumulating data from preclinical studies and clinical trials suggest that drugs targeting CNS cholinergic systems may be useful for symptomatic treatment of movement disorders. Nicotinic cholinergic drugs, including nicotine and selective nAChR receptor agonists, reduce L-dopa-induced dyskinesias, as well as antipsychotic-induced tardive dyskinesia, and may be useful in Tourette's syndrome and ataxia. Subtype selective muscarinic cholinergic drugs may also provide effective therapies for Parkinson's disease, dyskinesias and dystonia. Continued studies/trials will help address this important issue.
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http://dx.doi.org/10.1093/ntr/nty063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379038PMC
February 2019

Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson's disease.

Mov Disord 2018 Jul 23;33(6):928-936. Epub 2018 Mar 23.

University of Cincinnati Academic Health Center, Cincinnati, Ohio, USA.

Background: Levodopa-carbidopa intestinal gel (designated as carbidopa-levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long-term safety and efficacy outcomes from an open-label phase 3 treatment program.

Methods: PD patients (n = 262) who completed a 12-week double-blind study and its 52-week open-label extension or a separate 54-week open-label study were enrolled in this ongoing phase 3 open-label, multinational study (NCT00660673). Safety and efficacy assessments were collected every 6 months.

Results: Mean total duration of exposure to levodopa-carbidopa intestinal gel was 4.1 years (range, 1.2 to 6.9 years). The overall discontinuation rate was 34% (average annual discontinuation rate, 10%). Although most patients (94%) reported an adverse event, the rate of adverse events decreased over time; 53% experienced a serious adverse event. Of patients in this extension study, 54% required jejunal tube replacement during the study, and 37% required percutaneous endoscopic gastrostomy tube replacement. Most patients were on levodopa monotherapy. Patients maintained reductions in "off" time and increases in mean "on" time without dyskinesia from initial levodopa-carbidopa intestinal gel infusion to he study end point (P < 0.001; n = 81). Activities of daily living and quality-of-life assessments demonstrated significant improvements that persisted through the study.

Conclusions: This long-term study demonstrates sustained and clinically meaningful benefits from levodopa-carbidopa intestinal gel in advanced PD patients. Although adverse event rates decreased over time, vigilance is required for device-related complications and adverse events. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27338DOI Listing
July 2018

Systematic evaluation of levodopa-carbidopa intestinal gel patient-responder characteristics.

NPJ Parkinsons Dis 2018 24;4. Epub 2018 Jan 24.

4AbbVie Inc., North Chicago, IL USA.

Levodopa-carbidopa intestinal gel (LCIG, carbidopa-levodopa enteral suspension in the United States) is a treatment option for advanced Parkinson's disease (PD) patients with motor fluctuations. The objective of this investigation was to identify the baseline characteristics predictive of treatment response, measured by improvement in motor symptom severity, in advanced PD patients treated with LCIG during a 54-week, open-label phase 3 study. Patients with ≥1 h improvement from baseline in "Off" time were categorized as "Responders"; whereas those with <1 h improvement, any worsening, or no post-baseline assessment were "Non-Responders". A subgroup of Responders with ≥3 h improvement in "Off" time was also examined; this subgroup was identified as "Robust Responders". Baseline demographics and disease characteristics were analyzed and their predictive relationship to change from baseline in normalized "Off" time was assessed. Out of the 324 patients included in the analysis, 272 (84.0%) were categorized as Responders and 52 (16.0%) were Non-Responders. A majority of patients (65.7%) had ≥3 h improvement in "Off" time. In general, baseline characteristics were similar between Non-responders, Responders, and the subgroup of Robust Responders. A conditional tree-structured regression analysis identified baseline "Off" time as the only factor that had significant effect on Responder and Robust Responder status. The safety profile of LCIG was similar between patient groups. Overall, this analysis showed that 84% of LCIG-treated advanced PD patients had ≥1 h improvement in "Off" time and the number-needed-to-treat to observe one patient responder was 1.19 patients. Notably, Responders and Robust Responders to LCIG were observed across the range of baseline demographics and clinical characteristics examined.
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http://dx.doi.org/10.1038/s41531-017-0040-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784118PMC
January 2018

Association of metabolic syndrome and change in Unified Parkinson's Disease Rating Scale scores.

Neurology 2017 Oct 29;89(17):1789-1794. Epub 2017 Sep 29.

From the Department of Neurology (M.L.) and Department of Clinical Pharmacy (J.L.B.), Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Neurology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora; Department of Biostatistics (S.L., Y.Z.), University of Texas Health Science Center at Houston; Center for Human Experimental Therapeutics (S.S.), University of Rochester, NY; Department of Neurology (A.-M.A.W.), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Pharmacy (P.S.W.), Singapore General Hospital; Department of Neurology (D.K.S.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Department of Pathology, Anatomy, & Cell Biology (J.S.), Thomas Jefferson University, Philadelphia, PA; Department of Biostatistics (Y.Z.), School of Public Health, University of Texas Health Science Center, Houston; Department of Biostatistics (A.P.), School of Public Health, University of Texas Health Science Center at Houston-UTHealth, Austin; Department of Neurology (R.D.), University of Arkansas for Medical Sciences, Little Rock; Department of Neurology (C.W.C.), University of California San Francisco; Department of Neurology (C.S.), Leonard M. Miller School of Medicine, University of Miami, FL; Department of Neurology (F.C.), University of Pittsburgh, PA; and Department of Neurological Sciences (J.T.B.), Larner College of Medicine, University of Vermont, Burlington. Dr. Luo is currently with the Department of Biostatistics and Bioinformatics, Duke University, Durham, NC.

Objective: To explore the association between metabolic syndrome and the Unified Parkinson's Disease Rating Scale (UPDRS) scores and, secondarily, the Symbol Digit Modalities Test (SDMT).

Methods: This is a secondary analysis of data from 1,022 of 1,741 participants of the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1, a randomized, placebo-controlled trial of creatine. Participants were categorized as having or not having metabolic syndrome on the basis of modified criteria from the National Cholesterol Education Program Adult Treatment Panel III. Those who had the same metabolic syndrome status at consecutive annual visits were included. The change in UPDRS and SDMT scores from randomization to 3 years was compared in participants with and without metabolic syndrome.

Results: Participants with metabolic syndrome (n = 396) compared to those without (n = 626) were older (mean [SD] 63.9 [8.1] vs 59.9 [9.4] years; < 0.0001), were more likely to be male (75.3% vs 57.0%; < 0.0001), and had a higher mean uric acid level (men 5.7 [1.3] vs 5.3 [1.1] mg/dL, women 4.9 [1.3] vs 3.9 [0.9] mg/dL, < 0.0001). Participants with metabolic syndrome experienced an additional 0.6- (0.2) unit annual increase in total UPDRS ( = 0.02) and 0.5- (0.2) unit increase in motor UPDRS ( = 0.01) scores compared with participants without metabolic syndrome. There was no difference in the change in SDMT scores.

Conclusions: Persons with Parkinson disease meeting modified criteria for metabolic syndrome experienced a greater increase in total UPDRS scores over time, mainly as a result of increases in motor scores, compared to those who did not. Further studies are needed to confirm this finding.

Clinicaltrialsgov Identifier: NCT00449865.
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http://dx.doi.org/10.1212/WNL.0000000000004572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664310PMC
October 2017

Factors associated with falling in early, treated Parkinson's disease: The NET-PD LS1 cohort.

J Neurol Sci 2017 Jun 11;377:137-143. Epub 2017 Apr 11.

Struthers Parkinson's Center, Golden Valley, MN, United States.

Background: Recognizing the factors associated with falling in Parkinson's disease (PD) would improve identification of at-risk individuals.

Objective: To examine frequency of falling and baseline characteristics associated with falling in PD using the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1) dataset.

Methods: The LS-1 database included 1741 early treated PD subjects (median 4year follow-up). Baseline characteristics were tested for a univariate association with post-baseline falling during the trial. Significant variables were included in a multivariable logistic regression model. A separate analysis using a negative binomial model investigated baseline factors on fall rate.

Results: 728 subjects (42%) fell during the trial, including at baseline. A baseline history of falls was the factor most associated with post-baseline falling. Men had lower odds of post-baseline falling compared to women, but for men, the probability of a post-baseline fall increased with age such that after age 70, men and women had similar odds of falling. Other baseline factors associated with a post-baseline fall and increased fall rate included the Unified PD Rating Scale (UPDRS) Activities of Daily Living (ADL) score, total functional capacity (TFC), baseline ambulatory capacity score and dopamine agonist monotherapy.

Conclusion: Falls are common in early treated PD. The biggest risk factor for falls in PD remains a history of falling. Measures of functional ability (UPDRS ADL, TFC) and ambulatory capacity are novel clinical risk factors needing further study. A significant age by sex interaction may help to explain why age has been an inconsistent risk factor for falls in PD.
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http://dx.doi.org/10.1016/j.jns.2017.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518305PMC
June 2017

Longer Duration of MAO-B Inhibitor Exposure is Associated with Less Clinical Decline in Parkinson's Disease: An Analysis of NET-PD LS1.

J Parkinsons Dis 2017 ;7(1):117-127

Department of Biostatistics, The University of Texas Health Science Center at Houston (UTHealth) School of Public Health, Houston, TX, USA.

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 < 0.001), Ambulatory Capacity (p < 0.001), and the Rankin (p = 0.002).

Conclusions: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered.
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http://dx.doi.org/10.3233/JPD-160965DOI Listing
November 2017

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

JAMA 2016 Jul;316(1):40-50

Boston University Medical Campus, Boston, Massachusetts.

Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.

Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.

Design, Setting, And Participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.

Interventions: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.

Main Outcomes And Measures: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.

Results: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.

Conclusions And Relevance: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.

Trial Registration: clinicaltrials.gov Identifier: NCT01795859.
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http://dx.doi.org/10.1001/jama.2016.8655DOI Listing
July 2016

Choice of dopaminergic therapy among early, mild Parkinson disease subjects in North America.

J Neurol Sci 2016 Jul 16;366:74-81. Epub 2016 Apr 16.

Department of Neurology, Georgia Regent's University, 1120 15th St, Augusta, GA 30912, USA. Electronic address:

The choice of dopaminergic therapy in early Parkinson disease (PD) is an important clinical decision, yet factors influencing this decision have not been extensively studied. We sought to investigate the factors that may be associated with the choice of dopaminergic therapy at the NINDS Exploratory Trials in PD (NET-PD) Long-Term Study-1 (LS1). NET-PD LS1 was a clinical trial of creatine versus placebo in participants with early, mild PD on stable doses of dopaminergic therapy. Baseline data from 1616 out of the 1741 participants were evaluated using univariable and multivariable logistic or generalized logit regression analyses for available factors associated with the choice of dopaminergic therapy. The dopaminergic therapy choice was determined as: (i) therapy that subjects recalled taking 180days before the study; (ii) therapy at baseline; and (iii) the longest duration of therapy reported by participants. Younger age, higher education level, longer length of time since PD diagnosis and use of an adjunctive, non-dopaminergic or monoamine oxidase inhibitor medication were associated with more frequent use of dopamine agonist compared to levodopa or combination therapy.
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http://dx.doi.org/10.1016/j.jns.2016.04.021DOI Listing
July 2016

Effect of levodopa-carbidopa intestinal gel on dyskinesia in advanced Parkinson's disease patients.

Mov Disord 2016 Apr 28;31(4):530-7. Epub 2016 Jan 28.

AbbVie, Inc., North Chicago, Illinois, USA.

Objective: The purpose of this study was to assess the effect of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) in advanced Parkinson's disease patients with troublesome dyskinesia.

Methods: Post hoc analyses of patient data from a 12-week, randomized, double-blind study and a 54-week open-label study were performed. Efficacy was assessed in the subgroup of patients defined by ≥1 hour of "on" time with troublesome dyskinesia at baseline as recorded in Parkinson's disease symptom diaries (double blind: n = 11 levodopa-carbidopa intestinal gel, n = 12 oral levodopa-carbidopa; open label: n = 144 levodopa-carbidopa intestinal gel). The changes in "off" time, "on" time with and without troublesome dyskinesia, and the overall safety and tolerability of levodopa-carbidopa intestinal gel were analyzed.

Results: Although not significantly different from oral levodopa treatment (P > .05) in the double-blind study, levodopa-carbidopa intestinal gel treatment resulted in a reduction from baseline in "on" time with troublesome dyskinesia (mean [standard deviation] hours: baseline = 3.1 [1.7], change from baseline to final = -1.8 [1.8], P = .014), increase in "on" time without troublesome dyskinesia (baseline = 7.4 [2.2], change = 4.4 [3.6], P = .004), and decrease in "off" time (baseline = 5.5 [1.3], change = -2.7 [2.8], P = .015). Similar trends were found in the open-label study. An increase in levodopa-carbidopa intestinal gel dose was not significantly correlated with increased "on" time with troublesome dyskinesia in either study (double blind: r = -.073, P = .842; open label: r = -0.001, P = .992). Adverse events were usually mild to moderate in severity and related to the gastrointestinal procedure.

Conclusion: Our exploratory analyses suggest that optimizing levodopa delivery with levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease.
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http://dx.doi.org/10.1002/mds.26528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066747PMC
April 2016

Parkinsonism in Patients With Chronic Hepatitis C Treated With Interferons: Case Reports and Review of the Literature.

Clin Neuropharmacol 2016 Jan-Feb;39(1):1-5

*Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA; and †Department of Medicine, University of Vermont College of Medicine; and ‡Department of Neurological Sciences, Binter Center for Parkinson's Disease and Movement Disorders, University of Vermont Medical Center, Burlington, VT.

Interferons are a set of cytokines that activate antiviral responses by the body's immune cells and have been a mainstay of treatment of hepatitis C. Well-known neuropsychiatric effects of interferons include depression, irritability, and impaired concentration. A condition reported rarely in association with this treatment is parkinsonism. We report 2 patients who developed parkinsonism in conjunction with treatment of hepatitis C with alpha interferons. The first is a 51-year-old man who developed intermittent rest and postural tremor during treatment with pegylated interferon alpha ribavirin, and amantadine, with resolution of the symptoms after completing a 36-week course. Similar tremor recurred 3 years later with progressive parkinsonism, compatible with Parkinson disease (PD). The second patient is a 71-year-old man who developed postural tremor 8 weeks into a regimen of consensus interferon. Tremor resolved at completion of 48 weeks of interferon. Pegylated interferon alpha and ribavirin were started 2 years later because of lack of sustained virologic response. At 24 weeks of treatment, postural tremor returned along with features and a progressive course compatible with PD. Thus, both patients presented here developed (rest and/or postural) tremor during interferon therapy followed by delayed onset of parkinsonism. We identified 10 other cases in the literature of parkinsonism/PD associated with interferon administration. This report reviews the clinical presentation and potential pathophysiological mechanisms and recommends that physicians who prescribe interferon be vigilant for symptoms of PD in their patients.
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http://dx.doi.org/10.1097/WNF.0000000000000120DOI Listing
October 2016

Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials.

Mov Disord 2016 Apr 23;31(4):538-46. Epub 2015 Dec 23.

AbbVie Inc, North Chicago, Illinois, USA.

Background: Continuous administration of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) through a percutaneous endoscopic gastrojejunostomy is a treatment option for advanced Parkinson disease (PD) patients with motor fluctuations resistant to standard oral medications. Safety data from 4 prospective studies were integrated to assess the safety of this therapy.

Methods: Safety data from 4 studies were summarized using 2 overlapping data sets, permitting the separation of procedure/device-associated (n = 395) from non-procedure/device adverse events (n = 412).

Results: At the data cutoff, median exposure to levodopa-carbidopa intestinal gel was 911 days (range, 1-1980 days) with 963 total patient-years of exposure. Procedure/device adverse events occurred in 300 patients (76%), and serious adverse events occurred in 68 (17%); most frequently reported procedure/device adverse events and serious adverse events were complications of device insertion (41% and 8%, respectively) and abdominal pain (36% and 4%, respectively). Non-procedure/device adverse events occurred in 92% (379), with most frequently reported being insomnia (23%) and falls (23%); 42% (171) had non-procedure/device serious adverse events, with most frequently reported being pneumonia (5%) and PD symptoms (2%). Adverse events led to discontinuation in 17% (72), most frequently because of complication of device insertion (2.4%). There were 34 treatment-emergent deaths (8.3%) in the overlapping data sets, 2 of which (0.5%) were considered "possibly related" to the treatment system.

Conclusion: In the largest collection of levodopa-carbidopa intestinal gel safety data from prospective clinical studies, procedure/device events were frequently reported and occasionally life threatening. Most non-procedure/device events were typical for levodopa treatment and an elderly population. These factors combined with high treatment efficacy led to a relatively low discontinuation rate in advanced PD patients.
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http://dx.doi.org/10.1002/mds.26485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064722PMC
April 2016

Domains and correlates of clinical balance impairment associated with Huntington's disease.

Gait Posture 2015 Mar 9;41(3):867-70. Epub 2015 Mar 9.

Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.

This study sought to (a) determine the domains of clinical balance impairments associated with Huntington's disease (HD), and (b) evaluate associations between balance test scores and other disease-related impairments. Eighteen subjects with genetically definite HD and 17 age-matched control subjects were evaluated on the Mini-BESTest for their clinical balance impairments as well as the Unified HD Rating Scale (UHDRS) motor and total functional capacity scales, Activity-Specific Balance Confidence (ABC) Scale-short form, Montreal Cognitive Assessment (MoCA), and Symbol Digit Modalities Test (SDMT). Results showed that subjects with HD exhibited significantly lower total Mini-BESTest scores than subjects without HD (mean (95% CI)=76 (64-87)% with HD, 98 (96-99)% without HD; p=0.0011). Mini-BESTest item scores were significantly lower for subjects with HD on one-leg stance, postural responses, standing with eyes closed on foam, and dual-task timed up-and-go. Mini-BESTest scores significantly correlated with UHDRS motor (r(2)=0.68; p=0.00003) and total functional capacity (r(2)=0.75; p=0.000006) scores as well as with scores on the ABC short form (r(2)=0.45; p=0.0024), SDMT (r(2)=0.42; p=0.0036), and MoCA (r(2)=0.23; p=0.046) assessments. This study, therefore, demonstrates that balance impairments associated with HD span domains of anticipatory postural adjustments, postural responses, stance in challenging sensory conditions, and gait. Although preliminary, clinical balance impairment appears to be an efficient proxy evaluation of multiple HD-related factors due to associations with functional capacity, other motor impairments, balance confidence, and cognitive abilities.
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http://dx.doi.org/10.1016/j.gaitpost.2015.02.018DOI Listing
March 2015

Parkinson's disease severity and use of dopaminergic medications.

Parkinsonism Relat Disord 2015 Mar 15;21(3):297-9. Epub 2014 Dec 15.

Department of Neurology, Michigan State University, 804 Service Rd, Room A217, USA.

Background: The effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected.

Objective: The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD.

Methods: A non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life.

Results: The outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cog-meds and amantadine.

Conclusion: This observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy.
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http://dx.doi.org/10.1016/j.parkreldis.2014.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340731PMC
March 2015

Validation of an ambulatory capacity measure in Parkinson disease: a construct derived from the Unified Parkinson's Disease Rating Scale.

J Parkinsons Dis 2015 ;5(1):67-73

Struthers Parkinson's Center, Golden Valley, MN, USA.

Background: A construct calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) has been used as an "Ambulatory Capacity Measure" (ACM) in Parkinson disease (PD). Its construct validity has never been examined. A similar construct, consisting of the mean value of the same UPDRS items has been used under the acronym PIGD as a measure of postural instability and gait disorder in PD.

Objective: To examine the construct validity of the ACM and PIGD in PD.

Methods: We analyzed data in an existing database of 340 PD patients, Hoehn and Yahr stages (HYS) 1-5 who participated in a study of falls. Number of falls (NOF) was recorded over 4 weeks, and UPDRS (mental, ADL, and motor subscales), HYS, Activities Based Confidence Scale (ABC), Freezing of Gait Questionnaire (FOG), Five Times Sit-to-Stand (FTSS), Timed Up-and Go (TUG), Gait Velocity (GV), and Berg Balance Scale (BBS) evaluations were performed. Internal consistency was assessed by Cronbach's alpha. Construct validity was assessed through correlations of the ACM and PIGD to these measures and to their summed-ranks. A coefficient of determination was calculated through linear regression.

Results: Mean age was 71.4, mean age at diagnosis 61.4 years; 46% were women; mean UPDRS subscale scores were: Mental 3.7; ADL 15.7; motor: 27.1; mean ACM was 6.51, and mean PIGD 1.30. Cronbach's alpha was 0.78 for both ACM and PIGD. Spearman correlation coefficients between the ACM/PIGD and ABC, FOG, TUG, GV and BBS were 0.69, 0.72, 0.67, 0.58, and 0.70 respectively. Correlation between the ACM/PIGD and summed-ranks of HYS, NOF, ABC, FOG, FTSS, TUG, GV and BBS was high (Spearman r = 0.823, p < 0.0001); 68% of the variability in the summed-ranks was explained by ACM/PIGD.

Conclusion: The ACM and the PIGD are valid global measures and accurately reflect the combined effects of the various components of ambulatory capacity in PD patients with HY stages 1-4.
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http://dx.doi.org/10.3233/JPD-140405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478048PMC
November 2015

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

JAMA Neurol 2014 May;71(5):543-52

Columbia University Medical Center, Neurological Institute, New York, New York.

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.
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http://dx.doi.org/10.1001/jamaneurol.2014.131DOI Listing
May 2014

A novel presentation of an ocular geste antagoniste in cervical dystonia: a case report.

Tremor Other Hyperkinet Mov (N Y) 2013 14;3. Epub 2013 Nov 14.

Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.

Background: A geste antagoniste or sensory trick is a well described phenomenon associated with primary cervical dystonia. Craniocervical tactile stimulation or stereotyped limb movements allow patients to transiently ameliorate dystonic activation of cervical musculature.

Case Report: We report a patient with primary cervical dystonia who presented with a novel "ocular" geste antagoniste. Through a sensory trick of tonic left eye deviation, the patient transiently reduces cervical dystonic activity (improved range of motion and reduced dystonic tremor). Multi-channel surface electromyography and video are used to illustrate these findings.

Discussion: This case presents a unique clinical observation of specific voluntary eye movements attenuating cervical dystonia. The phenomenon is phenotypically consistent with previously described limb sensorimotor tricks.
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http://dx.doi.org/10.7916/D8416VSJDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849767PMC
January 2014

Parkinson's disease.

Subcell Biochem 2012 ;65:389-455

Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, NW NRB WP-24A, 20057, Washington, DC, USA,

Parkinson's disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800's by James Parkinson as the 'Shaking Palsy'. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, α-synuclein. The presence of toxic aggregated forms of α-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of α-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded α-synuclein.
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http://dx.doi.org/10.1007/978-94-007-5416-4_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372387PMC
February 2014
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