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Aim: Due to active engagement of sensory and afferent nerve fibers in reflex tearing which could be affected in Parkinson's disease (PD), we tested reflex tears as a source of potential PD biomarkers. Patients & methods: Reflex tears collected from 84 PD and 84 age- and sex-equivalent healthy controls (HC) were used to measure levels of oligomeric α-Syn (α-SynOligo), total α-Syn (α-SynTotal), CCL2, DJ-1, lactoferrin and MMP9. Results: α-synOligo (p < 0.0001), CCL2 (p = 0.003) and lactoferrin (p = 0.002) were significantly elevated in PD patient tears relative to HC tears. Tear flow was significantly lower in PD relative to HC (p = 0.001). Conclusion: Reflex tears are a potential source for detection of characteristic changes in PD patients.

Aim: Secretion of proteins into basal tears of Parkinson’s disease (PD) patients may be altered by changes in nerve function. Materials & methods: Oligomeric α-SynOligo and total α-SynTotal, CCL-2, DJ-1, LF and MMP-9 were measured in basal tears from 93 PD patients and 82 age- and sex-equivalent healthy controls. Results: α-SynTotal was decreased (p = 0.0043), whereas α-SynOligo (p Oligo/α-SynTotal (p Oligo and α-SynOligo/α-SynTotal contents were 0.70 (95% confidence limits: 0.621–0.774) and 0.72 (95% confidence limits: 0.642–0.792). Conclusion: PD patient basal tears may contain biomarkers that can be assayed noninvasively and inexpensively.

Highlights This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients. Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use. Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey. Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TETRAS) and 68% (BF-ADL) of ‘severe’ or ‘moderate’ patients improving to ‘mild’ or ‘slight’. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported. Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients.

RimabotulinumtoxinB (RIMA) may be preferable as an anti-sialorrhea treatment compared with current oral anticholinergic drugs in people with neurological disorders.To assess the safety, efficacy, and tolerability of RIMA injections for the treatment of sialorrhea in adults.This randomized, parallel, double-blind, placebo-controlled clinical trial of RIMA 2500 U and 3500 U was conducted from November 14, 2013, to January 23, 2017. A total of 249 adult patients with troublesome sialorrhea secondary to any disorder or cause were screened. Of them, 13 refused further participation in the study or were lost to follow-up and 49 did not fulfill the criteria for participation; 187 were ultimately enrolled. Patients had to have a minimum unstimulated salivary flow rate (USFR) of 0.2 g/min and a minimum Drooling Frequency and Severity Scale score of 4.Patients were randomized 1:1:1 to RIMA, 2500 U (n = 63); RIMA, 3500 U (n = 64); or placebo (n = 60).Primary outcomes were the change in USFR from baseline to week 4 and the Clinical Global Impression of Change (CGI-C) at week 4. The CGI-C scores were recorded on a 7-point scale ranging from very much improved to very much worse. Adverse events were recorded throughout the trial period.Of 187 patients enrolled (147 men [78.6%]; mean [SD] age, 63.9 [13.3] years), 122 patients had Parkinson disease (65.2%), 13 (7.0%) were stroke survivors, 12 had amyotrophic lateral sclerosis (6.4%), 6 had medication-induced sialorrhea (3.2%), 4 had adult cerebral palsy (2.1%), and 30 had sialorrhea owing to other causes (16.0%). A total of 176 completed the study. Treatment with both doses of RIMA significantly reduced USFR at week 4 vs placebo (mean treatment difference, -0.30 g/min [95% CI, -0.39 to -0.21] for both doses vs placebo, P .001). The CGI-C scores were statistically significantly improved at week 4 for both treatment groups vs placebo (-1.21 [95% CI, -1.56 to -0.87] for 2500 U, -1.14 [95% CI, -1.49 to -0.80] for 3500 U, both P .001). Treatment benefits were seen as early as 1 week after injection and were maintained over the treatment cycle of approximately 13 weeks. The RIMA injections were well tolerated compared with placebo. The most common adverse events were self-limited mild to moderate dry mouth, dysphagia, and dental caries.Treatment with RIMA (2500 U and 3500 U) in adults was well tolerated and reduced sialorrhea, with the onset of the effect at 1 week after the injection. These data support the clinical use of RIMA in the management of sialorrhea in adults.ClinicalTrials.gov Identifier: NCT01994109.

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. © 2015 International Parkinson and Movement Disorder Society

Summary Background Patients with Parkinson's disease chronically treated with levodopa commonly have delayed or unpredictable onset of its benefits after oral intake. In this study, we assessed the safety and efficacy of CVT-301, a self-administered levodopa oral inhalation powder, for the treatment of patients with Parkinson's disease during off periods. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial, patients were recruited at 65 sites in Canada, Poland, Spain, and the USA. Eligible participants were patients with Parkinson's disease aged 30–85 years, who had daily off periods of 2 h or longer and showed an improvement of 25% or greater in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score from off to on state after use of an oral levodopa plus a dopa-decarboxylase inhibitor combination. Patients were assigned (1:1:1) with a computer-generated randomisation code, in fixed blocks of six, to either CVT-301 60 mg, CVT-301 84 mg, or placebo. Spirometry results and modified Hoehn and Yahr disease stage at screening were used for stratification of treatment groups. Patients, the sponsor, and site personnel were masked to treatment assignment. Each study dose consisted of two capsules administered with an inhaler. Patients were instructed to use the study drug as needed for off periods, and could self-administer up to five doses per day. The primary endpoint was the change in UPDRS motor score from predose to 30 min postdose, assessed at week 12 during an in-clinic off period, in the CVT-301 84 mg group compared with the placebo group. Analysis was by intention to treat. Safety was assessed in all patients who received at least one dose of experimental treatment. This trial is registered with ClinicalTrials.gov, number NCT02240030. Findings Between Dec 4, 2014, and Aug 26, 2016, 351 patients were enrolled and randomly assigned to receive CVT-301 60 mg (115 patients), CVT-301 84 mg (120 patients), or placebo (116 patients). Of these, 339 received the assigned study treatment (CVT-301 60 mg, n=113; CVT-301 84 mg, n=114; placebo, n=112) and 290 completed the study (CVT-301 60 mg, n=96; CVT-301 84 mg, n=97; placebo, n=97). The least-squares mean difference in UPDRS motor score change from predose to 30 min postdose was −5·91 (SE 1·50, 95% CI −8·86 to −2·96) for the placebo group and −9·83 (1·51; −12·79 to −6·87) for the CVT-301 84 mg group (between-group difference −3·92 [–6·84 to −1·00]; p=0·0088). Treatments were safe and well tolerated. Severe adverse events were reported by 2 (2%) of 112 patients in the placebo group, 7 (6%) of 113 in the CVT-301 60 mg group, and 5 (4%) of 114 in the CVT-301 84 mg group, with no severe adverse event occurring in more than one patient in any treatment group. 11 (3%) of 339 patients had 19 serious adverse events (three [3%] of 112 patients in placebo, six [5%] of 113 in CVT-301 60 mg, and two [2%] of 114 in CVT-301 84 mg). Of these, hypotension and atrial fibrillation were assessed by investigators to be possibly related to the study drug. Interpretation CVT-301 can improve UPDRS motor scores of patients with Parkinson's disease during in-clinic off periods, with few severe or serious adverse events. The long-term safety and efficacy of CVT-301 need to be investigated in future studies. Funding Acorda Therapeutics.

Purpose/aim: AbobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA) is an acetylcholine release inhibitor and a neuromuscular blocking agent. The United States prescribing information for abobotulinumtoxinA previously indicated only one dilution for cervical dystonia: 500 U/1 mL. Clinical trial data supporting a larger volume with a 500 U/2 mL dilution would offer clinicians flexibility with injection volume to better meet patient needs.We conducted a 12-week, phase 3b, multicenter, randomized, double-blind, placebo-controlled trial (NCT01753310). Adult subjects with a primary diagnosis of cervical dystonia were randomized (2:1) to receive a single injection of either abobotulinumtoxinA, 500 U/2 mL dilution, or placebo. The primary efficacy endpoint was changed from baseline in Toronto Western Spasmodic Torticollis Rating Scale total score at Week 4.A total of 134 subjects (abobotulinumtoxinA, n = 89; placebo, n = 45) were randomized (intent-to-treat population) and 129 (abobotulinumtoxinA, n = 84; placebo, n = 45) completed the Week 4 primary endpoint evaluation (modified intent-to-treat population). In the modified intent-to-treat population, subjects receiving abobotulinumtoxinA experienced significantly greater changes from baseline versus placebo on the primary endpoint (weighted overall treatment difference -8.3, P0.001). The most common treatment-emergent adverse events (TEAEs) were dysphagia, muscle weakness, neck pain and headache. Overall, TEAEs were consistent with those reported in the abobotulinumtoxinA prescribing information (1 mL dilution) for cervical dystonia patients.This trial provides evidence that a 500 U/2 mL dilution is an effective treatment for cervical dystonia and exhibits a safety profile consistent with the known safety profile of abobotulinumtoxinA.

Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov , number NCT01280123 . Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. Funding National Institute of Neurological Disorders and Stroke.

Background Levodopa-carbidopa intestinal gel (LCIG) provides continuous infusion and reduces “off” time in advanced Parkinson's disease (PD) patients with motor fluctuations despite optimized pharmacotherapy. Methods Clinical experience with 2 LCIG dosing paradigms from phase 3 studies was examined. In an open-label, 54-week study, LCIG was initiated as daytime monotherapy via nasojejunal (NJ) tube then switched to percutaneous endoscopic gastrojejunostomy (PEG-J) tube; adjunctive therapy was permitted 28 days postPEG-J. In a 12-week, double-blind, placebo-controlled, double-dummy trial, patients continued stable doses of existing anti-PD medications, but LCIG replaced daytime oral levodopa-carbidopa and was initiated directly via PEG-J. Results In the open-label study, 92% of 354 patients received monotherapy at post–PEG-J week 4; mean titration duration was 7.6 days; dosing remained stable post-titration (mean total daily dose [TDD] was 1572 mg at last visit). In the double-blind trial, 84% received polypharmacy; mean titration took 7.1 days for the LCIG arm (TDD post-titration: 1181 mg; n = 37). At post–PEG-J week 4, mean “off” time with LCIG was reduced by 3.9 h (open-label/monotherapy study) and 3.7 h (double-blind/polypharmacy trial). NJ treatment (open-label study only) required an additional procedure with related adverse events (AEs) and withdrawals. The most common AEs during PEG-J weeks 1–4 in the open-label/monotherapy and double-blind/polypharmacy trials, respectively, were complication of device insertion (35%, 57%) and abdominal pain (26%, 51%). Discontinuations due to nonprocedure/nondevice AEs were low (2.2%, 2.7%). Conclusion These results support the option of initiating LCIG with or without NJ and as either monotherapy or polypharmacy.

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces l-dopa-plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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.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.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 (P0.001; n = 81). Activities of daily living and quality-of-life assessments demonstrated significant improvements that persisted through the study.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.

Background The ANCHOR-CD prospective observational registry study evaluated the effectiveness of abobotulinumtoxinA in adult idiopathic cervical dystonia (CD) in clinical practice. Methods Adults with CD were eligible. Treating physicians determined abobotulinumtoxinA dose and treatment interval. The primary endpoint was patient response rate (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] score reduction ≥ 25% and Patient Global Impression of Change [PGIC] score of + 2 or + 3 at Week 4 of Cycle 1). Results 350 patients enrolled (75% women; mean age 59 ± 13.6 years; 27.4% botulinum neurotoxin-naive) and 347 received at least 1 treatment. The median abobotulinumtoxinA dose for Cycle 1 was 500 Units. At Week 4, the responder rate was 30.6% (n = 304) and the TWSTRS total score decreased 27.4% from baseline. PGIC of at least “Much improved” was documented in 43.6% of patients and maintained in Cycles 2 through 4 (43.3%, 48.9%, and 52.8%, respectively). A total of 39 adverse events (31 study drug-related) were reported in 17 patients (5%); the most common were dysphagia (n = 6), muscle weakness (n = 4), and neck pain (n = 3). Conclusion This study confirmed the beneficial effect of abobotulinumtoxinA on CD in routine clinical practice as measured by improvements in TWSTRS and PGIC. No new safety concerns were identified.

Summary Background Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A 2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa. Methods We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594. Findings Of 420 randomised patients (mean age 63·3 [SD 8·3] years; mean duration of Parkinson's disease 8·7 [4·7] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (−1·1 h, 95% CI −1·8 to −0·5; p=0·0006), the tozadenant 120 mg twice-daily group (−1·1 h, −1·8 to −0·4; p=0.0039), and the tozadenant 180 mg twice-daily group (−1·2 h, −1·9 to −0·4; p=0·0039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients). Interpretation Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted. Funding Biotie Therapies.

Rasagiline and pramipexole act to improve striatal dopaminergic transmission in PD via distinct and potentially synergistic mechanisms. We performed a placebo-controlled study to determine whether 2 doses of a novel slow-release, low-dose combination of rasagiline and pramipexole (P2B001) are effective and have a good safety profile in patients with early untreated PD.Previously untreated patients with early PD were randomized (1:1:1) to once-daily treatment with P2B001 (0.3 mg pramipexole/0.75 mg rasagiline), P2B001 (0.6 mg pramipexole/0.75 mg rasagiline) or placebo in a 12-week multicenter double-blind, placebo-controlled trial. The primary endpoint was the change from baseline to final visit in Total-UPDRS score versus placebo. Secondary measures included responder analyses of patients achieving ≥4 UPDRS point reduction, and changes in Parkinson Disease Quality of Life Scale-39 and UPDRS activities of daily living and motor scores.A total of 149 participants were randomized and 136 (91.3%) completed the study. Adjusted mean change from baseline to final visit versus placebo in Total-UPDRS score was -4.67 ± 1.28 points for the P2B001 0.6/0.75 mg group (P = .0004) and -3.84 ± 1.25 points for the 0.3/0.75 mg group (P = .003). Significant benefits were also observed for both doses in the responder analysis (P = .0002 and P = .0001), Parkinson Disease Quality of Life Scale-39 scores (P = .05 and P = .01), and the UPDRS motor (P = .02 and P = .006) and activities of daily living (P = .005 and P = .0004) subscores. Adverse events of P2B001 were comparable to placebo apart from transient nausea and somnolence, which were more common with P2B001 treatment.P2B001 offers a promising treatment option for patients with early PD with good clinical efficacy and a low risk of adverse events. © 2017 International Parkinson and Movement Disorder Society.

Assess motor function and quality of life (QoL) in Parkinson's disease (PD) subjects with end-of-dose wearing off (EODWO), comparing immediate and delayed switch (IS, DEL) to levodopa/carbidopa/entacapone (LCE).LCE treatment improves motor function in PD patients with EODWO. Correlations with QoL have not been previously assessed.A 16-week, prospective, randomized, multicenter, open-label study in PD subjects on stable levodopa/carbidopa (LC) doses with EODWO. The IS subjects switched to LCE at baseline; DEL subjects at week 4. The primary efficacy variable was UPDRS III score (baseline to week 4). QoL measurements (PDQUALIF, PDQ-39) were assessed at baseline, weeks 4, 8, and study endpoint.The intent-to-treat population comprised 350/359 patients (IS, n = 177; DEL, n = 173). A significant decrease in UPDRS III scores at week 4 was observed (IS, 3.7U, p.0001; DEL, 1.8U, p = .0018). Group differences favored IS (1.9U, p = .0148). At week 8, IS subjects had significant total score decreases in PDQUALIF (2.5U, p = .0133) and PDQ-39 (5.8U, p = .0001). In the mobility and activities of daily living PDQ-39 subdomains, IS subjects had significantly larger week 4 decreases (versus DEL p = .0331 and p = .0125, respectively). Adverse events included diarrhea (14.5%), nausea (12.3%), and dizziness (8.4%).The IS provided greater motor improvement at week 4 and improved QoL at week 8.

Patients receiving levodopa for Parkinson's disease experience motor fluctuations and immobility ('off' episodes) between doses. This study assessed adjunctive Zelapar (selegiline orally disintegrating tablet (ODT)) for managing off episodes and for long-term safety.This open-label extension evaluated long-term safety, efficacy, and tolerability of adjunctive selegiline ODT 2.5 mg in patients who completed either of two large phase 3 double-blind studies. The study was to end after 12 months but was amended to be open-ended. Investigators could increase levodopa doses and introduce controlled-release formulations of levodopa or dopamine agonists if warranted. Additionally, results of a small randomized trial of open-label selegiline ODT 1.25 mg in comparison to conventional selegiline was added only to the safety analysis. Efficacy variables included changes in daily off time and Patient's Global Impression of Improvement (PGI-I) and Clinical Global Impressions Severity of Disease (CGI-S) ratings. Safety assessments included adverse events and oropharyngeal findings.This study enrolled 254 patients: 248 from the large phase 3 studies (efficacy analysis) and an additional six from the prior open-label comparison (safety analysis) in order to evaluate a larger population for safety purposes. Mean reduction from baseline in daily off time was 9.4% (1.6 h) for patients previously given selegiline ODT, 6.0% (1.2 h) for those switched from placebo, and 8.1% (1.4 h) overall. PGI-I and CGI-S ratings indicated little or no change from baseline. Treatment-related adverse events occurred in 132 (52%) patients. No severe oral irritations were attributed to selegiline ODT or prompted discontinuation.Long-term selegiline ODT 2.5 mg/day was effective, safe, and well tolerated in patients with Parkinson's disease experiencing off episodes during levodopa therapy.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Background: Polymorphisms in the glutathione S-transferase pi gene ( GSTP1 ), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the Gene PD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. Methods: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. Results: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. Conclusions: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Botulinum toxin type A (Dysport) has been shown in European studies to be a safe and effective treatment for cervical dystonia. This multicenter, double-blind, randomized, controlled trial assessed the safety and efficacy of Dysport in cervical dystonia patients in the United States. Eighty patients were randomly assigned to receive one treatment with Dysport (500 units) or placebo. Participants were followed up for 4 to 20 weeks, until they needed further treatment. They were assessed at baseline and weeks 2, 4, 8, 12, 16, and 20 after treatment. Dysport was significantly more efficacious than placebo at weeks 4, 8, and 12 as assessed by the Toronto Western Spasmodic Torticollis Rating Scale (10-point vs. 3.8-point reduction in total score, respectively, at week 4; P < or = 0.013). Of participants in the Dysport group, 38% showed positive treatment response, compared to 16% in the placebo group (95% confidence interval, 0.02-0.41). The median duration of response to Dysport was 18.5 weeks. Side effects were generally similar in the two treatment groups; only blurred vision and weakness occurred significantly more often with Dysport. No participants in the Dysport group converted from negative to positive antibodies after treatment. These results confirm previous reports that Dysport (500 units) is safe, effective, and well-tolerated in patients with cervical dystonia.

Background Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. Methods In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. Results Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. Conclusion Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

We enrolled and treated 122 patients with idiopathic cervical dystonia in a double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B (BotB). Both A-responsive and A-resistant patients were enrolled. Patients received intramuscular injections of either BotB (2,500 U, 5,000 U, or 10,000 U) or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at 4 weeks following study drug administration. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, and Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events. The primary and most of the secondary analyses indicated a statistically significant treatment effect and a dose response. BotB is safe, well tolerated, and efficacious in the treatment of cervical dystonia at the doses tested.

Tremor is a common symptom of Parkinson's disease (PD). The underlying pathophysiology of parkinsonian rest tremor is not well understood. Rest tremor is less responsive to dopaminergic therapy than are symptoms of bradykinesia and rigidity. This paper reviews the effects of 1 mg daily oral rasagiline, as monotherapy and as adjunct therapy, on parkinsonian tremor. A literature search of the EMBASE database was conducted to identify relevant articles in English published between 2000 and October, 2012 using the search terms "rasagiline," or "Azilect®," or "Agilect®," and refined using the terms "Parkinson's disease" and "clinical trial." Of 22 identified publications, two large placebo-controlled trials of rasagiline monotherapy (TEMPO and ADAGIO) and two large placebo-controlled trials of rasagiline as adjunctive therapy with levodopa (PRESTO and LARGO) specifically evaluated the effect of rasagiline on tremor using the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. Prospective and post-hoc analyses from these phase III studies show rasagiline monotherapy significantly improved tremor symptoms in early PD, independent of disease duration, compared with placebo. In levodopa-treated patients with motor fluctuations who were already receiving optimized dopaminergic treatment, the addition of rasagiline adjunct therapy significantly improved tremor symptoms. Significant improvement was evident as early as 10 weeks from treatment initiation. Tremor symptoms also improved in a subset of patients with severe tremor when rasagiline was added to their existing PD treatment regimen. These data suggest that rasagiline used as monotherapy and as adjunctive therapy is effective for reducing tremor severity in patients with PD.

Objective Therapeutic botulinum toxins are antigenic proteins with the potential to produce antibodies (Abs). It is, however, unclear whether Abs to Myobloc® (rimabotulinumtoxinB, botulinum toxin type B, BoNT-B) impact the efficacy and safety of BoNT-B treatment of cervical dystonia (CD). The objective was to determine if Abs to BoNT-B impact the efficacy or safety of long-term BoNT-B treatment of CD. Methods Four separate prospective clinical trials, with a combined total of 1134 subjects evaluable for immunogenicity over total treatment durations of up to 6+ years, were conducted studying the efficacy, safety, and immunogenicity of BoNT-B treatment of CD. Botulinum toxin type B injections were administered approximately every 3 months. Efficacy was assessed using the Toronto Western Spasmodic Torticollis Rating Scale-Total Score, the Subject Global Assessment, or the Treatment Assessment Scale. The presence of Abs to BoNT-B was assessed using the mouse neutralizing antibody (MNA) assay. Cross-sectional and longitudinal statistical analyses were performed to compare efficacy by MNA status at each time point and over time in Ab-positive individuals before and after seroconversion. Safety was assessed by summarizing adverse events by Ab status. Results Long-term efficacy was observed with multiple treatments of BoNT-B. Across all 4 studies, there was no correlation between MNA status and rates of clinical response, study withdrawal, or safety profile. Conclusions Botulinum toxin type B is effective and safe in the repeat, long-term treatment of CD. The presence of Abs to BoNT-B as detected by the MNA assay does not have any meaningful clinical impact or correlation.

Background: Swedish population-based national health registers are widely used data sources in epidemiological research. Register-based diagnoses of Parkinson’s disease have not been validated against clinical information. Methods: Parkinson’s disease (PD) and other parkinsonian disorder diagnoses were ascertained in two registers, i.e. the National Patient Register (NPR) and the Cause of Death Register (CDR). Diagnoses were validated in terms of accuracy (positive predictive value) and sensitivity against data from a population-based study of PD in 1998–2004 that screened more than 35,000 persons and identified 194 cases of parkinsonian disorders including 132 PD cases (the gold standard for the purposes of this study). Results: Accuracy for any parkinsonian disorder diagnoses was 88.0% in the NPR and 94.4% in the CDR. Accuracy of PD diagnoses was 70.8% in the NPR and 66.7% in the CDR. Misclassification between differential parkinsonian diagnoses was common. The accuracy of PD diagnoses in the NPR improved to 83.0% by restricting the definition to primary diagnoses only. The sensitivity of PD diagnoses in the NPR and CDR combined was 83.1%, with a mean time to detection of 6.9 years. Conclusions: Population-based national health registers are valid data sources in epidemiological studies of PD or parkinsonian disorder etiology but are less suitable in studies of incidence or prevalence.

Long-term safety and efficacy of once-daily ropinirole prolonged release (PR) were evaluated in subjects with early Parkinson's disease (PD). Subjects (n = 83) who completed one of two studies were enrolled in this open-label, multicenter, extension study, and followed for up to 78 months. Ropinirole PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/day). L-dopa and other non-dopamine agonist PD medications were permitted. Safety outcomes included adverse events (AEs). Efficacy outcomes included Unified Parkinson's Disease Rating Scale (UPDRS) II and III scores, and Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I) scores. The median duration of ropinirole PR exposure was 1,069 days. Most subjects (97.6%) reported at least one AE, most commonly (≥ 30%) nausea (42.2%), dizziness (41.0%), peripheral edema (38.6%), back pain (33.7%), and headache (31.3%). Seventeen (20.5%) subjects discontinued due to an AE. UPDRS and CGI scores indicated that the clinical status of subjects was maintained throughout the treatment period. In patients with early PD, long-term treatment with once-daily ropinirole PR was not associated with any new safety concerns, and was effective in maintaining clinical status. These results support the extended use of ropinirole PR for treatment of PD.

The aim of this study was to evaluate the efficacy and safety of intramuscular (IM) administration of botulinum toxin type A (Dysport((R)), Ipsen Biopharm Ltd.) for the treatment of cervical dystonia (CD) and the long-term safety and efficacy of repeated treatments. During the randomized, double-blind, placebo-controlled phase patients were randomized to 500 units Dysport (n = 55) or placebo (n = 61). Efficacy assessments included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total and subscale scores, visual analogue scale (VAS) for pain, subject/investigator's VAS for symptom assessments. Patients completing the double-blind treatment could enter an open-label extension phase and receive up to 4 additional Dysport treatments. Dysport produced a significant decrease from baseline in mean (+/-SE) TWSTRS total scores compared with placebo at Week 4 (primary efficacy endpoint; -15.6 +/- 2.0 vs. -6.7 +/- 2.0; p < 0.001) with significant improvements sustained to Week 12 (p = 0.019). Dysport also produced significant improvements in TWSTRS subscale scores, VAS pain scores, and subject/investigator's VAS symptom assessments compared to placebo. The mean duration of open-label study participation was 51.9 weeks (range 3.9-94.0 weeks). During open-label treatment, all treatment cycles resulted in improvements in mean TWSTRS total and subscale scores at Week 4 post-treatment; greatest improvement was seen in cycle 1. The mean duration between treatment cycles was 15-17 weeks. Dysport demonstrated a good long-term safety profile; most adverse events were mild or moderate and typical of the known safety profile of Dysport in this indication. These results confirm that Dysport (500 units) is safe, effective, and well-tolerated in patients with CD.

Objective To determine whether adding orally disintegrating selegiline (ODS) while decreasing dopamine agonist (DA) dosages would reduce DA-related adverse effects (AEs) of excessive daytime sleepiness (EDS), pedal edema, hallucinations, and impulse control disorders (ICDs) without compromising efficacy in Parkinson disease (PD) patients. Methods This was a 12-week open-label study of 60 PD patients with motor fluctuations and DA-related AEs of EDS, pedal edema, hallucinations, and ICDs. Orally disintegrating selegiline was initiated at 1.25 mg once daily, and down titration of the DA was started with a goal of a 50% reduction by 1 week. At week 6, ODS was increased to 2.5 mg, and further reductions of the DA were allowed if the AEs were not resolved. Results The addition of ODS allowed a reduction in the mean daily dose of pramipexole from 2.3 to 0.5 mg and immediate-release ropinirole from 11.2 to 2.9 mg. Most subjects reported a reduction or resolution of DA-related AEs; 94% with EDS (n = 50), 73% with pedal edema (n = 26), 86% with hallucinations (n = 15), and 84% with ICDs (n = 25). Mean activities of daily living and motor scores from the Unified Parkinson's Disease Rating Scale as well as quality-of-life scores were significantly improved without an increase in daily "off" time. The most common AEs, most of which resolved after titration, were worsening of PD, nausea/vomiting, dyskinesia, increased off time, body aches, insomnia, orthostatic hypotension, and increased anxiety and depression. Conclusions In most subjects, the addition of ODS with decreasing dosages of DAs substantially reduced EDS, pedal edema, hallucinations, and ICDs without compromising efficacy.

Udgivelsesdato: 2008-Aug-15 The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson's disease (PD), and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n = 495), with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range, 15-34) below the clinical range for HD, although 5.2% of the sample (n = 25) had repeats in the intermediate range (the intermediate range lower limit = 27; upper limit = 35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD.

The purpose of this study to compare the long-term clinical outcome of early versus delayed rasagiline treatment in early Parkinson's disease (PD). Subjects (N = 404) were randomly assigned to initial treatment with rasagiline (early-start group) or placebo for 6 months followed by rasagiline (delayed-start group) in the TEMPO study. Subjects who chose to participate in an open-label extension (N = 306) continued to receive rasagiline as well as other PD medications as needed. Average (+/-SD) duration in the study was 3.6 +/- 2.1 years; 177 subjects received rasagiline for > or =5.0 years. Over the entire 6.5-year follow-up period, the adjusted mean difference in change from baseline in total UPDRS scores was 2.5 units (SE 1.1; P = 0.021) or 16% (SE 5.7; P = 0.006) in favor of the early-start versus delayed-start rasagiline group. Although the interaction between treatment and time was significant, values for the early-start group were better than the delayed-start group across all time points. Significantly less worsening (percent change) in total UPDRS scores was observed in the early-start group at the time points 0.5, 1.5, 2.0, 3.0, 4.5, 5.0, and 5.5 years (P < 0.05). Compared to delayed start, early initiation of rasagiline provided long-term clinical benefit, even in the face of treatment with other dopaminergic agents. This might reflect enduring benefits due to neuroprotection or effects on compensatory mechanisms in early PD.

Background We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD. Methods A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample. Results Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families. Conclusion Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Background: Microtubule-associated protein tau ( MAPT ) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the Gene PD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT , and neighboring genes Saitohin ( STH ) and KIAA1267 , are altered in PD cerebellum. Methods: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the Gene PD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. Results: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT , STH , and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT . Conclusions: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT , specifically STH and KIAA1267 , may also have a role in PD and suggest complex effects for the genes in this region on PD risk.

Objectives: Tolcapone, administered with levodopa/carbidopa to patients with Parkinson disease, is an effective and generally well-tolerated adjunctive therapy. However, 4 early cases of hepatotoxicity causing 3 deaths in patients not properly monitored gave rise to more rigorous liver function test monitoring guidelines and a liver function test monitoring program in which blood samples from tolcapone-treated patients were tested and results were collected in a central database. We analyzed these results to determine the percentages of patients with at least 1 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation above the upper limit of normal (ULN) and at least 1 elevation greater than 2 times the ULN. Methods: This retrospective, observational analysis included all AST and ALT values recorded in the database from 11,883 samples from patients who received tolcapone for up to 2 years or longer (January 1999-January 2001). Results: Of 1725 patients who had at least 1 AST or ALT measurement, 3.9% (n = 67) had elevations above the ULN. Less than 1% (15/1725) of patients had AST or ALT elevations greater than 2 times the ULN. Most values returned to normal during continued tolcapone treatment. In 472 patients monitored biweekly while receiving tolcapone for 20 to 114 consecutive weeks, only 0.6% (n = 3) had an AST or ALT value greater than 2 times the ULN; no significant elevations occurred in the remaining 469 (99.4%). Conclusions: This analysis of results from the central monitoring program suggests that significant transaminase elevations are rare, typically transient, and may return to normal in the face of continued tolcapone therapy in most patients.

This report describes the ascertainment of Parkinson disease (PD) in all individuals aged 50 years or older (49,814 individuals) from the Swedish Twin Registry. In phase one of the study, all twins were screened for PD using telephone interviews, with a response rate of 72.7%. In phase two, twins with suspected PD were re-contacted to exclude anyone from follow-up who reported parkinsonian symptoms due to diseases other than PD. In the third phase, in-person clinical evaluations were completed for twins who were still considered PD suspects after phase two and for a sample of co-twins. During the clinical evaluations, we also collected blood samples and information about a variety of environmental exposures. Overall prevalence rate for PD was 496 per 100,000 individuals. Among the 132 PD cases identified, there were only three concordant twin pairs. In total 7.2% of PD cases reported a first degree relative with PD.

Importance There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. Objective To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. Design, Setting, and Patients The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. Interventions Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). Main Outcomes and Measures The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. Results The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t 1865.8 = −0.75 (2-sided P = .45). There were no detectable differences ( P Conclusions and Relevance Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. Trial Registration clinicaltrials.gov Identifier:NCT00449865

Background The PARK2 gene at 6q26 encodes parkin , whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). Objective To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. Design Clinical and genetic study. Setting Twenty collaborative clinical sites. Patients Patients with familial PD collected in the Gene PD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 ( D6S305 ) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2 . Main Outcome Measures Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. Results Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none ( P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation ( P = .04). Conclusions These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

We report a patient with Lubag (X-linked dystonia-parkinsonism) who presented with severe respiratory stridor from adductor laryngeal breathing dystonia. Emergency tracheostomy was necessary, and subsequent laryngeal injection with botulinum toxin led to worsening aspiration. Botulinum toxin injection for severe lingual dystonia was successful.

Background Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression. Objective To determine whether a range of dosages of coenzyme Q10is safe and well tolerated and could slow the functional decline in PD. Design Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. Setting Academic movement disorders clinics. Patients Eighty subjects with early PD who did not require treatment for their disability. Interventions Random assignment to placebo or coenzyme Q10at dosages of 300, 600, or 1200 mg/d. Main Outcome Measure The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. Results The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. ThePvalue for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was .09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P= .04). Conclusions Coenzyme Q10was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.

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

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with type A-resistant cervical dystonia (CD).Local intramuscular injections of BoNT are an effective therapy for CD. After repeated use, some patients become resistant to therapy. BoNT/B, effective in type A toxin-responsive patients, is proposed as an alternative therapy for type A-resistant patients.The authors performed a 16-week, double-blind, placebo-controlled trial of BoNT/B in type A-resistant patients with CD. After resistance to therapy was confirmed with the frontalis-type A test, placebo or 10,000 U BoNT/B was administered in a single session into two to four clinically involved muscles. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was the primary efficacy measurement. TWSTRS-Total, three visual analog scales (Patient Global Assessment of Change, Principal Investigator Global Assessment of Change, Patient Analog Pain Assessment), and adverse events were assessed at baseline and weeks 2, 4, 8, 12, and 16.A total of 77 patients participated (38 placebo, 39 active). Improvements in severity, disability, and pain were documented in the BoNT/B-treated group. TWSTRS-Total scores were improved in the BoNT/B-treated group at weeks 4 (p = 0.0001), 8 (p = 0.0002), and 12 (p = 0.0129). All three visual analog scales demonstrated improvements at week 4 (p0.0001, 0.0001, and 0.001). A Kaplan-Meier analysis supported a duration of effect of 12 to 16 weeks in the active group. Dry mouth and dysphagia were self-limited adverse effects, reported more commonly in the BoNT/B group.Botulinum toxin type B (BoNT/B) (NeuroBloc) is safe and efficacious for the management of patients with type A-resistant cervical dystonia with an estimated duration of treatment effect of 12 to 16 weeks.

In a preliminary study, the effects of ventroposterior medial pallidotomy were evaluated in five patients with advanced Parkinson's disease in whom medical therapy had failed. The mean age was 67.0 +/- 5.6 years, and the mean Hoehn and Yahr stage when "off" was 3.9 +/- 1.3. Three patients received unilateral pallidotomies; two of these received another pallidotomy after 8 weeks. Two other patients received staged bilateral pallidotomies. No significant differences in overall function could be seen before and after the first surgical procedure. All three patients with peak-dose dyskinesias or dystonia had marked contralateral reduction in these symptoms. Ventroposterior medial pallidotomy can ameliorate peak-dose dyskinesias in patients with advanced Parkinson's disease. Overall function improvement is not remarkable.

Objective To evaluate the possible association of Parkinson disease (PD) and melanoma in North America. Design, Setting, and Patients Thirty-one centers enrolled patients with idiopathic PD. At visit 1, a neurologist obtained a medical history. At visit 2, a dermatologist recorded melanoma risk factors, performed a whole-body examination, and performed a biopsy of lesions suggestive of melanoma for evaluation by a central dermatopathology laboratory. We compared overall prevalence of melanoma with prevalence calculated from the US Surveillance Epidemiology and End Results (SEER) cancer database and the American Academy of Dermatology skin cancer screening programs. Results A total of 2106 patients (mean [SD] age, 68.6 [10.6] years; duration of PD, 7.1 [5.7] years) completed the study. Most (84.8%) had received levodopa. Dermatology examinations revealed 346 pigmented lesions; dermatopathological findings confirmed 20 in situ melanomas (0.9%) and 4 invasive melanomas (0.2%). In addition, histories revealed 68 prior melanomas (3.2%). Prevalence (5-year limited duration) of invasive malignant melanoma in the US cohort of patients with PD (n = 1692) was 2.24-fold higher (95% confidence interval, 1.21-4.17) than expected in age- and sex-matched populations in the US SEER database. Age- or sex-adjusted relative risk of any melanoma for US patients was more than 7 times that expected from confirmed cases in American Academy of Dermatology skin cancer screening programs. Conclusions Melanoma prevalence appears to be higher in patients with PD than in the general population. Despite difficulties in comparing other databases with this study population, the study supports increased melanoma screening in patients with PD.