PREPARED: Comparison of prolonged and immediate release ropinirole in advanced Parkinson's disease

Background: PREPARED was a randomized, parallel‐group, double‐blind, multicenter study to evaluate the efficacy of adjunctive ropinirole prolonged release (PR) versus immediate release (IR) in patients with advanced Parkinson's disease (PD). Methods: Patients received once‐daily PR (2–24 mg/d; n = 177) or three‐times‐daily IR (0.75–24 mg/d; n = 173) for 24 weeks. The primary endpoint was the proportion of patients maintaining ≥20% reduction from baseline in “off” time over two consecutive visits at Week 24 last observation carried forward (LOCF). Results: At Week 24 LOCF, PR significantly increased the proportion of patients maintaining ≥20% reduction in “off” time versus IR (adjusted odds ratio: 1.82; 95% CI: 1.16, 2.86; P = 0.009). Mean (SD) doses at Week 24 LOCF were: PR, 18.6 (6.5) mg/d; IR, 10.4 (6.4) mg/d; mean (SD) reductions from baseline in levodopa (L ‐dopa) dose were –162 (226) mg and –113 (138) mg, respectively. Adverse events (AEs) were reported by 72% of patients in the PR group and 61% in the IR group; 12% and 9% of patients, respectively, withdrew from the study due to an AE, and 6% and 5%, respectively, reported serious AEs. Conclusions: Adjunctive PR provided a significantly greater improvement in symptom control in terms of the odds of achieving ≥20% maintained reduction in time spent “off” compared with IR. Interpretation may be confounded by the higher doses of PR versus IR that were achieved, in combination with lower doses of L ‐dopa by the study end. Despite dosing differences, the PR titration regimen was generally well tolerated, with an AE profile similar to that of IR. © 2011 Movement Disorder Society     

Onset of dyskinesia with adjunct ropinirole prolonged‐release or additional levodopa in early Parkinson's disease

Levodopa‐induced dyskinesia can result in significant functional disability and reduced quality of life in patients with Parkinson's disease (PD). The goal of this study was to determine if the addition of once‐daily ropinirole 24‐hour prolonged‐release (n = 104) in PD patients not optimally controlled with levodopa after up to 3 years of therapy with less than 600 mg/d delays the onset of dyskinesia compared with increasing doses of levodopa (n = 104). During the study, 3% of the ropinirole prolonged‐release group (mean dose 10 mg/d) and 17% of the levodopa group (mean additional dose 284 mg/d) developed dyskinesia (P < 0.001). There were no significant differences in change in Unified Parkinson's Disease Rating Scale activities of daily living or motor scores, suggesting comparable efficacy between the two treatments. Adverse events were comparable in the two groups with nausea, dizziness, insomnia, back pain, arthralgia, somnolence, fatigue, and pain most commonly reported. Ropinirole prolonged‐release delayed the onset of dyskinesia with comparable efficacy to increased doses of levodopa in early PD patients not optimally controlled with levodopa. © 2010 Movement Disorder Society     

Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson’s disease

Background: The 24‐week, double‐blind Efficacy and Safety Evaluation in PD–Adjunct (EASE‐PD Adjunct) study randomized patients with advanced Parkinson’s disease (PD) suboptimally controlled with levodopa to once‐daily placebo or adjunctive ropinirole prolonged release (2–24 mg/day). We investigated the effect of ropinirole prolonged release on nocturnal symptoms in these patients. Methods: Total and grouped item PD Sleep Scale (PDSS) scores were analyzed post hoc in patients with baseline PDSS total scores ≤ 100 (troublesome nocturnal symptoms) and >100. Results: Baseline PDSS total score was ≤ 100 in 93 of 198 (47%) and 89 of 189 (47%) patients receiving ropinirole prolonged release and placebo, respectively; this subgroup displayed evidence at baseline of greater daily awake ‘off’ time, reduced night‐time sleep and worse quality of life, than the PDSS >100 subgroup. Significant improvements with ropinirole prolonged release versus placebo in PDSS score from baseline to Week 24 last observation carried forward were observed for those with baseline PDSS ≤ 100 [adjusted mean treatment difference 9.0 (95% CI: 2.76, 15.33; P = 0.0051)], but not >100. The PDSS ≤ 100 subgroup demonstrated treatment benefits for PDSS groupings of motor symptoms on waking and global quality of sleep. Changes in daytime sleepiness were similar between treatment groups. The PDSS >100 subgroup demonstrated significant treatment benefit for global quality of sleep. The unadjusted odds ratio for a positive response with ropinirole prolonged release relative to placebo, for the PDSS ≤ 100 subgroup, was 2.90 (95% CI: 1.42, 5.95, P = 0.004). Conclusions: Once‐daily ropinirole prolonged release improves nocturnal symptoms in patients with advanced PD not optimally controlled with levodopa who suffer troublesome nocturnal disturbance.     

Randomized,double‐blind,multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease

The objective of this study was to evaluate the efficacy and safety of pramipexole extended release (ER) administered once daily in early Parkinson's disease (PD). Pramipexole immediate release (IR) administered three times daily (TID) is an efficacious and generally well‐tolerated treatment for PD. A pramipexole ER formulation is now available. We performed a randomized, double‐blind, placebo and active comparator–controlled trial in subjects with early PD. The primary efficacy and safety evaluation of pramipexole ER compared with placebo took place at week 18. Two hundred fifty‐nine subjects were randomized 2:2:1 to treatment with pramipexole ER once daily, pramipexole IR TID, or placebo. Levodopa rescue was required by 7 subjects in the placebo group (14%), 3 subjects in the pramipexole ER group (2.9%, P = 0.0160), and 1 subject in the pramipexole IR group (1.0%, P = 0.0017). Adjusted mean [standard error (SE)] change in Unified Parkinson Disease Rating Scale (UPDRS) II [activities of daily living (ADL)] + III (motor) scores from baseline to week 18, including post‐levodopa rescue evaluations, was ?5.1 (1.3) in the placebo group, ?8.1 (1.1) in the pramipexole ER group (P = 0.0282), and ?8.4 (1.1) in the pramipexole IR group (P = 0.0153). Adjusted mean (SE) change in UPDRS ADL + motor scores, censoring post‐levodopa rescue data, was ?2.7 (1.3) in the placebo group, ?7.4 (1.1) in the pramipexole ER group (P = 0.0010), and ?7.5 (1.1) in the pramipexole IR group (P = 0.0006). Adverse events more common with pramipexole ER than placebo included somnolence, nausea, constipation, and fatigue. Pramipexole ER administered once daily was demonstrated to be efficacious compared with placebo and provided similar efficacy and tolerability as pramipexole IR administered TID. © 2010 Movement Disorder Society     

Macrogol for the treatment of constipation in Parkinson's disease. A randomized placebo‐controlled study

Chronic constipation is the most frequent symptom of autonomic system involvement in Parkinson's disease (PD). Quite often the symptom is severe and impairs patients' quality of life. The objective of this study is to determine the efficacy and safety of an isosmotic macrogol solution for the treatment of constipation in PD patients, in a double‐blind, placebo‐controlled study. A total of 57 PD patients with constipation were randomly assigned to receive an isosmotic macrogol electrolyte solution (MC‐ES; 29 patients) or placebo (28 patients) for 8 weeks. Treatment efficacy was defined as complete relief of the symptom or a marked improvement of two of the following indicators: stool frequency, straining, stool consistency, use of rectal laxatives as a rescue therapy. The responder rates were significantly higher in the MC‐ES group both at the first (4 weeks; P < 0.0003) and at the final evaluation (8 weeks; P < 0.0012). The frequency of bowel movements (P < 0.002) and stool consistency (P < 0.006) were significantly changed in the MC‐ES group compared to the placebo group. At the final evaluation, a rectal laxative was used by 2 (12.5%) patients on placebo, whereas no use was recorded in the MC‐ES group. Responder rate for straining showed a favorable trend in patients treated with macrogol versus placebo. Unified Parkinson's Disease Rating Scale Part III and Parkinson's Disease Questionnaire (PDQ‐39) did not show any significant modification in either group during the 8‐week treatment period. The results of this placebo‐controlled study show the efficacy of MC‐ES in the treatment of constipation in PD. MC‐ES was well‐tolerated and did not affect the course of PD. © 2006 Movement Disorder Society     

Amantadine extended release for levodopa‐induced dyskinesia in Parkinson's disease (EASED Study)

ADS‐5102 is a long‐acting, extended‐release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy, and tolerability of ADS‐5102 in Parkinson's disease (PD) patients with levodopa‐induced dyskinesia. This was a randomized, double‐blind, placebo‐controlled, parallel‐group study of 83 PD patients with troublesome dyskinesia assigned to placebo or one of three doses of ADS‐5102 (260 mg, 340 mg, 420 mg) administered daily at bedtime for 8 weeks. The primary efficacy analysis compared change from baseline to week 8 in Unified Dyskinesia Rating Scale (UDysRS) total score for 340 mg ADS‐5102 versus placebo. Secondary outcome measures included change in UDysRS for 260 mg, 420 mg, Fatigue Severity Scale (FSS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), patient diary, Clinician's Global Impression of Change, and Parkinson's Disease Questionnaire (PDQ‐39). ADS‐5102 340 mg significantly reduced dyskinesia versus placebo (27% reduction in UDysRS, P = 0.005). In addition, ADS‐5102 significantly increased ON time without troublesome dyskinesia, as assessed by PD patient diaries, at 260 mg (P = 0.004), 340 mg (P = 0.008) and 420 mg (P = 0.018). Adverse events (AEs) were reported for 82%, 80%, 95%, and 90% of patients in the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. Constipation, hallucinations, dizziness, and dry mouth were the most frequent AEs. Study withdrawal rates were 9%, 15%, 14%, and 40% for the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. All study withdrawals in the active treatment groups were attributable to AEs. ADS‐5102 was generally well tolerated and resulted in significant and dose‐dependent improvements in dyskinesia in PD patients. © 2015 Adamas Pharmaceuticals, Inc. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week,randomized, dose‐finding study

AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinson's disease and moderate‐to‐severe levodopa (l ‐dopa)‐induced dyskinesia who were receiving stable l ‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, ?2.8; 95% confidence interval [CI], ?5.2, ?0.4; P = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, ?3.6; 95% CI, ?7.0, ?0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, ?0.7; 95% CI, ?1.1, ?0.2; P = 0.003; 200 mg daily: difference, ?0.5; 95% CI, ?0.8, ?0.1; P = 0.005). No significant changes were observed on the 26‐item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials. © 2013 International Parkinson and Movement Disorder Society     

Interventions for fatigue in Parkinson's disease: A systematic review and meta‐analysis

The authors sought to review the efficacy of interventions for fatigue in Parkinson's disease. A search was conducted of PubMed, Cinahl, Psychinfo, EMBASE, and Web of Knowledge up to November 2013. Methodological quality was assessed using the PEDro scale. For meta‐analyses, studies were weighted on variance. Effect sizes were calculated with 95% confidence interval (CI); overall effect was presented by means of a Z‐score; heterogeneity was investigated using the I². Fourteen articles (n = 1,890) investigating drugs and behavioral therapy were eligible. Ten studies demonstrated excellent, three good, and one fair methodological quality. Three articles (investigating amphetamines) were appropriate for meta‐analysis, which was performed according to scales used: Multidimensional Fatigue Inventory: mean difference, –6.13 (95%CI: –14.63‐2.37, Z = 1.41, P = 0.16; I² = 0); Fatigue Severity Scale: mean difference, –4.00 (95%CI: –8.72‐0.72, Z = 1.66, P = 0.10; I² = 0). Currently insufficient evidence exists to support the treatment of fatigue in PD with any drug or nondrug treatment. Further study is required. © 2014 International Parkinson and Movement Disorder Society     

The efficacy and safety of ropinirole prolonged release tablets as adjunctive therapy in Chinese subjects with advanced Parkinson's disease: A multicenter,double-blind,randomized, placebo-controlled study

AimThe first evaluation of the efficacy and safety of ropinirole prolonged release (PR) as an adjunct to L-dopa in Chinese patients with advanced Parkinson's disease (PD) not optimally controlled with L-dopa.MethodsIn a 24-week, double-blind, placebo-controlled, parallel-group study, subjects with advanced PD were randomized 1:1 to ropinirole PR (N = 175) or placebo (N = 170) as add-on therapy to L-dopa. Primary outcome measure was change from baseline in awake time spent “off”. Starting dose of ropinirole PR was 2 mg/day, titrated based on clinical response (maximum 24 mg/day).ResultsAt week 24, the mean dose of ropinirole PR was 11.4 mg/day with a mean reduction of L-dopa from 506.6 to 411.6 mg/day. Subjects receiving ropinirole PR experienced a significant reduction of “off” time (2.1 h) compared with placebo (0.4 h). Secondary outcome measures including hours of “on” time without troublesome dyskinesis were significantly increased in the ropinirole PR group (1.7 h) compared with placebo (0.3 h). Subjects classified as responders were significantly more frequent in the ropinirole PR (22.8%) than placebo group (2.5%). Efficacy outcomes including Unified Parkinson's disease Rating Scale and PDQ-39 subscales of mobility were significantly improved in the ropinirole PR versus placebo group. The most frequent adverse event experienced in the ropinirole PR group was dyskinesia.ConclusionsThis study demonstrated for the first time in Chinese subjects that ropinirole PR improved Parkinson's disease symptoms, permitting a reduction in L-dopa dose. The adverse events observed were consistent with the established safety profile of ropinirole, with no new safety signal identified.     

Rotigotine vs ropinirole in advanced stage Parkinson's disease: A double-blind study

ObjectiveTo confirm the superiority of transdermal rotigotine up to 16 mg/24 h over placebo, and non-inferiority to ropinirole, in Japanese Parkinson's disease (PD) patients on concomitant levodopa therapy.MethodsThis trial was a randomized, double-blind, double-dummy, three-arm parallel group placebo- and ropinirole-controlled trial. Four-hundred and twenty PD patients whose motor symptoms were not well controlled by levodopa treatment were randomized 2:2:1 to receive rotigotine, ropinirole (up to 15 mg/day) or placebo during a 16-week treatment period followed by a 4-week taper period. The primary variable was change in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON state) sum score from baseline to the end of the treatment period.ResultsThe difference in the change in the UPDRS Part III (ON state) sum score from baseline to the end of treatment between rotigotine and placebo groups was −6.4 ± 1.2 (95% CI: −8.7 to −4.1; p < 0.001), indicating superiority of rotigotine over placebo. The difference between rotigotine and ropinirole groups was −1.4 ± 1.0 (95% CI: −3.2 to 0.5), below the non-inferiority margin, indicating the non-inferiority of rotigotine to ropinirole. Application site reaction was seen in 57.7% of the patients in the rotigotine group and in 18.6% in the ropinirole group (P < 0.001). No other safety issue was noted.ConclusionsRotigotine was well tolerated at doses up to 16 mg/24 h and showed similar efficacy to ropinirole except that the application site reaction was much higher in the rotigotine group.     

Rivastigmine for mild cognitive impairment in Parkinson disease: A placebo‐controlled study

Mild cognitive impairment (MCI) in Parkinson's disease (PD) may be associated with subtle functional impairment and worse quality of life. The objective of this study was to determine the efficacy and tolerability of rivastigmine for PD‐MCI. Patients with PD‐MCI (n = 28) were enrolled in a 24‐week, randomized, double‐blind, placebo‐controlled, crossover, single‐site study of the rivastigmine transdermal patch. The primary outcome measure was the Alzheimer's Disease Cooperative Study—Clinical Global Impression of Change (ADCS‐CGIC). Secondary outcomes included the Montreal Cognitive Assessment (MoCA), Dementia Rating Scale‐2 (DRS‐2), Neurotrax computerized cognitive battery, the Everyday Cognition Battery (ECB), and the Parkinson's Disease Questionnaire (PDQ‐8). Twenty‐six participants (92.9%) completed both study phase assessments, and 23 (82.1%) completed both phases on study medication. The CGIC response rate demonstrated a trend effect in favor of rivastigmine (regression coefficient for interaction term in linear mixed‐effects model = 0.44, F[df] = 3.01 [1, 24], P = 0.096). For secondary outcomes, a significant rivastigmine effect on the ECB (regression coefficient = –2.41, F[df] = 5.81 [1, 22.05], P = 0.03) was seen, but no treatment effect was found on any cognitive measures. Trend effects also occurred in favor of rivastigmine on the PDQ‐8 (regression coefficient = 4.55, F[df] = 3.93 [1, 14. 79], P = 0.09) and the State Anxiety Inventory (regression coefficient = –1.24, F[df] = 3.17 [1, 33], P = 0.08). Rivastigmine in PD‐MCI showed a trend effect for improvements on a global rating of cognition, disease‐related health status, and anxiety severity, and significant improvement on a performance‐based measure of cognitive abilities. © 2015 International Parkinson and Movement Disorder Society     

Randomized,controlled trial of rasagiline as an add‐on to dopamine agonists in Parkinson's disease

Dopamine agonists (DA) are often used as first‐line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase‐B (MAO‐B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18‐week, randomized, double‐blind, placebo‐controlled trial of rasagiline 1 mg/d as an add‐on to DA therapy (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The modified intent‐to‐treat (ITT) population included 321 subjects whose mean ± SD age was 62.6 ± 9.7, and duration of PD was 2.1 ± 2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, ?2.4 ± 0.95; 95% confidence interval [CI], ?4.3, ?0.5; P = 0.012). Mean improvement (LS mean ± SE) was ?3.6 ± 0.68 in the rasagiline group and ?1.2 ± 0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society     

Mild depressive symptoms are associated with gait impairment in early Parkinson's disease

The association between nonmotor characteristics and gait in Parkinson's disease (PD) is well established, particularly the role of cognition. Evidence is emerging that depression, an underrecognized symptom in PD is also associated with gait impairment. This cross‐sectional study examined the association between depressive symptomatology and gait in early PD. Depression was measured with the Geriatric Depression Scale (GDS), disease severity with the Unified Parkinson's Disease Rating Scale III, and cognition with the Mini Mental Status Examination. Gait speed and gait variability were measured using a 7‐m walkway (GAITRite). Linear regression was used to examine the association between depression and gait for PD and controls, controlling for age, cognition, and severity. PD participants who presented with clinically relevant depressive symptoms (GDS ≥ 5) were compared with those who scored < 5. One hundred and twenty‐two people with newly diagnosed PD and 184 controls were assessed. Depression scores were significantly higher for PD patients than for controls (P < .001), although neither group presented with clinically relevant symptomatology (mean [SD] for PD, 2.7 [2.3]; for controls, 1.1 [1.8]). For gait speed there was a main effect for depression (P < .001) and a group × depression interaction that approached significance (P = .054). For gait variability there was a main effect for depression (P < .01). PD participants with GDS scores ≥ 5 had a slower and more variable gait. Very mild depressive symptoms are associated with gait disturbance in early PD. Depression may be a marker for degeneration in nondopaminergic systems in early PD and influence mechanisms of gait disturbance. © 2013 Movement Disorder Society     

Effectiveness of acupuncture for Parkinson's disease: A systematic review

The objective of this review is to assess the clinical evidence for or against acupuncture as a treatment for Parkinson's disease (PD). We searched the literature using 17 databases from their inception to September 2007 (searched again 3rd January 2008), without language restrictions. We included all randomized clinical trials (RCTs) regardless of their design. Methodological quality was assessed using the Jadad score. Eleven RCTs met all inclusion criteria. Three RCTs assessed the effectiveness of acupuncture on Unified Parkinson's Disease Rating Scale (UPDRS) compared with placebo acupuncture. A meta‐analysis of these studies showed no significant effect (n = 96, WMD, 5.7; 95% CI ?2.8 to 14.2, P = 0.19, heterogeneity: tau² = 0, χ² = 0.97, P = 0.62, I² = 0%). Another six RCTs compared acupuncture plus conventional drugs on improvement of symptoms of PD with drugs only. A meta‐analysis of two of these studies suggested a positive effect of scalp acupuncture (n = 106, RR, 1.46, 95% CI = 1.15 to 1.87, P = 0.002; heterogeneity: tau² = 0.00, χ² = 1.14, P = 0.29, I² = 12%). Two further RCTs tested acupuncture versus no treatment. The meta‐analysis of these studies also suggested beneficial effects of acupuncture. The results of the latter two types of RCTs fail to adequately control for nonspecific effects. In conclusion, the evidence for the effectiveness of acupuncture for treating PD is not convincing. The number and quality of trials as well as their total sample size are too low to draw any firm conclusion. Further rigorous trials are warranted. © 2008 Movement Disorder Society     

Long‐term antidyskinetic efficacy of amantadine in Parkinson's disease

Several randomized placebo‐controlled trials have consistently shown antidyskinetic effects of amantadine in levodopa treated patients with advanced Parkinson's disease (PD). However, all of these were of short duration and there have been claims that the effect of amantadine on levodopa induced dyskinesias (LID's) wear off after about 9 months of treatment. This randomized placebo‐controlled parallel‐group study was performed to assess the long‐term antidyskinetic effect of amantadine in 32 PD patients, who after having been on stable amantadine therapy for LID over at least one year‐ were switched in a double blind manner to amantadine or placebo and followed for 3 weeks. Dyskinesia duration and intensity were assessed by UPDRS IV items 32 and 33 as well as by patient's diaries. The primary outcome was the score change of UPDRS IV items 32 + 33 between baseline and 3 weeks after treatment as well as the between treatment group comparison of the score change of UPDRS IV items 32 + 33. There was a significant increase of UPDRS IV items 32 + 33 in patients treated with placebo from 3.06 (95% CI, 2.1–4.03) at baseline to 4.28 (95% CI, 3.1–5.4) at three‐week follow‐up (P = 0.02) compared with no significant change between baseline 3.2 (95% CI, 2.1–4.4) to follow‐up 3.6 (95% CI, 2.3–4.8) in patients staying on amantadine. These findings argue for long‐term antidyskinetic efficacy of amantadine in PD patients with LID's. © 2010 Movement Disorder Society     

Freezing of gait and executive functions in patients with Parkinson's disease

Freezing of gait (FOG) is a frequent, disabling symptom of Parkinson's disease (PD). FOG usually lasts a few seconds. It refers to brief paroxysmal events during which a subject is unable to start or continue locomotion. Despite its frequency, FOG pathophysiology is unclear. Because a frontal lobe dysfunction or a disconnection between the frontal lobe and basal ganglia has been implicated in FOG, we explored frontal functions in PD patients using neuropsychological tests. Thirteen early‐stage PD patients [Hoehn & Yahr score (H&Y) ≤ 2.5] with freezing during “on ” state (FOG+), and 15 age‐, H&Y score‐, and disease‐duration‐matched PD patients without freezing (FOG?) were investigated. No patient was demented or depressed. Assessment included the Unified Parkinson's Disease Rating Scale (UPDRS), FOG questionnaire, Mini Mental State Examination (MMSE), frontal assessment battery (FAB), phonemic verbal fluency, Stroop test (parts II and III), and ten‐point clock test (TPCT). UPDRS and MMSE scores did not differ between the two groups. FAB, verbal fluency, and TPCT scores were significantly lower in FOG+ patients than in FOG? patients (FAB: P = 0.008; phonemic verbal fluency: P = 0.011; TPCT: P = 0.024). FOG correlated with lower scores at frontal tests in patients with early‐stage PD. © 2007 Movement Disorder Society     

Levodopa response in early Parkinson's disease

To further characterize the short‐term levodopa response in early PD, we performed a retrospective analysis of the ELLDOPA study which randomized 361 early PD subjects to placebo, levodopa 150, 300, or 600 mg/day. We evaluated change in UPDRS motor scores (UPDRSm) from baseline to weeks 9 and 24, and identified changes in UPDRSm that best discriminated treatment with levodopa from placebo. Linear regressions were used to determine associations between baseline characteristics and changes in UPDRSm. Mean percent improvement in UPDRSm in levodopa‐treated subjects was greater than that for placebo‐treated subjects (27.4% vs. 5.8% at 9 weeks, P < 0.001 and 26.2% vs. 4.0% at 24 weeks, P < 0.001). UPDRSm change at 9 weeks ranged from –92.9% (improvement) to 85.7% (worsening) for levodopa and –86.7% to 160% for placebo, and at 24 weeks ranged from –100.0% to 242.9% for levodopa and –87.5% to 112.5% for placebo. UPDRSm improvements of 22.0% at 9 weeks and 23.8% at 24 weeks best discriminated treatment with levodopa 300 mg/day (a common initial maintenance dosage in clinical practice) from placebo. Significant associations were not observed between baseline subject characteristics and magnitude of response from baseline to week 24. We conclude that although levodopa treatment significantly improved PD signs when compared with placebo, there was a wide range and considerable overlap in clinical responses to levodopa and placebo. A substantial proportion of subjects with early PD did not experience a robust response to levodopa. An improvement in UPDRSm of ～22% best discriminated levodopa treatment from placebo. © 2009 Movement Disorder Society     

Long-term study of ropinirole patch in Parkinson's disease patients with/without basal l-dopa

IntroductionA dopamine agonist patch could be an important treatment option for Parkinson's disease. This study evaluated the long-term efficacy and safety of the ropinirole hydrochloride patch. The steady state plasma ropinirole concentration was also assessed.MethodsIn a multicenter, open-label, uncontrolled study, Parkinson's disease patients with/without basal levodopa and with/without prior dopamine agonist therapy (any of these four regimens) received application of a ropinirole patch once daily for up to 52 weeks with unforced titration from 8 to 64 mg. For patients with prior dopamine agonist therapy, the initial dose of ropinirole patch was determined from the prior dopamine agonist dose by using a conversion table.ResultsMost adverse events were mild or moderate. All application site adverse events were mild, except for moderate application site erythema in one patient. In patients with prior dopamine agonist therapy, switching to ropinirole patch did not lead to a significant early increase of adverse events. A change from baseline in the UPDRS Part III total score, the primary efficacy endpoint, showed improvement until Week 16 compared with baseline, followed by little subsequent change until Week 52, indicating maintenance of efficacy. The plasma ropinirole concentration was at steady state throughout the study period and showed a dose-proportional increase.ConclusionOnce-daily application of ropinirole patch showed long-term efficacy and safety (52 weeks) for Parkinson's disease. Switching from other dopamine agonists to ropinirole patch was effective and safe. The plasma ropinirole concentration was at steady state throughout the study period and showed a dose-proportional increase.     

Familial aggregation of Parkinson's disease in the Faroe Islands

The Faroe Islands are a geographic population isolated in the North Atlantic with a high prevalence of Parkinson's disease (PD). Although environmental risk factors are well described, the familial aggregation of PD on the Islands has yet to be explored. Complete ascertainment of all patients with PD was performed, including 217 cases and 251 control subjects. All patients were neurologically assessed and diagnosed using UK Brain Bank criteria and Hohn and Yahr staging. Comprehensive genealogical and detailed cartographic analyses were performed. Relative risk and risk ratios were calculated with respect to the general population. Patients with PD in the Faroes have a higher age at symptom onset and diagnosis than for neighboring countries. Clinically, patients are similar; however, they are more likely to have affected relatives than randomly selected control subjects, matched by sex and age. Disease is most prevalent within two geographic regions. Overall, the relative risk for PD was 2.3 (95% confidence interval [CI], 1.2‐4.3; P = 0.008) for siblings and 1.4 (95% CI, 1.01‐1.99, P = 0.04) for first cousins. The etiology and excess prevalence of PD on the Faroes is complicated. Regional and familial clustering, and subsequent segregation analysis, suggests the disease best fits a genetic etiology with limited support for an environmental contribution. Pedigree‐based analysis of PD on the Faroe Islands which has few founders and a relatively homogeneous background may elaborate on these possibilities and their joint contribution. © 2015 International Parkinson and Movement Disorder Society     

Long‐term outcome of early versus delayed rasagiline treatment in early Parkinson's disease

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 ≥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. © 2008 Movement Disorder Society