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Background: There are no effective treatments for multiple system atrophy (MSA)., Objective: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA., Methods: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score., Results: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo)., Conclusion: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Impact of subthalamic deep brain stimulation (DBS) on impulse control disorders (ICD) in Parkinson's disease (PD) remains controversial., Objectives: The objectives of this study were to analyze the natural history of ICD between baseline and 1 year after subthalamic DBS in patients with PD and to identify predictive factors, taking into account the positions of the active contact and stimulation parameters., Methods: We analyzed postoperative modifications of ICD based on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. ICD status and Ardouin Scale of Behaviour in PD were assessed at baseline and 1 year following subthalamic DBS. Location of active contacts within the 3 subthalamic nucleus functional territories was investigated., Results: A total of 217 were patients included. Of the patients, 10.6% had ICD at baseline of which 95.6% improved at 1 year following subthalamic DBS; 3.6% of the patients experienced de novo ICD at 1 year following subthalamic DBS. Dopamine agonist dose reduction (from 309.8 to 109.3 mg) was the main driver of ICD regression (P = 0.05). Higher preoperative dyskinesias were associated with poorer ICD evolution (P = 0.04). Whereas baseline apathy was a risk factor of de novo ICD (P = 0.02), ICD improvement correlated with postoperative apathy (P = 0.004). Stimulation power and position of active contacts-mainly located within the sensorimotor part of the subthalamic nucleus-did not influence ICD., Conclusions: This 1-year, postoperative follow-up study showed ICD regression and dopaminergic drug reduction with optimal position of the active contacts within the subthalamic nucleus. Whereas patients with PD with preoperative ICD were prone to postoperative apathy, we also showed that those with preoperative apathy had a higher risk to experience postoperative de novo ICD, further highlighting the meaningful influence of postoperative management of dopaminergic medication on outcome and the continuum between apathy and ICD. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Objective: To assess the association between rapid eye movement sleep behavior disorder (RBD) and other determinants and incident impulse control disorder behaviors (ICBs) in patients with early Parkinson disease (PD) using longitudinal data from the Parkinson's Progression Markers Initiative., Methods: Four hundred one newly diagnosed PD patients were prospectively evaluated at baseline (BL), month 6, and annually for 5 years. Probable RBD (pRBD) was assessed with the RBD Screening Questionnaire (RBDSQ) and dichotomized using a cutoff value of ≥6. The association of BL and time-dependent (TD) pRBD and other covariates with the development of ICB symptoms was evaluated using Cox proportional hazards regression and general estimating equation logistic regression. Models considered adjustment for age, sex, Movement Disorders Society Unified Parkinson's Disease Rating Scale part III, Geriatric Depression Scale (GDS-15), RBD medication use, total levodopa equivalent daily dose, and dopamine agonist (DA) and antidepressant medication use., Results: Both BL pRBD and TD pRBD were not associated with an increased risk for incident ICB symptoms after adjustment for covariates (adjusted hazard ratio [HR] = 1.17, p = 0.458 and HR = 1.27, p = 0.257, respectively). In a modified TD pRBD model (ie, considering subjects as pRBD onward from the first time point with RBDSQ score ≥ 6), the risk for incident ICB symptoms was higher in pRBD in unadjusted (HR = 1.48, p = 0.038) but not adjusted (HR = 1.29, p = 0.203) models. TD DA use (HR = 1.64, p = 0.039), TD GDS-15 score (HR = 1.12, p < 0.001), and male sex (year 3: HR = 2.10, p = 0.009; year 4: HR = 3.04, p = 0.006; year 5: HR = 4.40, p = 0.007) were associated with increased ICB symptom risk., Interpretation: pRBD is not clearly associated with ICB symptom development in early PD, in contrast to DA use, depression, and male sex. ANN NEUROL 2020;88:759-770., (© 2020 American Neurological Association.)

Background: Whether reserve plays a role in Parkinson's disease (PD) patients has received less attention than in dementia and has been mainly examined in relation with cognitive function., Objective: To investigate whether reserve plays a role in the severity and progression of motor, cognitive, and nonmotor PD symptoms by examining whether education level (proxy of reserve) is associated with baseline performance and rate of progression., Methods: We used data from a longitudinal cohort of PD patients (≤5-year disease duration at baseline) annually followed up to 5 years (n = 393; 41% women; mean age = 62.3 years, standard deviation = 10.0; mean disease duration = 2.6 years, standard deviation = 1.5). We examined the relationship of education with time to reach Hoehn and Yahr stage ≥3 using Cox regression and with baseline severity and progression of motor (Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts II and III, gait speed), cognitive (Mini-Mental State Examination), and nonmotor (depression, anxiety, nonmotor symptoms scale, quality of life) symptoms using mixed models., Results: Education level was not associated with age at onset or diagnosis. Compared with the low-education group, the incidence of Hoehn and Yahr ≥3.0 was 0.42 times lower (95% confidence interval, 0.22-0.82, P = 0.012) in the high-education group. Higher education was associated with better baseline motor function (P < 0.001), but not with the rate of motor decline (P > 0.15). Similar results were observed for cognition. Education was not associated with nonmotor symptoms., Conclusions: Higher education is associated with better baseline motor/cognitive function in PD, but not with rate of decline, and with a lower risk of reaching Hoehn and Yahr ≥3 during the follow-up. Our observations are consistent with a passive reserve hypothesis for motor/cognitive symptoms. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD., Methods: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset., Results: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105)., Conclusions: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD)., Methods: The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose., Results: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28., Conclusions: Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Background: This phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinson's disease and levodopa-induced dyskinesia., Methods: Patients with idiopathic Parkinson's disease and moderate to severe levodopa-induced dyskinesia were randomized to AQW051 10 mg (n = 24), AQW051 50 mg (n = 24), or placebo (n = 23) once daily for 28 days. Coprimary end points were change in Modified Abnormal Involuntary Movement Scale and Unified Parkinson's Disease Rating Scale part III scores. Secondary outcomes included pharmacokinetics., Results: In total, 67 patients completed the study. AQW051-treated patients experienced no significant improvements in Modified Abnormal Involuntary Movement Scale or Unified Parkinson's Disease Rating Scale part III scores by day 28. AQW051 was well tolerated; the most common adverse events were dyskinesia, fatigue, nausea, and falls., Conclusions: AQW051 did not significantly reduce dyskinesia or parkinsonian severity. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

The "Ardouin Scale of Behavior in Parkinson's Disease" is a new instrument specifically designed for assessing mood and behavior with a view to quantifying changes related to Parkinson's disease, to dopaminergic medication, and to non-motor fluctuations. This study was aimed at analyzing the psychometric attributes of this scale in patients with Parkinson's disease without dementia. In addition to this scale, the following measures were applied: the Unified Parkinson's Disease Rating Scale, the Montgomery and Asberg Depression Rating Scale, the Lille Apathy Rating Scale, the Bech and Rafaelsen Mania Scale, the Positive and Negative Syndrome Scale, the MacElroy Criteria, the Patrick Carnes criteria, the Hospital Anxiety and Depression Scale, and the Mini-International Neuropsychiatric Interview. Patients (n=260) were recruited at 13 centers across four countries (France, Spain, United Kingdom, and United States). Cronbach's alpha coefficient for domains ranged from 0.69 to 0.78. Regarding test-retest reliability, the kappa coefficient for items was higher than 0.4. For inter-rater reliability, the kappa values were 0.29 to 0.81. Furthermore, most of the items from the Ardouin Scale of Behavior in Parkinson's Disease correlated with the corresponding items of the other scales, depressed mood with the Montgomery and Asberg Depression Rating Scale (ρ=0.82); anxiety with the Hospital Anxiety and Depression Scale-anxiety (ρ=0.56); apathy with the Lille Apathy Rating Scale (ρ=0.60). The Ardouin Scale of Behavior in Parkinson's disease is an acceptable, reproducible, valid, and precise assessment for evaluating changes in behavior in patients with Parkinson's disease without dementia., (© 2015 International Parkinson and Movement Disorder Society.)

Background: Substance and behavioral addictions have already been described separately or in combination in Parkinson's disease. However, no comparisons of the prevalence of addictive behaviors in patients with Parkinson's disease and the general population have been published. The objective of this study was to compare the prevalence and characteristics of addictions (gambling, hypersexuality, tobacco, and alcohol) in patients with Parkinson's disease and in a matched, paired sample from the general population., Methods: After matching for age, sex, and complete field questionnaires on addictions, we had 115 data sets., Results: No difference was observed between Parkinson's disease and control populations concerning pathological gambling (0.87% vs 0.87%, P = .99), tobacco addiction (1.7% vs 1.7%, P = .99), and alcohol dependence (2.6% vs 3.5%, P = .71). The Parkinson's disease group showed 2 cases of sexual addiction (1.7% vs 0, P = .15)., Conclusions: Our results indicate that patients with Parkinson's disease do not have specific profiles for tobacco or alcohol addiction and pathological gambling compared with the general population., (Copyright © 2011 Movement Disorder Society.)

Parkinson's disease (PD) is mainly characterized by its motor manifestations, but it is also frequently associated with dementia. Early diagnosis of PD dementia (PDD) is particularly important because effective cholinesterase inhibitor treatments are available. This study aimed at validating a short procedure for screening for PDD in routine clinical practice and which adopts recently published diagnostic criteria. One hundred eighty-eight patients with PD participated in the study. The examination procedure comprised three steps: standard clinical examination, a short cognitive function assessment fulfilling the requirements of the Movement Disorders Society (Mini Mental State Examination, five-word test, word generation task, and impact on daily life, including a questionnaire on compliance with medication) and an extensive evaluation of cognitive functions and behavior. After each step, the suspected presence or absence of dementia was recorded. After the short cognitive function assessment, PDD was suspected in 18.62% of the patients [95% confidence interval (CI): 13.32-24.93%]. After the extensive assessment, 21.81% (95% CI: 16.13-28.40%) met the criteria for probable PDD. The short battery's sensitivity and specificity were 65.85% (95% CI = 49.41-79.92%) and 94.56% (95% CI = 89.56-97.62%), respectively. A stepwise logistic regression analysis showed that use of a specific cut-off considerably enhanced the short battery's sensitivity (85.37%, 95% CI = 70.83-94.43%) without decreasing its specificity (83.67%, 95% CI = 76.69-89.25%). With an easy-to-use, short battery of tests that are commonly used in routine clinical practice, it is possible to diagnose PDD in accordance with reference criteria and with the same sensitivity and specificity as in a more extensive evaluation., (© 2010 Movement Disorder Society.)

S90049, a novel sublingual formulation of the non-ergoline D(2)-D(3) agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single-dose double-blind double-placebo 3 x 3 cross-over study. Optimal tested doses were determined during a previous open-label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (Delta UPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 +/- 8 years, PD duration: 12 +/- 6 years, UPDRS III OFF: 37 +/- 15) participated. S90049 was superior to placebo on Delta UPDRS III (-13 +/- 12 versus -7 +/- 9 respectively; estimated difference -5.2, 95% Confidence Interval (CI)[-10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, Delta UPDRS III was similar on S90049 (-21.2 +/- 10.1) and apomorphine (-23.6 +/- 14.1) (estimated difference: 4.0 95% CI [-2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate., ((c) 2009 Movement Disorder Society.)

The impact of motor complications of Parkinson's disease (PD), especially levodopa-induced dyskinesias, on quality of life (QL) was studied in 143 patients with PD. All were evaluated on the Hoehn and Yahr (H&Y) scale, and the Motor part of the Unified Parkinson's Disease Rating Scale (UPDRS). Motor complications were analyzed using the UPDRS Parts IV(A) and IV(B) and the Abnormal Involuntary Movement Scale. A specific Parkinson's disease quality of life questionnaire (39-item version, PDQ-39) was used. Motor complications significantly worsened the PDQ-39 Summary Index (PDQ-SI) of patients with PD. The dimensions of Mobility, Activities of Daily Living, Stigma, and Communication were the most strongly affected. "Peak dose" dyskinesia decreased Mobility, Emotional Well-Being, and Cognition, whereas biphasic dyskinesia affected Mobility, Stigma, Communication, and Activities of Daily Living. Morning akinesia, end-of-dose fluctuations, and "unpredictable offs" decreased QL on the dimensions of Mobility, Activities of Daily Living, Stigma, and Communication. Nocturnal akinesia led to a deterioration of all dimensions of the PDQ-39. Thus, motor complications and especially nocturnal akinesia and biphasic dyskinesias worsened the QL of PD patients., (Copyright 2004 Movement Disorder Society.)

We investigated whether administration of the catechol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson's disease patients experiencing severe motor fluctuations. In addition, the pharmacodynamics and safety of entacapone and apomorphine coadministration in these patients were examined. The study followed a three-sequence, three-period, crossover design. Patients were randomly assigned to one of three sequences that included single oral doses of entacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 separate test days, study treatment was administered before apomorphine. The study evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation [Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. Furthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were evaluated at baseline and study end. Pharmacokinetic parameters for apomorphine (C(max), AUC, t(max), t(1/2)) were unchanged by the administration of entacapone, and changes in both the tapping test and AIMS score were similar with all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There was no significant difference in mean total UPDRS scores between baseline and study end. The administration of entacapone did not change the pharmacokinetic or pharmacodynamic effects of apomorphine in these patients or prolong the clinical effect of apomorphine. Thus, apomorphine may be safely administered to patients receiving therapy with levodopa and entacapone, providing a useful addition to treatment for patients with advanced Parkinson's disease.

To assess the long-term follow-up of the globus pallidus internus (GPi) stimulation, six patients were evaluated every year by using the Unified Parkinson's Disease Rating Scale (UPDRS). Three years postoperatively, GPi stimulation led to a significant improvement of dyskinesia severity (50%, P = 0.05) and activities of daily living (subscore of quality of life scale, 9%, P = 0.05). However, the improvement induced by chronic pallidal stimulation on the mean daily duration in the off state was lost at the last assessment., (Copyright 2002 Movement Disorder Society)

Ten patients who had Parkinson's disease with disabling dyskinesia were included in this study to evaluate the role of mental (mental calculation) and motor (flexion/extension of right fingers, flexion/extension of left fingers, flexion/extension of the neck, speaking aloud) tasks on the worsening of peak-dose dyskinesia following administration of an effective single dose of apomorphine. Compared with the score at rest (1.3+/-0.3), a significant aggravation of the dyskinesia score was observed during speaking aloud (5.2+/-1.1, p<0.05), movements of right (4.5+/-1.0, p<0.05) and left (3.7+/-0.8, p<0.05) fingers, movements of the neck (5.1+/-1.0, p<0.05), and mental calculation (3.1+/-1.0, p<0.05). These results suggest that activation tasks such as "speaking aloud" could be used for objective assessment of dyskinesia severity.