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Background: The impact of expectation of benefit on outcomes is well established in Parkinson's disease (PD). A reduction of a treatment effect due to a perceived placebo allocation (lessebo effect) in randomized controlled trials (RCTs) was documented for symptomatic treatments., Objectives: To evaluate the lessebo effect in disease modification RCTs (DMT) in PD., Methods: Subject-level meta-analyses of active treatment arms of DMT (n = 1149 subjects): FS-1, FS-TOO (probability of placebo allocation/P (placebo)  = 0.33) and DATATOP, PRECEPT, QE2 (P (placebo)  = 0.25). We tested the association between P (placebo) and time to dopaminergic treatment initiation using a marginal Cox proportional hazards model., Results: The adjusted hazard ratio (P (placebo)  = 0.25 vs. 0.33) for initiation of dopaminergic treatment was 1.15 (95% CI: 0.92-1.43)., Conclusions: We did not observe the lessebo effect in DMT. The necessary use of a placebo (and no active comparator) is a limitation. The prospective measurement of expectation of benefit could help to evaluate the many impacts of placebo use. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia., Methods: We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson's severity, site, and initial treatment with pramipexole or levodopa., Results: For subjects who consumed >12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.61 (95% CI, 0.37-1.01) compared with subjects who consumed <4 ounces/day. For subjects who consumed between 4 and 12 ounces/day, the adjusted hazard ratio was 0.73 (95% CI, 0.46-1.15; test for trend, P = .05)., Conclusions: These results support the possibility that caffeine may reduce the likelihood of developing dyskinesia., (Copyright © 2013 Movement Disorder Society.)

The rate of progression of Parkinson's disease (PD) is highly variable. Knowledge of factors associated with disease milestones and commonly used research outcome measures helps with patient counseling and guides the design and interpretation of clinical studies. The objective of the study was to identify prognostic factors for time to acquiring disability requiring dopaminergic therapy that are reproducible within 2 large prospectively followed cohorts. Potential prognostic factors were identified using data from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial, and their reproducibility was examined using data from the Parkinson Research Examination of CEP-1347 trial (PRECEPT). In multivariable analyses of the DATATOP cohort, higher baseline Unified Parkinson's Disease Rating Scale (UPDRS) scores, full-time employment, a lesser smoking history, and onset on the left side were associated with a shorter time to disability requiring dopaminergic therapy. PRECEPT data confirmed the associations of higher baseline UPDRS scores and full-time employment with shorter time to requiring treatment. Any clinical trial using the end point of time to disability requiring dopaminergic therapy should ensure that groups are well balanced with respect to baseline UPDRS scores and the proportion of subjects employed full time and should consider including these variables as covariates in the statistical model for primary analysis of treatment effects. We suspect that individuals employed full time may have a lower threshold for requiring dopaminergic therapy because of occupational demands., (Copyright © 2011 Movement Disorder Society.)

Perhaps the most important unmet need in Parkinson's disease (PD) is the ability to slow or prevent progression of the neurodegeneration that underlies the motor and nonmotor features of this disorder. Pramipexole, a dopamine agonist used for the symptomatic treatment of PD, has demonstrated neuroprotective properties in laboratory studies. The PRamipexole On Underlying Disease (PROUD) study is a randomized, double-blind clinical trial evaluating the ability of pramipexole to modify disease progression using a delayed-start design. PD patients (n = 535) with mean age 62.5 years, mean duration since diagnosis of 4.4 months, and mean total Unified Parkinson's disease Rating Scale (UPDRS) score of 24.5 were recruited. In Phase I, patients were randomly assigned to be titrated to 1.5 mg pramipexole or placebo and maintained on study drug for 6-9 months. In Phase II, all patients were titrated to 1.5 mg pramipexole and maintained on study drug until the end of the study at 15 months. No rescue medication was allowed in the protocol. The primary endpoint is the change in total UPDRS score (parts I-III) from baseline to 15 months. A range of secondary endpoints separately assess UPDRS subscales, quality of life, depression, and impulse control disorders. A sub-study examined dopamine transporter uptake scans at baseline and 15 months. The results of PROUD will provide insight into the potential for early versus delayed treatment with pramipexole to modify motor outcome at 15 months in recently diagnosed PD patients.

Uric acid (UA) may be associated with the progression of Parkinson's disease and related neurodegenerative conditions; however, its association with Huntington's disease (HD) progression has not been explored. A secondary analysis of 347 subjects from the CARE-HD clinical trial was performed to examine the relationship between baseline UA levels and the level of functional decline in HD. Outcomes included change in scores at 30 months for the Unified Huntington's Disease Rating Scale components. There was less worsening of total functional capacity over time with increasing baseline UA levels (adjusted mean worsening in scores: 3.17, 2.99, 2.95, 2.28, 2.21, from lowest to highest UA quintile, P = 0.03). These data suggest a possible association between higher UA levels and slower HD progression, particularly as measured by total functional capacity. If confirmed, UA could be an important predictor and potentially modifiable factor affecting the rate of HD progression., ((c) 2009 Movement Disorder Society.)

The objective of this study was to examine the relationship between CAG repeat length (CAGn) and clinical progression in patients with Huntington's disease (HD). There are conflicting reports about the relationship between CAGn and clinical progression of HD. We conducted an analysis of data from the Coenzyme Q10 and Remacemide Evaluation in Huntington's Disease (CARE-HD) clinical trial. We modeled progression over 30 months on the Unified Huntington's Disease Rating Scale (UHDRS) and supplemental neuropsychological and behavioral tests using multiple linear regression. Mean subject age was 47.9 +/- 10.5 years and mean CAGn was 45.0 +/- 4.1. Multiple linear regression revealed statistically significant associations between CAGn and worsening on several motor, cognitive, and functional outcomes, but not behavioral outcomes. Many effects were clinically important; 10 additional CAG repeats were associated with an 81% increase in progression on the Independence Scale. These associations were not observed in the absence of age adjustment. Age at the time of assessment confounds the association between CAGn and progression. Adjusting for age shows that longer CAGn is associated with greater clinical progression of HD. This finding may account for the variable results from previous studies examining CAGn and progression. Adjusting for CAGn may be important for clinical trials., ((c) 2008 Movement Disorder Society.)

Placebo-associated improvements have been previously documented in small series of Parkinson's disease (PD) patients. Using a strict definition of placebo-associated improvement, we examined rates and timing of placebo responses to identify patient- and study-based characteristics, predicting positive placebo response in several PD clinical trials. We collected individual patient data from the placebo groups of 11 medical and surgical treatment trials involving PD patients with differing PD severities and placebo-assignment likelihoods. We defined a positive placebo response as > or = 50% improvement in total Unified Parkinson's Disease Rating Scale motor (UPDRSm) score or a decrease by > or = 2 points on at least two UPDRSm items compared to baseline. We calculated positive placebo response rates at early (3-7 weeks), mid (8-18 weeks), and late (23-35 weeks) stages of follow-up. Odds ratios for patient- and study-based characteristics were obtained from a model fitted using generalized estimating equations. There were 858 patients on placebo who met inclusion criteria for analysis. Three studies involved patients without need of symptomatic treatment, two involved patients without motor fluctuations needing symptomatic treatment, and six (three medical and three surgical) involved patients with motor fluctuations. The overall placebo response rate was 16% (range: 0-55%). Patients with higher baseline UPDRSm scores and studies that focused on PD with motor fluctuations, surgical interventions, or those with a higher probability of placebo assignment showed increased odds of positive placebo response. Placebo responses were temporally distributed similarly during early, mid, and late phases of follow-up. Placebo-related improvements occur in most PD clinical trials and are similarly distributed across all 6 months of follow-up. Recognition of factors that impact placebo response rates should be incorporated into individual study designs for PD clinical trials., (2008 Movement Disorder Society)

The aim of this study was to investigate factors associated with decline in health-related quality of life in Parkinson's disease, by a retrospective cohort study from referral centers in Canada and the United States. Subjects were patients with early Parkinson's disease (N = 362) enrolled in a clinical trial of deprenyl (selegiline) and tocopherol (DATATOP) and followed prospectively. The main outcome measure was change in health-related quality of life using SF-36 Mental and Physical Component Summary scores. The mean interval between SF-36 measurements was 1.7 +/- 0.1 years, beginning 5 to 6 years after enrolment into the trial. In multivariable analysis, baseline Hamilton Depression Scale scores and self-rated cognitive function were associated with subsequent decline in Physical Component Summary scores, while older age and Schwab and England activities of daily living scores were associated with decline in Mental Component Summary scores. The Postural Instability Gait Disorder score was the only variable found to decline concurrently with HRQOL. Our results suggest that depression, self-rated cognitive function, and one's degree of functional independence are predictors of subsequent changes in HRQOL. Our focus in clinical care needs to be broadened beyond assessing and treating Parkinsonism, recognizing the impact of mood, cognition and function on HRQOL., (2007 Movement Disorder Society)

Dyskinesias are a major complication of dopaminergic therapy in the long-term treatment of Parkinson's disease. In the CALM-PD trial, subjects were initially randomized to levodopa or pramipexole and could later add levodopa if needed. After adjusting for disease duration and daily levodopa dosage, the incidence of dyskinesias after initiating levodopa was not significantly different among subjects initially randomized to levodopa and those initially randomized to pramipexole., (2007 Movement Disorder Society)

We report on the development and results of preliminary psychometric testing of a disease specific health-related quality of life (HRQoL) scale intended for use in individuals diagnosed with idiopathic Parkinson's disease (PD). Results from an initial qualitative study provided content for item development and scale construction of the Parkinson's disease quality of life scale (PDQUALIF). The 33-item instrument includes seven domains: social/role function, self-image/sexuality, sleep, outlook, physical function, independence, and urinary function, plus one item of Global HRQoL. Initial psychometric testing of the instrument was conducted in 233 outpatient clinic attendees with physician-confirmed idiopathic PD. Factor structure, reliability and validity of the scale have been established in this cross-sectional study. Continuing development of the PDQUALIF will be directed at enhancing the psychometric properties, establishing responsiveness and determining appropriateness in culturally diverse samples., (Copyright 2003 Movement Disorder Society)

The objective of this study was to examine the experience of spouses caregiving for their spouse with Parkinson's disease (PD) and to determine whether their experiences differed by stage of disease. By using a cross-sectional design and mail questionnaire data from 380 spouse caregivers across 23 sites of the Parkinson Study Group, key caregiver variables were examined by stage of PD. Three categories of variables--caregiver role strain (10 measures), caregiver situation (four measures), and caregiver characteristics (four measures)--were analyzed by using t tests with Bonferroni correction. Specific types and amounts of role strain accumulated as the disease progressed, and they differed significantly between stages (p < 0.05). In the caregiving situation, the mean number of caregiving tasks tripled by stage 4/5. Negative changes in lifestyle plus decreases in predictability in caregivers' lives increased significantly in late-stage disease (p < 0.05). Caregiver characteristics of physical health and preparedness did not significantly differ across stages of disease. Depression was significantly higher by stage 4/5. Mutuality, the positive quality of the relationship as perceived by the caregiving spouse, declined beginning at stage 2. Caregiver strain is experienced across all stages of PD and accumulates significantly as the disease progresses. This study defines types and amounts of strain by stage of disease, which will be helpful in designing formal intervention trials to provide more effective help for spouse caregivers.

To examine the antidepressant specificity of fluoxetine in Huntington's disease (HD), we carried out a randomized, double-blind, placebo-controlled trial of this medication in nondepressed HD patients. Thirty patients with early HD who were depressed (Hamilton Depression Inventory < 16) were randomized to placebo (N = 13) or fluoxetine 20 mg/day (N = 17) and were followed up for 4 months. Outcome measures included changes in total functional capacity (TFC) and in standardized neurological, cognitive, and behavioral ratings. After adjustment for the higher education level found in the placebo group at baseline, no differences between the treatment groups were found in TFC, neurological, or cognitive ratings. Fluoxetine-treated patients did show a slight reduction in agitation and in the need for routine. Although fluoxetine may be a useful antidepressant in depressed HD patients, it failed to exert substantial clinical benefits in nondepressed HD patients.