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BACKGROUND The Quality of Life in Neurological Disorders (Neuro-QoL) is a publicly available health-related quality-of-life measurement system. OBJECTIVE The aim of this study was to evaluate the utility of Neuro-QoL item banks as outcome measures for clinical trials in Parkinson's disease. METHODS An analysis of Neuro-QoL responsiveness to change and construct validity was performed in a multicenter clinical trial cohort. RESULTS Among 310 participants over 3 years, changes in five of eight Neuro-QoL domains were significant (P

BACKGROUND: The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed. OBJECTIVES: To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression. METHODS: We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single-center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS-25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS-21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single-center cohort using proportional hazards models. RESULTS: The mPSPRS-25 showed excellent agreement (0.99; P < 0.001) with the original PSPRS at baseline, 0.98 (P < 0.001) agreement in measuring change over 6 months, and 0.98 (P < 0.001) over 12 months. The mPSPRS-21 showed agreement of 0.94 (P < 0.001) with the original PSPRS at baseline, 0.92 (P < 0.001) at 6 months, and 0.95 (P < 0.001) at 12 months. Baseline and 6-month change in both modified scales were highly predictive of survival in the single-center cohort. CONCLUSIONS: Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology.

ObjectiveTo investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.MethodsThe Safety of Urate Elevation in Parkinson’s Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1–7.0 mg/dL) or moderate (7.1–8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.ResultsInosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson’s Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = −0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = −0.44; p = 0.006). No significant associations were observed in men.ConclusionsInosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.Clinicaltrials.gov identifierNCT00833690.Classification of evidenceThis study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.

Background Optimal management in expert centers for Parkinson's disease (PD) usually involves pharmacological and non-pharmacological interventions, delivered by a multidisciplinary approach. However, there is no guideline specifying how this model should be organized. Consequently, the nature of multidisciplinary care varies widely. Objective To optimize care delivery, we aimed to provide recommendations for the organization of multidisciplinary care in PD. Methods Twenty expert centers in the field of multidisciplinary PD care participated. Their leading neurologists completed a survey covering eight themes: elements for optimal multidisciplinary care; team members; role of patients and care partners; team coordination; team meetings; inpatient versus outpatient care; telehealth; and challenges towards multidisciplinary care. During a consensus meeting, outcomes were incorporated into concept recommendations that were reviewed by each center's multidisciplinary team. Three patient organizations rated the recommendations according to patient priorities. Based on this feedback, a final set of recommendations (essential elements for delivery of multidisciplinary care) and considerations (desirable elements) was developed. Results We developed 30 recommendations and 10 considerations. The patient organizations rated the following recommendations as most important: care is organized in a patient-centered way; every newly diagnosed patient has access to a core multidisciplinary team; and each team has a coordinator. A checklist was created to further facilitate its implementation. Conclusion We provide a practical tool to improve multidisciplinary care for persons with PD at the organizational level. Future studies should focus on implementing these recommendations in clinical practice, evaluating their potential applicability and effectiveness, and comparing alternative models of PD care.

Contains fulltext : 229744.pdf (Publisher’s version ) (Open Access) BACKGROUND: Quality of life in Parkinson's disease (PD) is affected by motor and nonmotor symptoms, necessitating an integrated care approach. Existing care models vary considerably in numerous domains. The objectives of this study were to perform a systematic review and meta-analysis of PD integrated care models and develop recommendations for a representative model. METHODS: We conducted a systematic review of published integrated care models and a meta-analysis of randomized, controlled trials examining integrated care versus standard care. The primary outcome was health-related quality of life using a validated PD scale. We evaluated levels of care integration using the Rainbow Model of Integrated Care. RESULTS: Forty-eight publications were identified, including 8 randomized, controlled trials with health-related quality of life data (n = 1,149 total PD patients). Qualitative evaluation of individual care model integration guided by the Rainbow Model of Integrated Care revealed frequent clinical and professional integration, but infrequent organizational and population-based integration elements. Meta-analysis of randomized, controlled trials revealed significant heterogeneity (I(2) = 90%, P

BackgroundWe undertook this study to identify patients with Parkinson disease (PD) with no or rare falls who may progress to frequent falling by their next annual follow-up visit.MethodsWe analyzed data in the National Parkinson Foundation Quality Improvement Initiative database to identify factors predicting which patients with PD with no or rare falls at the baseline visit will report at least monthly falls at the annual follow-up visit. Multivariable models were constructed using logistic regression. Variables were introduced in 4 blocks: in the 1st block, variables present at or before the baseline visit were entered; in the 2nd, baseline visit assessments; in the 3rd, interventions implemented during baseline visit; and, in the 4th block, changes in comorbidities, living situation, and treatment between visits.ResultsOf 3,795 eligible participants, 3,276 (86.3%) reported no or rare falls at baseline visit, and of them, 382 (11.7%) reported at least monthly falls at follow-up visit. Predictors included female sex, ConclusionsThis large-scale analysis identified several predictors of progression to falling in PD. Such identifiers may help target patient subgroups for falls prevention intervention. Some factors are modifiable, offering opportunities for developing such interventions.

Introduction Clinical cohort studies suggest that mild cognitive impairment (MCI) is common in early Parkinson's disease (PD). The objectives of this paper were to describe cognitive function in a large clinical trial of early treated PD patients at baseline and over time using two brief cognitive screening tests. Methods In total 1741 participants were enrolled in the NINDS Exploratory Trials in Parkinson's disease (NET-PD) Long-term Study-1 (LS-1). The Symbol Digit Modalities Test (SDMT) was collected annually. The SCales for Outcomes in PArkinson's disease-COGnition (SCOPA-COG) was collected at baseline and at year 5. The trial was stopped early based on a planned interim analysis after half the cohort completed 5 years of follow-up. The median length of follow-up was 4 years (range 3–6 years). Predictors of cognitive change were examined using cross sectional (baseline) and longitudinal multivariable linear regression. Results The mean (SD) change from baseline to 5 years was −1.9 (5.1) for the SCOPA-COG and −2.1 (11.1) for the SDMT. Age and baseline UPDRS motor scores were associated with a more rapid decline in SDMT scores and 5 year SCOPA-COG scores. Male gender was associated with more rapid decline in SDMT. Self-reported income was a novel predictor of baseline cognitive function, even adjusted for educational status, although not significantly associated with change over time. Conclusion This large prospective cohort study demonstrated mild cognitive decline in early treated Parkinson's disease. The study identified income level as a novel predictor of cognitive function.

INTRODUCTION: PD is associated with impairments that progress over time to disability. A large number of disability scales exist with little information on the best choice in PD. METHODS: Following methodology adopted by the International Parkinson and Movement Disorder Society Task Force, a review of disability scales used in PD was completed. Based on prespecified criteria, the review categorized scales into: "Recommended"; "Recommended with Further Validation in PD Required" when well-validated scales have not been specifically tested for clinimetric properties in PD; "Suggested"; and "Listed." RESULTS: Twenty-nine disability instruments were identified with nine scales fulfilling criteria for "Recommended" and 7 "Recommended with Further Validation in PD Required." Eight scales are "Suggested" and five scales are "Listed" for use in PD. The nine Recommended scales (Functional Status Questionnaire, Lawton-Brody Activities of Daily Living, Nottingham Activities of Daily Living, Schwab and England Activities of Daily Living, Self-Assessment PD Disability, Short Parkinson's Evaluation Scale/Scales for Outcomes in PD, Unified PD Rating Scale-II: Activities of Daily Living, Movement Disorders Society UPDRS Motor Experiences of Daily Living, PROMIS(R) and Neuro-QoL Physical Function), and the seven Recommended with Further Validation in PD Required are reviewed. CONCLUSION: Many disability measures are available and recommended for application in PD. The Task Force does not recommend the development of a new scale. Selection of the most appropriate instrument for a particular objective requires consideration of the characteristics of each scale and the goals of the assessment. (c) 2016 International Parkinson and Movement Disorder Society.

Background Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson’s disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day. Objective In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials. Patients and Methods The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled. Results At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was − 17.7 (standard error [SE] 1.3) vs. − 7.6 (1.3) points, respectively (− 10.1 points, 95% confidence interval [CI] − 13.8, − 6.5; p

Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson’s disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day. In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials. The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled. At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was − 17.7 (standard error [SE] 1.3) vs. − 7.6 (1.3) points, respectively (− 10.1 points, 95% confidence interval [CI] − 13.8, − 6.5; p

Background Depression is one of the most common nonmotor symptoms associated with Parkinson's disease (PD), yet the impact of depression on progression of disease is unclear. Objective The aim of this study was to prospectively characterize the relationship between depressive symptoms and measures of disease progression in a large sample of patients with early, medically treated PD. Methods Baseline and longitudinal Beck Depression Inventory (BDI) scores from participants in the NINDS Exploratory Trials in PD Long Term Study 1 were correlated with changes in multiple measures of disease severity over 5 years. Multivariate analysis of predictors of change in BDI was performed. Results Of 1,741 participants, 746 completed 5-year assessments and were included. Mean age was 62.00 years (standard deviation [SD]: 9.22) and mean disease duration was 1.69 years (SD, 1.16). Mean BDI score was 6.24 (SD, 5.02) at baseline and 8.57 (SD, 6.60) at 5 years. Baseline BDI score was strongly associated with rate of change in all examined measures of disease severity. In multivariate analysis, BDI 5-year change was associated with change in UPDRS Part I (excluding depression item; P

We conducted an exploratory analysis of the utility of the modified Rankin Scale (mRS) as a global measure of disability in early Parkinson’s diesase (PD) using the baseline data from a large cohort of PD patients enrolled in a longitudinal study of creatine. The mRS is scored 0–6 with lower scores reflecting less disability. For the analysis the mRS score was dichotomized at

Background Recognizing the factors associated with falling in Parkinson's disease (PD) would improve identification of at-risk individuals. Objective To examine frequency of falling and baseline characteristics associated with falling in PD using the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1) dataset. Methods The LS-1 database included 1741 early treated PD subjects (median 4 year follow-up). Baseline characteristics were tested for a univariate association with post-baseline falling during the trial. Significant variables were included in a multivariable logistic regression model. A separate analysis using a negative binomial model investigated baseline factors on fall rate. Results 728 subjects (42%) fell during the trial, including at baseline. A baseline history of falls was the factor most associated with post-baseline falling. Men had lower odds of post-baseline falling compared to women, but for men, the probability of a post-baseline fall increased with age such that after age 70, men and women had similar odds of falling. Other baseline factors associated with a post-baseline fall and increased fall rate included the Unified PD Rating Scale (UPDRS) Activities of Daily Living (ADL) score, total functional capacity (TFC), baseline ambulatory capacity score and dopamine agonist monotherapy. Conclusion Falls are common in early treated PD. The biggest risk factor for falls in PD remains a history of falling. Measures of functional ability (UPDRS ADL, TFC) and ambulatory capacity are novel clinical risk factors needing further study. A significant age by sex interaction may help to explain why age has been an inconsistent risk factor for falls in PD.

We assess the effects of EEG biofeedback training on levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD) using a sham feedback controlled study design. Nine subjects were randomized into either a treatment group or control group and underwent 24 sessions of either active feedback training or sham feedback. The training protocol aimed at increasing 8–15 Hz activity while inhibiting excess 4–8 Hz and 23–34 Hz activity at the C3-C4 derivation. There were no statistically significant differences baseline to post-active neurofeedback training as compared to sham feedback training in primary outcome measures assessing change in dyskinesia severity, nor in secondary outcome measures assessing change in clinical features of PD. Nonsignificant trends were observed in subjects’ PD home diaries indicating a decrease in the severity of motor fluctuations. Baseline to post-training comparisons of secondary outcome measures in quantitative EEG analysis showed significant interaction effects with...

Item does not contain fulltext OBJECTIVES: To explore current practices and opinions regarding hospital management of Parkinson disease (PD) patients in specialized PD Centers. METHODS: Fifty-one out of 54 National Parkinson Foundation (NPF) Centers worldwide completed an online survey regarding hospitalization of PD patients. RESULTS: Many Centers were concerned about the quality of PD-specific care provided to their patients when hospitalized. Primary concerns were adherence to the outpatient medication schedule and poor understanding by hospital staff of medications that worsen PD. Few Centers had a policy with their primary hospital that notified them when their patients were admitted. Rather, notification of hospitalization came often from the patient or a family member. Several Centers (29%) reported not finding out about a hospitalization until a routine clinic visit after discharge. Quick access to outpatient PD care following discharge was a problem in many Centers. Elective surgery, fall/fracture, infection, and mental status changes, were identified as common reasons for hospitalization. CONCLUSIONS: There is a perceived need for PD specialists to be involved during hospitalization of their patients. Improvement in communication between hospitals and PD Centers is necessary so that hospital clinicians can take advantage of PD specialists' expertise. Education of hospital staff and clinicians regarding management of PD, complications of PD, and medications to avoid in PD is critical. Most importantly, outpatient access to PD specialists needs to be improved, which may prevent unnecessary hospitalizations in these patients.

Cognitive dysfunction is an important aspect of Parkinson disease (PD) and is increasingly being examined in various large scale PD clinical studies. However, the sensitivity of some of the cognitive measures used for detecting change in cognitive status in early PD patients is not known nor is the relationship between cognitive outcome measures and other motor and non-motor disease characteristics and various demographic parameters in early PD patients. The current analysis of the NET-PD cohort (i.e., untreated patients) was undertaken to: 1) assess which (if any) baseline demographic parameters correlate with baseline cognitive measures and any potential change in cognitive measures over the 12-18 months evaluation period; 2) assess the extent to which cognitive measures employed (i.e., Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Frontal Assessment Battery (FAB) and Letter-Number Sequencing) are sensitive to change over time; 3) examine whether initiation of symptomatic therapy is associated with change in cognitive status. At baseline, NET-PD subjects had no significant impairment on the assessments employed. Only education and age were significant predictors of cognitive score at baseline. None of the summary measures were indicative of change in cognitive status over the 12-18 months of study. These results suggest either the cognitive domains examined are not affected in the population examined or that more sensitive measures of cognition than those currently employed may need to be considered for use in a large trial setting in which an early, highly educated PD population is studied.

Contains fulltext : 89746.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To pilot a data-driven quality care program in National Parkinson Foundation (NPF) Centers of Excellence. BACKGROUND: Evidence from comparative effectiveness research (CER) can be used to guide decisions regarding health care and to improve quality and efficiency of care. We propose to develop the infrastructure required to conduct CER across an extensive network of NPF Centers of Excellence. METHODS: We present the staged planning for a pilot study which will demonstrate the development and implementation of the infrastructure that will be needed for a large standardized patient-centered, clinical practice database for PD. This database will support CER and drive quality improvement studies. RESULTS: We describe the infrastructure for the ongoing pilot feasibility testing in a subset of six NPF Centers of Excellence, and we discuss the impact that the data (available in 2010) could have in guiding PD management. CONCLUSION: This preliminary experience will facilitate the longitudinal tracking of therapies and of outcomes in PD clinical practice. Further, we are hopeful that the information will provide insight into PD that will extend beyond the clinical trials population (the population included in most available PD databases). This prospective standardized real-world multi-center clinical practice database will aim to identify positive health outcomes associated with treatment approaches, and to identify variations in clinical outcomes that may suggest improvements in best clinical practice patterns. 01 september 2010

IntroductionParkinson’s disease (PD) presents unique personal and social challenges, particularly for those with onset before the age of 50 years.AimThe aim of this article is to evaluate sexual and non-sexual aspects of relationship satisfaction among persons with young-onset PD and their partners.Main Outcome MeasuresThe main outcome measures were Index of Sexual Satisfaction (ISS) and Golombok–Rust Inventory of Marital State (GRIMS).MethodsPersons with PD (PWP) and partners who attended the 2005 National Parkinson Foundation Young Onset Network Conference were asked to complete a survey. Each survey included demographics, a clinical history questionnaire, the Beck Depression Inventory (BDI), ISS, and GRIMS.ResultsSixty PWP (63% men, 85% in a relationship) responded to the survey. Median age was 50 years (range 29–62), with a median age at symptom onset of 43 years (range 17–55). ISS scores indicated clinically significant sexual dissatisfaction in 37%. Relationship dissatisfaction measured by the GRIMS was scored as “poor” or worse in 57%. Depressive symptomatology was severe in 19% and mild in 33%. Sexual dissatisfaction (ISS) correlated with relationship dissatisfaction (GRIMS) (correlation coefficient [CC]=0.58, P ConclusionsIn this study, sexual and relationship dissatisfaction were prevalent among young-onset PD patients. PD patients were similar to their partners in their level of sexual and relationship dissatisfaction. The degree of dissatisfaction did not correlate with demographics or self-reported disease characteristics. Self-reported depressive symptomatology among PD patients was adversely associated with both their and their partner’s relationship satisfaction.

Objective: To evaluate the Cognitive Linguistic Quick Test (CLQT) as a cognitive screening tool in Parkinson disease (PD). Methods: A total of 93 patients with PD were evaluated with the Mini-Mental State Examination (MMSE) and the CLQT. The CLQT provides separate ratings for 5 cognitive domains. Descriptive statistics, correlations between the tests, and diagnostic value for dementia were analyzed. Results: Cognitive Linguistic Quick Test correlated well with MMSE. Diagnostic values for dementia were similar for the 2 instruments. Unlike the MMSE, the CLQT also provided domain-specific information on cognitive deficits. Cognitive domains were differentially affected between and within the demented and nondemented patient groups with PD: memory was the weakest domain in the demented group and attention in the nondemented. Conclusions: The CLQT is a valuable instrument in assessing cognitive dysfunction in PD. The CLQT is superior to the MMSE as it also provides cognitive domain-specific information.

Contains fulltext : 153006.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To determine (1) the relationship between assisted timed Up and Go (TUG) performance and the Parkinson's Disease Questionnaire-39 (PDQ-39), and (2) whether adjusting the TUG score (adding time) improves the relationship between TUG performance and the PDQ-39 in persons with Parkinson disease (PD) who use assistive devices or push off, or both. DESIGN: Cross-sectional. SETTING: Twenty participating National Parkinson Foundation Centers of Excellence. PARTICIPANTS: Data were obtained from participants (N=6624) without exclusion at the 20 participating sites. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The relationship between TUG scores and PDQ-39 mobility scores was determined using the method of linear least squares. Adjusted scores were determined through minimizing the sum of the squared error. RESULTS: The correlation between assisted TUG scores and PDQ-39 mobility scores was slightly lower (R(2)=.384) compared with the correlation between nonassisted TUG scores and PDQ-39 mobility scores (R(2)=.409). Adjusting assisted TUG performance scores for push off and for use of an assistive device resulted in a modest increase in correlation (R(2)=.399). CONCLUSIONS: Applying adjustments to assisted TUG may provide clinically important information for evaluating balance, mobility, and falls, and for determining the most effective therapeutic strategies for persons with PD.

Objectives To investigate prognostic outcomes and utilization of medical services by patients with Parkinson disease (PD) and to identify predictors of such use. Patients and Methods Using the medical records linkage system of the Rochester Epidemiology Project, we identified an incidence cohort of 89 PD cases (Olmsted County, Minnesota, 1979-1988) and a reference group of 89 subjects without PD of the same age and sex and from the same population. Both patients with PD and reference subjects were followed up historically by medical record review from onset of PD (or index year) through death, last contact with the system, or end of study. Results Patients with PD had significantly more physician consultations per year (median, 7.9 vs 5.9; P =.001) and more emergency department visits per year (median, 0.6 vs 0.4; P =.05) than did reference subjects. Response to dopaminergic medications and higher education predicted more physician consultations among patients. The PD patients used neuroleptics and antidepressants significantly more frequently than reference subjects. The risk of nursing home placement was significantly increased for PD patients compared with reference subjects (relative risk, 6.7; 95% confidence interval, 3.7-12.1; P>.001). Poor response to dopaminergic medications, lower education level, older age at onset of PD, and dementia predicted a shorter time between onset and nursing home placement among PD patients. Survival was significantly reduced in PD patients compared with reference subjects (relative risk, 2.2; 95% confidence interval, 1.4-3.4; P>.001). Good response to dopaminergic medications, higher education, younger age at onset of PD, and absence of dementia predicted better survival among PD patients. Conclusions Patients with PD used outpatient and nursing home services more often than subjects without PD. Patients with PD also experienced a reduced survival time. Demographic and clinical characteristics influenced utilization patterns and outcomes.

Background: A construct calculated as the sum of items 13–15, 29, 30 of the Unified Parkinson’s Disease Rating Scale (UPDRS) has been used as an “Ambulatory Capacity Measure” (ACM) in Parkinson disease (PD). Its construct validity has never been examined. A similar construct, consisting of the mean value of the same UPDRS items has been used under the acronym PIGD as a measure of postural instability and gait disorder in PD. Objective: To examine the construct validity of the ACM and PIGD in PD. Methods: We analyzed data in an existing database of 340 PD patients, Hoehn and Yahr stages (HYS) 1–5 who participated in a study of falls. Number of falls (NOF) was recorded over 4 weeks, and UPDRS (mental, ADL, and motor subscales), HYS, Activities Based Confidence Scale (ABC), Freezing of Gait Questionnaire (FOG), Five Times Sit-to-Stand (FTSS), Timed Up-and Go (TUG), Gait Velocity (GV), and Berg Balance Scale (BBS) evaluations were performed. Internal consistency was assessed by Cronbach’s alpha. Construct validity was assessed through correlations of the ACM and PIGD to these measures and to their summed-ranks. A coefficient of determination was calculated through linear regression. Results: Mean age was 71.4, mean age at diagnosis 61.4 years; 46% were women; mean UPDRS subscale scores were: Mental 3.7; ADL 15.7; motor: 27.1; mean ACM was 6.51, and mean PIGD 1.30. Cronbach’s alpha was 0.78 for both ACM and PIGD. Spearman correlation coefficients between the ACM/PIGD and ABC, FOG, TUG, GV and BBS were 0.69, 0.72, 0.67, 0.58, and 0.70 respectively. Correlation between the ACM/PIGD and summed-ranks of HYS, NOF, ABC, FOG, FTSS, TUG, GV and BBS was high (Spearman r = 0.823, p < 0.0001); 68% of the variability in the summed-ranks was explained by ACM/PIGD. Conclusion: The ACM and the PIGD are valid global measures and accurately reflect the combined effects of the various components of ambulatory capacity in PD patients with HY stages 1–4.

Importance Optimizing assessments of rate of progression in Parkinson disease (PD) is important in designing clinical trials, especially of potential disease-modifying agents. Objective To examine the value of measures of impairment, disability, and quality of life in assessing progression in early PD. Design, Setting, and Participants Inception cohort analysis of data from 413 patients with early, untreated PD who were enrolled in 2 multicenter, randomized, double-blind clinical trials. Interventions Participants were randomly assigned to 1 of 5 treatments (67 received creatine, 66 received minocycline, 71 received coenzyme Q10, 71 received GPI-1485, and 138 received placebo). We assessed the association between the rates of change in measures of impairment, disability, and quality of life and time to initiation of symptomatic treatment. Main Outcomes and Measures Time between baseline assessment and need for the initiation of symptomatic pharmaceutical treatment for PD was the primary indicator of disease progression. Results After adjusting for baseline confounding variables with regard to the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II score, the UPDRS Part III score, the modified Rankin Scale score, level of education, and treatment group, we assessed the rate of change for the following measurements: the UPDRS Part II score; the UPDRS Part III score; the Schwab and England Independence Scale score (which measures activities of daily living); the Total Functional Capacity scale; the 39-item Parkinson’s Disease Questionnaire, summary index, and activities of daily living subscale; and version 2 of the 12-item Short Form Health Survey Physical Summary and Mental Summary. Variables reaching the statistical threshold in univariate analysis were entered into a multivariable Cox proportional hazards model using time to symptomatic treatment as the dependent variable. More rapid change (ie, worsening) in the UPDRS Part II score (hazard ratio, 1.15 [95% CI, 1.08-1.22] for 1 scale unit change per 6 months), the UPDRS Part III score (hazard ratio, 1.09 [95% CI, 1.06-1.13] for 1 scale unit change per 6 months), and the Schwab and England Independence Scale score (hazard ratio, 1.29 [95% CI, 1.12-1.48] for 5 percentage point change per 6 months) was associated with earlier need for symptomatic therapy. Conclusions and Relevance In early PD, the UPDRS Part II score and Part III score and the Schwab and England Independence Scale score can be used to measure disease progression, whereas the 39-item Parkinson’s Disease Questionnaire and summary index, Total Functional Capacity scale, and the 12-item Short Form Health Survey Physical Summary and Mental Summary are not sensitive to change. Trial Registration clinicaltrials.gov Identifiers:NCT00063193andNCT00076492

Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial.The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month.The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD.clinicaltrials.gov Identifier: NCT00833690.

BACKGROUND: Falls remain a significant cause of morbidity in PD. Risk factors are not well understood. OBJECTIVE: In this study we explore risk factors for falls in PD utilizing the cross-sectional, baseline data in the National Parkinson Foundation Quality Improvement Initiative (NPF-QII) database. Subjects are being followed prospectively, and this study will provide the basis for subsequent longitudinal analyses. METHODS: A cross-sectional analysis of data from 2,876 ambulatory patients with Parkinson disease enrolled in the NPF-QII at 18 sites. Main outcome measure was falling history in the 3 months preceding assessment. The following were considered as possible predictor variables: age, sex, height, weight, body mass index, disease duration, age at disease onset, investigator's confidence in the diagnosis, Hoehn and Yahr stage, rest tremor, ability to stand unassisted, coexistent pathologies (cardiovascular, respiratory, diabetes, cancer, neurological, osteoarthritis, and "other" comorbidities), anticholinergics, antidepressants, antipsychotics, cognitive enhancers, deep brain stimulation surgery, timed-up-and-go, semantic fluency, and 5 word recall. Variables with associations to the outcome measure in univariate analyses were analyzed in multivariable models using logistic regression. RESULTS: 37.2% of subjects experienced falls. In the multivariable regression model the following variables were found to be independently associated with falls: disease duration; Hoehn and Yahr stage; absence of rest tremor; cardiovascular, arthritis, or "other" comorbidity; antidepressants; deep brain stimulation surgery; timed-up-and-go; and, semantic fluency. CONCLUSION: Disease duration but not age is independently associated with falls in Parkinson disease. Timed-up-and-go accurately reflects falls risk. Impaired semantic fluency is independently associated with falls, while verbal memory is not. Comorbidities, antidepressants, and deep brain stimulation also contribute to falls risk. Language: en

Objective: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson’s disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). Background: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. Methods: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. Results: The variability in the PDQ-39 summary index score correlated with H&Y stage (R 2 ¼ 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. Conclusions: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices.

Administration of exogenous levodopa triggers locomotion in young rats prior to the onset of quadripedal movement. The same substance decreases locomotion in adult animals. The ontogenetic development of the response to levodopa was investigated in rats. Intraperitoneal injection of levodopa (150 mg/kg body weight) caused characteristic "crawling" or "swimming-like" locomotion patterns in 5- to 6-day-old animals. Noradrenergic mechanisms may be involved in this behavior. In 18- to 20-day-old rats, levodopa caused excessive locomotor activity, including running, jumping, and wall climbing. This effect can be attributed to the activation of postsynaptic dopaminergic receptors that are already present during the early stages of life. At 25–30 days of age, levodopa-induced motor activity was decreased in comparison with that of the 18- to 20-day-old rats, possibly due to changing patterns of D1D2-dopamine receptor subtype interactions. In contrast to observations in younger rats, the same dose of levodopa suppressed motor activity in 60- to 75-day-old rats. The presence of functional dopamine autoreceptors at this age may account for the change.

Item does not contain fulltext OBJECTIVE: To review the literature and to identify practice gaps in the management of the hospitalized Parkinson's disease (PD) patient. BACKGROUND: Patients with PD are admitted to hospitals at higher rates, and frequently have longer hospital stays than the general population. Little is known about outpatient interventions that might reduce the need for hospitalization and also reduce hospital-related complications. METHODS: A literature review was performed on PubMed about hospitalization and PD between 1970 and 2010. In addition, in press peer-reviewed papers or published abstracts known to the authors were included. Information was reviewed by a National Parkinson Foundation workgroup and a narrative review article was generated. RESULTS: Motor disturbances in PD are believed to be a causal factor in the higher rates of admissions and complications. However, other conditions are commonly recorded as the primary reason for hospitalization including motor complications, reduced mobility, lack of compliance, inappropriate use of neuroleptics, falls, fractures, pneumonia, and other important medical problems. There are many relevant issues related to hospitalization in PD. Medications, dosages and specific dosage schedules are critical. Staff training regarding medications and medication management may help to avoid complications, particularly those related to reduced mobility, and aspiration pneumonia. Treatment of infections and a return to early mobility is also critical to management. CONCLUSIONS: Educational programs, recommendations, and guidelines are needed to better train interdisciplinary teams in the management of the PD patient. These initiatives have the potential for both cost savings and improved outcomes from a preventative and a hospital management standpoint.

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.

Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from I to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateratized topography of degeneration across all affected individuals. (C) 2007 Elsevier Inc. All rights reserved.

The contribution of dopaminergic mechanisms to the generalization of epileptic activity was studied in rats given pilocarpine after pretreatment with selective dopamine agonists. At the dose of 200 mg/kg, pilocarpine produced limbic stereotypies but not convulsions or seizure-related brain damage. Pilocarpine, 200 mg/kg, following pretreatment with the D1 agonist (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3 benzazepine, but not its (S)-enantiomer, induced convulsive activity as revealed by behavioral, electroencephalographic alterations and widespread brain damage. These features were identical to those produced by a higher, convulsant dose of pilocarpine (400 mg/kg). On the other hand, pretreatment with the D2 agonist 4,4a,5,6,7,8,8a,9-octahydro-5-n-propyl-2H-pyrazolo-3,4-g-quinoline failed to induce convulsions. Furthermore, the D1 receptor antagonist (R)-(+)-8-chloro-2,3,4,5-n-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol prevented the convulsive activity induced by both 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3 benzazepine plus pilocarpine (200 mg/kg) and pilocarpine (400 mg/kg), given alone. However, neither dopamine agonists nor antagonists altered the limbic stereotypies induced by pilocarpine, suggesting a dopamine system involvement primarily in the mechanisms of epilepsy generalization. The results suggest that pharmacological manipulation of dopaminergic transmission may provide an alternative approach to therapy of secondarily generalized epilepsy.

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

We sought to ascertain frequency, type, risk factors of falling, and resulting injuries among parkinsonian patients. A survey was mailed to all patients treated at our center between 1/1/2000 and 4/30/2002 (N = 1,417). Information was collected on falls within the past 2 years, related injuries, and use of health care services. A total of 1,131 responses (response rate, 79.8%) were received. After the exclusion of nonparkinsonian disorders, statistics for the remaining group (n = 1,092) and predictive statistics for those diagnosed before 1/1/2000 (n = 1,013) were calculated. Outcomes included falls, fractures, injuries, surgery, and related use of health care services. Explanatory variables included sex, age, age at diagnosis, disease duration, atypical parkinsonism, and dementia. Most patients (55.9%) were men; 12.2% had atypical parkinsonism; 12.5% had dementia; median age was 74.7 years; median disease duration was 7 years; 55.9% had at least one fall in the past 2 years; 65.0% of them sustained an injury; 33.0% sustained a fracture; 75.5% of injuries required health care services; 40.6% of fractures required surgery. Older age, atypical parkinsonism, longer disease duration, and dementia were risk factors for falling; female sex and older age were predictors of fractures. Need for health care services after an injury was higher among older patients. Further prospective studies will be necessary to elucidate the specific prognostic outcomes of injuries due to falls among parkinsonian patients, and the impact of these injuries on disease progression and quality of life.

Objectives To determine the rate of and identify reasons for discontinuation of entacapone treatment in Parkinson disease patients. Methods A retrospective study design was used, including medical record reviews and telephone call to the patient as needed. Results Two hundred and twenty-two Parkinson disease patients were started on entacapone over a period of 3 years. One hundred and twenty-two patients (56%) had discontinued the medication by the end of the follow up period. Reasons for discontinuation included lack of efficacy (46%), worsening of parkinsonian symptoms (28%), worsened cognition (20%), dyskinesia (17%), nausea (11%), diarrhea (9%), cost (4%), other side effect (8%), and other, non-medication related reasons (19%). Presence of wearing off at the time of initial treatment and male sex were associated with decreased dropout rates, while the presence of orthostatic hypotension increased the likelihood of discontinuation. Patient age, disease duration, Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale section II score, presence of dementia, hallucinations, dyskinesias, or depression, number of daily L-dopa doses, and concomitant treatment with dopamine agonists did not affect dropout rate. Conclusions Lack of efficacy seems to be the main reason for entacapone discontinuation. Male patients with wearing off and no orthostatic hypotension seem to tolerate the medication better. Advanced disease stage, presence of cognitive dysfunction, and presence of dyskinesia should not necessarily preclude patients from being treated with entacapone, when otherwise indicated.

The relationship between trauma and movement disorders was recognized as early as the 19th century. Different types of trauma (e.g., mechanical injury, electrical injury, anoxic injury, repetitive injury) incurred on different parts of the nervous system (brain, spinal cord, peripheral nerves) in various ways (single or repetitive injury) have produced a great variety of movement disorders (parkinsonism, dystonia, tremors, hyperkinesis). Trauma can cause movement disorders directly, it can increase the risk for certain diseases affecting the extrapyramidal system, or it can act as a catalyst for the manifestation of an underlying subclinical condition. The significance of risk factors (such as family history of movement disorders and previous use of antidopaminergic agents) for the development of post-traumatic movement disorders remains controversial. The underlying pathophysiology is poorly understood, but it appears that regardless of the location of the trauma, both peripheral and central nervous system mechanisms may be involved.

The contribution of D1 and D2 dopamine (DA) receptor mechanisms to the behavioral supersensitivity and receptor upregulation induced by chronic DA antagonist administration were compared. Rats received either the selective D1 DA receptor antagonist SCH23390, the selective D2 DA receptor antagonist raclopride, their combination, or haloperidol, a predominantly D2 antagonist, for 21 days. Equivalent cataleptogenic doses of all drugs and drug combinations were employed. Tolerance to the cataleptic response was observed only in the haloperidol-treated group. Apomorphine-induced stereotypies were significantly enhanced in SCH23390-, raclopride-, and haloperidol-treated rats. In contrast, coadministration of both SCH23390 and raclopride had no effect on apomorphine-induced stereotypy. These findings suggest that neuroleptics blocking in equal proportion D1 and D2 receptor sites might be less likely to induce tardive dyskinesia and drug tolerance than those acting selectively on one or the other of these receptor subtypes.

Objective To assess the predictive value of baseline measures of impairment, disability, and quality of life for the timing of initiation of symptomatic treatment in early Parkinson disease (PD). Design Inception cohort analysis. Setting Ambulatory population from multiple sites in the United States and Canada. Participants Four hundred thirteen patients with early, untreated PD who participated in 2 double-blind trials that assessed the potential of experimental drugs to serve as disease-modifying agents in PD. Intervention Participants were randomized into treatment groups: creatine (n = 67), minocycline (n = 66), coenzyme Q10 (n = 71), GPI-1485 (n = 71), and placebo (n = 138). Main Outcome Measure Time between baseline assessment and need for the initiation of symptomatic treatment for PD. The following baseline variables were assessed for their relation to the main outcome measure, while adjusting for possible treatment effect: sex; age; level of education; race/ethnicity; disease duration; occupational status; and Unified Parkinson Disease Rating Scale (UPDRS), Medical Outcomes Study Short Form Survey, Modified Rankin Scale, Schwab and England Activities of Daily Living Scale, Total Functional Capacity Scale, 39-item Parkinson Disease Questionnaire, and Geriatric Depression Scale scores. Variables reaching statistical threshold in univariate analyses (α = .15) were entered into a multivariable Cox proportional hazards regression model using time to symptomatic treatment as the dependent variable. Results Approximately half (48.5%) of the participants reached end point within 12 months. Higher baseline impairment and disability, as determined by UPDRS III (motor section), UPDRS II (activities of daily living section, participant rating), and Modified Rankin Scale scores and level of education were independently associated with an earlier need for symptomatic treatment. Conclusions In early PD, greater impairment and disability and higher level of education are independently associated with an earlier need for symptomatic treatment. Published online July 13, 2009 (doi:10.1001/archneurol.2009.159).

The effect of G i protein modification produced by intrastriatal pertussis toxin injection on dopcmine (DA)-mediated behaviors was studied. Administration of the selective D 2 agonist quinpirole induced ipsilateral rotation but the selective D 1 agonist SKF 38393 did not. However, SKF 38393 was able to increase the rotation induced by quinpirole. The selective D 2 antagonist raclopride and the selective D 1 antagonist SCH 23390 both blocked the effect of quinpirole. Striatal levels of cAMP were measured in both intact and pertussis toxin injected striatum. SKF 38393 induced a significant increase in cAMP, but quinpirole had no effect. When both drugs were administered together, quinpirole attenuated the SKF 38393-induced increase in cAMP levels. Moreover, quinpirole-induced attenuation of SKF 38393 effect was greater in intact striatum. In pertussis toxin-injected striatum, quinpirole only attenuated SKF 38393-induced increase of cAMP to control levels. This imbalance between intact and injected striatum might be the cause of the rotation in pertussis toxin-injected rats suggesting an important role for G proteins in DA receptor interactions.

Both substantia nigra (SN) and caudate-putamen (CP) are brain regions documented to be involved in the regulation of seizure susceptibility (Gale, 1984). Nigral microinjection of gamma-amino-butyric-acid (GABA) agonists or antagonists respectively attenuates or potentiates seizures in several experimental models of epilepsy (Iadarola and Gale, 1982; Turski et al., 1986, 1987a). Similarly, pilocarpine induced-seizures convulsions are prevented by chemical stimulation of striatal cells but facilitated by lesioning of the caudateputamen (Turski et al., 1987b).

The effects of chronic D-1 and/or D-2 dopamine (DA) receptor blockade on a putative D-1 DA receptor-mediated behavioral function was studied in rats treated for 21 days with the selective D-1 antagonist SCH 23390, the predominantly D-2 antagonist haloperidol, or the combination of both drugs at the same daily doses. Four days after the last drug dose, the nonstereotyped grooming response to the selective D-1 agonist SKF 38393 increased in SCH 23390-pretreated rats and decreased in haloperidol-pretreated rats compared to controls, but remained unchanged in animals receiving both drugs. Underlying DA receptor changes and the resulting imbalance between D-1 and D-2 receptor presumably contribute to these effects, suggesting that the upregulation of one DA receptor subtype may modify the expression of behaviors associated with the other subtype.