Which dyskinesia scale best detects treatment response?

Numerous scales assess dyskinesia in Parkinson's disease (PD), variably focusing on anatomical distribution, phenomenology, time, severity, and disability. No study has compared these scales and their relative ability to detect change related to an established treatment. We conducted a randomized placebo-controlled trial of amantadine, assessing dyskinesia at baseline and at 4 and 8 weeks using the following scales: Unified Dyskinesia Rating Scale (UDysRS), Lang-Fahn Activities of Daily Living Dyskinesia Rating Scale (LF), 26-Item Parkinson's Disease Dyskinesia scale (PDD-26), patient diaries, modified Abnormal Involuntary Movements Scale (AIMS), Rush Dyskinesia Rating Scale (RDRS), dyskinesia items from the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and Clinical Global Impression (severity and change: CGI-S, CGI-C). Scale order was randomized at each visit, but raters were aware of each scale as it was administered. Sensitivity to treatment was assessed using effect size. Sixty-one randomized dyskinetic PD subjects (31 amantadine, 30 placebo) completed the study. Four of the 8 scales (CGI-C, LF, PDD-26, and UDysRS) detected a significant treatment. The UDysRS Total Score showed the highest effect size (η(2) = 0.138) for detecting treatment-related change, with all other scales having effect sizes < 0.1. No scale was resistant to placebo effects. This study resolves 2 major issues useful for future testing of new antidyskinesia treatments: among tested scales, the UDysRS, having both subjective and objective dyskinesia ratings, is superior for detecting treatment effects; and the magnitude of the UDysRS effect size from amantadine sets a clear standard for comparison for new agents.

ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.

Medication adherence and associated outcomes in medicare health maintenance organization-enrolled older adults with Parkinson's disease.

Maintenance of symptom control in Parkinson's disease (PD) requires continuous titration of medication and addition of multiple therapies over the course of the disease. Adherence to medication is vital to symptom control and key to maximizing the efficacy of existing therapies. However, adherence is compromised by a variety of factors, including motor symptoms, complex dosing regimens, multiple medications, and lack of patient/physician awareness of the impact and prevalence of suboptimal adherence. This retrospective, longitudinal cohort study assessed the prevalence of suboptimal adherence [measured as the medication possession ratio (MPR)] to PD medications, and its impact on the worsening of PD symptoms (measured as increase in monotherapy dose, augmentation of therapy, PD-related emergency department visit, or hospitalization), in a Medicare Health Maintenance Organization population in the United States. Irrespective of the MPR threshold chosen, a high percentage of patients were categorized as suboptimally adherent to their PD medications, and patients with suboptimal adherence to their PD medications had higher risks of worsening of PD symptoms, compared with those who were adherent. Increased awareness of both the magnitude and impact of suboptimal adherence to PD medications, coupled with dosage simplification and a unified effort by healthcare professionals and patients, may improve adherence to PD medications and ultimately improve symptom control.

Pesticide exposure and risk of Parkinson's disease: a family-based case-control study.

BACKGROUND: Pesticides and correlated lifestyle factors (e.g., exposure to well-water and farming) are repeatedly reported risk factors for Parkinson's disease (PD), but few family-based studies have examined these relationships. METHODS: Using 319 cases and 296 relative and other controls, associations of direct pesticide application, well-water consumption, and farming residences/occupations with PD were examined using generalized estimating equations while controlling for age-at-examination, sex, cigarette smoking, and caffeine consumption. RESULTS: Overall, individuals with PD were significantly more likely to report direct pesticide application than their unaffected relatives (odds ratio = 1.61; 95% confidence interval, 1.13-2.29). Frequency, duration, and cumulative exposure were also significantly associated with PD in a dose-response pattern (p

Smoking, caffeine, and nonsteroidal anti-inflammatory drugs in families with Parkinson disease.

OBJECTIVE: To assess associations between Parkinson disease (PD) and putatively protective factors-smoking, caffeine (coffee, tea, and soft drinks), and nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, and naproxen). DESIGN: Family-based case-control study. SETTING: Academic medical center clinic. PARTICIPANTS: A total of 356 case subjects and 317 family controls who self-reported environmental exposures. MAIN OUTCOME MEASURES: Associations between PD and environmental measures (history, status, dosage, duration, and intensity) of smoking, coffee, caffeine, nonsteroidal anti-inflammatory drugs, and non-aspirin nonsteroidal anti-inflammatory drugs were examined using generalized estimating equations with an independent correlation matrix while controlling for age and sex. RESULTS: Individuals with PD were significantly less likely to report ever smoking (odds ratio = 0.56; 95% confidence interval, 0.41-0.78). Additional measures of smoking revealed significant inverse associations with PD (P<.05) and trends in odds ratios (P<.005). Increasing intensity of coffee drinking was inversely associated with PD (test for trend P = .05). Increasing dosage (trend P = .009) and intensity (trend P = .01) of total caffeine consumption were also inversely associated, with high dosage presenting a significant inverse association for PD (odds ratio = 0.58; 95% confidence interval, 0.34-0.99). There were no significant associations between nonsteroidal anti-inflammatory drugs and PD. CONCLUSIONS: Inverse associations of smoking and caffeine were corroborated using families with PD, thus emphasizing smoking and caffeine as important covariates to consider in genetic studies of PD.

Dopamine Transporter Imaging has no Impact on Functional Outcomes in de Novo Probable Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is among the most prevalent neurodegenerative conditions. While motor and non-motor aspects of this disease have been well characterized, no objective biomarker exists to support an accurate clinical diagnosis. However, newer imaging techniques, including [123I]-FP-CIT (DaTSCAN), have demonstrated utility in differentiating between PD and non-neurodegenerative tremor disorders. OBJECTIVE: DaTSCAN has been primarily investigated in situations where diagnostic confusion exists, and in these instances has been shown to significantly impact clinical management. The goal of this pilot study was to evaluate the impact of DaTSCAN on the clinical management of patients with early probable PD, where no diagnostic uncertainty exists. METHODS: This was a prospective, 54-week, comparative pilot study, in which twenty subjects with de novo PD were randomly assigned to DaTSCAN either immediately upon diagnosis (and again at 6 and 12 months) or delayed to 6 months (and again at 12 months). The primary outcome measure was the frequency of deviation from the initial treatment plan from baseline to 54 weeks between the two groups. Secondary outcomes included motor and non-motor assessments. RESULTS: There was no significant difference in the number of treatment changes over the course of the study between the two groups: initial imaging group = 4.2 (SD:2.74) vs. delayed imaging group = 2.3 (SD:2.0, p = 0.11). In addition, there were no group differences in medication requirements, motor performance, or patient expectations of disease. CONCLUSIONS: In patients with early, probable PD, DaTSCAN contributes no additional impact on clinical management or functional outcomes when added to the diagnostic algorithm.

Physiology and pathophysiology of cortico-basal ganglia-thalamocortical loops: theoretical and practical aspects.

A new theoretical framework is used to analyze functions and pathophysiological processes of cortico-basal ganglia-thalamocortical loops and to demonstrate the hierarchical relationships between various loops. All hierarchical levels are built according to the same functional principle: Each loop is a neural optimal control system (NOCS) and includes a model of object behavior and an error distribution system. The latter includes dopaminergic neurons and is necessary to tune the model to a controlled object (CO). The regularities of pathophysiological processes in NOCSs are analyzed. Mechanisms of current functional neurosurgical procedures like lesioning and deep brain stimulation (DBS) of various basal ganglia structures and neurotransplantation are described based on proposed theoretical ideas. Parkinson's disease (PD) is used to exemplify clinical applications of the proposed theory. Within the proposed theoretical framework, PD must be considered as a disease of the error distribution system. The proposed theoretical views have broad fundamental and clinical applications.

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

IMPORTANCE: Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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. CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00833690.

Research management team (RMT): a model for research support services at Duke University.

Collecting and managing data for clinical and translational research presents significant challenges for clinical and translational researchers, many of whom lack needed access to data management expertise, methods, and tools. At many institutions, funding constraints result in differential levels of research informatics support among investigators. In addition, the lack of widely shared models and ontologies for clinical research informatics and health information technology hampers the accurate assessment of investigators' needs and complicates the efficient allocation of crucial resources for research projects, ultimately affecting the quality and reliability of research. In this paper, we present a model for providing flexible, cost-efficient institutional support for clinical and translational research data management and informatics, the research management team, and describe our initial experiences with deploying this model at our institution.

Responsiveness of motor and nonmotor symptoms of Parkinson disease to dopaminergic therapy.

BACKGROUND: The duration of clinical control of motor symptoms of Parkinson disease (PD) treated with levodopa/carbidopa preparations eventually starts to shorten, a phenomenon known as end-of-dose "wearing off." The involvement of core nonmotor symptoms of "wearing off" (depressed mood, pain/aching, anxiety, and cloudy/slowed thinking) is not well understood. METHODS: A post hoc analysis from a study to validate the self-rated 9-item, Wearing-Off Questionnaire (WOQ-9), which was designed to identify motor and nonmotor symptoms of "wearing off" in PD patients, was performed to compare the frequency and sensitivity of motor and nonmotor symptoms of "wearing off" from dopaminergic therapy. RESULTS: Analysis of responses to the WOQ-9 from 216 PD patients found that individual nonmotor symptoms were reported by 25% to 50% and motor symptoms by 55% to 80% of patients. Individual nonmotor symptoms improved following the next dose of dopaminergic therapy in 43% to 53% of the patients who presented with such symptoms, whereas motor symptoms improved in 48% to 66% of the cases, suggesting both types of symptoms respond to dopaminergic therapies. CONCLUSION: Nonmotor symptoms of PD appear sensitive to dopaminergic treatment. These symptoms resemble those seen with depressive, anxiety, and somatoform disorders suggesting potential shared mechanisms as well as possible treatment implications.

Myoclonus and tremor response to thalamic deep brain stimulation parameters in a patient with inherited myoclonus-dystonia syndrome.

We present a 74-year-old woman with inherited myoclonus-dystonia, with predominant myoclonus and a novel mutation in the epsilon-sarcoglycan gene. The patient reports a life-long history of rapid, jerking movements, most severe in the upper extremities as well as a postural and action tremor. Bilateral deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus was performed, and the patient demonstrated moderate clinical improvement in myoclonus. We studied the effects on myoclonus and tremor of varying DBS frequency and amplitude. The frequency tuning curve for myoclonus was similar to that of tremor, suggesting similar mechanisms by which DBS alleviates both disorders.

What's in the pipeline for the treatment of Parkinson's disease?

Parkinson's disease (PD) is a common, debilitating neurodegenerative disorder that creates a significant burden for patients, family members and society at large. Major unmet needs include effective therapies that could favorably modify the underlying pathogenetic processes in PD, and better control of motor and nonmotor symptoms in advanced-stage disease. This review examines the current state of development of potential PD therapies, including dopaminergic therapies, modulators of adenosine and glutamate receptors, cell-based therapies, genetic therapies and device-based therapies. In addition, research into potential neuroprotective agents and pipeline therapies for nonmotor symptoms of PD are summarized.

Assessment of interrater and intrarater reliability of the Fahn-Tolosa-Marin Tremor Rating Scale in essential tremor.

The purpose of this study was to evaluate interrater and intrarater reliability of the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) in essential tremor (ET). Proper treatment of ET is contingent upon correct assessment of the severity, loss of function, and disability related to tremor. Videotape recordings of 17 subjects with ET evaluated with the TRS were produced and sent to 59 raters. Once the raters returned the videotape and completed the score sheet, they were mailed a second tape with the same recordings presented in a different order. In the interrater reliability evaluation, modified Kappa statistics for seven tremor type composites ranged from 0.10 to 0.65 in the first videotape and 0.17 to 0.62 in the second videotape. Interrater reliabilities were greater for Part A items (magnitude of tremor in different body parts) than for Part B items (tremor in writing and drawings) of the TRS. The average Spearman correlation was 0.87, indicating very good consistency between the two videotapes, but correlations for Part A were somewhat better than for Part B. It is best when the same rater performs repeated measures of tremor on a patient, particularly when judging tremor in handwriting and drawings. Training of raters on use of the TRS would help standardize judgement.

NOS2A and the modulating effect of cigarette smoking in Parkinson's disease.

OBJECTIVE: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. METHODS: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. RESULTS: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. INTERPRETATION: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking.