Explore the vast range of titles available.

Motor fluctuations complicate the treatment of patients with Parkinson’s disease receiving levodopa. Extended-release carbidopa–levodopa has a pharmacokinetic profile that provides a more continuous levodopa serum concentration. Patients taking this formulation can expect longer duration of action and fewer doses per day, similar clinical improvement when compared to other levodopa formulations, and with a theoretically lower risk of developing motor fluctuations. Several studies, including three randomized control trials provide evidence for the efficacy, safety and tolerability of extended release carbidopa–levodopa in patients with both early and advanced Parkinson’s disease are reviewed here. Also provided is guidance for dosing of and conversion to extended release carbidopa–levodopa as well as a discussion of its place in the clinical practice.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms. We performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300), sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008) upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03) and amygdala (p = 0.003). To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls) and found a significant upregulation of the upstream (5') exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04) of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression) in PD blood versus controls. The consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease.

Sleep disorders are prevalent in Parkinson's disease but underreported in clinical settings. The contribution of sleep disorders to health-related quality of life (HRQOL) for patients with this degenerative neurological disease are not well known. To evaluate the impact of insomnia symptoms, obstructive sleep apnea (OSA), and poor sleep quality on HRQOL in a cohort of patients with idiopathic Parkinson's disease. We enrolled a convenience sample of 66 adults seen in the University of Miami Movement Disorders Clinic between July 2011 and June 2013. Participants completed validated questionnaires to determine insomnia symptoms, OSA risk, depression, anxiety, and HRQOL. All patients underwent unattended polysomnography to confirm OSA. Results were compared for those with and without insomnia symptoms. Principal component and regression analyses were performed to evaluate determinants of HRQOL. Participants were predominately Hispanic males with mild to moderate Parkinson's disease. Insomnia symptoms were reported for 46% of the study subjects. OSA (apnea-hypopnea index, ≥5) was noted in 47%, with a mean apnea-hypopnea index of 8.3 ± 11.0. Fairly bad to very bad sleep quality was reported by 21% of the participants. Insomnia (r = 0.71; P < 0.001), daytime sleepiness (r = 0.36; P = 0.003), depression symptoms (r =  0.44; P < 0.001), and anxiety symptoms (r = 0.33; P = 0.006) were significant correlates of poor sleep quality. OSA, severity of Parkinson's disease, and dopaminergic therapy were not. In the principal component analysis, sleep quality was a significant component of the \"psychological factor\" that in turn was a significant determinant of overall HRQOL. Insomnia symptoms, OSA, and subsequent poor sleep quality are prevalent in Parkinson's disease. In this single-center, exploratory study, we found that insomnia and poor sleep quality, but not OSA, play important roles in determining overall quality of life for patients with this disease. Clinical trial registered with www.clinicaltrials.gov (NCT02034357).

Tandem gait testing is an integral part of the neurological exam. It is informative in a wide variety of disorders ranging from cerebellar disease to vestibular and peripheral neuropathies, parkinsonism, and other neurodegenerative conditions. We discuss the history and development of tandem gait testing as well as its technique, utility, and limitations in the assessment of neurological conditions. Tandem gait has emerged as a tool in the assessment of cerebellar disease, Huntington disease, idiopathic Parkinson’s disease, atypical parkinsonism, peripheral neuropathies, and vestibulopathies. Its origin can be deduced from experimental observation and clinical experience as far back as the early nineteenth century. Despite the long history and ubiquitous performance of tandem gait testing, there is no standardized, guideline-based protocol to model for more homogenous research and clinical practices. Such a protocol should be developed using historical texts and manuscripts as well as the consensus of the medical research community. With standard protocols, further studies could define the sensitivity of abnormal tandem gait testing in cerebellar disorders, more diffuse neurodegeneration, and peripheral pathologies. Tandem gait can be a useful marker of dysfunction in neurologic conditions whose pathologies extend beyond the vermis or vestibulocerebellar module to include interconnected networks throughout the nervous system.

The best practice for the initiation of symptomatic motor treatment for Parkinson’s disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson’s disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson’s disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson’s disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.

The Movement Disorder Society-UPDRS (MDS-UPDRS) was published in 2008, showing satisfactory clinimetric results and has been proposed as the official benchmark scale for Parkinson’s disease. The present study, based on the official MDS-UPDRS Spanish version, performed the first independent testing of the scale and adds information on its clinimetric properties. The cross-culturally adapted MDS-UPDRS Spanish version showed a comparative fit index ≥0.90 for each part (I–IV) relative to the English-language version and was accepted as the Official MDS-UPDRS Spanish version. Data from this scale, applied with other assessments to Spanish-speaking Parkinson’s disease patients in five countries, were analyzed for an independent and complementary clinimetric evaluation. In total, 435 patients were included. Missing data were negligible and moderate floor effect (30 %) was found for Part IV. Cronbach’s α index ranged between 0.79 and 0.93 and only five items did not reach the 0.30 threshold value of item-total correlation. Test–retest reliability was adequate with only two sub-scores of the item 3.17, Rest tremor amplitude, reaching κ values lower than 0.60. The intraclass correlation coefficient was higher than 0.85 for the total score of each part. Correlation of the MDS-UPDRS parts with other measures for related constructs was high (≥0.60) and the standard error of measurement lower than one-third baseline standard deviation for all subscales. Results confirm those of the original study and add information on scale reliability, construct validity, and precision. The MDS-UPDRS Spanish version shows satisfactory clinimetric characteristics.

A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov, number NCT01280123. 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. National Institute of Neurological Disorders and Stroke.

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 (GOCOVRI TM ) 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  < 0.0001). The relative treatment difference between groups was 27.3% ( p  < 0.0001). At 12 weeks, the LS mean change in OFF time was − 0.59 (0.21) vs. +0.41 (0.20) h/day, a difference of − 1.00 h/day (95% CI − 1.57, − 0.44; p   =  0.0006). For both efficacy measures, a significant difference from placebo was attained by two weeks, the first post-baseline assessment, and was maintained throughout 12 weeks. In the pooled ADS-5102 group, the most common adverse events were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. Conclusions These analyses provide further evidence supporting ADS-5102 as an adjunct to levodopa for treating both dyskinesia and OFF time in PD patients with dyskinesia. Clinicaltrials.gov identifier: NCT02136914 and NCT02274766