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Background: The wearing-off phenomenon is a key driver of medication change for patients with Parkinson's disease (PD) treated with levodopa. Common first-line options include increasing the levodopa dose or adding a catechol-O-methyltransferase (COMT) inhibitor, but there are no trials comparing the efficacy of these approaches. We evaluated the effectiveness of adjunct opicapone versus an additional 100 mg levodopa dose in PD patients with early wearing-off using pooled data from 2 randomized studies. Methods: The ADOPTION study program included two similarly designed 4-week, open-label studies conducted in South Korea (NCT04821687) and Europe (NCT04990284). Patients with PD, treated with 3–4 daily doses of levodopa therapy and with signs of early wearing-off were randomized (1:1) to adjunct opicapone 50 mg or an additional dose of levodopa 100 mg. Patient-level data from the two studies were pooled. Results: The adjusted mean [SE] change from baseline to week 4 in absolute OFF time (key endpoint) was − 62.8 min [8.8] in the opicapone group and − 33.8 min [9.0] in the levodopa 100 mg group, the difference significantly favoring opicapone (− 29.0 [− 53.8, − 4.2] min, p = 0.02). Significant differences in the Movement Disorder Society—Unified Parkinson's Disease Rating Scale Part III subscore (− 4.1 with opicapone vs − 2.5 with levodopa 100 mg), also favored opicapone (− 1.7 [− 3.3, − 0.04], p < 0.05). Dyskinesia was the most frequently reported adverse event (opicapone 7.2% vs. levodopa 100 mg 4.2%). Conclusions: In these short-term trials, introducing adjunct opicapone was more effective at reducing OFF time than adding another 100 mg levodopa dose in PD patients with early signs of wearing-off. [ABSTRACT FROM AUTHOR]

Abstract Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence (‘wearing-off’) before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab’s effect on MS-related fatigue. Forty-five relapsing–remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Objective: The wearing-off phenomenon is common in people with multiple sclerosis (MS) treated with ocrelizumab. We aim to evaluate the presence and severity of wearing-off to ocrelizumab in relation to demographic and MS clinical variables, immune profiling, and a marker of neuroaxonal damage (plasma neurofilament light chain (pNfl)). Methods: This cross-sectional study included MS patients treated with ocrelizumab from at least 1 year. Wearing-off questionnaire and blood samples were collected between 21 and 23 weeks after the previous ocrelizumab infusion. Lymphocyte subpopulations were evaluated on peripheral blood using flow cytometry. PNfl was evaluated using fully automated chemiluminescent enzyme immunoassay. Results: We included 106 people with MS (age 49.5 ± 11.6 years; females 42.3%; wearing-off 57.6%). On regression models, wearing-off was associated with higher pNfl, CD8, CD3, and CD3CD27 lymphocytes. Most frequent wearing-off symptoms were cognitive, sensory, and balance problems; wearing-off started < 1 week (9.4%), 1–4 weeks (10.7%) or > 4 weeks (10.7%) before infusion; 44.8% of the complaints were moderate to severe. Severity of wearing-off was associated with higher pNfl and CD8 lymphocytes. Conclusions: Wearing-off is common in people with MS treated with ocrelizumab, and is associated with reduced immunomodulation (higher T lymphocytes) and increased neuroaxonal damage, suggesting reduced treatment response. [ABSTRACT FROM AUTHOR]

Background: Cognition in Parkinson's Disease can be impacted by the wearing-off phenomenon which results from changes in dopaminergic tone throughout the day. Given the well-established role of the cholinergic basal forebrain in cognition, we hypothesized that the Nucleus Basalis of Meynert may support cognitive processes during wearing-off periods. Specifically, we evaluated whether worsening of cognitive symptoms during wearing-off is more likely to occur with structural degeneration of the Nucleus Basalis of Meynert. Methods: Cognitive wearing-off was evaluated via the Movement Disorders Society Non-Motor Fluctuation Assessment Questionnaire in 33 Parkinson's Disease participants undergoing evaluation for deep brain stimulation. Pre-operative diffusion MRIs were used to measure brain diffusion metrics of the Nucleus Basalis of Meynert and control regions (caudate and putamen). Results: The number of cognitive symptoms which worsened during OFF periods positively correlated with mean diffusivity (ρ = 0.561, p = 0.0007) and generalized fractional anisotropy (ρ=-0.447, p = 0.009) within the Nucleus Basalis of Meynert but not in the caudate or putamen. Meanwhile, stable cognitive symptoms, and ON-state cognitive performance as measured by the DRS-2 did not correlate with Nucleus Basalis of Meynert metrics. Correlations were corrected for age, sex, scanner type, disease duration, education and LEDD. Conclusions: Our study suggests that reduced structural integrity of the Nucleus Basalis of Meynert is associated with worsening of participant-reported cognitive deficits during OFF periods, but not overall cognitive functioning in the ON-state. These findings support the hypothesis that structural integrity of the cholinergic Nucleus Basalis of Meynert may provide resilience to cognitive worsening during dopamine-related wearing-off. [ABSTRACT FROM AUTHOR]

Objective: Our study aimed to explore the functional connectivity alterations between cortical nodes of resting-state networks in Parkinson's disease (PD) patients with wearing-off (WO) at different levels. Methods: Resting-state functional magnetic resonance imaging was performed on 36 PD patients without wearing-off (PD-nWO), 30 PD patients with wearing-off (PD-WO), and 35 healthy controls (HCs) to extract functional networks. Integrity, network, and edge levels were calculated for comparison between groups. UPDRS-III, MMSE, MOCA, HAMA, and HAMD scores were collected for further regression analysis. Results: We observed significantly reduced connectivity strength in the dorsal attention network and limbic network in the PD-WO group compared with the HC group. The PD-WO group showed a decreased degree of functional connectivity at 12 nodes, including the bilateral orbital part of the superior frontal gyrus, right olfactory cortex, left medial orbital part of the superior frontal gyrus, bilateral gyrus rectus, right parahippocampal gyrus, right thalamus, left Heschl's gyrus, right superior temporal gyrus part of the temporal pole, left middle temporal gyrus part of the temporal pole, and right inferior temporal gyrus. Furthermore, the PD-WO group showed a significantly lower degree of functional connectivity in the left orbital part of the superior frontal gyrus and right gyrus rectus than the PD-nWO group. Internetwork analysis indicated reduced functional connectivity in five pairs of resting-state networks. Conclusion: Our results demonstrated altered intra- and internetwork connections in PD patients with WO. These findings will facilitate a better understanding of the distinction between the network changes in PD pathophysiology. [ABSTRACT FROM AUTHOR]

This retrospective review on patients with Parkinson's disease, focusing on using mucuna beans (MB), its dosing, and administration methods. Two hundred patients taking 1–3 g of MP dissolved in hot water daily orally. Besides, MB administration via enema may be viable, especially when oral L-dopa efficacy is insufficient.

Introduction: The efficacy and safety of galcanezumab as a preventive treatment in Japanese patients with episodic migraine was demonstrated in a phase 2, randomized, placebo-controlled trial (conducted December 2016–January 2019). This post hoc analysis assessed the consistency of galcanezumab efficacy through the monthly dosing interval. Methods: Patients with 4–14 migraine headache days/month were randomized (2:1:1, stratified by baseline migraine frequency) to subcutaneous placebo (n = 230), 120-mg galcanezumab (with 240-mg loading dose; n = 115) or 240-mg galcanezumab (n = 114) once monthly for 6 months. Outcomes included change from baseline in weekly migraine headache days, proportion of patients with migraine headache on each day, and proportion of patients with worsening migraine headache days during each month ([average of weeks 3–4] − [average of weeks 1–2] > 0). Results: In the 120-mg (approved dose) galcanezumab group, mean change from baseline in weekly migraine headache days was consistent and significantly greater (p < 0.05) than placebo for weeks 1–4; efficacy was consistent when averaged across months 1–6 and in most individual months. Averaged across months 1–6, the proportion of patients with migraine headache was significantly lower with galcanezumab than placebo on every day in both dose groups and was not significantly different between days 2 and 28 with 120-mg galcanezumab (p = 0.161). Within each month, the proportion of patients with migraine headache was generally consistent from days 2–28. The proportion of patients with worsening during the dosing interval did not significantly exceed 50% in any group during any month. Conclusions: This post hoc analysis supports the consistency of efficacy of galcanezumab across 6 months of treatment and suggests that wearing-off within the dosing interval does not occur on a population level in Japanese patients with episodic migraine. Trial Registration: ClinicalTrials.gov identifier, NCT02959177. [ABSTRACT FROM AUTHOR]

Our study aimed to investigate the grey matter (GM) changes using voxel-based morphometry (VBM) in Parkinson's disease (PD) patients with wearing-off (WO). 3D-T1-weighted imaging was performed on 48 PD patients without wearing-off (PD-nWO), 39 PD patients with wearing-off (PD-WO) and 47 age and sex-matched healthy controls (HCs). 3D structural images were analyzed by VBM procedure with Statistical Parametric Mapping (SPM12) to detect grey matter volume. Widespread areas of grey matter changes were found in patients among three groups (in bilateral frontal, temporal lobes, lingual gyrus, inferior occipital gyrus, right precuneus, right superior parietal gyrus and right cerebellum). Grey matter reductions were found in frontal lobe (right middle frontal gyrus, superior frontal gyrus and precentral gyrus), right parietal lobe (precuneus, superior parietal gyrus, postcentral gyrus), right temporal lobe (superior temporal gyrus, middle temporal gyrus), bilateral lingual gyrus and inferior occipital gyrus in PD-WO group compared with the PD-nWO group. Our results suggesting that wearing-off may be associated with grey matter atrophy in the cortical areas. These findings may aid in a better understanding of the brain degeneration process in PD with wearing-off. [ABSTRACT FROM AUTHOR]

Objective: Chronic migraine (CM) is a significant public health problem that affects 2.2% of the global population. Onabotulinumtoxin A (OnabotA) is a safe and effective prophylactic treatment for patients with CM. The standard injection interval for OnabotA is 12 weeks. Nevertheless, some patients experience a wearing-off effect (WOE) in the weeks preceding the next scheduled cycle. The objectives of this study are to determine the prevalence of early WOE, to analyze variables that could be clinical predictors and to specify which interval is the most appropriate to define the existence of this phenomenon. Methods: This is a prospective single-center study of consecutive adult patients with CM who, after failing previous prophylactic therapies, started OnabotA treatment following the PREEMPT protocol between June and December of 2021. Results: A total of 59 patients (93.2% female, age 44 ± 12 years) were included. A total of 37 patients (64.9%) fulfilled medication overuse criteria. Of the total patients, 40.6% reported WOE and this was more frequent after the first cycle (35.6%). Depression and anxiety disorder was a statistically significant clinical predictor of WOE (OR 3.4; CI 95% 1.22–10.84; p = 0.028). A better cut-off point to consider WOE seems to be at 10 weeks. Conclusions: Early WOE is common in patients on OnabotA treatment for CM. Individualizing the standard 12-week injection, using total doses of 195 U, and managing psychiatric comorbidities with pharmacological and non-pharmacological strategies may improve treatment outcomes and reduce OnabotA WOE. [ABSTRACT FROM AUTHOR]

The primary treatment for Parkinson's disease (PD) is supplementation of levodopa (L-dopa). With disease progression, people may experience motor and non-motor fluctuations, whereby the PD symptoms return before the next dose of medication. Paradoxically, in order to prevent wearing-off, one must take the next dose while still feeling well, as the upcoming off episodes can be unpredictable. Waiting until feeling wearing-off and then taking the next dose of medication is a sub-optimal strategy, as the medication can take up to an hour to be absorbed. Ultimately, early detection of wearing-off before people are consciously aware would be ideal. Towards this goal, we examined whether or not a wearable sensor recording autonomic nervous system (ANS) activity could be used to predict wearing-off in people on L-dopa. We had PD subjects on L-dopa record a diary of their on/off status over 24 hours while wearing a wearable sensor (E4 wristband®) that recorded ANS dynamics, including electrodermal activity (EDA), heart rate (HR), blood volume pulse (BVP), and skin temperature (TEMP). A joint empirical mode decomposition (EMD) / regression analysis was used to predict wearing-off (WO) time. When we used individually specific models assessed with cross-validation, we obtained > 90% correlation between the original OFF state logged by the patients and the reconstructed signal. However, a pooled model using the same combination of ASR measures across subjects was not statistically significant. This proof-of-principle study suggests that ANS dynamics can be used to assess the on/off phenomenon in people with PD taking L-dopa, but must be individually calibrated. More work is required to determine if individual wearing-off detection can take place before people become consciously aware of it. [ABSTRACT FROM AUTHOR]

Abstract Background Fluctuations in motor function in Parkinson’s Disease (PD) are frequent and cause significant disability. Frequently device assisted therapies are required to treat them. Currently, fluctuations are self-reported through diaries and history yet frequently people with PD do not accurately identify and report fluctuations. As the management of fluctuations and the outcomes of many clinical trials depend on accurately measuring fluctuations a means of objectively measuring time spent with bradykinesia or dyskinesia would be important. The aim of this study was to present a system that uses wearable sensors to measure the percentage of time that bradykinesia or dyskinesia scores are above a target as a means for assessing levels of treatment and fluctuations in PD. Methods Data in a database of 228 people with Parkinson’s Disease and 157 control subjects, who had worn the Parkinson’s Kinetigraph ((PKG, Global Kinetics Corporation™, Australia) and scores from the Unified Parkinson’s Disease Rating Scale (UPDRS) and other clinic scales were used. The PKG’s provided score for bradykinesia and dyskinesia every two minutes and these were compared to a previously established target range representing a UPDRS III score of 35. The proportion of these scores above target over the 6 days that the PKG was worn were used to derive the percent time in bradykinesia (PTB) and percent time in dyskinesia (PTD). As well, a previously describe algorithm for estimating the amplitude of the levodopa response was used to determine whether a subject was a fluctuator or non-fluctuator. Results Using this approach, a normal range of PTB and PTD based on Control subject was developed. The level of PTB and PTD experienced by people with PD was compared with their levels of fluctuation. There was a correlation (Pearson’s ρ = 0.4) between UPDRS II scores and PTB: the correlation between Parkinson Disease Questionnaire scores and UPDRS Total scores and PTB and slightly lower. PTB and PTD fell in response to treatment for bradykinesia or dyskinesia (respectively) with greater sensitivity than clinical scales. Conclusions This approach provides an objective assessment of the severity of fluctuations in Parkinson’s Disease that could be used in in clinical trials and routine care.

Introduction: Parkinson's disease (PD) is associated with gut dysbiosis. However, whether gut dysbiosis can cause motor complications is unclear.Methods: Subjects were enrolled from four independent movement disorder centers in Japan. We performed 16S ribosomal RNA gene sequence analysis of gut microbiota. Relative abundance of gut microbiota and relationships between them and clinical characteristics were statistically analyzed. Analysis of co-variance (ANCOVA) was used to assess altered gut microbiota associated with wearing-off or dyskinesia.Results: We enrolled 223 patients with PD. Wearing-off was noted in 47.5% of patients and dyskinesia in 21.9%. We detected 98 genera of bacteria. Some changes in the gut microbiota were observed in patients with PD and motor complications. After Bonferroni correction, patients with wearing-off showed decreased relative abundance of Lachnospiraceae Blautia (p < 0.0001) and increased relative abundance of Lactobacillaceae Lactobacillus (p < 0.0001), but patients with dyskinesia no longer showed significant changes in the gut microbiota. Adjustment with two models of confounding factors followed by ANCOVA revealed that age (p < 0.0001), disease duration (p = 0.01), and wearing-off (p = 0.0004) were independent risks for the decreased relative abundance of Lachnospiraceae Blautia, and wearing-off (p = 0.009) was the only independent risk factor for the increased relative abundance of Lachnospiraceae Lactobacillus.Conclusion: Relative abundance of Lachnospiraceae Blautia and Lactobacillaceae Lactobacillus was significantly decreased and increased, respectively, in the gut microbiota of PD patients with motor complications. This indicates that an altered gut microbiota is associated with the development of motor complications in patients with advanced PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) patients experience motor and non-motor symptoms, which affect their quality of life (QoL). Despite the use of Levodopa treatment to alleviate these symptoms, the "wearing-off phenomenon" (WO) occurs, and symptoms resurface. Thus, PD patients have to closely monitor and report their symptoms, the effects, and the duration of levodopa treatment to their doctors for a customized treatment. Towards predicting the WO among PD patients, this paper aims to understand the relationship between the WO symptoms and the collected fitness tracker data using a fitness tracker and a smartphone application. Our preliminary study among two patients within a 30-day collection period showed that PD patients experience WO symptoms with a unique relationship and association with fitness tracker datasets. The participant's sleep duration was negatively correlated with sharp pain and tremors. On the other hand, the other participant's total sleep duration was positively correlated with symptoms. Our analysis also showed that the time elapsed since the last medicine intake was a strong predictor of WO, aside from sleep duration and step count. These results suggest the possibility of using the fitness tracker dataset to estimate the WO among PD patients. The results would be helpful in the management of WO and PD in general. [ABSTRACT FROM AUTHOR]

Introduction: Opicapone (OPC) was efficacious in reducing OFF-time in two pivotal trials in patients with Parkinson's disease (PD) and end-of-dose motor fluctuations (BIPARK-I and -II). Post-hoc analyses of these trials evaluated the efficacy of OPC following pre-defined segmentation of the wide spectrum of motor fluctuations in PD.Methods: Data from matching treatment arms in BIPARK-I and -II were combined for the placebo (PLC) and OPC 50-mg groups, and exploratory post-hoc analyses were performed to investigate the efficacy of OPC 50 mg vs. PLC in subgroups of patients who were in “earlier” vs. “later” stages of both their disease course (e.g., duration of PD

Introduction: Opicapone (OPC) was efficacious in reducing OFF-time in two pivotal trials in patients with Parkinson's disease (PD) and end-of-dose motor fluctuations (BIPARK-I and -II). Post-hoc analyses of these trials evaluated the efficacy of OPC following pre-defined segmentation of the wide spectrum of motor fluctuations in PD. Methods: Data from matching treatment arms in BIPARK-I and -II were combined for the placebo (PLC) and OPC 50-mg groups, and exploratory post-hoc analyses were performed to investigate the efficacy of OPC 50 mg vs. PLC in subgroups of patients who were in "earlier" vs. "later" stages of both their disease course (e.g., duration of PD <6 years vs. ≥6 years) and levodopa treatment pathway (e.g., number of daily levodopa intakes <4 vs. ≥4). Efficacy variables included changes from baseline in absolute OFF-time and total ON-time. Results: The Full Analysis Set included 517 patients (PLC, n = 255; OPC 50 mg, n = 262). OPC 50 mg was significantly more effective than PLC in reducing OFF-time and increasing ON-time in the majority of subgroup analyses (p < 0.05). Moreover, patients in "earlier" stages of both their disease course and levodopa treatment pathway experienced numerically greater efficacy when using OPC 50 mg, in comparison with those in "later" stages. Conclusion: OPC 50 mg was efficacious over the whole trajectory of motor fluctuation evolution in PD patients. There was also a signal for enhanced efficacy in patients who were earlier vs. later in their disease course and levodopa treatment pathway. [ABSTRACT FROM AUTHOR]

Introduction: Making Informed Decisions to Aid Timely Management of Parkinson's Disease (MANAGE-PD) is a clinician-reported tool designed to facilitate timely identification and management of patients with advancing Parkinson's disease (PD) with suboptimal symptom control while on standard therapy. The objective of this study was to evaluate the validity and clinical value of the tool.Methods: Driven by structured inputs from a steering committee and panel of PD experts, the tool was developed to classify patients into 3 categories. Validity and clinical value were elucidated using a two-pronged approach: (i) hypothetical patient vignettes (n = 10) developed based on the MANAGE-PD tool and rated by 17 PD specialists and 400 general neurologists (GN) and (ii) patients with PD (n = 2546) managed in real-world clinical settings. Vignette validity was based on concordance between PD experts' clinical judgement and MANAGE-PD vignette categorization. Patient-level data was used for known-group comparisons (validity) and discordant pair analysis (clinical value).Results: The tool demonstrated strong validity and clinical value among PD specialists (intraclass coefficient [ICC] 0.843; Fleiss weighted kappa [ƙweighted] 0.79) and GN (ICC 0.690; ƙweighted 0.65) using patient vignettes. MANAGE-PD also demonstrated real-world validity and clinical value based on ability to identify patients with incrementally higher clinical, economic, and humanistic PD burden across categories of the tool (p < 0.01).Conclusions: MANAGE-PD demonstrated robust validity and clinical value in identifying patients with suboptimal PD symptom control. Clinical use of MANAGE-PD may complement treatment decision-making and facilitate timely and comprehensive management of patients with advancing PD. [ABSTRACT FROM AUTHOR]

Besides the inhibition of monoamine-oxidase-B, high-dose safinamide (100 mg) also blocks voltage-gated Na+ and Ca++ channels and inhibits glutamate release at overactive synapses. This latter mechanism may provide further benefit to fluctuating Parkinson's disease (PD) patients compared to rasagiline. Here, we retrospectively investigated the consequences of shifting from rasagiline to high-dose safinamide in PD patients reporting symptoms of wearing-off, defined by the Wearing-Off-Questionnaire-19 (WOQ-19) score ≥3 at baseline. Seventeen PD patients were switched from rasagiline 1 mg to safinamide 100 mg because of the report of symptoms of fluctuations while under therapy with either levodopa+rasagiline or levodopa+rasagiline+dopamine agonists, or re-occurrence of fluctuations previously corrected by add-on with rasagiline. Patients were re-evaluated 4–6 months after switch. Switch to safinamide 100 mg produced benefit in 9/17 (52.9%) subjects, together with significant reduction of subjective symptoms of wearing-off. There was no report of adverse events. Findings from this retrospective, exploratory study suggest that safinamide 100 mg may produce more powerful benefit that rasagiline 1 mg as add-on to levodopa in fluctuating PD patients, possibly because of the bimodal mechanism of action of the former drug. [ABSTRACT FROM AUTHOR]

Introduction: The non-motor symptoms (NMSs) of Parkinson's disease (PD) significantly impact the patient's health-related quality of life. This subanalysis of the J-FIRST study evaluated the effect of istradefylline, a selective adenosine A2A receptor antagonist, on NMSs in istradefylline-naïve Japanese patients with PD.Methods: Patients with PD and ≥1 NMS and 'wearing-off' with their current antiparkinsonian treatment were observed for up to 52 weeks. The effect of istradefylline on NMSs was measured in terms of changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 total, individual sub-items scores and the 8 item PD questionnaire (PDQ-8) estimated by the marginal structural model.Results: Overall, 732 patients were istradefylline-naïve prior to the study, of whom 171 were treated with istradefylline for ≥8 weeks during the observation period (istradefylline-treated patients). At baseline, istradefylline-treated patients were more likely to have a dyskinesia (49.7% vs 40.8%) and received a significantly higher daily dose of levodopa (462.8 mg vs 413.0 mg) than those who did not receive istradefylline (n = 561). MDS-UPDRS Part 1 total score at the end of the 52-week observational period slightly increased in patients who received istradefylline and those who did not (0.49 ± 0.41 vs 0.07 ± 0.20; P = 0.36). There were no statistically significant differences between the two groups of patients in terms of changes in the MDS-UPDRS Part 1 total score or any sub-items, or in the PDQ-8 total score.Conclusion: NMSs remained generally controlled in istradefylline-treated Japanese patients with PD who exhibited wearing-off with their current antiparkinsonian treatment. Istradefylline could be a feasible treatment option for patients with advanced PD, without worsening existing NMSs. [ABSTRACT FROM AUTHOR]

Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4–7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations. • Many natalizumab treated MS patients experience wearing-off symptoms. • Extension of natalizumab treatment intervals does not increase wearing-off symptoms. • Wearing-off symptoms are not related to natalizumab drug concentrations. [ABSTRACT FROM AUTHOR]

Levodopa remains the gold-standard Parkinson's disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery. Peripheral inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once 'wearing-off' has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in 'fluctuating' disease, but it has not yet been included in the algorithm for early treatment. This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease. [ABSTRACT FROM AUTHOR]

Background: Fluctuations in motor function in Parkinson's Disease (PD) are frequent and cause significant disability. Frequently device assisted therapies are required to treat them. Currently, fluctuations are self-reported through diaries and history yet frequently people with PD do not accurately identify and report fluctuations. As the management of fluctuations and the outcomes of many clinical trials depend on accurately measuring fluctuations a means of objectively measuring time spent with bradykinesia or dyskinesia would be important. The aim of this study was to present a system that uses wearable sensors to measure the percentage of time that bradykinesia or dyskinesia scores are above a target as a means for assessing levels of treatment and fluctuations in PD.Methods: Data in a database of 228 people with Parkinson's Disease and 157 control subjects, who had worn the Parkinson's Kinetigraph ((PKG, Global Kinetics Corporation™, Australia) and scores from the Unified Parkinson's Disease Rating Scale (UPDRS) and other clinic scales were used. The PKG's provided score for bradykinesia and dyskinesia every two minutes and these were compared to a previously established target range representing a UPDRS III score of 35. The proportion of these scores above target over the 6 days that the PKG was worn were used to derive the percent time in bradykinesia (PTB) and percent time in dyskinesia (PTD). As well, a previously describe algorithm for estimating the amplitude of the levodopa response was used to determine whether a subject was a fluctuator or non-fluctuator.Results: Using this approach, a normal range of PTB and PTD based on Control subject was developed. The level of PTB and PTD experienced by people with PD was compared with their levels of fluctuation. There was a correlation (Pearson's ρ = 0.4) between UPDRS II scores and PTB: the correlation between Parkinson Disease Questionnaire scores and UPDRS Total scores and PTB and slightly lower. PTB and PTD fell in response to treatment for bradykinesia or dyskinesia (respectively) with greater sensitivity than clinical scales.Conclusions: This approach provides an objective assessment of the severity of fluctuations in Parkinson's Disease that could be used in in clinical trials and routine care. [ABSTRACT FROM AUTHOR]

Safinamide (SF) is a third-generation monoamine-oxidase-B inhibitor that proved efficacy as add-on to levodopa in fluctuating Parkinson's disease (PD) patients. Despite the high prevalence of complicated PD in older population, the data on the tolerability, safety and efficacy of SF in elderly patients are rather poor. Here we studied retrospectively the consequences of add-on with SF in PD patients older than 65 years. Fifty-three fluctuating PD patients were included (30 subjects aged between 65 and 75 years, the remaining 23 subjects aged > 75 years). Patients were treated with either 50 (n = 27) or 100 mg (n = 26) SF for at least 6 months. In all patients, fluctuations were identified by the report of a Wearing-Off-Questionnaire-19 (WOQ-19) score ≥ 3 at baseline. Add-on with SF was well tolerated and safe. Adverse events occurred in 30% of patients and led to drug discontinuation in 11% of cases. At follow-up visits, 60% of patients reported lowering of the WOQ-19 score to ≤ 2. There were no significant differences related to age or daily drug dose in tolerability, safety or efficacy. The results of this study provide evidence of the efficacy, tolerability and safety of SF in elderly PD patients. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to evaluate the base-peak difference in levodopa response for detecting patients with motor fluctuations in Parkinson's disease (PD). Methods: Two independent PD samples were evaluated at baseline and 2 h after the administration of the usual morning dose of levodopa using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). The presence of motor fluctuations was defined by the UPDRS-IV. We quantified the magnitude of motor variation as absolute (Δ) and percentage (Δ%) change in UPDRS-III scores. Optimal cut-offs for each index distinguishing patients with or without fluctuations were calculated on the exploratory population. The accuracy of the identified cut-offs was then verified in a testing population. Results: In the exploratory population (N = 26), the optimal cut-off for detecting fluctuations was a Δ of 6 points and a Δ% of 18.4%. When we applied the identified thresholds to the testing population (N = 139), we found a sensitivity of 93.8% (95% CI: 89.7 to 97.8) and a specificity of 91.2% (95% CI: 86.5 to 95.9) for Δ, 83.3% (95% CI: 77.1 to 89.5) and 86.8% (95% CI: 81.2 to 92.4) for Δ%, respectively. Conclusions: The assessment of levodopa usual morning dose response through the base-peak evaluation represents an accurate method for detecting parkinsonian patients with motor fluctuations, and for defining the Minimal Important Difference (MID) in levodopa response suggesting the presence of motor fluctuations in PD patients demanding further therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether quarterly or monthly administration of fremanezumab for migraine prevention exhibits a pattern of decreased efficacy toward the end of the dosing interval (wearing‐off effect). Background: The main goals of migraine preventive treatment are to reduce the frequency, severity, and duration of migraine attacks, and migraine‐associated disability. Wearing‐off refers to the phenomenon whereby clinical symptoms return or worsen before the next dose of a drug is due and has been reported previously with migraine preventive medications. Design and Methods: This was a long‐term, 12‐month, multicenter, randomized, double‐blind, parallel‐group phase 3 study (NCT02638103) that included chronic (CM) and episodic migraine (EM) patients who rolled over from the 12‐week phase 3 HALO CM (NCT02621931) and EM trials (NCT02629861), as well as an additional subset of 312 new patients. Patients with CM or EM received fremanezumab either monthly or quarterly. In this post hoc analysis, for selected months, the difference in the average number of migraine days between weeks 1‐2 and weeks 3‐4, between weeks 1‐3 and week 4, and between weeks 1‐2 and weeks 11‐12 were calculated. Results: A total of 1890 patients (CM, 1110; EM, 780) were enrolled. At months 3, 6, 9, and 15, there were no substantial differences in mean weekly migraine days between weeks 1‐2 and weeks 3‐4 or between weeks 1‐3 and week 4 with quarterly or monthly fremanezumab in the CM or EM subgroups. There were no substantial increases in mean weekly migraine days between weeks 1‐2 and weeks 11‐12 during the first quarter of treatment (months 1‐3) or the second quarter of treatment (months 4‐6) with quarterly or monthly fremanezumab in the CM or EM subgroups. Across both dosing subgroups in CM and EM patients, the mean weekly number of migraine days decreased substantially (30%‐42%) during the first 2 weeks; decreases in weekly migraine days remained steady during the last 2 weeks of the first quarter, with a similar maintenance of response during the second quarter. Conclusions: This analysis of data from a long‐term, phase 3 study showed that patients receiving quarterly fremanezumab or monthly fremanezumab did not experience a wearing‐off effect toward the end of the dosing interval. [ABSTRACT FROM AUTHOR]

Up to two thirds of patients with multiple sclerosis (MS) under natalizumab report a resurgence of symptoms at the end of the natalizumab cycle (wearing-off (WO) effect). At the outbreak of COVID-19, in line with the international recommendations for MS management, our centre switched all clinically stable patients on natalizumab therapy for more than one year from standard interval dosing (SID) to extended interval dosing (EID) with every six weeks infusions. This study aimed to evaluate the impact of EID in WO in MS patients under natalizumab. An observational retrospective study in patients with MS under natalizumab on EID was conducted. A questionnaire regarding current (on EID) and past (on SID) experience of WO effect was applied. Seventy-six patients were included. No significant differences were found in the annual relapse rate after the switch to EID (p = 0.083). However, there was a significant increase in the proportion of patients complaining of WO from 38.2% to 56.6% (p = 0.001). Moreover, patients with WO on SID, referred a significant increase in severity (p = 0.019) and duration of WO symptoms (p = 0.029), due to an anticipation of the symptoms relative to the day of natalizumab infusion (p = 0.019), when switching to EID. Symptoms improved with treatment maintenance in 23.3% of patients; instead, a reduction in interval dosing was needed in 54.8% with symptom improvement. WO affects a significant proportion of MS patients under natalizumab. Its prevalence, severity, and duration increase on EID, therefore despite clinical effectiveness maintenance of this posology should be individualized. • Wearing-off is prevalent among multiple sclerosis patients under natalizumab. • Wearing-off prevalence, severity and duration increase on natalizumab extended interval dosing. • Switching natalizumab from standard to extended interval dosing should be an individualized decision. [ABSTRACT FROM AUTHOR]

The antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes.

Rasagiline is a monoamine oxidase type-B inhibitor in development in Japan for Parkinson's disease (PD). This open-label study evaluated the long-term safety and efficacy of rasagiline in Japanese patients with PD receiving levodopa. Patients were aged 30-79 years and had wearing-off or weakened effect. Patients received rasagiline 1 mg/day for 52 weeks. The primary objective was to evaluate safety. Secondary endpoints included MDS-UPDRS Part II and Part III total scores (ON-state) and change from baseline in mean daily OFF-time. An additional endpoint was the Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index (SI) score. In total, 222 patients were enrolled; 52.3% had wearing-off phenomena. Treatment-emergent adverse events (TEAEs) were mostly mild or moderate and occurred in 83.3% of patients; 63.1% had drug-related TEAEs; and 21.2% had TEAEs resulting in discontinuation. Fall (16.7%), nasopharyngitis (14.0%), and dyskinesia (10.8%) were the most frequent TEAEs. Serious TEAEs were reported in 17.6% of patients, and led to discontinuation in 9.5%. At week 52 (last-observation-carried forward), the mean change from baseline in MDS-UPDRS Part III total score (ON-state) was − 7.6; the mean change from baseline in daily OFF-time was − 0.89 h in patients with wearing-off phenomena at the start of the run-in period. The mean change from baseline in PDQ-39 SI was − 0.64. No major safety issues were observed during this 52-week trial of rasagiline as an adjunct to levodopa in Japanese patients. Mean changes in MDS-UPDRS scores and daily OFF-time suggested that adjunctive rasagiline treatment with levodopa was efficacious, with efficacy maintained for at least 52 weeks. [ABSTRACT FROM AUTHOR]

Background: Lack of a global consensus on the definition of advanced Parkinson's disease (APD) and considerations for timing of device-aided therapies may result in heterogeneity in care.Objectives: To reach consensus among movement disorder specialists regarding key patient characteristics indicating transition to APD and guiding appropriate use of device-aided therapies in the management of PD symptoms.Methods: A Delphi-panel approach was utilized to synthesize opinions of movement disorder specialists and build consensus.Results: A panel was comprised of movement disorder specialists from 10 European countries with extensive experience of treating PD patients (mean =24.8 ± 7.2 years). Consensus on indicators of suspected APD and eligibility for device-aided therapies were based on motor symptoms, non-motor symptoms, and functional impairments. Key indicators of APD included: (i) motor-moderate troublesome motor fluctuations, ≥1 h of troublesome dyskinesia/day, ≥2 h "off" symptoms/day, and ≥5-times oral levodopa doses/day; (ii) non-motor-mild dementia, and non-transitory troublesome hallucinations; (iii) functional impairment-repeated falls despite optimal treatment, and difficulty with activities of daily living. Patients with good levodopa response, good cognition, and <70 years of age were deemed as good candidates for all three device-aided therapies. Patients with troublesome dyskinesia were considered good candidates for both levodopa-carbidopa intestinal gel and Deep Brain Stimulation (DBS). PD patients with levodopa-resistant tremor were considered good candidates for DBS.Conclusion: Identifying patients progressing to APD and suitable for device-aided therapies will enable general neurologists to assess the need for referral to movement disorder specialists and improve the quality of care and patient outcomes. [ABSTRACT FROM AUTHOR]

Development of motor fluctuations and dyskinesia characterizes the transition from early to advanced Parkinson disease stage. Current therapeutic strategies to manage motor complications aim at increasing the number of levodopa administrations and extending its benefit by the association of enzyme blockers and dopamine agonists. However, as disease progresses, mobility becomes progressively dependent on levodopa absorption and its plasma bioavailability, resulting in loss of independence, worse quality of life and increased caregiver burden. If patients continue to experience off-time with functional impact on activities of daily living after best medication adjustments, implementation of infusion with apomorphine or levodopa, and surgical therapies should be considered. Presence of troublesome dyskinesia would also favor the choice of an advanced treatment. Compared with pulsatile oral therapy, both apomorphine and levodopa infusion determine more continuous striatal dopamine receptors stimulation than oral levodopa resulting in significant reduction of off-time and dyskinesia, particularly peak-dose, although not in their complete resolution. This observation proves that abnormal synaptic plasticity and connectivity changes cannot be reversed once they are established. Early implementation of these therapeutic strategies ideally would target patients as soon as motor complications begin rather than at late stage of advanced Parkinson’s disease (PD) before dyskinesia have manifested. Preliminary evidence from early deep brain stimulation in patients with short disease duration and modest motor complications suggests that this approach can positively impact quality of life. It is conceivable that changing our PD treatment algorithm and implementing device-aided therapies at the beginning of the advanced phase before dyskinesia has established, will provide more stable motor conditions and longer functional autonomy. [ABSTRACT FROM AUTHOR]

Introduction: The present study aimed to investigate whether the level of presynaptic dopamine neuronal loss predicts future development of wearing-off in de novo Parkinson's disease.Methods: This retrospective cohort study included a total of 342 non-demented patients with de novo Parkinson's disease who underwent dopamine transporter positron emission tomography scans at their initial evaluation and received dopaminergic medications for 24 months or longer. Onset of wearing-off was determined based on patients' medical records at their outpatient clinic visits every 3-6 months. Predictive power of dopamine transporter activity in striatal subregions and other clinical factors for the development of wearing-off was evaluated by Cox proportional hazard models.Results: During a median follow-up period of 50.2 ± 18.9 months, 69 patients (20.2%) developed wearing-off. Patients with wearing-off exhibited less dopamine transporter activity in the putamen, particularly the anterior and posterior putamens, compared to those without wearing-off. Multivariate Cox proportional hazard models revealed that dopamine transporter activities of the anterior (hazard ratio 0.556; p = 0.008) and whole putamens (hazard ratio 0.504; p = 0.025) were significant predictors of development of wearing-off. In addition, younger age at onset of Parkinson's disease, lower body weight, and a motor phenotype of postural instability/gait disturbance were also significant predictors for development of wearing-off.Conclusion: The present results provide in vivo evidence to support the hypothesis that presynaptic dopamine neuronal loss, particularly in the anterior putamen, leads to development of wearing-off in Parkinson's disease. [ABSTRACT FROM AUTHOR]

3,4-Dihydroxy- l -phenylalanine ( l -Dopa) remains the most effective drug for treating the motor symptoms of Parkinson’s disease (PD). However, its long-term use is limited due to motor complications such as wearing-off and dyskinesia. A clinical study in PD patients with motor complications has demonstrated that selegiline, a monoamine oxidase type B inhibitor, is effective in reducing off time without worsening dyskinesia, although another study has shown worsening dyskinesia. Here, using unilateral 6-hydroxydopamine-lesioned rats showing degeneration of nigrostriatal dopaminergic neurons and l -Dopa-induced motor complications, we determined the efficacy of selegiline in controlling l -Dopa-induced motor fluctuations and exacerbated dyskinesia. Repeated administration of l -Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, twice daily for 22 days) progressively shortened rotational response duration ( on time) and augmented peak rotation in lesioned rats. Single subcutaneous injection of selegiline (10 mg/kg) extended l -Dopa-induced shortened on time without augmenting peak rotation. Furthermore, l -Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, once daily for 7 days) progressively increased abnormal involuntary movements ( l -Dopa-induced dyskinesia, LID) and peak rotation. Single subcutaneous injection of selegiline (10 mg/kg) did not exacerbate LID or alter mRNA expression of prodynorphin ( PDy ) and activity-regulated cytoskeleton-associated protein ( Arc ), both mRNAs associated with LID in the lesioned striatum. Despite undetectable plasma concentrations of selegiline and its metabolites at 24 h post-administration, these on time and LID effects did not decrease, suggesting involvement of irreversible mechanisms. Altogether, these results indicate that selegiline is effective in increasing on time without worsening dyskinesia. [ABSTRACT FROM AUTHOR]

Advanced Parkinson's disease is characterized by the presence of motor fluctuations, various degree of dyskinesia, and disability with functional impact on activities of daily living and independence. Therapeutic management aims to extend levodopa benefit while minimizing motor complications and includes, in selected cases, the implementation of drug infusion and surgical techniques. In milder forms of motor complications, these can often be controlled with manipulation of levodopa dose and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase B inhibitors, and dopamine agonists including apomorphine. Clinical experience and evidence from published studies indicate that when these agents cannot satisfactorily control motor complications, patients should be assessed and considered for device-aided therapies. This review article summarizes some of the newer available therapeutic opportunities such as use of enzyme inhibitors like opicapone and safinamide, adenosine A2A receptor antagonists, apomorphine and levodopa/carbidopa intestinal gel infusion, deep brain stimulation including the role of closed-loop and adaptive stimulation, and MRI-guided focused ultrasound. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective (1) To evaluate whether the Nine Items Questionnaire (WOQ-9) for the detection of wearing-off (WO) in Parkinson Disease (PD), by means of its screening ability, is a helpful tool to assist neurologists in diagnosing WO; (2) To determine the sensitivity and the specificity of a free Brazilian Portuguese translation of WOQ-9. Method A sample obtained by convenience included 60 patients. The WOQ-9 was answered by the patients themselves before their routine consultations. The detection of the WO by the WOQ-9 was compared with the neurologist assessment. Statistical significance was 5%. Results The WOQ-9 showed sensitivity of 100%, specificity of 10.3%, positive and negative predictive values of 54.4% and 100% respectively. The identification of WO by the WOQ-9 was congruent in 54.5% of cases with neurological evaluation. Conclusion The WOQ-9 is a convenient screening tool to aid physicians to detect WO in PD patients, and it is a quick and easy self-administered questionnaire.

Background: In Parkinson's disease (PD) patients, fluctuations in symptoms commonly occur after many years of dopamine replacement therapy. The so-called wearing-off phenomenon exists of both motor and non-motor symptoms, such as rigidity and anxiety. Current treatment options are limited and an integrated approach is needed to address the complex interactions between motor and non-motor symptoms. Since wearing-off is eventually inevitable, treatment needs to focus on coping, acceptance and self-efficacy. We developed the body awareness training, named BEWARE, combining physical therapy with acceptance and commitment therapy to help PD patients deal better with wearing-off related anxiety (WRA).Methods: This was an investigator-blinded randomized controlled trial. Forty PD patients with WRA were randomly assigned to the BEWARE or to the treatment as usual (TAU) condition. Assessments were performed prior to and immediately after the treatment period, and at 3-months follow up. The primary outcome was self-efficacy, secondary outcomes focused on mobility, daily functioning, anxiety, depression and quality of life.Results: There was no significant improvement in self-efficacy in the BEWARE treatment condition when compared to TAU. However, standing balance and emotional wellbeing showed a significant improvement, and feelings of stigmatization showed a trend-significant decrease in the BEWARE condition.Conclusions: We consider the BEWARE training to be a promising therapeutic approach to address WRA. Improvement points from the participants included 1) less frequent but longer therapy sessions; 2) active involvement of caregivers; and 3) the development of a supportive workbook. The optimized treatment protocol needs further evaluation in a phase III RCT.Trial Registration: ClinicalTrials.gov identifier: NCT02054845. [ABSTRACT FROM AUTHOR]

Objectives: To provide a quantitative estimation of motor fluctuations in PD through a 12-h Waking-day Motor Assessment (WDMA) and to develop new WDMA-based tools, the Motor Fluctuation Indices.Methods: Two independent samples of PD patients (exploratory population N = 51, testing population N = 109) were examined. Patients underwent a WDMA using the Unified Parkinson's Disease Rating Scale (UPDRS) and were classified as either having or not having motor fluctuations. To quantify motor fluctuations, the Worsening Index (WI), the Mean Fluctuation Index (MFI) and the Coefficient of Variation (CV) were computed. The optimal cut-off for each index distinguishing patients with or without fluctuations was calculated on the exploratory population. Cut-offs' accuracy was then verified in the testing population.Results: Optimal cut-off scores to differentiate stable patients from fluctuating ones were 8.3 for WI, 5 for MFI and 12.9 for CV. Sensitivity and a specificity were 91.2% (95%CI: 85.9 to 96.5) and 87.8% (95%CI: 81.7 to 93.9) for WI; 75% (95%CI: 66.9 to 83.1) and 90.2% (95%CI: 84.7 to 95.8) for MFI; 69.1% (95%CI: 60.4 to 77.8) and 95.1% (95%CI: 91.1 to 99.2) for CV. Patients with a larger magnitude of fluctuation had higher values for all three indices, whereas patients with multiple daily fluctuations presented only higher WI values.Conclusions: WDMA-derived Motor Fluctuation Indices may represent reliable tools for evaluating and quantifying the severity of motor fluctuations in PD patients. Even if WDMA is a time-consuming procedure, the detection of Motor Fluctuation Indices could be helpful in assessing therapeutic efficacy on motor fluctuations. [ABSTRACT FROM AUTHOR]

Background: levodopa while transitioning to levodopa/carbidopa/entacapone (LCE) in Parkinson's disease (PD) during the wearing-off period is unclear. Aims: The relative therapeutic efficacy and safety of different doses of levodopa were assessed when transitioning to the LCE combination for optimizing combined levodopa therapy. Materials and Methods: A randomized, multicenter, double-arm, open-label study was conducted in Korea. The patients were randomly assigned to either a maintained levodopa dose (Group 1, n = 66) or a reduced levodopa dose by 15-25% (Group 2, n = 41). Treatment efficacy, safety, and tolerability were assessed during an 8-week treatment period. Results: Eighty of the 107 (74.8%) participants completed the study (Group 1, n = 50; Group 2, n = 30). The patients' global impression of a change in scores indicated significant benefits of maintaining the levodopa dose (Group 1) compared to reducing the dose (Group 2). Although changes in the unified Parkinson's disease rating scale (UPDRS) scores, Hoehn and Yahr (H and Y) stages, and duration of ON, OFF and dyskinesia were not statistically different between the groups, an increased ON time and a reduced OFF time occurred in both the groups after LCE administration. Twenty-four participants (26.7%) experienced adverse events and 15 of them did not complete the study in the safety population (Group 1, n = 57; Group 2, n = 38). Significant drug-related withdrawal caused troublesome dyskinesia and aggravation of Parkinsonism in both Group 1 and Group 2, respectively. [ABSTRACT FROM AUTHOR]

Introduction: Opicapone is a third generation, highly potent and effective catecholO‑methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L-DOPA therapy. Areas covered: In this review, the authors describe the preclinical and clinical development of opicapone. In PD patients with motor fluctuations, once daily opicapone administration was well-tolerated and consistently reduced OFF-time and increased ON-time without increasing the frequency of troublesome dyskinesia, and these benefits were maintained over at least a year of continued open-label therapy. Expert commentary: With its convenient once-daily regimen, adjunct opicapone should be considered as an effective option for use in L-DOPA treated PD patients experiencing motor fluctuations. [ABSTRACT FROM PUBLISHER]

Background: In a precedent paper, we validated part IV of the Unified Parkinson's Disease Rating Scale (UPDRS) for detecting motor fluctuations in Parkinson's Disease (PD) patients using a 12-h Waking-Day Motor Assessment (WDMA) as gold standard, showing a high sensitivity (> 80%) and a lower specificity (< 45%). The aim of this study was to validate the Movement Disorder Society-UPDRS (MDS-UPDRS) part IV, especially items 4.3 and 4.5, using the same methodology.Methods: PD patients attending the Movement Disorders Clinic at the University Hospital in Catania were consecutively enrolled in the study. A diurnal WDMA was performed to detect motor fluctuations. At each time interval, the motor impairment was evaluated using the motor section of the MDS-UPDRS. Presence or absence of motor fluctuations and the type of motor fluctuation were assessed by four blinded expert raters in movement disorders, by evaluating the graphical representations of the WDMA. We evaluated sensitivity and specificity together with 95% Confidence Interval (CI) of items 4.3 and 4.5, using WDMA as gold standard.Results: We estimated for item 4.3 of the MDS-UPDRS a sensitivity of 74.3% (95% CI 56.7-87.5) and a specificity of 70.6% (95% CI 44-89.7), while for item 4.5, a sensitivity of 67.9% (95% CI 47.6-84.1) and a specificity of 66.7% (95% CI 44.7-84.4).Conclusions: The present showed a higher specificity level for MDS-UPDRS with respect to the UPDRS, while a slightly lower sensitivity mainly for predictable OFF. [ABSTRACT FROM AUTHOR]

This study had the objective to verify if the presence of wearing-off phenomenon in patients with Parkinson's disease (PD) could be better identified by the administration of the "Wearing-off Questionnaire Card" (QC). The participant patients were first evaluated by resident doctors in neurology and then invited to answer the QC for detection of motor and nonmotor wearing-off manifestations. Seventy and nine patients were enclosed in the study. The questionnaire revealed that 63 patients (80%) presented wearing-off, whereas the consultation by the resident doctors only identified 33 subjects (41%) with this phenomenon. The motor wearing-off manifestations were more frequent then the nonmotor. We conclude that the administration of the QC in patients with PD may be a useful tool for the diagnosis of wearing-off phenomena.Este estudo teve como objetivo verificar se a presença do fenômeno wearing-off em pacientes com doença de Parkinson pode ser melhor identificada pela aplicação do cartão questionário wearing-off (QC). Os pacientes participantes foram avaliados pelos médicos residentes em neurologia e depois foram convidados a responder as questões do QC para detecção das manifestações motoras e não motoras do wearing-off. O número de pacientes estudados foi de 79. O questionário revelou que 63 pacientes (80%) apresentaram wearing-off, enquanto que a consulta dos residentes identificou apenas 33 indivíduos (41%) com este fenômeno. As manifestações motoras foram mais freqüentes do que as não motoras. Nós concluímos que a aplicação do QC em pacientes com doença de Parkinson pode ser uma ferramenta útil para o diagnostico do fenômeno wearing-off.

Dyskinesia frequently occurs during long-term treatment with levodopa in patients with Parkinson's disease (PD) and impacts quality of life. Few studies have examined risk factors for developing dyskinesia in PD patients exhibiting wearing-off. Therefore, we investigated the risk factors and impact of dyskinesia in PD patients exhibiting wearing-off. We investigated the risk factors and impact of dyskinesia in a 1-year observational study of Japanese PD patients exhibiting wearing-off (J-FIRST). Risk factors were assessed by logistic regression analyses in patients without dyskinesia at study entry. Mixed-effect models were used to evaluate the impact of dyskinesia on changes in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Part I and PD Questionnaire (PDQ)-8 scores from one timepoint before dyskinesia was observed. Of 996 patients analyzed, 450 had dyskinesia at baseline, 133 developed dyskinesia within 1 year, and 413 did not develop dyskinesia. Female sex (odds ratio [95% confidence interval]: 2.636 [1.645–4.223]) and administration of a dopamine agonist (1.840 [1.083–3.126]), a catechol- O -methyltransferase inhibitor (2.044 [1.285–3.250]), or zonisamide (1.869 [1.184–2.950]) were independent risk factors for dyskinesia onset. MDS-UPDRS Part I and PDQ-8 scores increased significantly after the onset of dyskinesia (least-squares mean change [standard error] at 52 weeks: 1.11 [0.52], P = 0.0336; 1.53 [0.48], P = 0.0014; respectively). Female sex and administration of a dopamine agonist, a catechol- O -methyltransferase inhibitor, or zonisamide were risk factors for dyskinesia onset within 1 year in PD patients exhibiting wearing-off. Nonmotor symptoms and quality of life deteriorated after dyskinesia onset. [Display omitted] • Dyskinesia is common in levodopa-treated PD patients and affects QoL. • We performed a 1-year observational study of 996 Japanese PD patients. • We investigated risk factors for dyskinesia in PD patients with wearing-off. • Risk factors were female sex and use of dopamine agonist, COMT inhibitor, or zonisamide. • NMS (MDS-UPDRS Part I) and QoL (PDQ-8) deteriorated after the onset of dyskinesia. [ABSTRACT FROM AUTHOR]

Glutamate receptors were studied in the brains of controls and Parkinson's disease (PD) patients, of which 10 of 14 developed motor complications (dyskinesias and/or wearing-off) following levodopa therapy. 125I-RTI binding to the dopamine transporter and dopamine concentrations show comparable nigrostriatal denervation between the subgroups of PD patients. 3H-Ro 25-6981 binding to the NR1/NR2B NMDA receptor was increased in the putamen of PD patients experiencing motor complications compared to those who did not (+53%) and compared to controls (+18%) whereas binding remained unchanged in the caudate nucleus. 3H-AMPA binding was increased in the lateral putamen (+23%) of PD patients with motor complications compared to those without whereas it was decreased in the caudate nucleus of the PD patients (−16%) compared to controls. Caudate and putamen 3H-CGP39653 binding to NR1/NR2A NMDA receptor and NR1 subunit mRNA levels measured by in situ hybridization were unchanged in subgroups of PD patients compared to controls. These findings suggest that glutamate receptor supersensitivity in the putamen plays a role in the development of motor complications (both wearing-Off and dyskinesias) following long-term levodopa therapy in PD.

Mucuna pruriens is a levodopa-containing legume and its favorable effects on motor complications in Parkinson disease patients have been reported. The aim of this study was to investigate the effects of another legume, soybeans, on the pharmacokinetics and metabolism of levodopa. Seven parkinsonian patients with the wearing-off phenomenon and dyskinesia and five healthy volunteers participated in this study. We conducted a crossover study of the clinical effects on the participants before and after taking either levodopa (100 mg)/carbidopa (10 mg) only (LD/CD) or levodopa/carbidopa with 11 g of ground soybeans (LD/CD/soy). Parkinsonism and dyskinesia before and after ingestion of these substances were evaluated using UPDRS partIII, the modified Abnormal Involuntary Movement Scale (mAIMS) and a self-rating scale. The concentrations of plasma levodopa and its major metabolites were measured by high-performance liquid chromatography. Clinical assessment and blood sampling were conducted before and three hours after the ingestion of ground soybeans. When the patients took LD/CD/soy, they had a significantly longer on-period ( p = 0.028) and a lower mAIMS score ( p < 0.001). From the comparison of the results of pharmacokinetic study before and after taking LD/CD or LD/CD/soy, the estimated marginal mean (EMM) of HVA after LD/CD/soy increased in the PD group. EMMs of 3-OMD after LD/CD/soy significantly decreased both in PD patients and healthy controls. These results indicate that soy partly increased the bioavailability of levodopa and suppressed levodopa degradation through COMT. Soybeans may have favorable effects on the motor complications occurring under current levodopa therapy. Further investigation to clarify the mechanism underlying such effects is required. [ABSTRACT FROM AUTHOR]

Most Parkinson’s disease patients will receive levodopa therapy, and of these, the majority will develop some levodopa-induced complications. For many patients, the first complication to develop is the decline in the duration of therapeutic benefit of each levodopa dose, a phenomenon commonly termed ‘wearing-off’. There is already extensive literature documenting the epidemiology and management of wearing-off in Parkinson’s disease patients of western descent. However, data derived from these studies might not always apply to patients of Asian descent due to genetic variations, differences in co-morbidities or non-availability of certain drugs. This review summarizes the current literature regarding the epidemiology of wearing-off in Asian (including Arab) patients and discusses the management issues in the context of drug availability in Asia. [ABSTRACT FROM PUBLISHER]

Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy. This article reviews the recent trial results published from 2013 to April 2015 about pharmacological and nonpharmacological interventions to treat motor complications. Randomized controlled trials conducted in patients suffering from already established complications showed that new levodopa (l-dopa) formulations such as intrajejunal l-dopa-carbidopa infusion and bilayered extended-release l-dopa-carbidopa (IPX066) can improve motor fluctuations. Positive results were also obtained with a new monoamine oxidase B (MAO-B) inhibitor (safinamide) and a catechol-O-methyltransferase COMT inhibitor (opicapone). Pilot data suggest that new formulations of dopamine agonists (inhaled apomorphine) are also of potential interest. The development of novel nondopaminergic adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) to treat motor fluctuations showed conflicting results in phase 2 and phase 3 trials. For dyskinesia, trials with new amantadine extended-release formulations confirmed the interest of the glutamatergic N-methyl-d-aspartate (NMDA) antagonist approach. Positive pilot antidyskinetic effects were also recently reported using serotonin agents such as eltoprazine and glutamate mGluR5 modulators such as mavoglurant. However, the translation to clinical practice of such innovative concepts remains challenging, because subsequent phase 2 trials conducted to confirm the antidyskynetic effects of mavoglurant failed, leading to the interruption of the development of this compound for this indication. [ABSTRACT FROM AUTHOR]