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To systematically evaluate the effectiveness and safety of safinamide in the treatment of levodopa-induced motor complications of Parkinson's disease (PD). A search strategy was developed and PubMed, Embase, Web of Science, Cochrane Library, Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), and WanFang Data were searched to find randomized controlled trials on the treatment of PD motor complications caused by levodopa with safinamide. A manual reference search was conducted for articles published until June 2022 to independently screen references, extract data, and evaluate the risk of bias in the included studies. RevMan 5.3 software was utilized to analyze the data. A total of 5 randomized controlled trials with 2061 PD patients were included, containing 1277 patients in the safinamide group (trial group) and 784 patients in the control group. Meta-analysis results exhibited that regarding effectiveness, the duration of continuous optimal drug effect without dyskinesia (On-time) of the 50 mg trial group was longer than that of the control group. The On-time of the 100 mg trial group was longer than that of the control group.The improvement of the Unified Parkinson's Disease Rating Scale Part III (UPDRSIII) score in the 50 mg trial group was better than that in the control group. The improvement of the UPDRSIII score of the 100 mg trial group was better than that of the control group.There was no significant difference in the incidence of adverse events between the two groups. Safinamide is effective and safe in the treatment of PD motor complications caused by levodopa. [ABSTRACT FROM AUTHOR]

To systematically review and conduct a meta-analysis to evaluate the safety and efficacy of the unilateral focused ultrasound (FUS) pallidotomy on motor complications in Parkinson's disease (PD) patients. A comprehensive search strategy was implemented through August 15, 2023, and updated on February 13, 2024, across six databases, identifying studies relevant to unilateral focused ultrasound pallidotomy and PD. Eligibility criteria included observational studies, clinical trials, and case series reporting on the impact of the intervention on motor complications in PD patients. The screening and data extraction were done by two independent reviewers. Risk of bias assessment utilized appropriate tools for different study designs. Statistical analysis involved narrative synthesis and meta-analysis. Subgroup analyses and leave-one-out analyses were performed. Five studies were included in our study, involving 112 PD patients undergoing FUS pallidotomy. UPDRS-II analysis revealed a significant improvement from baseline (mean difference (MD): -3.205, 95% CI: -4.501, -1.909, P < 0.001). UPDRS-III overall change was significant (MD: -10.177, 95% CI: [-12.748, -7.606], P < 0.001). UPDRS-IV showed a significant change from baseline (MD: -5.069, 95% CI: [-5.915, -4.224], P < 0.001). UDysRS demonstrated a significant overall improvement (MD: -18.895, 95% CI: [-26.973, -10.818], P < 0.001). The effect of FUS pallidotomy on motor complications in PD patients was effective, with a significant decrease in the UPDRS and UDysRS, reflecting improvement. The incidence of adverse events (headaches, pin-site pain, difficulty walking, and sonication-related head pain) of the FUS pallidotomy was not statistically significant, indicating its safety. [ABSTRACT FROM AUTHOR]

Objective: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). Background: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. Methods: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). Results: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12–18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. Conclusions: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs. [ABSTRACT FROM AUTHOR]

Background: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. Objectives: To quantify the presence, severity, impact and associated factors for motor complications in PD. Methods: Analysis of three large prospective cohort studies of recent‐onset PD patients followed for up to 12 years. The MDS‐UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. Results: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4–6 years and 59.0% (55.6, 62.3) at 8–10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4–6 years and 42.1% (38.7, 45.5) at 8–10 years. Dystonia affected 13.4% (12.1, 14.9) at 4–6 years and 22.8% (20.1, 25.9) at 8–10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2–4 years post‐diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). Conclusions: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications. [ABSTRACT FROM AUTHOR]

Levodopa/carbidopa remains the gold standard for treating Parkinson disease (PD), but chronic pulsatile administration contributes to motor complications. This Phase 1 study used a new immediate‐release (IR) formulation of carbidopa/levodopa 25/100 mg that is functionally scored for easy and precise splitting to evaluate the effects on levodopa plasma variability when smaller doses are taken more frequently. These functionally scored tablets were shown to be bioequivalent to carbidopa/levodopa 25‐/100‐mg IR generic reference tablets. Twenty‐two healthy volunteers received a whole tablet every 4 hours versus half of the tablet every 2 hours. Plasma levodopa fluctuations were significantly reduced with half‐tablets dosed every 2 hours, with a 44% reduction in peaks (P <.0001). While drug exposure did not differ, parameters that underlie motor response variations, including mean peak‐to‐trough difference and variance, were 51% and 56% less, respectively, with more frequent dosing (both P ≤.0024). Safety and tolerability of both regimens were similar. In conclusion, more frequent administration of half‐tablets of the new functionally scored IR formulation safely provided more constant levodopa levels than whole tablets dosed less often. This tablet technology could facilitate the benefits of more physiologic dopamine replenishment in patients with PD, particularly those with reduced manual dexterity. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) is an established therapeutic option in advanced Parkinson's disease (PD). Literature data and recent guidelines remain inconclusive about the best choice as a target between the subthalamic nucleus (STN) and the globus pallidus internus (GPi). Materials and methods: We retrospectively reviewed the clinical efficacy outcomes of 48 DBS-implanted patients (33 STN-DBS and 15 GPi-DBS) at a short- (<1 year from the surgery) and long-term (2–5 years) follow-up. Also, clinical safety outcomes, including postoperative surgical complications and severe side effects, were collected. Results: We found no difference between STN-DBS and GPi-DBS in improving motor symptoms at short-term evaluation. However, STN-DBS achieved a more prominent reduction in oral therapy (l-dopa equivalent daily dose, P =.02). By contrast, GPi-DBS was superior in ameliorating motor fluctuations and dyskinesia (MDS-UPDRS IV, P <.001) as well as motor experiences of daily living (MDS-UPDRS II, P =.03). The greater efficacy of GPi-DBS on motor fluctuations and experiences of daily living was also present at the long-term follow-up. We observed five serious adverse events, including two suicides, all among STN-DBS patients. Conclusion: Both STN-DBS and GPi-DBS are effective in improving motor symptoms severity and complications, but GPi-DBS has a greater impact on motor fluctuations and motor experiences of daily living. These results suggest that the two targets should be considered equivalent in motor efficacy, with GPi-DBS as a valuable option in patients with prominent motor complications. The occurrence of suicides in STN-treated patients claims further attention in target selection. [ABSTRACT FROM AUTHOR]

BackgroundMotor complications are a consequence of the chronic dopaminergic treatment of Parkinson's disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA-associated PD differ in their risk of developing motor complications compared to the general PD population.ObjectiveTo evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD.MethodsMotor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models.ResultsIn 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p = 0.43).ConclusionThis study does not provide evidence that GBA-carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA-associated PD.

Background: Different screening tools to identify advanced Parkinson's disease (APD) have emerged in recent years. Among them, wearable medical devices, such as STAT-ON™, have been proposed to help to objectively detect APD. Objectives: To analyze the correlation between STAT-ON™ reports and other assessment tools to identify APD and to assess the accuracy of screening tools in APD patients, using the STAT-ON™ as the gold standard. Methods: In this retrospective, observational study, data from the University Hospital Complex of Pontevedra database on 44 patients with potential APD who wore STAT-ON™ were extracted. Data were collected according to different sources of tools for identifying APD: (1) STAT-ON™, (2) information provided by the patient, (3) questionnaire for advanced Parkinson's disease (CDEPA), (4) 5-2-1 Criteria, and (5) Making Informed Decisions to Aid Timely Management of Parkinson's Disease (MANAGE-PD). Considering STAT-ON™ recordings as a reference, the sensitivity, specificity, and positive and negative predictive values for each tool were calculated. The kappa index assessed the degree of agreement between the gold standard and the other instruments. Results: Although no statistically significant association was found between STAT- ON™ recordings and any screening methods evaluated, the CDEPA questionnaire demonstrated the highest sensitivity and VPN values to detect patients with APD candidates for second-line therapy (SLT). According to the correlation analyses, MANAGE-PD demonstrated the highest degree of concordance with STAT-ON™ recordings to identify the SLT indication and to predict the SLT decision. Conclusion: STAT-ON™ device may be a helpful tool to detect APD and to guide treatment decisions. [ABSTRACT FROM AUTHOR]

Nbaa Masood, Joohi Jimenez-Shahed Department of Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai West, New York, NY, USACorrespondence: Joohi Jimenez-Shahed, Associate Professor of Neurology & Neurosurgery, Icahn School of Medicine at Mount Sinai, Bonnie and Tom Strauss Movement Disorders Center, 1000 10th Avenue, Suite 10C, New York, NY, 10019, USA, Tel +1 212-523-8335, Fax +1 212-523-8342, Email Joohi.Jimenez-Shahed@mountsinai.orgAbstract: Motor complications related to the chronic administration of levodopa and failure to prevent the neurodegenerative disease process counterbalance the pivotal discovery of levodopa as the cornerstone of PD treatment. Excellent motor control is offered early during the course of treatment, but this diminishes as pathological changes in the striatum lead to synaptic dopamine levels becoming completely dependent on exogenous dopamine. This non-physiologic stimulation of dopamine receptors eventually manifests as OFF episodes. As no disease modifying therapy exists for PD that can disrupt these pathological changes, most research and treatment focuses on optimization of dopaminergic stimulation of striatal receptors so that they mimic tonic, physiologic stimulation as closely as possible. Strategies focusing on these challenges have included non-pharmacologic approaches, optimizing levodopa pharmacokinetics, using adjunctive treatments including those with non-dopaminergic mechanisms, and implementing rescue therapies. Device aided therapies, including surgery, are also available. In this review, we will focus on effective management of motor symptoms related to OFF periods, including emerging strategies. Unmet clinical needs will be discussed, including non-motor symptoms, targeted molecular therapies and disease modifying therapy.Keywords: continuous dopaminergic stimulation, advanced Parkinson’s Disease, motor complications, nonmotor symptoms, dyskinesias, chronic levodopa complications

Introduction: Effective management and therapies for the motor complications of Parkinson's disease (PD) require appropriate clinical evaluation. The Parkinson's KinetiGraph™ (PKG) is a wearable biosensor system that can record the motion characteristics of PD objectively and remotely. Objective: The study aims to investigate the value of PKG in identifying and quantitatively assessing motor complications including motor fluctuations and dyskinesia in the Chinese PD population, as well as the correlation with the clinical scale assessments. Methods: Eighty-four subjects with PD were recruited and continuously wore the PKG for 7 days. Reports with 7-day output data were provided by the manufacturer, including the fluctuation scores (FS) and dyskinesia scores (DKS). Specialists in movement disorders used the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-IV (MDS-UPDRS IV), the wearing-off questionnaire 9 (WOQ-9), and the unified dyskinesia rating scale (UDysRS) for the clinical assessment of motor complications. Spearman correlation analyses were used to evaluate the correlation between the FS and DKS recorded by the PKG and the clinical scale assessment results. Receiver operating characteristic (ROC) curves were generated to analyze the sensitivity and specificity of the FS and DKS scores in the identification of PD motor complications. Results: The FS was significantly positively correlated with the MDS-UPDRS IV motor fluctuation (items 4.3-4.5) scores (r = 0.645, p < 0.001). ROC curve analysis showed a maximum FS cut-off value of 7.5 to identify motor fluctuation, with a sensitivity of 74.3% and specificity of 87.8%. The DKS was significantly positively correlated with the UDysRS total score (r = 0.629, p < 0.001) and the UDysRS III score (r = 0.634, p < 0.001). ROC curve analysis showed that the maximum DKS cut-off value for the diagnosis of dyskinesia was 0.7, with a sensitivity of 83.3% and a specificity of 83.3%. Conclusion: The PKG assessment of motor complications in the PD population analyzed in this study has a significant correlation with the clinical scale assessment, high sensitivity, and high specificity. Compared with clinical evaluations, PKG can objectively, quantitatively, and remotely identify and assess motor complications in PD, providing a good objective recording for managing motor complications. [ABSTRACT FROM AUTHOR]

Our suggestion is that a new approach to PD diagnosis and management beyond dopamine replacement therapy should be rapidly adopted, encompassing all clinical features and addressing their contribution to early disease detection, prognosis, progression and quality of life. Impulsivity and ICD are more common in patients on DA replacement treatment especially dopamine agonists.[[24], [26]] This supports the notion that ICD is related to dopaminergic dysfunction and can be managed only by modulation of dopamine replacement therapy. Keywords: l-dopa; Parkinson; motor complications; progression EN l-dopa Parkinson motor complications progression S50 S55 6 08/28/23 20230802 NES 230802 Introduction Diagnosis and clinical burden in people with Parkinson's disease (PD) is often related to the cardinal motor features (tremor, bradykinesia, rigidity) and occurs when at least 40-60% of striatal dopamine nerve terminals are lost.[1] However, in the "Essay on the shaking palsy" James Parkinson already reported presence of constipation, cognitive dysfunction or sleep disorders in addition to motor involvement.[2] With the introduction of l-dopa therapy it became evident that only specific clinical features would improve while many others would show limited or no benefit from medications even if they significantly contribute to quality of life decline and disability. Recent discoveries in disease biomarkers indicate that it is important to change our dopamine-centric perspective for PD diagnosis if we want to test and possibly implement disease modifying therapies before motor symptoms become manifest.[40] Acknowledgments Figure 1 was created with BioRender.com. [Extracted from the article]

Since its first introduction, levodopa has become the cornerstone for the treatment of Parkinson's disease and remains the leading therapeutic choice for motor control therapy so far. Unfortunately, the subsequent appearance of abnormal involuntary movements, known as dyskinesias, is a frequent drawback. Despite the deep knowledge of this complication, in terms of clinical phenomenology and the temporal relationship during a levodopa regimen, less is clear about the pathophysiological mechanisms underpinning it. As the disease progresses, specific oscillatory activities of both motor cortical and basal ganglia neurons and variation in levodopa metabolism, in terms of the dopamine receptor stimulation pattern and turnover rate, underlie dyskinesia onset. This review aims to provide a global overview on levodopa-induced dyskinesias, focusing on pathophysiology, clinical manifestations, therapy management strategies and future directions. [ABSTRACT FROM AUTHOR]

BackgroundDifferent screening tools to identify advanced Parkinson’s disease (APD) have emerged in recent years. Among them, wearable medical devices, such as STAT-ON™, have been proposed to help to objectively detect APD.ObjectivesTo analyze the correlation between STAT-ON™ reports and other assessment tools to identify APD and to assess the accuracy of screening tools in APD patients, using the STAT-ON™ as the gold standard.MethodsIn this retrospective, observational study, data from the University Hospital Complex of Pontevedra database on 44 patients with potential APD who wore STAT-ON™ were extracted. Data were collected according to different sources of tools for identifying APD: (1) STAT-ON™, (2) information provided by the patient, (3) questionnaire for advanced Parkinson’s disease (CDEPA), (4) 5-2-1 Criteria, and (5) Making Informed Decisions to Aid Timely Management of Parkinson’s Disease (MANAGE-PD). Considering STAT-ON™ recordings as a reference, the sensitivity, specificity, and positive and negative predictive values for each tool were calculated. The kappa index assessed the degree of agreement between the gold standard and the other instruments.ResultsAlthough no statistically significant association was found between STAT-ON™ recordings and any screening methods evaluated, the CDEPA questionnaire demonstrated the highest sensitivity and VPN values to detect patients with APD candidates for second-line therapy (SLT). According to the correlation analyses, MANAGE-PD demonstrated the highest degree of concordance with STAT-ON™ recordings to identify the SLT indication and to predict the SLT decision.ConclusionSTAT-ON™ device may be a helpful tool to detect APD and to guide treatment decisions.

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder which requires complex medication regimens to mitigate motor symptoms. The use of digital health technology systems (DHTSs) to collect mobility and medication data provides an opportunity to objectively quantify the effect of medication on motor performance during day-to-day activities. This insight could inform clinical decision-making, personalise care, and aid self-management. This study investigates the feasibility and usability of a multi-component DHTS to remotely assess self-reported medication adherence and monitor mobility in people with Parkinson's (PwP). Methods: Thirty participants with PD [Hoehn and Yahr stage I (n = 1) and II (n = 29)] were recruited for this cross-sectional study. Participants were required to wear, and where appropriate, interact with a DHTS (smartwatch, inertial measurement unit, and smartphone) for seven consecutive days to assess medication adherence and monitor digital mobility outcomes and contextual factors. Participants reported their daily motor complications [motor fluctuations and dyskinesias (i.e., involuntary movements)] in a diary. Following the monitoring period, participants completed a questionnaire to gauge the usability of the DHTS. Feasibility was assessed through the percentage of data collected, and usability through analysis of qualitative questionnaire feedback. Results: Adherence to each device exceeded 70% and ranged from 73 to 97%. Overall, the DHTS was well tolerated with 17/30 participants giving a score > 75% [average score for these participants = 89%, from 0 (worst) to 100 (best)] for its usability. Usability of the DHTS was significantly associated with age (ρ = -0.560, BCa 95% CI [-0.791, -0.207]). This study identified means to improve usability of the DHTS by addressing technical and design issues of the smartwatch. Feasibility, usability and acceptability were identified as key themes from PwP qualitative feedback on the DHTS. Conclusion: This study highlighted the feasibility and usability of our integrated DHTS to remotely assess medication adherence and monitor mobility in people with mild-to-moderate Parkinson's disease. Further work is necessary to determine whether this DHTS can be implemented for clinical decision-making to optimise management of PwP. [ABSTRACT FROM AUTHOR]

Introduction: Patients with advanced Parkinson's disease (APD) commonly experience motor and nonmotor symptoms (NMS) associated with functional limitations and decreased quality of life. We compared motor and nonmotor outcomes in patients with APD receiving 24- versus 16-h levodopa-carbidopa intestinal gel (LCIG).Methods: Data from COSMOS, a large, real-world, retrospective and cross-sectional, observational study on LCIG and comedication in APD were obtained from medical records and a single patient visit for patients receiving 24- and 16-h LCIG infusion. Changes from baseline were evaluated for motor symptoms, NMS, and clinical characteristics. Safety was also assessed.Results: Data for 401 patients were included in this subanalysis. At the patient visit there were 35 patients on 24-h LCIG and 366 on 16-h LCIG. "Off" time and dyskinesia (duration and severity) were reduced in both groups. In both LCIG treatment groups, prevalence of most symptoms was reduced. There were significant differences in the change from baseline in severity and frequency of freezing of gait with 24-h LCIG versus 16-h LCIG (p = 0.011 and p = 0.038), severity of urinary symptoms (p = 0.006), and frequency of cognitive impairment (p = 0.014) with 24-h LCIG versus 16-h LCIG. Adverse events were similar for both treatment groups and considered tolerable.Conclusions: LCIG 24-h infusion may be a useful treatment option, when clinically justified, for select patients with APD.Clinical Trial Number: NCT03362879. [ABSTRACT FROM AUTHOR]

Background and purpose: While levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), its use is associated with an increased risk of motor complications (MCs) in the first 5 years of treatment compared to dopamine agonist (DA) first therapy. It is not known whether this translates into true benefit later in the disease. We aimed to determine whether there is a difference in the time between initial levodopa versus DA treatment and the development of disabling MCs prompting deep brain stimulation (DBS) consideration. Methods: This was a retrospective cohort study of patients with PD attending the DBS Clinic at Toronto Western Hospital, Canada between March 2004 and February 2022, who underwent globus pallidus interna (GPI) or subthalamic nucleus (STN) DBS in 2005 or later for disabling MCs. Results: Of the 438 patients included in the study, 352 underwent STN DBS and 86 underwent GPi DBS. The median (range) disease duration was 9 (2–30) years. The majority of patients (n = 312) received levodopa first and 126 received a DA. There was no significant difference in disease duration or amantadine use between the two groups. The duration from the first treatment to assesment for DBS (levodopa: median 8 years, interquartile range [IQ] 4 years; DA: median 9, IQR 4 years) or DBS surgery (levodopa: median 10 years, IIQR 5 years; DA: median 10 years, IQR 5 years) did not differ. Conclusion: To our knowledge, this is the only study to date to evaluate the duration between levodopa/DA‐first treatment and the development of MCs of sufficient severity to warrant consideration of DBS. No association was found. The results suggest that the development of disabling MCs warranting DBS is independent of the type of first dopaminergic treatment. [ABSTRACT FROM AUTHOR]

Non-motor symptoms and non-motor fluctuations (NMF) in Parkinson's disease (PD) strongly affect health-related quality of life (HRQoL) and disability. The impact of deep brain stimulation (DBS) on NMF remains an area of uncertainty. The aim is to evaluate the impact of DBS on NMF, using the recently validated Non-Motor Fluctuation Assessment (NoMoFa), and to explore the correlation between NMF and motor symptoms, motor complications (MC), and HRQoL post-surgical improvement. We prospectively evaluated consecutive patients undergoing subthalamic DBS (STN-DBS), at baseline and 6-months after surgery. Assessments included the NoMoFa questionnaire, the MDS-sponsored Unified Parkinson's Disease Rating Scale, and the 39-Item Parkinson's Disease Questionnaire. Pre- and post-surgical NoMoFa scores were compared using the Wilcoxon Signed rank-test. Linear regression analysis evaluated: a) the correlation between NoMoFa scores, motor and MC improvement, correcting for age, disease duration, and dopaminergic therapy reduction; b) the correlation between HRQoL and NMF improvement, correcting for age, disease duration, motor and MC improvement. Twenty patients were evaluated. Total NMF score significantly improved (44.6 %, [IQR = 18.3–100]; p = 0.022), particularly in Off condition (52.0 %, [IQR = 25.4–100]; p = 0.009); we observed strong correlation between NMF and MC improvement (Beta = 0.728; p = 0.006), mainly driven by the mitigation of unpredictable Off (Beta = 0.905; p < 0.001). Even after adjusting for potential confounders, the reduction of NMF independently correlated with increased HRQoL (Beta = 0.714; p = 0.010). STN-DBS demonstrated strong beneficial effect on NMF, resulting in significant improvement of HRQoL. This underlines the importance of recognizing NMF as a significant factor to be considered in the selection of patients eligible for STN-DBS. • STN-DBS significantly improves non-motor fluctuations (NMF) 6-months after surgery. • We assessed the impact of STN-DBS on NMF using the recently validated NoMoFa scale. • NMF improvement is strictly related to the mitigation of unpredictable Off. • The reduction of NMF independently correlates with improvement in quality of life. • The presence of severe NMF should be considered during the STN-DBS selection work-up. [ABSTRACT FROM AUTHOR]

Background and purpose: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited disorder that manifests as a mixture of cerebellar ataxia, parkinsonism, and polyneuropathy; in type IV SCA3, pure parkinsonism is the only symptom. Currently, no disease‐modifying treatment is available, but variable responses to antiparkinsonism agents have been reported. However, the benefits of deep brain stimulation (DBS) for treating parkinsonism in this subtype of SCA3 remain unclear. Methods: A 39‐year‐old male patient with a rare disorder of type IV SCA3 presented with pure parkinsonism including unilateral resting tremor, rigidity, and bradykinesia at the age of 30 years. Young‐onset Parkinson disease was diagnosed at the age of 32 years. His family history revealed a mild ataxia in his father since the age of 55 years. Genetic testing confirmed an expanded CAG repeated number, with 66 in this case and 63 in his father for SCA3 mutation. Excellent response to levodopa and dopamine agonists in the first 3 years was noted, but wearing‐off phenomena, levodopa‐induced dyskinesia, and severe impulse control disorders later developed. To alleviate drug‐induced complications, he received bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) in the absence of cerebellar signs, depression, and cognitive impairment. Results: As of 2019, no impulsive control disorders, motor fluctuations, or DBS‐related complications were observed during a 4‐year follow‐up, with 66% Unified Parkinson's Disease Rating Scale Part III reduction at medication OFF state noted, whereas levodopa equivalent daily dosage decreased by almost half. Conclusions: STN‐DBS may be considered as adjunct treatment for severe dopa‐related motor/nonmotor complications in patients with parkinsonian phenotype of SCA 3. [ABSTRACT FROM AUTHOR]

Growing evidence has highlighted that angiotensin-converting enzyme (ACE)-inhibitors (ACEi)/AT1 receptor blockers (ARBs) may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway, thus affecting the development of levodopa-induced dyskinesia in Parkinson's disease (PD). In the present study, we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia, using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital “Maggiore della Carità". We conducted a retrospective case-control study identifying PD patients with dyskinesias (PwD; n = 47) as cases. For each PwD we selected a non-dyskinetic control (NoD), nearly perfectly matched according to sex, Unified Parkinson's Disease Rating Scale (UPDRS) part III score, and duration of antiparkinsonian treatment. Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use. Ninety-four PD patients were included, aged 72.18 ± 9 years, with an average disease duration of 10.20 ± 4.8 years and 9.04 ± 4.9 years of antiparkinsonian treatment. The mean UPDRS part III score was 18.87 ± 7.6 and the median HY stage was 2. In the NoD group, 25 (53.2%) were users and 22 (46.8%) non-users of ACEi/ARBs. Conversely, in the PwD group, 11 (23.4%) were users and 36 non-users (76.6%) of this drug class (Pearson chi-square = 8.824, P = 0.003). Concerning general medication, there were no other statistically significant differences between groups. After controlling for tremor dominant phenotype, levodopa equivalent daily dose, HY 3-4, and disease duration, ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia (OR = 0.226, 95% CI: 0.080-0.636, P = 0.005). Therefore, our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and, thanks to good tolerability and easy management, represent a feasible choice when dealing with the treatment of hypertension in PD patients. The study was approved by the Ethics Committee of Novara University Hospital “Maggiore della Carità” (CE 65/16) on July 27, 2016.

Background: Wearable technology research suggests that nocturnal movements are disturbed in early Parkinson's disease (PD). In this study, we investigate if patients also already experience impaired bed mobility before PD diagnosis. Furthermore, we explore its association with motor and nonmotor features and its value for phenoconversion and disease progression prediction.Methods: PPMI data were downloaded for de novo PD subjects, subjects at-risk for developing a synucleinopathy (with isolated REM sleep behavior disorder, hyposmia or a pathogenic genetic variant) and controls. Impaired bed mobility was assessed with the MDS-UPDRS part 2 item 9. A frequency analysis was performed. Multivariable logistic regression analyses were used to investigate the association with other PD variables. Cox proportional-hazards models were used to test if difficulties with turning in bed could predict phenoconversion. Linear mixed models were used to evaluate if difficulties with turning in bed could predict disease progression.Results: Of the at-risk subjects, 9.2-12.5% experienced difficulties with turning in bed vs. 25.0% of de novo PD subjects and 2.5% of controls. Impaired turning ability was associated with MDS-UPDRS motorscore (axial signs in the at-risk group, bradykinesia in the de novo PD group) and SCOPA-AUT score (gastrointestinal symptoms). In addition, difficulties with turning in bed were a significant predictor for phenoconversion in the at-risk group and for development of motor complications in the de novo PD group.Conclusion: Our findings suggest that difficulties with turning in bed can be helpful as clinical symptom for a prodromal PD screening and for motor complication prediction in early PD. [ABSTRACT FROM AUTHOR]

Background/Objectives: Non-ergot dopamine agonist (NEDA) are recommended as the first-line treatment for patients with early Parkinson's disease (PD) because of their efficacy in treating PD motor symptoms. However, systematic evaluations of the risk of motor complications induced by NEDA and risk factors potentially associated with motor complications are still lacking. Methods: Medline, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched for potentially eligible randomized controlled trials. The incidence of motor complications (dyskinesia, motor fluctuations), impulsive-compulsive behaviors and adverse events and clinical disability rating scale (UPDRS) scores were evaluated using standard meta-analytic methods. Metaregression was conducted on the incidence of motor complications (dyskinesia) with treatment duration and NEDA dose as covariates. Results: Patients treated with NEDA had significantly lower UPDRS total scores, motor scores and activity of daily living (ADL) scores than those receiving a placebo (weighted mean difference (WMD) −4.81, 95% CI −6.57 to −3.05; WMD −4.901, 95% CI −7.03 to −2.77; WMD −1.52, 95% CI −2.19 to −0.84, respectively). Patients in the NEDA and NEDA+open Levodopa (LD) groups had lower odds for dyskinesia than patients in the LD group (OR = 0.21, 95% CI: 0.15–0.29; OR = 0.31, 95% CI 0.24–0.42, respectively). Metaregressions indicated that the mean LD dose of the NEDA group increased, and the odds of developing dyskinesia increased (p = 0.012). However, the odds of developing dyskinesia in the NEDA group were not related to treatment duration (p = 0.308). PD patients treated with NEDA or NEDA+open LD had a lower risk of wearing-off implications than those treated with LD (all p < 0.05). No significant difference was found between the NEDA and placebo groups in impulsive-compulsive behavior development (p > 0.05). Patients in the NEDA group were more likely to suffer somnolence, edema, constipation, dizziness, hallucinations, nausea and vomiting than those in the placebo or LD group. Conclusion: NEDA therapy reduces motor symptoms and improves ADLs in early PD. The odds of developing motor complications were lower with NEDA than with LD, and dyskinesia increased with increasing LD equivalent dose and was not influenced by NEDA treatment duration. Therefore, long-term treatment with an appropriate dosage of NEDA might be more suitable than LD for early PD patients. Registration: PROSPERO CRD42021287172. [ABSTRACT FROM AUTHOR]

Background: Dopamine deficiency causes Parkinson's disease (PD), and on treatment, levodopa is the gold standard. Various drug-metabolizing enzymes and drug receptors are believed to be involved in prompting dyskinesias due to the extended usage of levodopa. Shreds of evidence in genomic studies have presented that ADORA2A receptor antagonism has beneficial outcomes to avoid these drug-induced side effects.Objective: The aim of this study was to study the polymorphisms of rs2298383, rs35060421, and rs5751876 in the ADORA2A in patients diagnosed as PD and describe their possible relationships with levodopa-induced dyskinesias (LID).Methods: One-hundred and seventy-two patients were recruited and separated as the study and the control group. DNA was achieved from peripheral venous blood, high resolution melting analysis, and reverse-transcriptase PCR was performed.Results: The allele differences among the groups were not statistically significant. Although it was not statistically significant, the rs35060421 allele was observed to repeat more frequently. However, we did not find an association between such polymorphisms of ADORA2A and LID.Conclusions: Although this result showed that a higher sample number might produce different results as possible, current results in the Turkish sample indicated that these alleles of ADORA2A might not be related to LID in patients. [ABSTRACT FROM AUTHOR]

Background/ObjectivesNon-ergot dopamine agonist (NEDA) are recommended as the first-line treatment for patients with early Parkinson's disease (PD) because of their efficacy in treating PD motor symptoms. However, systematic evaluations of the risk of motor complications induced by NEDA and risk factors potentially associated with motor complications are still lacking.MethodsMedline, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched for potentially eligible randomized controlled trials. The incidence of motor complications (dyskinesia, motor fluctuations), impulsive-compulsive behaviors and adverse events and clinical disability rating scale (UPDRS) scores were evaluated using standard meta-analytic methods. Metaregression was conducted on the incidence of motor complications (dyskinesia) with treatment duration and NEDA dose as covariates.ResultsPatients treated with NEDA had significantly lower UPDRS total scores, motor scores and activity of daily living (ADL) scores than those receiving a placebo (weighted mean difference (WMD) −4.81, 95% CI −6.57 to −3.05; WMD −4.901, 95% CI −7.03 to −2.77; WMD −1.52, 95% CI −2.19 to −0.84, respectively). Patients in the NEDA and NEDA+open Levodopa (LD) groups had lower odds for dyskinesia than patients in the LD group (OR = 0.21, 95% CI: 0.15–0.29; OR = 0.31, 95% CI 0.24–0.42, respectively). Metaregressions indicated that the mean LD dose of the NEDA group increased, and the odds of developing dyskinesia increased (p = 0.012). However, the odds of developing dyskinesia in the NEDA group were not related to treatment duration (p = 0.308). PD patients treated with NEDA or NEDA+open LD had a lower risk of wearing-off implications than those treated with LD (all p < 0.05). No significant difference was found between the NEDA and placebo groups in impulsive-compulsive behavior development (p > 0.05). Patients in the NEDA group were more likely to suffer somnolence, edema, constipation, dizziness, hallucinations, nausea and vomiting than those in the placebo or LD group.ConclusionNEDA therapy reduces motor symptoms and improves ADLs in early PD. The odds of developing motor complications were lower with NEDA than with LD, and dyskinesia increased with increasing LD equivalent dose and was not influenced by NEDA treatment duration. Therefore, long-term treatment with an appropriate dosage of NEDA might be more suitable than LD for early PD patients.RegistrationPROSPERO CRD42021287172.

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]

Introduction: Gocovri, a bedtime-administered delayed-release/extended-release capsule formulation of amantadine, is the only drug approved by the US Food and Drug Administration as levodopa-adjunctive therapy for the treatment of OFF episodes and/or dyskinesia in Parkinson's disease (PD). Part II of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) assesses patient-perceived disability on experiences of daily living affected by PD motor symptoms. We analyzed Gocovri-related changes in MDS-UPDRS Part II ratings in two placebo-controlled clinical trials. Methods: Baseline to week 12 changes in MDS-UPDRS Part II total and item scores were compared for Gocovri and placebo using pooled data from phase 3 trials (EASE LID and EASE LID 3). Results: Baseline mean MDS-UPDRS Part II total score was 15.1 for Gocovri (n = 100) and 15.3 for placebo (n = 96) groups. At week 12, the least squares mean change from baseline was −3.4 for the Gocovri group and −1.4 for placebo (treatment difference, −2.0; 95% CI −3.3 to −0.7; P = 0.004). For Gocovri, change from baseline exceeded a published minimal clinically important difference threshold of 3.05. Gocovri-related treatment differences over placebo were driven primarily by improvement in the scale items of freezing (−0.4; P < 0.0001), tremor (−0.4; P = 0.002), getting out of bed/car/deep chair (−0.3; P = 0.002), and eating tasks (−0.2; P = 0.016). Conclusion: In addition to improvement in dyskinesia, Gocovri-treated participants experienced improvement in motor aspects of experiences of daily living. Analyses suggest that Gocovri may specifically improve freezing, tremor, getting out of bed/car/deep chair, and eating tasks. Trial Registration: ClinicalTrials.gov identifiers: NCT02136914, NCT02274766. [ABSTRACT FROM AUTHOR]

József Attila Szász,1,2,* Viorelia Adelina Constantin,2,3,* Károly Orbán-Kis,1,2 Attila Rácz,4 Ligia Ariana Bancu,1,5 Dan Georgescu,1,6 János Szederjesi,1,7 István Mihály,1,2 Ana-Mária Fárr,1 Krisztina Kelemen,1,2 Tamás Vajda,8 Szabolcs Szatmári1,2 1University of Medicine and Pharmacy of Târgu Mures, Târgu Mureş, Romania; 22nd Clinic of Neurology, Târgu Mures County Emergency Clinical Hospital, Târgu Mures, Romania; 3Doctoral School, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania; 42nd Clinic of Psychiatry, Târgu Mures County Emergency Clinical Hospital, Târgu Mures, Romania; 51st Clinic of Internal Medicine, Târgu Mures County Emergency Clinical Hospital, Târgu Mures, Romania; 6Department of Gastroenterology, Târgu Mures County Emergency Clinical Hospital, Târgu Mures, Romania; 7Department of Anesthesiology and Intensive Care, Târgu Mures County Emergency Clinical Hospital, Târgu Mures, Romania; 8Department of Computer Science, Faculty of Technical and Human Sciences, Sapientia Hungarian University of Transylvania, Târgu Mureș, Romania*These authors contributed equally to this workCorrespondence: Károly Orbán-Kis Gh. Marinescu Street No 38, Targu Mures 540142, RomaniaTel +40743754525Email karoly.orban-kis@umfst.roBackground: There is insufficient data in the literature regarding the real-life, daily clinical practice evaluation of patients with advanced Parkinson’s disease (APD). We are not sure what is the upper limit of dopaminergic medication, especially the levodopa (LD) dosage, and how it is influenced by access and suitability to the various add-on and device-aided therapies (DAT).Objective: This retrospective study explored the profile of APD patients that were considered and systematically evaluated regarding the suitability for DAT.Methods: We analyzed the data from 311 consecutive patients with APD hospitalized between 2011 and 2017 that 1) described at least 2 hrs/day off periods divided into at least two instances/day (except early morning akinesia), 2) were in stage 3 or above on the Hoehn and Yahr scale, 3) were with or without dyskinesia, and 4) received at least four levodopa doses/day combined with adjuvant therapy.Results: Of the 311 patients enrolled initially, 286 patients showed up for the second visit, of which in 125 cases we assessed that DAT would be necessary. Finally, 107 patients were tested in our clinic to confirm the efficacy of LCIG. Patients selected for DAT had significantly longer off periods, more frequent dyskinesia, early morning akinesia, and freezing despite having significantly higher LD doses than those with an improved conservative therapy.Conclusion: Patients with APD can have a variety of symptoms, and because symptoms and therapeutical efficacy can be manifested in many different combinations, it is not possible to decide using a single, rigid set of criteria which APD patient is eligible for DAT. Nevertheless, treating physicians should refer APD patients to a specialized movement disorder center when patients with an average daily dose of LD of at least 750–1000 mg and maximal complementary therapies present daily motor complications that significantly reduce the quality of life.Keywords: advanced Parkinson’s disease, motor complications, levodopa doses, levodopa-carbidopa intestinal gel

Objective: This study aimed to evaluate the direct anti-dyskinesia effect of deep brain stimulation (DBS) of subthalamic nucleus (STN) on levodopa-induced on-dyskinesia in Parkinson's disease (PD) patients during the early period after surgery without reducing the levodopa dosage.Methods: We retrospectively reviewed PD patients who underwent STN-DBS from January 2017 to October 2019 and enrolled patients with levodopa-induced on-dyskinesia before surgery and without a history of thalamotomy or pallidotomy. The Unified Dyskinesia Rating Scale (UDysRS) parts I+III+IV and the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) were monitored prior to surgery, and at the 3-month follow-up, the location of active contacts was calculated by postoperative CT–MRI image fusion to identify stimulation sites with good anti-dyskinesia effect.Results: There were 41 patients enrolled. The postoperative levodopa equivalent daily dose (LEDD) (823.1 ± 201.5 mg/day) was not significantly changed from baseline (844.6 ± 266.1 mg/day, P = 0.348), while the UDysRS on-dyskinesia subscores significantly decreased from 24 (10–58) to 0 (0–18) [median (range)] after STN stimulation (P < 0.0001). The levodopa-induced on-dyskinesia recurred in stimulation-off/medication-on state in all the 41 patients and disappeared in 39 patients when DBS stimulation was switched on at 3 months of follow-up. The active contacts which correspond to good effect for dyskinesia were located above the STN, and the mean coordinate was 13.05 ± 1.24 mm lateral, −0.13 ± 1.16 mm posterior, and 0.72 ± 0.78 mm superior to the midcommissural point.Conclusions: High-frequency electrical stimulation of the area above the STN can directly suppress levodopa-induced on-dyskinesia.

Background: Clinical trials for antiparkinsonian drugs aimed at managing motor complications typically use patient diaries to divide levodopa-induced dyskinesias (LID) into “troublesome” and “non-troublesome” categories. Yet, given the choice, most patients would prefer to live without experiencing any dyskinesia. However, the concept of evaluating time spent ON without any dyskinesia as an outcome has never been tested. We conducted analyses of pooled Gocovri pivotal trial data in order to evaluate the extent to which Gocovri increased the time PD patients spent ON without dyskinesia (troublesome or non-troublesome), beyond its already identified improvement in reducing troublesome dyskinesia.Methods: Patients enrolled in phase 3 trials (EASE LID [NCT02136914] or EASE LID 3 [NCT02274766]) recorded time spent in the following PD diary states at baseline and Week 12 (endpoint): asleep, OFF, ON with troublesome dyskinesia, ON with non-troublesome dyskinesia, and ON without dyskinesia. Mixed model repeated measures analyses with estimated Cohen D effect sizes were performed on the modified intent to treat population to evaluate changes in time spent in these states.Results: Patients randomized to receive Gocovri showed an increase in ON time without dyskinesia and corresponding decreases in ON time with dyskinesia and OFF time vs. placebo. Treatment effects were statistically significant for Gocovri vs. placebo starting at Week 2 and were sustained until Week 12. On MMRM analysis at Week 12, patients in the Gocovri group showed an adjusted mean ± SE increase over placebo of 2.9 ± 0.6 h in ON time without dyskinesia (Cohen D effect size 0.79) and an adjusted mean ± SE decrease of −1.9 ± 0.6 h in ON time with dyskinesia (troublesome + non-troublesome) (Cohen D effect size 0.49), that included a −1.5 ± 0.4 h placebo-adjusted reduction in ON time with troublesome dyskinesia and a −0.6 ± 0.4 h reduction in ON time with non-troublesome dyskinesia. OFF time was reduced by −1.0 ± 0.3 h compared to placebo.Conclusions: Gocovri treatment more than doubled the daily time patients spent ON without dyskinesia. These results suggest that the Gocovri treatment effect was driven by a reduction in overall motor complications including ON time with both troublesome and non-troublesome dyskinesia as well as time spent OFF.

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Objective: This study aimed to evaluate the direct anti-dyskinesia effect of deep brain stimulation (DBS) of subthalamic nucleus (STN) on levodopa-induced on-dyskinesia in Parkinson's disease (PD) patients during the early period after surgery without reducing the levodopa dosage. Methods: We retrospectively reviewed PD patients who underwent STN-DBS from January 2017 to October 2019 and enrolled patients with levodopa-induced on-dyskinesia before surgery and without a history of thalamotomy or pallidotomy. The Unified Dyskinesia Rating Scale (UDysRS) parts I+III+IV and the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) were monitored prior to surgery, and at the 3-month follow-up, the location of active contacts was calculated by postoperative CT–MRI image fusion to identify stimulation sites with good anti-dyskinesia effect. Results: There were 41 patients enrolled. The postoperative levodopa equivalent daily dose (LEDD) (823.1 ± 201.5 mg/day) was not significantly changed from baseline (844.6 ± 266.1 mg/day, P = 0.348), while the UDysRS on-dyskinesia subscores significantly decreased from 24 (10–58) to 0 (0–18) [median (range)] after STN stimulation (P < 0.0001). The levodopa-induced on-dyskinesia recurred in stimulation-off/medication-on state in all the 41 patients and disappeared in 39 patients when DBS stimulation was switched on at 3 months of follow-up. The active contacts which correspond to good effect for dyskinesia were located above the STN, and the mean coordinate was 13.05 ± 1.24 mm lateral, −0.13 ± 1.16 mm posterior, and 0.72 ± 0.78 mm superior to the midcommissural point. Conclusions: High-frequency electrical stimulation of the area above the STN can directly suppress levodopa-induced on-dyskinesia. [ABSTRACT FROM AUTHOR]

Background: Management of motor complications (MC) represents a major challenge in the long-term treatment of Parkinson's disease (PD) patients. In this context, the role of peripheral adaptive immunity may provide new insights, since neuroinflammatory mechanisms have been proved crucial in the disease. Objective: The aim of this study was to analyze the transcription factors genes involved in CD4 + T cells development to uncover specific molecular signatures in patients with (PMC) and without (WMC) motor complications. Methods: mRNA levels of CD4 + T lymphocytes transcription factor genes TBX21, STAT1, STAT3, STAT4, STAT6, RORC, GATA3, FOXP3, and NR4A2 were measured from 40 PD patients, divided into two groups according to motor complications. Also, 40 age- and sex-matched healthy controls were enrolled. Results: WMC patients had higher levels of STAT1 and NR4A2 (p = 0.004; p = 0.003), whereas in PMC we found higher levels of STAT6 (p = 0.04). Also, a ROC curve analysis confirmed STAT1 and NR4A2 as feasible biomarkers to discriminate WMC (AUC = 0.76, 95%CI 0.59–0.92, p = 0.005; AUC = 0.75, 95%CI 0.58–0.90, p = 0.007). Similarly, STAT6 detected PMC patients (AUC = 0.69, 95%CI 0.52–0.86, p = 0.037). Conclusion: These results provide evidence of different molecular signatures in CD 4 + T cells of PD patients with and without MC, thus suggesting their potential as biomarkers of MC development. [ABSTRACT FROM AUTHOR]

Background: Clinical trials for antiparkinsonian drugs aimed at managing motor complications typically use patient diaries to divide levodopa-induced dyskinesias (LID) into "troublesome" and "non-troublesome" categories. Yet, given the choice, most patients would prefer to live without experiencing any dyskinesia. However, the concept of evaluating time spent ON without any dyskinesia as an outcome has never been tested. We conducted analyses of pooled Gocovri pivotal trial data in order to evaluate the extent to which Gocovri increased the time PD patients spent ON without dyskinesia (troublesome or non-troublesome), beyond its already identified improvement in reducing troublesome dyskinesia. Methods: Patients enrolled in phase 3 trials (EASE LID [NCT02136914] or EASE LID 3 [NCT02274766]) recorded time spent in the following PD diary states at baseline and Week 12 (endpoint): asleep, OFF, ON with troublesome dyskinesia, ON with non-troublesome dyskinesia, and ON without dyskinesia. Mixed model repeated measures analyses with estimated Cohen D effect sizes were performed on the modified intent to treat population to evaluate changes in time spent in these states. Results: Patients randomized to receive Gocovri showed an increase in ON time without dyskinesia and corresponding decreases in ON time with dyskinesia and OFF time vs. placebo. Treatment effects were statistically significant for Gocovri vs. placebo starting at Week 2 and were sustained until Week 12. On MMRM analysis at Week 12, patients in the Gocovri group showed an adjusted mean ± SE increase over placebo of 2.9 ± 0.6 h in ON time without dyskinesia (Cohen D effect size 0.79) and an adjusted mean ± SE decrease of −1.9 ± 0.6 h in ON time with dyskinesia (troublesome + non-troublesome) (Cohen D effect size 0.49), that included a −1.5 ± 0.4 h placebo-adjusted reduction in ON time with troublesome dyskinesia and a −0.6 ± 0.4 h reduction in ON time with non-troublesome dyskinesia. OFF time was reduced by −1.0 ± 0.3 h compared to placebo. Conclusions: Gocovri treatment more than doubled the daily time patients spent ON without dyskinesia. These results suggest that the Gocovri treatment effect was driven by a reduction in overall motor complications including ON time with both troublesome and non-troublesome dyskinesia as well as time spent OFF. [ABSTRACT FROM AUTHOR]

Background: Development of "Wearing Off" (WO) of motor and non-motor function in Parkinson's disease (PD) adversely affects quality of life. This suggest that identifying and treating WO is important. However, identification of WO depends on people with PD (PwP) recognising and reporting WO and there is a perception that WO may be significantly underestimated. Objective: We investigate the feasibility of identifying "Wearing Off" using objective measurement and assess the clinical benefit in rectifying it. Method: In this study, 200 PwP were studied for evidence of WO using a continuously worn wearable system. Eighty-five patients (43%) were found to have WO and treatment was changed to mitigate the effects of WO. Results: Factors, such as duration of disease, high baseline MDS-UPDRS (motor component), high Percent Time in Bradykinesia (PTB), high Levodopa Equivalent Daily Dose (LEDD), frequent Levodopa doses and younger age of onset, are associated with severity of motor complications. Patients with more severe WO experienced worse motor and non-motor symptoms and lower quality of life. Quality of life significantly improved in PwP when WO was treated. Conclusion: The findings reported in this study provide evidence that identifying and treating WO improves outcomes of PwP and that objective measurements may help clinicians to identify and treat WO. [ABSTRACT FROM AUTHOR]

• Management of Parkinson's disease (PD) relies on knowledge of the motor complication. • Commercially available devices for PD management have limited adoption. • The obstacle relates to the limitations of these devices' underlying algorithms. • Future algorithmic developments need to address the essential requirements. [ABSTRACT FROM AUTHOR]

This paper introduces Professor ZHUANG Lixing 's experience in treating motor complications of Parkinson's disease (PD) with acupuncture combined with medication. Based on the characteristics of the alternation of "movement and stillness" in PD motor complications, Professor ZHUANG divides these complications into three distinct periods: "movement" stage, "stillness" stage and "alternation" stage, and proposes an integrated approach of acupuncture and medication, with staged treatment tailored to each period. The main acupoints include Jin's three needles to regulate spirit (four spirit needles, Shenting [GV 24], Yintang [GV 24 + ], Shenmen [HT 7], Sanyinjiao [SP 6]), along with hand tremor three needles (Hegu [LI 4], Quchi [LI 11], Dingchan), foot tremor three needles (Yinlingquan [SP 9], Yanglingquan [GB 34], Taichong [LR 3]), and Du 's three needles (Dazhui [GV 14], Jinsuo [GV 8], Mingmen [GV 4]). The primary medicinal formulas include Lingjiao Gouteng decoction, Banxia Baizhu Tianma decoction, Bazhen decoction combined with Buzhong Yiqi decoction, Sini decoction combined with Yougui pills, and Xiaochaihu decoction. This integrated approach effectively alleviates the motor symptom fluctuations in PD patients, helping them maintain a stable life.

Objective: We sought to evaluate demographic, clinical, and habits/occupational variables between phenotypic extremes in Parkinson's disease (PD). Methods: Databases from nine movement disorders centers across seven countries were retrospectively searched for subjects meeting criteria for very slowly progressive, benign, PD (bPD) and rapidly progressive, malignant, PD (mPD). bPD was defined as Hoehn and Yahr (H&Y) stage ≤ 3, normal cognitive function, and Schwab and England (S&E) score ≥ 70 after ≥ 20 years of PD (≥ 10 years if older than 60 at PD onset); mPD as H&Y > 3, S&E score < 70, and cognitive impairment within 10 years from PD onset. We performed between-group analysis of demographic, habits/occupational, and clinical features at baseline and follow-up and unsupervised data-driven analysis of the clinical homogeneity of bPD and mPD. Results: At onset, bPD subjects (n = 210) were younger, had a single limb affected, lower severity and greater asymmetry of symptoms, and lower prevalence of depression than mPD (n = 155). bPD was associated with active smoking and physical activity, mPD with agricultural occupation. At follow-up, mPD showed higher prevalence of depression, hallucinations, dysautonomia, and REM behaviour disorder. Interestingly, the odds of mPD were significantly reduced by the presence of dyskinesia and wearing-off. Data-driven analysis confirmed the independent clustering of bPD and mPD, with age at onset emerging as a critical discriminant between the two groups (< 46-year-old vs. > 68-year-old). Conclusions: Phenotypic PD extremes showed distinct demographic, clinical, and habits/occupational factors. Motor complications may be conceived as markers of therapeutic success given their attenuating effects on the odds of mPD. [ABSTRACT FROM AUTHOR]

Levodopa‐induced motor complications remain an important source of disability for many patients with Parkinson's disease. Substantial laboratory evidence indicates that motor complications relate to the nonphysiological restoration of brain dopamine with intermittent doses of standard oral levodopa. Dopamine levels are normally maintained at a relatively constant level, even following a dose of levodopa. However, in the Parkinsonian state, where dopamine terminals have degenerated with a loss of their buffering capacity, intermittent doses of levodopa lead to dramatic peak and trough fluctuations in striatal dopamine levels. This results in pulsatile stimulation of dopamine receptors, molecular changes in striatal neurons, physiological changes in pallidal neurons, and ultimately the development of motor complications. These observations led to the hypothesis that continuous delivery of levodopa might be associated with a reduced risk of motor complications. This concept is known as continuous dopamine stimulation (CDS). Preliminary studies in animal models and patients with Parkinson's disease supported this hypothesis, suggesting a reduced risk of both motor fluctuations and dyskinesias. The present review considers the scientific advances and the more definitive clinical trials testing this concept that have taken place during the past decade and considers ongoing experimental studies and future opportunities. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Parkinson‘s disease typically begins around the age of 60. It is manifested by parkinsonian syndrome (bradykinesia and at least one of the following symptoms – rigidity and rest tremor), other motor symptoms and a variety of non‑motor symptoms (neuropsychiatric symptoms, sleep disorders, autonomic disorders, hyposmia, non‑specific symptoms such as fatigue, pain). In the course of the disease motor complications appear (wearing‑off is the most common – worsening of motor symptoms at the end of the effect of levodopa dose). In addition to drug therapy (levodopa, dopa agonists, amantadine) and rehabilitation, invasive treatment methods are available for selected patients. The most commonly used methods are deep brain stimulation (DBS) and continuous application of Duodopa by means of intestinal tube. [ABSTRACT FROM AUTHOR]

Background: Previous molecular imaging studies comparing dopamine function in vivo between early-onset PD and late-onset PD patients have shown contradictory results, presumably attributable to the aging-related decline in nigrostriatal function.Objectives: (1) To investigate baseline dopamine transporter availability in early-onset PD (<55 years) and late-onset PD (>70 years) patients, z-scores values of putamen and caudate [123 I]-ioflupane uptake were calculated using the respective age-matched controls in order to correct for early presynaptic compensatory mechanisms and age-related dopamine neuron loss; (2) to examine the associations of such baseline single-photon emission computed tomography measures with the emergence of late-disease motor complications.Methods: In this retrospective study, 105 de novo PD patients who underwent [123 I]-ioflupane single-photon emission computed tomography at time of diagnosis were divided into three tertile groups according to age at disease onset (35 early-onset PD and 40 late-onset PD patients). Z-scores were compared between the two groups, and their predictive power for motor complications (during a mean follow-up of 7 years) was evaluated using Cox proportional hazard models.Results: Despite a less-severe motor phenotype, early-onset PD patients exhibited more reduced [123 I]-ioflupane binding in the putamen and had a higher and earlier risk for developing motor complications than those with late-onset PD. Lower [123 I]-Ioflupane uptake in the putamen and caudate increased the risk of motor complications.Conclusions: Our findings indicate that a lower dopamine transporter binding in early-onset PD predicts the later development of motor complications, but it is not related to severity of motor symptoms, suggesting age-related differences in striatal compensatory mechanisms in PD. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The increasing global burden of Parkinson's disease (PD) poses a particular challenge for developing countries, such as Thailand, when delivering care to a geographically diverse populace with limited resources, often compounded by a lack of expertise in the use of certain PD medications, such as device-aided therapies (DAT). A panel of local, regional, and international PD experts convened to review the unmet needs of PD in Thailand and share insights into effective delivery of DAT, focusing on experience with apomorphine infusion. Despite its proven efficacy and safety, implementation of apomorphine infusion as a new option was not straightforward. This has prompted a range of health-care professional and patient-focused initiatives, led by the Chulalongkorn Center of Excellence for Parkinson's Disease and Related Disorders in Bangkok, to help establish a more coordinated approach to PD management throughout the country and ensure patients have access to suitable treatments. Overcoming the challenges of education, proficiency, resource capacity and standard of care for PD patients in developing countries requires a coordinated effort both nationally and beyond. The best practices identified in Thailand following the introduction of apomorphine infusion might be helpful for other countries when implementing similar programs. [ABSTRACT FROM AUTHOR]

Levodopa therapy remains the most effective drug for the treatment of Parkinson's disease, and it is associated with the greatest improvement in motor function as assessed by the Unified Parkinson's Disease Rating Scale. Dopamine agonists have also proven their efficacy as monotherapy in early Parkinson's disease but also as adjunct therapy. However, the chronic use of dopaminergic therapy is associated with disabling motor and nonmotor side effects and complications, among which levodopa-induced dyskinesias and impulse control behaviors are the most common. The underlying mechanisms of these disorders are not fully understood. In the last decade, classic neuroimaging methods and more sophisticated techniques, such as analysis of gray-matter structural imaging and functional magnetic resonance imaging, have given access to anatomical and functional abnormalities, respectively, in the brain. This review presents an overview of structural and functional brain changes associated with motor and nonmotor therapy-induced complications in Parkinson's disease. Magnetic resonance imaging may offer structural and/or functional neuroimaging biomarkers that could be used as predictive signs of development, maintenance, and progression of these complications. Neurophysiological tools, such as theta burst stimulation and transcranial magnetic stimulation, might help us to integrate neuroimaging findings and clinical features and could be used as therapeutic options, translating neuroimaging data into clinical practice. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a chronic neurologic disease that has a great impact on the patient’s quality of life. The natural course of the disease is characterized by an insidious onset of symptoms, such as rest tremor, shuffling gait, bradykinesia, followed by improvement with the initiation of dopaminergic therapy. However, this “honeymoon period” gradually comes to an end with the emergence of motor fluctuations and dyskinesia. PD patients need long-term treatments and monitoring throughout the day; however, clinical examinations in hospitals are often not sufficient for optimal management of the disease. Technology-based devices are a new comprehensive assessment method of PD patient’s symptoms that are easy to use and give unbiased measurements. This review article provides an exhaustive overview of motor complications of advanced PD and new approaches to the management of the disease using sensors.

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient’s quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy.

Background: In the advanced stages of Parkinson’s disease (APD), complex forms of dyskinesia may severely impair the patient’s quality of life. Objective: In the present study, we aimed to analyze the evolution under LCIG therapy of the most important motor fluctuations and complex disabling dyskinesias, including diphasic dyskinesia. Methods: In this retrospective study, we analyzed the characteristics of patients with APD who had at least 30 min of diphasic dyskinesia (DID) in 3 consecutive days, were considered responders and were treated with LCIG in our clinic. Patients were evaluated before and after PEG and at 6, 12 and 18 months, when the changes in the therapy were recorded, and they completed a 7-point Global Patient Impression of Improvement (PGI-I) scale. Results: Forty patients fulfilled the inclusion criteria—out of which, 34 performed all visits. There was a substantial difference between the calculated and real LCIG (1232 ± 337 mg vs. 1823 ± 728 mg). The motor fluctuations and most dyskinesias improved significantly after starting LCIG, but an increasing number of patients needed longer daily administrations of LCIG (24 instead of 16 h). Conclusions: Patients with APD with complex dyskinesias must be tested in dedicated hospitals, and they need a special therapeutic approach. The properly adapted LCIG treatment regarding the dose and time of administration completed with well-selected add-on medication should offer improvement for patients who want to or can only choose this DAT vs. others.

Background: Long-term population-representative data on motor fluctuations and levodopa-induced dyskinesias in Parkinson's disease is lacking.Methods: The Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort comprises incident PD cases followed for up to 13 years (n = 141). Cumulative incidence of motor fluctuations and levodopa-induced dyskinesias and risk factors were assessed using Kaplan-Meyer and Cox regression analyses.Results: Cumulative incidence of motor fluctuations and levodopa-induced dyskinesias was 54.3% and 14.5%, respectively, at 5 years and 100% and 55.7%, respectively, at 10 years. Higher baseline UPDRS-total and SNCA rs356219(A) predicted motor fluctuations, whereas higher baseline Mini-mental State Examination and GBA mutations predicted levodopa-induced dyskinesias. Early levodopa use did not predict motor complications. Both early motor fluctuations and levodopa-induced dyskinesias predicted reduced mortality in older patients (age at diagnosis >70 years).Conclusions: Our data support the hypothesis that motor complications are related to the severity of nigrostriatal pathology rather than early levodopa use and indicate that early motor complications do not necessarily confer a negative prognosis. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]