Search

Purpose: An increased prevalence of peripheral polyneuropathy (PN) in Parkinson's disease (PD) associated with greater functional impairment has previously been reported. A possible cause has been suggested as levodopa therapy. The aim of this real-world study was to assess the prevalence and the characteristics of PN in PD and to investigate the putative association between PN and oral levodopa., Methods: A cohort of 692 consecutive patients with idiopathic PD had routine clinical, laboratory, and lower limb clinical neurophysiology assessment when attending the certified tertiary Parkinson center, Schön Klinik Neustadt, Neustadt in Holstein, Germany, between 2016 and 2019. Patients were sent by general neurologists for the medication adjustment, physiotherapy, ergotherapy, and logopaedic treatment. A retrospective cross-sectional review of the data was performed., Findings: The mean age of the cohort was 72.6 (8.44) years (range, 44-90 years) and 60% were male. The age of the first PD manifestation was 65.22 (10.09) years (range, 31-88 years). Of 692 patients with PD, 507 (73.27%) had clinical signs of neuropathy and PN was first diagnosed 6.3 (5.7) years after the PD onset. Of these 507 patients, 446 (87.96%) underwent the electrophysiological investigations with PN confirmed in 396 patients (88.79% out of 446 electrophysiologically investigated patients with PD). Peripheral polyneuropathy was ruled out in 50 patients (11.21% of 446 electrophysiologically investigated patients with PD). The half of patients had moderate and severe sensory axonal PN (201 patients or 53.03% of all 396 with confirmed PN). The mean motor examination part of the Movement Disorders Society's Unified PD Rating Scale score in patients with PN was significantly higher (off, 30.48 [11.60] points; on, 19.92 [10.27] points), than in patients without PN (off, 27.17 [14.57] points; on, 17.14 [11.98] points), with P < 0.01 in the both off and on states. The mean levodopa daily dosage was similar in patients with PN and without PN (565 mg vs 556 mg, P = nonsignificant). No difference between other dopaminergic medication in PN and non-PN group was found., Implications: PN is highly prevalent in patients with PD. There was no association between oral levodopa or other dopaminergic medication and PN. More awareness of PN in PD clinics and further understanding of the pathophysiology, which leads to the development of an axonal polyneuropathy in PD, are required., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Prasinezumab was shown to potentially delay motor progression in individuals with early-stage Parkinson's disease (PD) who were either treatment-naïve or on monoamine oxidase type B inhibitor (MAO-Bi) therapy in the PASADENA study. We report the rationale, design, and baseline patient characteristics of the PADOVA study, designed to evaluate prasinezumab in an early-stage PD population receiving standard-of-care (SOC) symptomatic medications., Methods: PADOVA (NCT04777331) is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, in which individuals with early-stage PD on SOC stable symptomatic monotherapy (levodopa or MAO-Bi) receive intravenous prasinezumab 1500 mg every 4 weeks. The primary endpoint is time to confirmed motor progression, defined as ≥5 points increase from baseline on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in practically defined OFF-medication state., Results: 586 participants were enrolled between May 5th, 2021 and March 22nd, 2023. At baseline, 74.2 % and 25.8 % of participants were receiving levodopa and MAO-Bi, respectively. Mean age was 64.2 years and 63.5 % were male. Mean time from diagnosis was 18.6 months, 85 % of participants were in Hoehn & Yahr (H&Y) Stage 2, and mean MDS-UPDRS Part III score was 24.5. Compared with the PASADENA population, PADOVA participants were older (∼5 years), with longer disease duration (∼8 months), and slightly more advanced based on H&Y stage (10 % more in Stage 2) and MDS-UPDRS Part III (∼3 points more)., Conclusions: PADOVA has successfully recruited an early-stage PD population to test the effect of prasinezumab when added to background SOC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tania Nikolcheva reports financial support was provided by F Hoffmann-La Roche Ltd. Tania Nikolcheva reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Gennaro Pagano reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Nathalie Pross reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Gesine Respondek reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Annabelle Monnet reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Nima Shariati reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Benedicte Ricci reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Loes Rutten-Jacobs reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Thomas Kustermann reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Kirsten I. Taylor reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Azad Bonni reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Dylan Trundell reports a relationship with F Hoffmann-La Roche Ltd that includes: equity or stocks. Dylan Trundell reports a relationship with Roche Products Ltd that includes: employment. Hanno Svoboda reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Tanya Simuni reports a relationship with Acurex that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Adamas that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with AskBio that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Amneal that includes: consulting or advisory and funding grants. Tanya Simuni reports a relationship with Blue Rock Therapeutics that includes: consulting or advisory. Tanya Simuni reports a relationship with Critical Path for Parkinson's Consortium that includes: consulting or advisory. Tanya Simuni reports a relationship with Denali that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with The Michael J Fox Foundation that includes: consulting or advisory. Tanya Simuni reports a relationship with NeuroDerm Ltd that includes: board membership, consulting or advisory, and funding grants. Tanya Simuni reports a relationship with Sanofi that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Sinopia that includes: consulting or advisory. Tanya Simuni reports a relationship with Roche that includes: board membership, consulting or advisory, and funding grants. Tanya Simuni reports a relationship with Takeda that includes: consulting or advisory. Tanya Simuni reports a relationship with Vanqua Bio, Inc. that includes: consulting or advisory. Tanya Simuni reports a relationship with UCB that includes: board membership and funding grants. Tanya Simuni reports a relationship with Biogen that includes: funding grants. Tanya Simuni reports a relationship with Prevail Therapeutics that includes: funding grants. Tanya Simuni reports a relationship with National Institute of Neurological Disorders and Stroke that includes: consulting or advisory. Tanya Simuni reports a relationship with Parkinson's Foundation that includes: consulting or advisory. Kenneth Marek reports a relationship with Michael J Fox Foundation for Parkinson's Research that includes: consulting or advisory. Kenneth Marek reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory. Kenneth Marek reports a relationship with UCB that includes: consulting or advisory. Kenneth Marek reports a relationship with Denali that includes: consulting or advisory. Kenneth Marek reports a relationship with Takeda that includes: consulting or advisory. Kenneth Marek reports a relationship with Biohaven Ltd that includes: consulting or advisory. Kenneth Marek reports a relationship with Neuron23 that includes: consulting or advisory. Kenneth Marek reports a relationship with Aprinoia that includes: consulting or advisory. Kenneth Marek reports a relationship with Prothena that includes: consulting or advisory. Kenneth Marek reports a relationship with Calico that includes: consulting or advisory. Kenneth Marek reports a relationship with Inhibikase that includes: consulting or advisory. Kenneth Marek reports a relationship with Invicro that includes: consulting or advisory. Kenneth Marek reports a relationship with Koneksa that includes: consulting or advisory. Kenneth Marek reports a relationship with Lilly that includes: consulting or advisory. Ronald B. Postuma reports a relationship with Fonds de la Recherche en Sante that includes: funding grants. Ronald B. Postuma reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Ronald B. Postuma reports a relationship with The Michael J Fox Foundation that includes: funding grants. Ronald B. Postuma reports a relationship with Webster Foundation that includes: funding grants. Ronald B. Postuma reports a relationship with Roche that includes: funding grants. Ronald B. Postuma reports a relationship with National Institutes of Health that includes: funding grants. Ronald B. Postuma reports a relationship with Takeda that includes: funding grants. Ronald B. Postuma reports a relationship with Biogen that includes: funding grants. Ronald B. Postuma reports a relationship with Abbvie that includes: funding grants. Ronald B. Postuma reports a relationship with Curasen that includes: funding grants. Ronald B. Postuma reports a relationship with Lilly that includes: funding grants. Ronald B. Postuma reports a relationship with Novartis that includes: funding grants. Ronald B. Postuma reports a relationship with Eisai that includes: funding grants. Ronald B. Postuma reports a relationship with Paladin that includes: funding grants. Ronald B. Postuma reports a relationship with Merck that includes: funding grants. Ronald B. Postuma reports a relationship with Vaxxinity that includes: funding grants. Ronald B. Postuma reports a relationship with Korro that includes: funding grants. Ronald B. Postuma reports a relationship with Bristol Myers Squibb that includes: funding grants. Ronald B. Postuma reports a relationship with International Parkinson and Movement Disorder Society that includes: board membership and funding grants. Nicola Pavese reports a relationship with Britannia that includes: board membership and funding grants. Nicola Pavese reports a relationship with Boston Scientific that includes: board membership and funding grants. Nicola Pavese reports a relationship with Benevolent AI that includes: board membership. Nicola Pavese reports a relationship with F Hoffmann-La Roche inc that includes: board membership. Nicola Pavese reports a relationship with AbbVie Inc that includes: board membership and funding grants. Nicola Pavese reports a relationship with GE Healthcare that includes: funding grants. Nicola Pavese reports a relationship with Independent Research Fund Denmark that includes: funding grants. Nicola Pavese reports a relationship with Danish Parkinson's Disease Association that includes: funding grants. Nicola Pavese reports a relationship with Parkinson's UK that includes: funding grants. Nicola Pavese reports a relationship with Center of Excellence in Neurodegeneration network award that includes: funding grants. Nicola Pavese reports a relationship with GE Healthcare Grant that includes: funding grants. Nicola Pavese reports a relationship with Multiple System Atrophy Trust that includes: funding grants. Nicola Pavese reports a relationship with Weston Brain Institute that includes: funding grants. Nicola Pavese reports a relationship with EU Joint Programme Neurodegenerative Disease Research that includes: funding grants. Nicola Pavese reports a relationship with EU Horizon 2020 research that includes: funding grants. Nicola Pavese reports a relationship with The Michael J Fox Foundation for Parkinson's Research that includes: funding grants. Nicola Pavese reports a relationship with F Hoffmann-La Roche Ltd that includes: funding grants. Fabrizio Stocchi reports a relationship with AbbVie that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Bial Pharma that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Biogen Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with H. Lundbeck A S that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Mitsubishi Tanabe Pharma America Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Sunovion Pharmaceuticals Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Teva Pharmaceutical Industries that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Zambon that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Britannia that includes: consulting or advisory. Klaus Seppi reports a relationship with FWF Austrian Science Fund that includes: funding grants. Klaus Seppi reports a relationship with The Michael J Fox Foundation that includes: funding grants. Klaus Seppi reports a relationship with International Parkinson and Movement Disorder Society that includes: funding grants. Klaus Seppi reports a relationship with AOP Orphan Pharmaceuticals AG that includes: funding grants. Klaus Seppi reports a relationship with EU (all to the institution) that includes: funding grants. Klaus Seppi reports a relationship with Ono Pharma UK Ltd that includes: consulting or advisory. Klaus Seppi reports a relationship with Lundbeck that includes: consulting or advisory. Klaus Seppi reports a relationship with Ever Pharma that includes: consulting or advisory. Klaus Seppi reports a relationship with Teva that includes: speaking and lecture fees. Klaus Seppi reports a relationship with UCB that includes: speaking and lecture fees. Klaus Seppi reports a relationship with AOP Orphan Pharmaceuticals AG that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Roche that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Grünenthal that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Stada that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Licher Pharma that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Biogen that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Bial that includes: consulting or advisory and speaking and lecture fees. Klaus Seppi reports a relationship with AbbVie that includes: consulting or advisory and speaking and lecture fees. Klaus Seppi reports a relationship with Stada that includes: consulting or advisory. Paulo Fontoura reports a relationship with F Hoffmann-La Roche Ltd that includes: equity or stocks, and relationships with Harness Therapeutics and Stalicla SA that includes: employment, equity or stocks, and a relationship with Xaira Therapeutics that includes: employment, equity or stocks. Rachelle Doody reports a relationship with F Hoffmann-La Roche Ltd that includes: past employment, current stock and stock options. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: ND0612 is being investigated as a continuous, subcutaneous levodopa/carbidopa infusion, in combination with oral levodopa/carbidopa, for motor fluctuations in Parkinson's disease (PD). One-year data from the ongoing BeyoND study (NCT02726386) showed that the ND0612 regimen was safe and well tolerated and provided a sustained ≥2-h improvement in daily Good ON-time through 12 months of treatment., Methods: We describe 3-year safety and efficacy outcomes for participants who completed 12 months of ND0612 treatment in the core study period and entered the extension phase., Results: Of the 214 enrolled participants, 120 completed the core 1-year period, and 114 participants continued into the extension phase. Of these, 95/114 (83.3 %) completed 2 years and 77/114 (67.5 %) completed 3 years of study treatment. Key reasons for discontinuation were treatment-emergent adverse events (TEAEs) (n = 5 and n = 11 after 2 and 3 years, respectively) and withdrawal of consent (n = 9 and n = 5, respectively). TEAEs were reported by 105/114 (92.1 %) participants in Year 1, 77/114 (67.5 %) in Year 2, and 73/95 (76.8 %) in Year 3. While most participants experienced infusion site reactions, these led to discontinuation in only five participants during this extension. At Month 36, the mean reduction in OFF-time from baseline was 2.81 h and the increase in Good ON-time was 2.79 h., Conclusions: Three-year results from this open-label study support the long-term safety, tolerability, and efficacy of ND0612. For participants who entered the extension phase, the high rate of retention supports a favorable benefit-risk ratio of the ND0612 regimen for patients with PD experiencing motor fluctuations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ALE, WP, AJE, TS, TG, and FS are study investigators, and they or their institutions report fees from NeuroDerm. TY, NL, and NS are employed by NeuroDerm. RC is employed by Mitsubishi Tanabe Pharma America, Inc., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: For Parkinson's disease patients with motor fluctuations, the duration of benefit per levodopa dose is a key metric that reflects a patient's clinical response., Objective: Determine the difference in mean durations of "Good On" time per dose of subjects randomized to extended-release carbidopa-levodopa (ER CD-LD; IPX203; CREXONT®) vs. immediate-release (IR) CD-LD in the RISE-PD trial., Methods: "Good On" time per dose was assessed at the end of the IR CD-LD dose adjustment phase (Visit 2/Week 3) and compared to End of Study (Visit 7/EOS) between IPX203 and IR CD-LD groups. In addition, to understand if "Good On" time per dose for IR CD-LD before conversion to IPX203 could impact the magnitude of change in "Good On" time per dose of IPX203 vs. IR CD-LD after conversion, subjects were rank-ordered and divided into quartiles based on their initial "Good On" time per dose optimized IR CD-LD values. Changes in "Good On" time per dose between IPX203 and IR CD-LD groups were then compared for each quartile from Visit 2 to EOS., Results: IPX203 increased "Good On" time per dose compared to IR CD-LD by a mean of 1.6 h (p < 0.0001). The mean differences in "Good On" time per dose between IPX203 and IR CD-LD were 1.53h for quartile one, 1.39h for quartile two, 1.83h for quartile three, and 1.56h for quartile four (p < 0.0001 for all quartiles)., Conclusion: IPX203 significantly increased "Good On" time per dose regardless of the duration of "Good On" time per dose observed with IR CD-LD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.A.H. has received speaking fees from Amneal Pharmaceuticals, Cerevel, Kyowa Kirin, Neurocrine Biosciences, and Supernus. R.A.H. has received consulting fees from Abbvie, Ameal, Avanex, Biogen, BlueRock, Cerevel, Forsee Pharmaceuticals, Inhibikase, Intrance (PSG), Jazz Pharmaceuticals, Kiefe RX, Kyowa Kirin, MDCE Suzhou, MedRythms, Merz, Mitsubishi Tanabe, Neurocrine, Neuroderm, Pharma Two B, Regenxbio, Revance, Serina Therapeutics, Stoparkinson, Supernus, Tolmar, Tremor Research Group, Tris Pharma, Truebinding, UCB, Vivifi, and Zambon. R.A.H. serves on a scientific advisory board for Stoparkinson and Inhibikase. R.A.H. holds stock in Revance Therapeutics and has stock options in Enterin, Inhibikase, and Axial Therapeutics. R.A.H. has received intellectual property interests from a PD Diary through his University. R.A.H. acknowledges a Center of Excellence grant from the Parkinson Foundation. R.A.H.’s University has received research support from Annovis Bio, Inc., Artizan Biosciences, Parkinson's & Movement Disorder Alliance, Inhibikase Therapeutics, AbbVie, Inc., Biogen MA, Bukwang Pharmaceutical Co., Ltd., Cavion, Inc., Cerevance, Inc., Cerevel Therapeutics, Cynapsus Therapeutics, Enterin, Inc., Genentech, Global Kinetics Corporation, Hoffman-La Roche Inc., Impax Laboratories, Integrative Research Laboratories Sweden, Lundbeck, Inc., Michael J. Fox Foundation for Parkinson's Research, National Parkinson's Foundation, Neuraly Inc., Neurocrine Biosciences, Neuroderm, Pharma Two B Ltd, Revance Therapeutics, Sage Therapeutics, Sanofi Pharmaceuticals, Scion NeuroStim, SunPharma and UCB BioPharma. H.H.F has received consulting fees from Abbvie, Amneal, Cerevel, and Neurocrine. H.H.F has received grants or contracts from Biogen, BlueRock, Michael J. Fox Foundation, Parkinson's Foundation, Parkinson Study Group and Roche. H.H.F. served on advisory board for Amneal and Cerevel. H.H.F receives royalties from Springer Publishing. H.H.F. serves as Editor in Chief of Parkinsonism and Related Disorders with Elsevier and Co-Chair of Executive Committee of Parkinson Study Group. J.J. has received consulting fees from Abbvie, BlueRock, Kyowa Kirin, Medtronic, Regenxbio, and Teva. J.J. has received research support from Annovis, BlueRock, ONO Pharmaceuticals, and Sage. J.J. served on advisory board for Photopharmics. J.J. served on the Data and Safety Monitory Board for BlueRock and Emalex Biosiences. S.A., G.B., S.F., and R.D. are employees of Amneal Pharmaceuticals, LLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Several measures of the center of pressure have been used to describe magnitude and structure of the postural sway in individuals with Parkinson's disease (PD). This study aimed to examine whether both the magnitude and structure of the center of pressure trajectory can differentiate PD individuals with and without freezing of gait in both On- and Off-medication states and with eyes open and closed., Methods: Twenty-four individuals with PD (14 without and 10 with freezing of gait) were tested. Participants stood as still as possible on a force plate for 30 s with eyes open and closed and On- and Off-medication. Analyses of variance were used to test the effect of group, medication state, and visual information on the magnitude (area) and structure (shape measured by the ratio between axes length and orientation) of the center of pressure ellipses., Findings: The center of pressure ellipses were less elongated in On-medication state and for PD with freezing of gait than without freezing of gait. Moreover, the magnitude of the ellipses was larger for PD with freezing than without freezing of gait only in the On-medication state. The orientation of the ellipses was more diagonal for individuals with freezing, in the On-medication state, and with the eyes closed when compared to individuals with PD without freezing under the same conditions., Interpretation: Magnitude and structure of the postural sway differed between PD individuals with and without freezing of gait, depending on the medication state and the availability of the visual information., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the loss of dopaminergic neurons and the consequent decline in motor and cognitive functions. The primary therapeutic agent levodopa necessitates precise dosing due to its narrow therapeutic window and complex pharmacokinetics. This study presents the development of a novel CuCoFe-LDHzyme-based sweat sensor for real-time monitoring of levodopa concentration in PD patients. Employing differential pulse voltammetry (DPV) technique, the sensor demonstrates high sensitivity and selectivity, achieving a detection limit of 28.1 nM. The sensor's design allows for non-invasive, continuous monitoring, significantly enhancing patient convenience compared to traditional blood sampling methods. Through pH correction, precise quantification of levodopa in sweat is accomplished, and a strong correlation (Pearson coefficient = 0.833) with blood levodopa levels is established. The pharmacokinetic profile of levodopa is reconstructed in real-time, offering a promising tool for optimizing PD treatment regimens. This study highlights the potential of CuCoFe-LDHzyme sensors to advance personalized treatment strategies, aiming to improve the quality of life for PD patients by providing clinicians with real-time data for medication adjustments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Catechol-O-methyl transferase (COMT) inhibitors are routinely used to manage motor fluctuations in Parkinson's disease (PD). We assessed the effect of opicapone on motor symptom severity in levodopa-treated patients without motor complications., Methods: This was a randomized, double-blind, 24-week, placebo-controlled study of opicapone 50 mg as adjunct to levodopa (NCT04978597). Levodopa-treated patients without motor complications were randomized to 24 weeks of double-blind treatment with adjunct opicapone 50 mg or matching placebo. The primary efficacy endpoint was the mean change from baseline to week 24 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) total score., Results: A total of 355 patients were randomized (opicapone 50 mg n = 177, placebo n = 178) and 322 (91%) completed the double-blind period. The adjusted mean [95% CI] change from baseline to week 24 in MDS-UPDRS-III subscore was -6.5 [-7.9, -5.2] in the opicapone group versus -4.3 [-5.7, 3.0] in the placebo group resulting in a significant difference of -2.2 [-3.9, -0.5] favoring opicapone (p = 0.010). There was no difference in the incidence of patients who developed motor complications (5.5% with opicapone vs. 9.8% with placebo) and the incidence of adverse events considered related to study medication was similar between groups (opicapone 10.2% vs. placebo 13.5%)., Conclusions: Treatment with once-daily adjunct opicapone was well tolerated, improved motor severity, and did not induce the development of motor complications. These results support the clinical usefulness of opicapone in the management of PD patients without motor complications., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Levodopa-entacapone-carbidopa intestinal gel (LECIG) was introduced on the Swedish market in 2019. The therapy is aimed at patients with Parkinson's disease (PD) with fluctuations and dyskinesias. Long-term efficacy and safety data are lacking., Objective: To investigate the efficacy, tolerability, and safety of LECIG in regular clinical practice for Parkinson's disease in Sweden., Methods: Real-world data were collected from the Swedish registry for Parkinson's disease (ParkReg) for all patients reported to receive LECIG during the period from 2019 until 31 August 2022., Results: A total of 150 patients were identified. Sixty-one (41%) of 150 patients were females. At the start of treatment, the median age was 73 years (range: 43-86). The median duration since motor symptoms onset was 17 years (IQR: 9). Fifty (33%) of 150 patients switched from another device-assisted therapy, mostly LCIG (39 patients). Reported complications were mainly related to PEG-J tube and stoma (30%). Twenty (13.3%) of 150 patients discontinued LECIG and 11 (7.3%) patients died while on LECIG. The Parkinson KinetiGraph scores for bradykinesia, dyskinesia, fluctuations, tremor, and immobility for 53 patients during LECIG showed good therapy control. The median (IQR) p-Hcy during LECIG was 12 (4.6) μmol/L (n = 44). The median (IQR) PDQ-8 summary index during LECIG was 31 (17) (n = 52). The median (IQR) EQ5D during LECIG was 0.62 (0.32) (n = 41)., Conclusions: Data from ParkReg covering 150 patients over 3 years show LECIG to be an effective and safe device-aided therapy for advanced PD. However, the long-term efficacy and tolerability of LECIG need to be further investigated., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: The first-line treatment for Parkinson's disease (PD) involves dopamine-replacement therapies; however, significant variability exists in patient responses. Pharmacogenomics has been explored as a potential approach to understanding and predicting treatment outcomes. This review aims to evaluate the current state of knowledge regarding the role of pharmacogenomics in PD, focusing on identifying challenges and proposing future directions., Methods: We conducted a systematic review following PRISMA 2020 guidelines. The PubMed database was searched for original, English-language studies using the R package 'RISmed.' Data were extracted and analyzed based on sample size, population origin, evaluated genes and polymorphisms, outcomes, and methodological approaches., Results: Out of 183 identified articles, 76 met the inclusion criteria. The COMT-rs4680 polymorphism was the most frequently studied, and levodopa-related motor complications were the most commonly assessed outcomes. All but two studies employed a candidate gene approach. In 75 % of the studies, the sample size was fewer than 225 individuals. There was a notable underrepresentation of Latino participants, with a lack of studies from Latin American countries other than Brazil. None of the studies produced consistent results across investigations., Conclusions: The variability in patient responses to PD treatments suggests a genetic predisposition. While current research has enhanced our understanding of PD medication metabolism, it has not yet fully elucidated the complex genetic interactions involved in PD pharmacogenomics. Novel approaches, larger and more genetically diverse cohorts, and improved data collection are essential for advancing pharmacogenomics in PD clinical practice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jennifer K. Hockings reports a relationship with MCG Health that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Tremor in Parkinson's disease (PD) is commonly regarded as less responsive to levodopa than bradykinesia and rigidity, with levodopa-resistant PD tremor considered relatively common., Objective: The aim was to assess the levodopa responsiveness of tremor, bradykinesia, and rigidity in a population with advanced PD., Methods: We performed a retrospective study of 526 people with PD screened for deep brain stimulation., Results: Levodopa's Cohen's d effect sizes were in the same order of magnitude for the 3 cardinal motor symptoms. Proportional improvement in tremor (86.8%) was higher than bradykinesia (45.7%) and rigidity (67.0%) (P < 0.0001). Full resolution was more frequent for tremor (67.9%) than for bradykinesia (0.4%) or rigidity (24.8%) (P < 0.0001). Levodopa-unresponsive tremor, defined as improvement less than 25%, was documented only in 4.0%, as opposed to 19.4% for bradykinesia and 9.8% for rigidity (P < 0.0001)., Conclusions: In advanced PD, tremor was more responsive to levodopa than bradykinesia and rigidity, and levodopa-unresponsive tremor was relatively rare., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD., Patients and Methods: PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview., Results: Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%)., Conclusion: This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.

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.

Parkinson's disease (PD), the most prevalent type of parkinsonism, is a progressive neurodegenerative condition marked by several non-motor and motor symptoms. PD is thought to have a complex aetiology that includes a combination of age, genetic predisposition, and environmental factors. Increased expression of α-synuclein (α-Syn) protein is central to the evolvement of neuropathology in this devastating disorder, but the potential of ribose-cysteine and levodopa in abating pathophysiologic changes in PD model is unknown. Crosses were set up between flies conditionally expressing a pathological variant of human α-Syn (UAS-α-Syn) and those expressing GAL4 in neurons (elav-GAL4) to generate offspring referred to as PD flies. Flies were randomly assigned to five groups ( n  = 40) from the total population of flies, with each group having five replicates. Groups of PD flies were treated with either 500 mg/kg ribose-cysteine diet, 250 mg/kg levodopa diet, or a combination of the two compounds for 21 days, whereas the control group (w 1118 ) and the PD group were exposed to a diet without ribose-cysteine or levodopa. In addition to various biochemical and neurochemical assays, longevity, larval motility, and gravitaxis assays were carried out. Locomotive capability, lifespan, fecundity, antioxidant state, and neurotransmitter systems were all significantly ( p  < 0.05) compromised by overexpression of α-Syn. However, flies treated both ribose cysteine and levodopa showed an overall marked improvement in motor functions, lifespan, fecundity, antioxidant status, and neurotransmitter system functions. In conclusion, ribose-cysteine and levodopa, both singly and in combination, potentiated a therapeutic effect on alpha-synuclein transgenic Drosophila melanogaster models of Parkinsonism.

Parkinson's disease (PD) is a common neurodegenerative disease in the older adults. The main pathological change in PD is the degenerative death of dopamine (DA) neurons in the midbrain substantia nigra, which causes a significant decrease in the DA content of the striatum. However, the exact etiology of this pathological change remains unclear. Genetic factors, environmental factors, aging, and oxidative stress may be involved in the degenerative death of dopaminergic neurons in PD. Pharmacological treatment using levodopa (L-DOPA) remains the main treatment for PD. Most patients with PD consuming L-DOPA for a long time usually develop levodopa-induced dyskinesia (LID) after 6.5 years of use, and LID seriously affects the quality of life and increases the risk of disability. Recently, studies have revealed that cerebral iron deposition may be involved in LID development and that iron deposition has neurotoxic effects and accelerates disease onset. However, the relationship between cerebral iron deposition and LID remains unclear. Herein, we reviewed the mechanisms by which iron deposition may be associated with LID development, which are mainly related to oxidative stress, neuroinflammation, and mitochondrial and lysosomal dysfunction. Using iron as an important target, the search and development of safe and effective brain iron scavengers, and thus the alleviation and treatment of LID, has a very important scientific and clinical value, as well as a good application prospect., Competing Interests: Declarations. Competing interests: The authors declare that they have no competing interests. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Aim of this review is to discuss the value of current ongoing research initiatives in Parkinson's disease from the clinicians' point of view. The repeat, recent failures on progress slowing reflect the drifting apart between initially promising experimental and then disappointing clinical outcomes in the translational trials with well selected Parkinson's disease patients. A similar development concerns the emerging gap between novel developed drugs with improved pharmacokinetic behaviour and their limited use in the clinical practice following approval. Restricted regional different worldwide availability and direct, respectively indirect budget limitations for neurologists in private practice are essential hurdles. They prevent the widespread prescription of these compounds. As a result return of investment for the pharmaceutical industry becomes more and more uncertain. The interest for research on novel treatment approaches for the amelioration of motor and non motor symptoms declines. Clinicians crucially scrutinize the claim for an optimum patient care by payers and regulators., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of individuals globally. It is characterized by the loss of dopaminergic neurons in Substantia Nigra pars compacta (SNc) and striatum. Neuroimaging techniques such as single-photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI) help diagnosing PD. In this study, the focus was on developing technetium-99 m ([ 99m Tc]Tc) radiolabeled drug delivery systems using plant-derived compounds for the diagnosis of PD. Madecassoside (MA), a plant-derived compound, was conjugated with Levodopa (L-DOPA) to form MA-L-DOPA, which was then encapsulated using Poly Lactic-co-Glycolic Acid (PLGA) to create MA-PLGA and MA-L-DOPA-PLGA nanocapsules. Extensive structural analysis was performed using various methods such as Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), liquid chromatography-mass spectrometry (LC-MS), thin layer chromatography (TLC), high performance liquid chromatography (HPLC), dynamic light scattering (DLS), and scanning electron microscopy (SEM) to characterize the synthesized products. Radiochemical yields of radiolabeled compounds were determined using thin layer radio chromatography (TLRC) and high performance liquid radio chromatography (HPLRC) methods. In vitro cell culture studies were conducted on human neuroblastoma (SH-SY5Y) and rat pheochromocytoma (PC-12) cell lines to assess the incorporation of [ 99m Tc]Tc radiolabeled compounds ([ 99m Tc]Tc-MA, [ 99m Tc]Tc-MA-L-DOPA, [ 99m Tc]Tc-MA-PLGA and [ 99m Tc]Tc-MA-L-DOPA-PLGA) and the cytotoxicity of inactive compounds (MA and MA-L-DOPA compounds and encapsulated compounds (MA-PLGA and MA-L-DOPA-PLGA). Additionally, the biodistribution studies were carried out on healthy male Sprague-Dawley rats and a Parkinson's disease experimental model to evaluate the compounds' bioactivity using the radiolabeled compounds. The radiochemical yields of all radiolabeled compounds except [ 99m Tc]Tc-L-DOPA-PLGA were above 95% and had stability over 6 h. The cytotoxic effects of all substances on SH-SY5Y and PC-12 cells increase with increasing concentration values. The uptake values of PLGA-encapsulated compounds are statistically significant in SH-SY5Y and PC-12 cells. The biodistribution studies showed that [99mTc]Tc-MA is predominantly retained in specific organs and brain regions, with notable uptake in the prostate, muscle, and midbrain. PLGA-encapsulation led to higher uptake in certain organs, suggesting its biodegradable nature may enhance tissue retention, and surface modifications might further optimize brain penetration. Overall, the results indicate that radiolabeled plant-derived encapsulated drug delivery systems with [ 99m Tc]Tc hold potential as diagnostic agents for PD symptoms. This study contributes to the advancement of drug delivery agents in the field of brain research., (© 2024. The Author(s).)

Objective Mucuna pruriens (MP) is a legume whose seeds contain levodopa (LD), which has potential therapeutic effects against Parkinson's disease (PD). However, further research is needed to thoroughly evaluate its efficacy and safety for treating this condition. In this study, we analyzed the pharmacokinetics of MP grown in Japan and investigated its mechanism of action in PD. Methods MP seeds ground after roasting (containing 4.02% LD per MP powder) were used as the reagent and compared with an equivalent LD/carbidopa (CD) preparation. This clinical trial was conducted using a crossover design among PD patients attending our institution. Each patient received a single dose of 100/10 mg LD/CD tablets and 11 g of MP reagent. Results Among the seven patients with PD, MP prolonged the ON time 2-fold compared to LD/CD. The LD concentrations after MP intake were higher than those after LD/CD intake, whereas dyskinesia did not increase. An analysis of the LD metabolites showed that the 3-O-methyl-dopa/LD metabolic ratio was significantly lower after MP ingestion than after LD/CD ingestion, indicating that MP has a catechol-O-methyl transferase inhibitory effect. Conclusions This is the first report of a pharmacokinetic analysis conducted on actual patients with PD showing that MP significantly prolongs the ON time. The advantages of MP as a treatment for PD have been confirmed: it is inexpensive, as effective as LD, works faster and longer than LD, and does not increase dyskinesia.

Background: Proton pump inhibitors (PPIs), which inhibit gastric acid secretion, are frequently prescribed to patients with Parkinson's disease (PD). Levodopa, the gold-standard treatment for PD, demonstrates enhanced solubility in acidic environments. Although PPIs increase gastric pH and may affect levodopa absorption, the effect of concomitant PPI use on levodopa pharmacokinetics in patients with PD remains unknown. This study aimed to investigate the effect of the concomitant use of esomeprazole, a PPI, on the pharmacokinetics of levodopa and carbidopa and clinical symptoms in patients with PD., Methods: We prospectively enrolled 40 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and clinical symptoms before and two weeks after the concomitant use of esomeprazole., Results: The plasma concentrations of levodopa 30 min after concomitant oral administration of levodopa and esomeprazole were significantly lower (4.92 ± 4.10 μmol/L) than those without concomitant esomeprazole use (6.26 ± 3.75 μmol/L; p = 0.027). The plasma concentrations of carbidopa showed no significant differences with respect to concomitant esomeprazole use. Significant elevation was recorded in all subscores of the Movement Disorder Society-sponsored revision of the Unified Parkinson's disease Rating Scale scores after concomitant use of esomeprazole. No significant differences were observed between Helicobacter pylori-negative and Helicobacter pylori-positive patients. Non-elderly patients (age ≤ 70 years) tended to be more susceptible to the effect of esomeprazole on levodopa pharmacokinetics and clinical symptoms., Conclusions: The unnecessary use of PPIs should be avoided in patients with PD, especially in non-elderly patients, to improve absorption of levodopa., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The ideal timing for initiating levodopa in newly diagnosed people with Parkinson's disease (PD) is uncertain due to limited data on the long-term effects of levodopa., Objective: The aim was to investigate whether early levodopa initiation postpones mortality (primary outcome), the requirement of device-aided therapies, and the incidence of PD-related complications, such as fall-induced injuries., Methods: Using nationwide claims data from Dutch hospitals (2012-2020), we grouped newly diagnosed PD individuals as "early initiators" (initiating levodopa within 2 years of diagnosis) or "nonearly initiators." We used the national death registry to assess mortality and health-care claims to assess PD-related complications and device-aided therapies. We used marginal structural models to compare mortality and device-aided therapy rates between groups, and a Poisson regression model to compare PD-related complication rates., Results: Among 29,943 newly diagnosed PD individuals (mean age at diagnosis: 71.6, 38.5% female), there were 24,847 early and 5096 nonearly levodopa initiators. Over a median 4.25 years, 8109 (27.1%) died. The causal risk ratio for mortality was 1.04 (95% confidence interval [CI] 0.92-1.19) for early versus nonearly initiators. The risk ratio of receiving any device-aided therapy was 3.19 (95% CI 2.56-5.80). No association was observed with incidence of PD-related complications (incidence rate ratio: 1.00, 95% CI 0.96-1.05)., Conclusions: Early levodopa initiation in PD does neither postpone nor accelerate mortality or PD-related complications, nor does it precipitate earlier occurrence of PD-related complications or mortality. However, we cannot exclude that the results were influenced by residual confounding due to unmeasured risk factors of mortality., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: There has been a long debate whether delaying treatment with levodopa prevents motor complications in Parkinson's disease (PD)., Objectives: We performed a meta-analysis on randomized clinical trials (RCTs) that compared early- versus delayed-start treatment with levodopa in PD., Methods: A systematic review was conducted in PubMed, EMBASE, and Web of Science databases from inception to July 1, 2023. Only RCTs that compared early and delayed levodopa treatment in PD were included. Non-randomized comparisons from follow-up studies were included as well. Our primary outcomes were occurrence of overall motor complications, motor fluctuations, and dyskinesias., Results: Seven studies with a total of 1149 patients (636 in the early-start group and 513 in the delayed-start) were included in our analysis. There was no difference between groups regarding motor complications (OR 1.39; 95% CI: 0.68-1.72; P = 0.37) or dyskinesias (OR 1.52; 95% CI: 0.90-2.57; P = 0.11). Motor fluctuations occurred less frequently in the early-start group (OR 0.70; 95% CI: 0.52-0.95; P = 0.02). Nonetheless, on subgroup analysis of dopamine agonists, rate of dyskinesias was smaller in the delayed-start group (OR 1.82; 95% CI: 1.08-3.07; P = 0.03)., Conclusions: Delaying treatment with levodopa does not seem to prevent levodopa-related motor complications in PD. Adjunct treatment with dopamine agonists may reduce the need for higher doses of levodopa and thus reduce the risk for dyskinesias but this practice is often associated with a higher frequency of adverse effects related to dopamine agonists., (© 2024 International Parkinson and Movement Disorder Society.)

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., (© 2024. The Author(s).)

The akinetic crisis is defined as an acute, potentially life-threatening, levodopa-resistant, severe aggravation of rigidity, severe akinesia, associated with high fever, disturbance of consciousness, dysphagia and autonomic symptoms often due to disruption of dopaminergic medication or infections. The akinetic crisis is a relatively rare event, however subacute mild-moderate motor symptom deterioration in Parkinson´s disease (PD) patients is a frequent cause of hospitalization. In this review, we propose that the akinetic crisis is the upper end of a continuous spectrum of acute akinetic states depending on the degree of the progressive levodopa-resistance. Clinical symptomatology, risk factors, and instrumental diagnostics as the DAT-SPECT reflecting a biomarker of levodopa-resistance will be discussed to evaluate the spectrum of akinetic states. Pathophysiological considerations about the potential role of proinflammatory cytokines on the progressive levodopa-resistance will be discussed and therapeutical, consensus-based guidelines will be presented., (© 2024. The Author(s).)

Introduction: Parkinson's disease (PD) is a highly prevalent disease characterized by motor and non-motor symptoms; the latter include constipation, which is considered a prodromal symptom. On the other hand, sarcopenia, polypharmacy, and malnutrition due to deficits are common in PD and lead to poorer health and quality of life., Objective: to associate constipation and use of levodopa with nutritional status, sarcopenia, duration and stage of the disease, and polypharmacy in individuals with PD., Materials and Methods: analytical cross-sectional observational study where an online survey was applied to 161 people suffering from PD., Results: a significant association is observed between constipation and BMI ( p = 0.022), as well as between the use of levodopa with BMI ( p = 0.049) and polypharmacy ( p = 0.046). On the other hand, there is a relationship between the average time of PD diagnosis and constipation ( p = 0.0047). Finally, there is a relationship between SARC-F score applied to those over 60 years of age ( p = 0.0446) and the use of levodopa. Having sarcopenia, being overweight, and having had the disease for less than five years is associated with a higher probability of experiencing constipation, according to the logistic regression analysis ( p > 0.005)., Conclusion: nutritional assessment and subsequent follow-up is of vital importance to avoid complications that could be associated with levodopa use, constipation, and sarcopenia.

Purpose: We aimed to elicit scientific evidence on the cost-effectiveness of two catechol-O-methyltransferase inhibitors (COMT-i) versus no COMT-i in patients with advanced Parkinson's disease., Methods: A mixed model of the decision tree and a Markov model with three health states by OFF-time level (<25%, ≥25%, and death) was constructed to compare opicapone (OPC), entacapone (ENT), and no COMT-i over a lifetime. A hypothetical cohort of 10,000 patients was created and simulated based on the characteristics of the BIPARK trial subjects., Findings: Two COMT-i (OPC and ENT) were identified as a cost-effective option compared to no COMT-i. Probabilistic sensitivity analysis showed that over 90% of the simulations proved the robust cost-effectiveness of COMT-i. When the time horizon as the most influential factor decreases to a 5- and 10-year period, COMT-i can be a cost-saving option. Although ENT may be the preferred option over OPC economically because of its lower price, OPC can be acceptable if the drug price is reduced by 17%., Implications: Add-on treatment with COMT-i in patients with PD receiving levodopa/carbidopa appears to be cost-saving compared with not using COMT-i. In the future, it is necessary to evaluate the economic evaluation of COMT-i based on long-term real-world evidence., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time., Objectives: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these., Methods: We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters., Results: 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1-74.3%). We identified 3 response groups: "Striking" (n = 29, 8.7%); "Excellent" (n = 110; 32.7%) and "Modest" (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01)., Conclusion: Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid., (© 2024 International Parkinson and Movement Disorder Society.)

Background: It has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and blocking central levodopa conversion to dopamine. We previously demonstrated equivalent plasma levodopa concentration in patients with Parkinson's disease during 16 h of (1) intravenous carbidopa/levodopa (DIZ101) infusion, (2) subcutaneous carbidopa/levodopa (DIZ102) infusion or (3) intestinal carbidopa/levodopa gel infusion. Plasma levels of carbidopa were however approximately four times higher with DIZ101 and DIZ102 than with LCIG, and higher than those usually observed with oral levodopa/carbidopa., Objectives: To investigate if high carbidopa blood concentrations obtained with parenteral levodopa/carbidopa (ratio 8:1) counter the effect of levodopa on motor symptoms., Methods: Eighteen patients with advanced Parkinson's disease were administered DIZ101, DIZ102, and intestinal levodopa/carbidopa gel for 16 h on different days in randomized order. Video recordings of a subset of the motor examination in the Unified Parkinson's Disease Rating Scale (UPDRS) were evaluated by raters blinded for treatment and time. Motor function was also measured using a wrist-worn device monitoring bradykinesia, dyskinesia, and tremor (Parkinson KinetiGraph)., Results: There was no tendency for poorer levodopa effect with DIZ101 or DIZ102 as compared to LCIG., Conclusion: Although DIZ101 or DIZ102 causes approximately four times higher plasma carbidopa levels than LCIG, patients responded equally well to all treatments. The results do not indicate that high plasma carbidopa levels hamper the motor efficacy of levodopa., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling., Objectives: We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP., Methods: OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses., Results: Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%)., Conclusions: The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: The main endpoint of the study was to evaluate if a daily intake of whey protein-based dietary supplement causes a worse response to levodopa in people with Parkinson's Disease (PWPD)., Background: In PWPD, the competition between large neutral aminoacids and levodopa at intestinal absorption level may interfere with dopaminergic therapy's (DRT) effect; therefore, protein redistribution dietary regimen has been suggested. Many dietary supplementations are available to help people in balancing the protein intake and overcoming muscle mass loss. However, most of the products contain protein and could potentially affect levodopa action in PWPD., Methods: We performed a randomised single blind monocentric study on PWPD admitted in the rehabilitative unit for a 4-week multidisciplined intensive aerobic rehabilitation treatment. All patients received a standard protein redistribution dietary regimen plus a whey protein-based oral formula ( N  = 26) or Magnesium ( N  = 25) twice daily for 28 days. Neurological assessment and physical evaluation were conducted before (T0) and after (T1) rehabilitative treatment; DRT was recorded T0 and T1 as well. The delta of changes within groups in neurological (UPDRS III) and physical (TUG, 6 MW) evaluation scales was compared between groups., Results: Groups were comparable at baseline in clinical and demographic data; at T1, both groups showed a decrease in UPDRS III, TUG and 6 MWT and no differences between deltas were found. DRT remained stable in both groups., Conclusions: Our results show that whey protein supplementation does not interfere with DRT's efficacy and can be used in PWPD who need a protein supplementation without restrictions in intake hours.

Innovative therapeutic strategies are urgently needed for Parkinson's disease due to limited efficacy of current treatments and a weak therapeutic pipeline. In this forum article, we propose targeting tyrosine hydroxylase phosphorylation as a novel mechanism of action to address this critical need., Competing Interests: Declaration of interests M.P.S. and L.P.v.d.H. are cofounders and shareholders of Parkinnova Therapeutics and Macrobian Biotech. The University of Amsterdam licenses patents related to this work (16/490,192 and 17/271,978) to Parkinnova Therapeutics., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Parkinson's disease (PD) causes gait abnormalities that may be associated with an arm swing reduction. Medication and freezing of gait (FoG) may influence gait characteristics. However, these comparisons do not consider differences in gait speed and clinical characteristics in individuals with PD., Objective: This study aims to analyze the effect of FoG and medication on the biomechanics of the trunk and upper limbs during gait in PD, controlling for gait speed and clinical differences between groups., Methods: Twenty-two people with a clinical diagnosis of idiopathic PD in ON and OFF medication (11 FoG), and 35 healthy participants (control) were selected from two open data sets. All participants walked on the floor on a 10-m-long walkway. The joint and linear kinematic variables of gait were compared: (1) Freezers and nonfreezers in the ON condition and control; (2) Freezers and nonfreezers in the OFF condition and control; (3) Group (freezers and nonfreezers) and medication., Results: The disease affects the upper limbs more strongly but not the trunk. The medication does not significantly influence the joint characteristics but rather the linear wrist displacement. The FoG does not affect trunk movement and partially influences the upper limbs. The interaction between medications and FoG suggests that the medication causes more substantial improvement in freezers than in nonfreezers., Conclusion: The study shows differences in the biomechanics of the upper limbs of people with PD, FoG, and the absence of medication. The future rehabilitation protocol should consider this aspect., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Parkinson's disease (PD) is estimated to impact up to 1 % of the global population aged 60 years and older. Among the non-motor manifestations of idiopathic PD, radicular neuropathic pain emerges as a noteworthy concern due to its potential for debility in affected individuals. In, this systematic review and meta-analysis we aimed to evaluate the prevalence of radicular neuropathic pain and thus provide evidence of how this painful symptom affects the lives of patients with idiopathic PD. We registered the research protocol for this study in PROSPERO (CRD42022327220). We searched the Embase, Scopus, and PubMed platforms for studies on PD and neuropathic pain until April 2023. The search yielded 36 articles considered to have a low risk of bias. The prevalence of radicular neuropathic pain in patients with PD was 12.7 %, without a difference when we consider the duration of diagnosis (cut-off < 7 years) or levodopa dosage (cut-off <600 mg/dL). Moreover, there was no variation in the prevalence of radicular neuropathic pain regarding a Hoehn and Yahr stage cut-off of <2.5 or >2.5. Of note, a limited number of patients received pain treatment (21.5 %). We also found that the source of publication bias is the use of the Ford criteria (FC), suggesting that this type of diagnostic criteria may contribute to an underdiagnosis of radicular neuropathic pain in patients with PD. This study underlines the necessity for a more discerning and comprehensive approach to the diagnosis and management of radicular neuropathic pain in patients with idiopathic PD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gabriela Trevisan reports financial support was provided by Coordination of Higher Education Personnel Improvement. Gabriela Trevisan reports a relationship with Coordination of Higher Education Personnel Improvement that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Although handwriting impairment is a frequent sign of Parkinson's disease (PD), its significance in the evaluation processes of these patients may be overlooked among physicians. Therefore, we would like to report an illustrative patient who presented with isolated micrographia initially; but received the diagnosis of PD in the follow-up.

Background: The gut microbiota has been implicated in Parkinson's disease (PD), with alterations observed in microbial composition and reduced microbial species richness, which may influence gastrointestinal symptoms in PD patients. It remains to be determined whether the severity of gastrointestinal symptoms correlates with microbiota variations in PD patients treated pharmacologically or with subthalamic nucleus deep brain stimulation (STN-DBS) therapy. This study aims to explore how these treatments affect gut microbiota and gastrointestinal symptoms in PD, identifying specific microbial differences associated with each treatment modality., Methods: A total of 42 individuals diagnosed with PD, along with 38 age-matched household control participants, contributed stool samples for microbiota characterization. Differences in the gut microbiota across various groups of PD patients and their households were identified through comprehensive sequencing of the 16S rRNA gene amplicon sequencing., Key Results: Differences in microbial communities were observed between PD patients and controls, as well as between PD patients receiving pharmacological treatment and those with STN-DBS. Pharmacologically treated advanced PD patients have higher gastrointestinal dysfunctions. Gut microbiota profile linked to STN-DBS and reduced levodopa consumption, characterized by its anti-inflammatory properties, might play a role in diminishing gastrointestinal dysfunction relative to only pharmacological treatments., Conclusions & Inferences: Advanced PD patients on medication exhibit more gastrointestinal issues, despite relatively stable microbial diversity, indicating a complex interaction between gut microbiota, PD progression, and treatment effects. An imbalanced gut-brain axis, particularly due to reduced butyrate production, may lead to constipation by affecting the enteric nervous system, which emphasizes the need to incorporate gut microbiome insights into treatment strategies., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Introduction: The wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological "honeymoon" period in Parkinson's disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study., Methods: WORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year., Results: A total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ± 3.39 vs 4.96 ± 3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ± 1.9 vs 1.5 ± 1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms., Discussion: Women showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Monotherapy is the recommended initial treatment for early Parkinson's disease. The pharmacological options for initial treatment include dopaminergic agonists, monoamine oxidase B inhibitors, and levodopa formulations. Several factors should be considered when selecting the optimal treatment, such as disease severity, disease duration, age, activity level, and the risk of developing motor and non-motor complications. Early evidence on the potential role of levodopa formulations in the risk of dyskinesia led to levodopa aversion in the late 1990s and early 2000s, favoring the use of levodopa-sparing options like dopamine agonists. This shift resulted in an increase in behavioral adverse effects, such as impulse control disorders, leading to a subsequent dopamine agonist aversion in the mid-2000s. This review aims to provide a comprehensive evaluation of the existing literature regarding the benefits and drawbacks of levodopa versus levodopa-sparing strategies in drug-naive early-stage Parkinson's disease.

Parkinson's disease (PD) is a progressive and disabling neurodegenerative disease that rapidly worsens and results in premature mortality if left untreated. Although levodopa is the gold standard treatment for PD globally, its accessibility and affordability are severely limited in low- and middle-income countries worldwide. In this scenario, Mucuna pruriens (MP), a leguminous plant growing wild in tropical regions, emerges as a potential alternative or adjunct to levodopa-based medications due to its cost-effectiveness and global natural availability. Recent studies have demonstrated that MP can significantly ameliorate motor symptoms, although tolerability may vary. The proposition that MP could play a pivotal role in providing affordable and symptomatic relief for PD in low- and middle-income countries is grounded in its promising therapeutic profile, yet caution is warranted until more comprehensive data on the long-term safety and efficacy of MP become available. This manuscript summarizes the knowledge gained about MP by the authors, focusing on how to cultivate, store, and provide it to patients in the safest and most effective way in clinical trials. We aim to increase clinical trials investigating its safety and efficacy in PD, before promoting individual use of MP on a global scale, particularly in countries where availability and affordability of levodopa-based medications is still limited., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roberto Cilia is an Associate Editor for Parkinsonism and Related Disorders If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Semantic fluency is the ability to name items from a given category within a limited time, which relies on semantic knowledge, working memory, and executive function. Similar to patients with Parkinson's disease (PD), patients with progressive supranuclear palsy (PSP) scored lower than healthy adults in the well-established semantic fluency test. However, it is unclear how unique are the produced words. This study examined the relationship between semantic fluency and words' uniqueness in patients with PSP., Methods: Twenty-seven patients with PSP Richardson's syndrome (PSP-RS), 37 patients with PD, and 41 healthy controls (HC) performed a standard semantic fluency test (animals), and their verbal responses were audio-recorded. We used the uniqueness to reflect the ability to produce both original and effective work, that is, creativity., Results: The PSP-RS group produced fewer correct words and fewer unique words than the PD and HC groups. Moreover, the correlation between fluency and uniqueness was positive in the HC and PD groups but negative in the PSP-RS group. Importantly, the actual levodopa dose was positively correlated with the fluency but negatively correlated with the uniqueness in PSP-RS. The PSP-RS patients who took a greater dose of levodopa tended to produce more correct words but fewer unique words., Conclusions: These results suggested that levodopa may modulate semantic fluency and uniqueness in the early stages of PSP-RS., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Introduction: Parkinson's disease (PD) is an incurable, progressive, neurodegenerative disorder. As PD advances and symptoms progress, patients become increasingly dependent on family and carers. Traditional cost-effectiveness analyses (CEA) only consider patient and payer-related outcomes, failing to acknowledge impacts on families, carers, and broader society. This novel Social Return on Investment (SROI) analysis aimed to evaluate the broader impact created by improving access to levodopa (LD) device-aided therapies (DATs) for people living with advanced PD (aPD) in Australia., Methods: A forecast SROI analysis over a three-year time horizon was conducted. People living with aPD and their families were recruited for qualitative interviews or a quantitative survey. Secondary research and clinical trial data was used to supplement the primary research. Outcomes were valued and assessed in a SROI value map in Microsoft Excel™. Financial proxies were assigned to each final outcome based on willingness-to-pay, economic valuation, and replacement value. Treatment cost inputs were sourced from Pharmaceutical Benefits Schedule (PBS) and Medicare Benefits Scheme (MBS) published prices., Results: Twenty-four interviews were conducted, and 55 survey responses were received. For every $1 invested in access to LD-based DATs in Australia, an estimated $1.79 of social value is created. Over 3 years, it was estimated $277.16 million will be invested and $406.77 million of social return will be created. This value is shared between people living with aPD (27%), their partners (22%), children (36%), and the Australian Government (15%). Most of the value created is social and emotional in nature, including reduced worry, increased connection to family and friends, and increased hope for the future., Discussion: Investment in LD-based DATs is expected to generate a positive social return. Over 50% of the value is created for the partners and children of people living with aPD. This value would not be captured in traditional CEA. The SROI methodology highlights the importance of investing in aPD treatment, capturing the social value created by improved access to LD-based DATs., Competing Interests: InD, IrD, RM, and CT are all paid employees of HTANALYSTS. AM and JBW are paid employees of AbbVie Pty Ltd., and own shares in AbbVie. The authors declare that this study received funding from AbbVie Pty Ltd. The funder had the following involvement in the study: AbbVie Pty Ltd. assisted in identifying neurologists who were treating patients with aPD and who had experience with LD-based DATs. AbbVie Pty Ltd. approved all study documents including participant recruitment flyers and interview guides. AbbVie Pty Ltd. were not involved in the collection of data to ensure patient privacy was maintained. Patients and health care professionals did not receive payment for their participation in this study., (Copyright © 2024 Denham, Maurin, Deltetto, Mikolaizak, Waern and Taylor.)

Carbidopa and levodopa remain the established therapeutic standard for managing Parkinson's disease. Nevertheless, their oral administration is hindered by rapid enzymatic degradation and gastrointestinal issues, limiting their efficacy, and necessitating alternative delivery methods. This work presents a novel strategy employing dissolving microarray patches (MAPs) loaded with carbidopa and levodopa, formulated with Tween® 80 to improve their transdermal delivery. The fabricated MAPs demonstrated an acceptable mechanical strength, resisting pressures equivalent to manual human thumb application (32 N) onto the skin. Additionally, these MAPs exhibited an insertion depth of up to 650 µm into excised neonatal porcine skin. Ex vivo dermatokinetic studies could achieve delivery efficiencies of approximately 53.35 % for levodopa and 40.14 % for carbidopa over 24 h, demonstrating their significant potential in drug delivery. Biocompatibility assessments conducted on human dermal fibroblast cells corroborated acceptable cytocompatibility, confirming the suitability of these MAPs for dermal application. In conclusion, dissolving MAPs incorporating carbidopa and levodopa represent a promising alternative for improving the therapeutic management of Parkinson's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Sleep disorders negatively impact quality of life in Parkinson's disease (PD), yet the role of antiparkinsonian drugs on sleep quality is still unclear. We aimed to explore the correlation between sleep dysfunction and dopaminergic therapy in a large cohort of advanced PD patients., Methods: Patients consecutively evaluated for device-aided therapies eligibility were evaluated by means of the PD Sleep Scale (PDSS-2; score ≥ 18 indicates poor sleep quality), and the Epworth Sleepiness Scale (ESS score ≥ 10 indicates excessive daytime sleepiness-EDS). Binary logistic regression analysis, adjusting for age, sex, disease duration, motor impairment, and sleep drugs, was employed to evaluate the association between dopaminergic therapy and PDSS-2 and ESS scores. Analysis of covariance assessed differences in PDSS-2 and ESS scores between patients without DA, and between patients treated with low or high doses of DA (cut-off: DA-LEDD = 180 mg)., Results: In a cohort of 281 patients, 66.2% reported poor sleep quality, and 34.5% reported EDS. DA treatment demonstrated twofold lower odds of reporting relevant sleep disturbances (OR 0.498; p = 0.035), while DA-LEDD, levodopa-LEDD, total LEDD, and extended-release levodopa were not associated with disturbed sleep. EDS was not influenced by dopaminergic therapy. Patients with DA intake reported significant lower PDSS-2 total score (p = 0.027) and "motor symptoms at night" domain score (p = 0.044). Patients with higher doses of DA showed lower PDSS-2 total score (p = 0.043)., Conclusion: Our study highlights the positive influence of DA add-on treatment on sleep quality in this group of advanced fluctuating PD patients., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients., Objectives: To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients., Methods: ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change., Results: The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied., Conclusions: Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Objective: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years., Methods: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose., Results: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups., Conclusions: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

COMT inhibitors are commonly used to improve the effectiveness of levodopa in treating Parkinson's disease by inhibiting its conversion to 3-O-methyldopa. Because of the serious side effect of nitrocatechol COMT inhibitors, it is necessary to develop non-nitrocatechol COMT inhibitors with a higher safety profile. Heparin has been observed to bind to COMT. However, the exact functional significance of this interaction is not fully understood. In this study, the contribution of different substitution of heparin to its binding with COMT was investigated. In vitro and in vivo, heparin oligosaccharides can bind to COMT and inhibit its activity. Furthermore, we enriched the functional heparin oligosaccharides that bind to COMT and identified the sequence UA2S-GlcN(S/Ac)6(S/H)-UA2S-GlcNS6(S/H)-UA2(S/H)-GlcNS6S as the characteristic structural domain of these functional oligosaccharides. This study has elucidated the relationship between the structure of heparin oligosaccharides and their activity against COMT, providing valuable insights for the development of non-nitrocatechol COMT inhibitors with improved safety and efficacy., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: FC received honorarium to participate in educational activities of the International Parkinson and Movement Disorder Society. ET declares no competing interests.

Purpose: Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or Parkinson's disease (PD) perform poorly in tests that require the flexible arrangement of thoughts or actions. This study investigated whether sequential working memory is differently impaired in patients with PSP versus PD., Method: Twenty-nine patients with PSP Richardson's syndrome (PSP-RS), 36 patients with PD, and 36 healthy controls (HC) completed 3 well-established neuropsychological tests, including digit span forward (DST-F), digit span backward (DST-B), and adaptive digit ordering tests (DOT-A). The DST-F required maintaining digit sequences, and the DST-B and DOT-A required maintaining and manipulating digit sequences., Finding: The PSP-RS group scored lower than the PD and HC groups in the DST-B and DOT-A but not in the DST-F, indicating that the ability to manipulate sequences was impaired, but the maintenance ability was preserved in PSP-RS patients. Moreover, in PSP-RS, the DST-B score negatively correlated with the severity of motor symptoms. The actual levodopa dose positively correlated with the DST-B ordering cost (DST-F score vs. DST-B score). The PSP patients who took a greater dose of levodopa tended to have higher DST-B ordering cost. There was no effect of levodopa on DST-B or DOT-A in PD., Conclusion: These results suggested that the ability to manipulate sequence was already reduced in patients with PSP-RS and was worse than in patients with PD., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Objective: One proposed mechanism of disease progression in Parkinson's disease includes the interplay of endogenous dopamine toxicity and mitochondrial dysfunction. However, the in-vivo effects of exogenous dopamine administration on cerebral bioenergetics are unknown., Methods: We performed a double-blinded, cross-over, placebo-controlled trial. Participants received either 200/50 mg levodopa/benserazide or a placebo and vice versa on the second study visit. Clinical assessments and multimodal neuroimaging were performed, including 31 phosphorus magnetic resonance spectroscopy of the basal ganglia and the midbrain., Results: In total, 20 (6 female) patients with Parkinson's disease and 22 sex- and age-matched healthy controls (10 female) were enrolled. Treatment with levodopa/benserazide but not with placebo resulted in a substantial reduction of high-energy phosphorus-containing metabolites in the basal ganglia (patients with Parkinson's disease: -40%; healthy controls: -39%) but not in the midbrain. There were no differences in high-energy phosphorus-containing metabolites for patients with Parkinson's disease compared to healthy controls in the OFF state and treatment response., Interpretation: Exogenously administered levodopa/benserazide strongly interferes with basal ganglia high-energy phosphorus-containing metabolite levels in both groups. The lack of effects on midbrain levels suggests that the observed changes are limited to the site of dopamine action. ANN NEUROL 2024;95:849-857., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The roots and rhizomes of Nardostachys jatamansi DC. are reported to be useful for the treatment of Parkinson's disease (PD). Previous research has also shown that Nardosinone, the main active component isolated from Nardostachys jatamansi DC., exhibits the potential to treat PD., Aim of the Study: To investigate how the effects of Nardosinone could assist levodopa in the treatment of PD, how this process changes the intestinal flora, and to explore the effective forms of Nardosinone in the intestinal flora., Material and Methods: We used behavioral experiments, and hematoxylin-eosin staining and immunohistochemical staining, to investigate the effects of a combination of Nardosinone and levodopa on rotenone-induced PD rats. In addition, we used LC/MS-MS to determine the levels of levodopa, 5-hydroxytryptamine, dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid, and homovanillic acid, to investigate the effect of the intestinal flora on co-administration in the treatment of PD. LC/MS-MS was also used to detect the metabolites of Nardosinone on the gastrointestinal tract and intestinal flora., Results: The behavioral disorders and neuronal damage associated with PD were significantly improved following the co-administration. Analysis also revealed that the co-administration increased the levels of five neurotransmitters in the striatum, plasma and feces. In vitro experiments further demonstrated that the levels of dopamine and levodopa were increased in the intestinal flora. In total, five metabolites of Nardosinone were identified., Conclusion: Our findings indicate that Nardosinone and its metabolites might act as a potential adjutant to enhance the efficacy of levodopa via the intestinal flora, thus expanding the therapeutic potential of the combination of Chinese and Western medicine as a treatment method for PD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD)., Objective: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG)., Methods: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity., Results: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups., Conclusions: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease., Trial Registration: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022., (© 2024. The Author(s).)

Aims: Parkinsonian tremor (PT) is regulated by numerous neurophysiological components across multiple temporospatial scales. The dynamics of tremor fluctuation are thus highly complex. This study aimed to explore the effects of different medications on tremor complexity, and how the underlying factors contribute to such tremor complexity., Methods: In this study, 66 participants received a 2-mg dose of benzhexol or a pre-determined dose of levodopa at two study visits in a randomized order. Before and after taking the medications, tremor fluctuation was recorded using surface electromyography electrodes and accelerometers in resting, posture, and weighting conditions with and without a concurrent cognitive task. Tremor complexity was quantified using multiscale entropy., Results: Tremor complexity in resting (p = 0.002) and postural condition (p < 0.0001) was lower when participants were performing a cognitive task compared to a task-free condition. After taking levodopa and benzhexol, participants had increased (p = 0.02-0.03) and decreased (p = 0.03) tremor complexity compared to pre-medication state, respectively. Tremor complexity and its changes as induced by medications were significantly correlated with clinical ratings and their changes (β = -0.23 to -0.39; p = 0.002-0.04), respectively., Conclusion: Tremor complexity may be a promising marker to capture the pathophysiology underlying the development of PT, aiding the characterization of the effects medications have on PT regulation., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)