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Background: While the gradually aggravated motor and non-motor disorders of Parkinson's disease (PD) lead to progressive disability and frequent falling, skeletal muscle impairment may contribute to this condition. The leucine-rich repeat kinase2 (LRRK2) is a common disease-causing gene in PD. Little is known about its role in skeletal muscle impairment and its underlying mechanisms., Methods: To investigate whether the mutation in LRRK2 causes skeletal muscle impairment, we used 3-month-old (3mo) and 14-month-old (14mo) LRRK2 G2019S transgenic (TG) mice as a model of PD, compared with the age-matched littermate wild-type (WT) controls. We measured the muscle mass and strength, ultrastructure, inflammatory infiltration, mitochondrial morphology and dynamics dysfunction through behavioural analysis, electromyography (EMG), immunostaining, transmission electron microscopy (TEM) and other molecular biology techniques., Results: The 3mo-TG mice display mild skeletal muscle impairment with spontaneous potentials in EMG (increased by 130%, p < 0.05), myofibre necrosis (p < 0.05) and myosin heavy chain-II changes (reduced by 19%, p < 0.01). The inflammatory cells and macrophage infiltration are significantly increased (CD8a + and CD68 + cells up 1060% and 579%, respectively, both p < 0.0001) compared with the WT mice. All of the above pathogenic processes are aggravated by aging. The 14mo-TG mice EMG examinations show a reduced duration (by 31%, p < 0.01) and increased polyphasic waves of motor unit action potentials (by 28%, p < 0.05). The 14mo-TG mice present motor behavioural deficits (p < 0.05), muscle strength and mass reduction by 37% and 8% (p < 0.05 and p < 0.01, respectively). A remarkable increase in inflammatory infiltration is accompanied by pro-inflammatory cytokines in the skeletal muscles. TEM analysis shows muscle fibre regeneration with the reduced length of sarcomeres (by 6%;p < 0.05). The muscle regeneration is activated as Pax7 + cells increased by 106% (p < 0.0001), andmyoblast determination protein elevated by 71% (p < 0.01). We also document the morphological changes and dynamics dysfunction of mitochondria with the increase of mitofusin1 by 43% (p < 0.05) and voltage-dependent anion channel 1 by 115% (p < 0.001) in the skeletal muscles of 14mo-TG mice., Conclusions: Taken together, these findings may provide new insights into the clinical and pathogenic involvement of LRRK2 G2019 mutation in muscles, suggesting that the diseases may affect not only midbrain dopaminergic neurons, but also other tissues, and it may help overall clinical management of this devastating disease., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Introduction: Rasagiline is indicated for treating idiopathic Parkinson's disease (PD) as monotherapy and adjunct therapy to levodopa in patients., Objectives: To assess the post-marketing safety and tolerability of rasagiline in Chinese PD patients, as well as its effectiveness in improving motor symptoms., Methods: This prospective, non-interventional, multicenter, cohort study included PD patients administered rasagiline monotherapy or adjunct therapy to levodopa. The primary outcome was the incidence of adverse drug reactions (ADRs) according to MedDRA ® (version 22.0), and the secondary outcomes were the Parkinson's Disease Unified Rating Scale (UPDRS) part III, Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Global-Improvement (CGI-I), assessed at Weeks 4, 12, and 24., Results: In total, 734 patients, 95 in the monotherapy subgroup and 639 in the adjunct therapy subgroup, were included in the safety population. The incidence rates of all ADRs were comparable between the monotherapy (15.8%) and adjunct therapy (13.6%) subgroups. The most common ADRs by system organ class were nervous system disorders (5.6%), gastrointestinal disorders (3.3%), psychiatric disorders (1.8%), vascular disorders (1.2%), and general disorders and administration site conditions (1.1%). Five (0.7%) participants experienced 5 serious ADRs. Improvements in UPDRS part III, CGI-S and CGI-I at Weeks 4, 12 and 24 from baseline were observed., Conclusions: Safety data in this study indicated no extra safety concerns. Rasagiline is generally safe and well tolerated in Chinese PD patients. The safety profile and tolerability were in line with the established safety profile. Moreover, rasagiline reduced the severity of PD motor symptoms, confirming findings by previous clinical trials., (© 2023. The Author(s).)

Objective: Previous studies have revealed that, compared with Parkinson's disease (PD) patients without freezing of gait (FoG), the ones with FoG showed greater prefrontal activation while doing lower-limb movements involving standing, walking and turning, which require both locomotor and balance control. However, the relation between FoG and pure locomotor control as well as its underlying mechanism remain unclear., Methods: A total of 56 PD subjects were recruited and allocated to PD-FoG and PD-noFoG subgroups, and 34 age-matched heathy adults were included as heathy control (HC). Functional near-infrared spectroscopy was used to measure their prefrontal activation in a sitting lower-limb movement task, wherein subjects were asked to sit and tap their right toes as big and as fast as possible., Results: Result of one-way ANOVA (Group: PD-FoG vs. PD-noFoG vs. HC) revealed greater activation in the right prefrontal cortex in the PD-FoG group than in the other 2 groups. Linear mixed-effects model showed consistent result. Furthermore, the right prefrontal activation positively correlated with the severity of FoG symptoms in PD-FoG patients., Conclusion: These findings suggested that PD patients with FoG require additional cognitive resources to compensate their damaged automaticity in locomotor control, which is more pronounced in severe FoG patients than milder ones., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The use of the anti-parkinsonian drug trihexyphenidyl (THP) to treat patients with Parkinson's disease (PD), particularly those with tremor-dominant PD (tdPD), has been well documented. Despite growing concerns about THP causing cognitive decline in tdPD patients, the underlying neural correlates remain unclear. Therefore, we investigated the effects of THP on prefrontal executive function and spontaneous neural activity in patients with tdPD by utilizing functional near-infrared spectroscopy (fNIRS)., Methods: We recruited 30 patients with tdPD, including 15 patients receiving THP and 15 patients not receiving THP. We performed comprehensive neuropsychological and clinical assessments to evaluate each patient's cognitive function, mental status, and clinical symptoms. We measured brain activation elicited from the verbal fluency task (VFT) and changes in amplitude of low-frequency fluctuations (ALFF) at rest to investigate executive function and spontaneous neural activity, respectively. In addition, we examined the relationship between altered activation during task and resting state and neuropsychological and clinical data., Results: Compared with tdPD patients not taking THP, tdPD patients taking THP showed no differences on neuropsychological tests. However, there was insufficient activity of the dorsolateral prefrontal cortex (DLPFC) during VFT and reduced ALFF values for the DLPFC, ventrolateral prefrontal cortex (VLPFC), and the orbitofrontal cortex (OFC) related to the frontoparietal network (FPN) at rest. Furthermore, ALFF values of the VLPFC were positively correlated with scores of multiple cognitive domain functions., Conclusion: These findings suggest that THP treatment may lead to prefrontal dysfunction in tdPD patients, attenuating brain activation in executive function and cognition-related spontaneous neural activity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: A thorough understanding of the factors that influence patient survival in Parkinson's disease (PD) will aid in prognosis prediction and provide a new direction for disease modification treatment. Currently, there are no standardized mortality ratio (SMR) data for PD patients in the northern Chinese mainland. The main focus of this study was to determine which factors in the prospectively collected baseline characteristics can affect the survival of PD patients. In addition, for the first time, we investigated the SMR of PD patients in northern China., Methods: Between 2009 and 2012, 218 PD patients were continuously recruited from the movement disorder clinic of the First Affiliated Hospital of Dalian Medical University and followed up until death or May 31, 2021. The prespecified prognostic variables were demographics, clinical features, lifestyle factors, and drug dose prospectively collected at baseline. To determine the independent predictors of survival during follow-up, the Cox proportional hazards model was used. Kaplan-Meier analysis was applied to estimate the overall survival curve and to compare survival between layers based on statistically significant predictors. The SMR of this northern Chinese mainland PD cohort was calculated., Results: After a mean follow-up of 9.58 ± 2.27 years, 50 patients (22.90%) died. Factors that could individually predict shortened survival during follow-up included older age at onset (hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.06-1.15), Hoehn and Yahr (H&Y) stage ≥ 3 (HR 9.36, 95% CI 2.82-31.03) and severe cognitive impairment (HR 6.18, 95% CI 2.75-13.88). Univariate Cox regression revealed that a certain amount of physical activity was associated with better survival (HR 0.41, 95% CI 0.22-0.74), while fatigue was associated with an increased risk of death (HR 2.54, 95% CI 1.37-4.70). The overall SMR was 1.32 (95% CI 0.98-1.74)., Conclusions: Older age at onset, higher baseline H&Y stage, and severe cognitive impairment have a negative impact on survival. The 10-year survival of PD patients is not significantly different from that of the general population in China., (© 2022. The Author(s).)

Background: Quality of life (QoL) in patients with Parkinson's disease (PD) is increasingly used as an efficacy outcome in clinical studies of PD to evaluate the impact of treatment from the patient's perspective. Studies demonstrating the treatment effect of pramipexole on QoL remain inconclusive. This study aims to evaluate the effect of pramipexole on QoL in patients with PD by conducting a systematic review and meta-analysis of existing clinical trials., Methods: A systematic literature search of PubMed, Embase and the Cochrane Library was performed from inception to 30 April 2022 to identify randomised, placebo-controlled trials of patients with idiopathic PD receiving pramipexole, who reported a change from baseline in their QoL as measured by the 39-item Parkinson's Disease Questionnaire (PDQ-39). Risk of bias was independently assessed by two reviewers using the Cochrane Collaboration's tool for bias assessment., Results: Of 80 eligible articles screened, six trials consisting of at least 2000 patients with early or advanced PD were included. From the synthesis of all six selected trials, a significant mean change from baseline in the PDQ-39 total score of -2.49 (95% CI, -3.43 to -1.54; p < 0.0001) was observed with pramipexole compared with placebo. A trend toward improvement in QoL was consistently observed among patients who received optimal doses of pramipexole (≥ 80% of the study population on 1.5 mg dosage), regardless of disease severity (advanced versus early) or baseline QoL levels., Conclusion: This meta-analysis provides evidence for the potential treatment benefit of pramipexole in improving QoL in patients with PD., (© 2022. The Author(s).)

Parkinson's disease (PD) is a prevailing neurodegenerative disorder. This study discussed the mechanism of lncRNA distal-less homeobox 6 antisense 1 (DLX6-AS1) on inflammatory responses in PD. With healthy male C57BL/6 mice (8-10 weeks) and BV2 microglia as study subjects, we established PD models in vivo/in vitro by injection of 1-methyl-4-phenyl-2, 3, 6-tetrahydropyridine (MPTP) for 4 weeks and treatment of lipopolysaccharide (LPS) for 24 h, respectively. DLX6-AS1 expression in PD mice and BV2 microglia was examined using reverse transcription quantitative-polymerase chain reaction and then down-regulated via stereotaxic catheter injection or cell transfection to evaluate its effect on neurological function. Meanwhile, the cell number of TH+ /Caspase3 + /IBA1 + in substantia nigra, cell viability, and apoptosis rate of BV2 microglia, inflammatory levels, and NLR family pyrin domain containing 3 (NLRP3) inflammasome were determined using immunohistochemistry, MTT assay, flow cytometry, ELIZA assay, and Western blot. The binding relationship between miR-223-3p and DLX6-AS1/Neuropilin-1 (NRP1) was verified by dual-luciferase assay and RNA immunoprecipitation assay. After down-regulation of DLX6-AS1, we down-regulated/overexpressed miR-223-3p/NRP1 levels in BV2 microglia. DLX6-AS1 was overexpressed in PD mice. Silencing DLX6-AS1 improved neurological function and alleviated microglial inflammation in PD mice. Specifically, the latency of mice falling from the rotating rod was longer, and the latency of climbing rod test was shorter; TH+ cells increased, while Caspase3 + /IBA1 + cells decreased; the levels of inflammatory were lowered. Silencing DLX6-AS1 inhibited LPS-induced inflammation of BV2 microglia. DLX6-AS1 acted as the ceRNA of miR-223-3p to promote NRP1. Down-regulation of miR-223-3p or overexpression of NRP1 partially annulled the effect of silencing DLX6-AS1 on BV2 microglial inflammation. Overall, DLX6-AS1 promotes the microglial inflammatory response in PD through the ceRNA mechanism of miR-223-3p/NRP1., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Music therapy improves neuronal activity and connectivity of healthy persons and patients with clinical symptoms of neurological diseases like Parkinson's disease, Alzheimer's disease, and major depression. Despite the plethora of publications that have reported the positive effects of music interventions, little is known about how music improves neuronal activity and connectivity in afflicted patients., Methods: For patients suffering from Parkinson's disease (PD), we propose a daily 25-min music-based synchronous finger tapping (SFT) intervention for 8 weeks. Eligible participants with PD are split into two groups: an intervention group and a control arm. In addition, a third cohort of healthy controls will be recruited. Assessment of finger tapping performances, the Unified Parkinson's Disease Rating Scale (UPDRS), an n-back test, the Montreal Cognitive Assessment (MoCA), as well as oxygenated hemoglobin (HbO 2 ), deoxygenated hemoglobin (HbR), and total hemoglobin activation collected by functional near-infrared spectroscopy (fNIRS) are measured at baseline, week 4 (during), week 8 (post), and week 12 (retention) of the study. Data collected from the two PD groups are compared to baseline performances from healthy controls., Discussion: This exploratory prospective trial study investigates the cortical neuronal activity and therapeutic effects associated with an auditory external cue used to induce automatic and implicit synchronous finger tapping in patients diagnosed with PD. The extent to which the intervention is effective may be dependent on the severity of the disease. The study's findings are used to inform larger clinical studies for optimization and further exploration of the therapeutic effects of movement-based music therapy on neural activity in neurological diseases., Trial Registration: ClinicalTrials.gov NCT04212897 . Registered on December 30, 2019. The participant recruitment and study protocol have received ethical approval from the First Affiliated Hospital of Dalian Medical University. The hospital Protocol Record number is PJ-KY-2019-123. The protocol was named "fNIRS Studies of Music Intervention of Parkinson's Disease." The current protocol is version 1.1, revised on September 1, 2020.

Background: Deep-brain stimulation targeting the subthalamic nucleus (STN) can be used to treat motor symptoms and dyskinesia in the advanced stages of Parkinson's disease (PD). High-frequency stimulation (HFS) of the STN can lead to consistent, long-term improvement of PD symptoms. However, the effects of HFS on the axial symptoms of PD, specifically freezing of gait, can be limited or cause further impairment. While this can be alleviated via relatively low-frequency stimulation (LFS) in selected patients, LFS does not control all motor symptoms of PD. Recently, the National Engineering Laboratory for Neuromodulation reported preliminary findings regarding an efficient way to combine the advantages of HFS and LFS to form variable-frequency stimulation (VFS). However, this novel therapeutic strategy has not been formally tested in a randomized trial., Methods/design: We propose a multicenter, double-blind clinical trial involving 11 study hospitals and an established deep-brain stimulation team. The participants will be divided into a VFS and a constant-frequency stimulation group. The primary outcome will be changes in stand-walk-sit task scores after 3 months of treatment in the "medication off" condition. Secondary outcome measures include specific item scores on the Freezing of Gait Questionnaire and quality of life. The aim of this trial is to investigate the efficacy and safety of VFS compared with constant-frequency stimulation., Discussion: This is the first randomized controlled trial to comprehensively evaluate the effectiveness and safety of VFS of the STN in patients with advanced PD. VFS may represent a new option for clinical treatment of PD in the future., Trial Registration: ClinicalTrials.gov, NCT03053726. Registered on February 15, 2017.

Sleep dysfunctions, including rapid eye movement sleep behavior disorder, sleep fragmentation, excessive daytime sleepiness and various other dysfunctions, can seriously affect quality of life in patients with Parkinson's disease (PD). Emerging evidence suggests that deep brain stimulation (DBS) exerts a substantial effect when used to treat sleep dysfunctions, which are common nonmotor symptoms experienced by patients with PD. However, far less is known about the specific mechanisms underlying the effects of DBS on sleep processes and the factors that potentially influence these effects. These issues therefore need to be further clarified. Intriguingly, a number of recent studies have evaluated the effects of applying DBS to various brain targets on sleep in patients with PD. Deeper research into the efficacy of applying DBS to each brain target may help determine which region should be targeted during surgery in PD patients. Furthermore, compared with pharmacological therapy, DBS had more beneficial effects on sleep symptoms, and appropriate management involving the joint application of dopamine replacement therapy and DBS might accelerate the effects of treatment. Here, we review the potential roles DBS may play and provide clinical guidance for the use of DBS in treating sleep dysfunctions in PD patients.

(-)-Epigallocatechin-3-gallate (EGCG) is the most widely studied catechin in green tea and has been identified to regulate immune function. The objective of the present study was to explore the possible application of EGCG in the treatment of Parkinson's disease (PD) by examining its effects on the peripheral immune system in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)‑induced PD mouse model. The results demonstrated that EGCG treatment restored the movement behavior of the mice impaired by MPTP, and protected tyrosine hydroxylase‑positive cells in the substantia nigra pars compacta region from MPTP toxicity. Flow cytometric analysis indicated that the ratio of CD3+CD4+ to CD3+CD8+ T lymphocytes in the peripheral blood increased in MPTP‑treated mice following treatment with EGCG, and EGCG reduced expression of inflammatory factors tumor necrosis factor‑α and interleukin‑6 in serum. The present findings indicated that EGCG serves neuroprotective effects in an MPTP‑induced PD mice model and may exert this through modulating peripheral immune response.

The relationship between the nuclear factor erythroid-derived 2-like 2 (NFE2L2) rs35652124 (A/G) polymorphism and the risk of Parkinson's disease (PD) is controversial. To evaluate the association of the NFE2L2 rs35652124 polymorphism with the risk of PD, a meta-analysis was carried out. A total of 2264 PD cases and 2582 controls were included in the meta-analysis on the basis of strict inclusion and exclusion criteria. The pooled odds ratio (OR) and 95% confidence interval were calculated to assess the genetic association between the NFE2L2 rs35652124 polymorphism and the risk of PD. There was no significant association between rs35652124 and PD (G vs. A: OR=1.001, P=0.986; GG vs. AA: OR=1.026, P=0.785; GA vs. AA: OR=1.023, P=0.786; GG+GA vs. AA: OR=1.224, P=0.070; GG vs. GA+AA: OR=0.994, P=0.926). The data of our meta-analysis indicate that the G allele, GG, and GA genotype of the rs35652124 (A/G) polymorphism were not associated with the risk of PD.

In order to develop a cell-based vaccine against the Parkinson disease (PD) associated protein α-synuclein (α-Syn) 3 peptides were synthesized based upon predicted B cell epitopes within the full length α-Syn protein sequence. These peptide fragments as well as the full length recombinant human α-Syn (rh- α-Syn) protein were used to sensitize mouse bone marrow-derived dendritic cells (DC) ex vivo, followed by intravenous delivery of these sensitized DCs into transgenic (Tg) mice expressing the human A53T variant of α-Syn. ELISA analysis and testing of behavioral locomotor function by rotometry were performed on all mice after the 5th vaccination as well as just prior to euthanasia. The results indicated that vaccination with peptide sensitized DCs (PSDC) as well as DCs sensitized by rh-α-Syn induced specific anti-α-Syn antibodies in all immunized mice. In terms of rotometry performance, a measure of locomotor activity correlated to brain dopamine levels, mice vaccinated with PSDC or rh- α-Syn sensitized DCs performed significantly better than non-vaccinated Tg control mice during the final assessment (i.e. at 17 months of age) before euthanasia. As well, measurement of levels of brain IL-1α, a cytokine hypothesized to be associated with neuroinflammation, demonstrated that this proinflammatory molecule was significantly reduced in the PSDC and rh- α-Syn sensitized DC vaccinated mice compared to the non-vaccinated Tg control group. Overall, α-Syn antigen-sensitized DC vaccination was effective in generating specific anti- α-Syn antibodies and improved locomotor function without eliciting an apparent general inflammatory response, indicating that this strategy may be a safe and effective treatment for PD.