Myricetin mitigates motor disturbance and decreases neuronal ferroptosis in a rat model of Parkinson's disease.

Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), respectively. Ferroptosis was identified by assessing the levels of Fe2+, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe2+, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP+-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP+-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.

Association of body mass index with rapid eye movement sleep behavior disorder in Parkinson's disease.

Background: The association between body mass index (BMI) and rapid eye-movement (REM) sleep-related behavioral disorder (RBD) in Parkinson's disease (PD) remains unknown. Our study was to investigate the association of BMI with RBD in PD patients. Methods: In this cross-sectional study, a total of 1,115 PD participants were enrolled from Parkinson's Progression Markers Initiative (PPMI) database. BMI was calculated as weight divided by height squared. RBD was defined as the RBD questionnaire (RBDSQ) score with the cutoff of 5 or more assessed. Univariable and multivariable logistic regression models were performed to examine the associations between BMI and the prevalence of RBD. Non-linear correlations were explored with use of restricted cubic spline (RCS) analysis. And the inflection point was determined by the two-line piecewise linear models. Results: We identified 426 (38.2%) RBD. The proportion of underweight, normal, overweight and obese was 2.61, 36.59, 40.36, and 20.44%, respectively. In the multivariate logistic regression model with full adjustment for confounding variables, obese individuals had an odds ratio of 1.77 (95% confidence interval: 1.21 to 2.59) with RBD compared with those of normal weight. In the RCS models with three knots, BMI showed a non-linear association with RBD. The turning points of BMI estimated from piecewise linear models were of 28.16 kg/m2, 28.10 kg/m2, and 28.23 kg/m2 derived from univariable and multivariable adjusted logistic regression models. The effect modification by depression on the association between BMI and RBD in PD was also found in this study. Furthermore, the sensitivity analyses linked with cognition, education, and ethnic groups indicated the robustness of our results. Conclusion: The current study found a significant dose-response association between BMI and RBD with a depression-based difference in the impact of BMI on RBD in PD patients.

Autonomic function and motor subtypes in Parkinson's disease: a multicentre cross-sectional study.

Autonomic symptoms (AS) are critical in Parkinson's disease (PD). We aimed to determine the relative significance of clinical factors allowing predictions about incidence of AS, and examine AS profiles among PD patients by motor subtype and its relation to AS. The cross-sectional data of a multicentre sample, including 714 PD patients and 194 healthy controls from Parkinson's Progression Marker Initiative study and Pingchan granule study were analyzed, stratified by PD subtypes [postural instability and gait disturbances (PIGD), tremor dominant (TD), and indeterminate] and domain autonomic dysfunction. Compared with healthy controls, PD patients scored higher in the total Scales for Outcomes in Parkinson's Disease-Autonomic dysfunction score and in several domain scores in particular, and there was a significant overlap in domain AS. Risk factors of individual domain autonomic dysfunction were heterogeneous. PIGD and indeterminate were the predominant subtypes in pupillomotor and thermoregulatory symptoms. TD and indeterminate were more likely to suffer from cardiovascular problem. The odd in sexual dysfunction was significant for PIGD. Gastrointestinal and urinary symptoms seemed not to be associated with a specific subtype. Our study demonstrated that AS were highly heterogeneous and 3 subtypes differed in autonomic performance, providing clues to understand mechanisms underlying AS in PD.

Traditional Chinese medicine Pingchan granule for motor symptoms and functions in Parkinson's disease: A multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Pingchan granule (PCG) is a traditional Chinese medicine for Parkinson's disease (PD). HYPOTHESIS/PURPOSE: This was the first study aiming to evaluate the efficacy and safety of PCG for motor symptoms, gait impairments and quality of life in PD. STUDY DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 292 participants were included and followed for 9 months, randomly assigned at a 1:1 ratio to receive PCG or placebo. The primary outcome was the severity of motor symptoms assessed by Movement Disorder Society Unified Parkinson's Rating Scale III (MDS-UPDRS-III) motor score. Secondary outcomes included timed up and go test (TUG), functional gait assessment (FGA), freezing of gait (FOG), and quality of life assessed by Parkinson's disease questionnaire (PDQ-39). Assessments were done at baseline (T0), 3 months (T1), 6 months (T2) and 9 months (T3). TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR-INR-1,701,194. RESULTS: Generalized estimating equation analyses revealed that PCG group had significantly better improvement in MDS-UPDRS-III motor score than placebo group, as well as its domain scores of axial symptoms, bradykinesia, rigidity, and tremor. Improvements of TUG time, FGA, FOG questionnaire (FOGQ), and PDQ39 scores were also observed. CONCLUSION: PCG had a long-lasting efficacy for motor symptoms and function in PD with good tolerance, supporting that PCG might be a viable alternative in the management of PD.

The Importance of Early Identification for Parkinson's Disease Patients with Postural Instability and Gait Disturbance.

Background: More and more evidence-based medicine has proved that Parkinson's disease (PD) patients of tremor-dominant (TD) and postural instability and gait difficulty (PIGD) subtype express great individual differences and heterogeneity. Early identification of different subtypes may be an important way to delay disease progression and improve patients' prognosis. Objective: The study aimed to compare the spectrum of motor symptoms (MS) and nonmotor symptoms (NMS) between TD and PIGD dominant in the early and middle stages of PD, and determine predictive factors that are associated with different motor subtypes. Methods: 292 PD patients in this study were divided into TD-PD and PIGD-PD, and the clinical characteristics between different motor subtypes were compared based on scales related to sleep, mood, and autonomic function. Univariate and multivariate ordered logistic regression analyses were used to analyze the independent influencing factors of disease severity between different motor subtypes. Through the establishment of binary logistic regression model, the potential independent risk factors for distinguishing TD-PD and PIGD-PD were studied. Results: Compared with TD subtype, patients with PIGD subtype have longer course of disease, higher disease severity, and higher daily dosage of levodopa. The severity of nontremor motor symptoms in PIGD-PD is greater than that of TD subtype. Only PIGD score was independently associated with disease severity for the two motor subtypes. Meanwhile, high scores (LED, total UPDRS, PIGD score, gastrointestinal, thermoregulatory, RBDSQ) and low tremor scores were the potential independent risk factors for distinguishing PIGD-PD from TD-PD. Conclusion: Specific nonmotor symptoms (RBD, gastrointestinal function and thermoregulation function) were associated with the PIGD subtype. Prompt detection and early treatment of NMSs related to the PIGD subtype based on the treatment of motor symptoms may improve patient outcomes.

Pingchan Granule for Motor Symptoms and Non-Motor Symptoms of Parkinson's Disease: A Randomized, Double-Blind, Placebo-Controlled Study.

Background: Pingchan granule (PCG) is a traditional Chinese medicine for treating Parkinson's disease (PD). Objective: This study aimed at evaluating the efficacy and safety of PCG for motor and non-motor symptoms of PD. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, 292 participants with mild-to-moderate PD were included and followed for 36 weeks (24 week treatment, 12-week follow-up after intervention), randomly assigned at a 1:1 ratio to receive PCG or placebo. The primary outcomes included the severity of motor symptoms assessed by the Unified Parkinson's disease Rating Scale (UPDRS) part 3 (UPDRS-III) score and the rate of disease progression assessed by the total UPDRS score. Secondary outcomes included non-motor symptoms assessed using the Scale for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Parkinson's disease Sleep Scale (PDSS), 24-item Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), UPDRS part 2 (UPDRS-II), and 39-item Parkinson's Disease Questionnaire (PDQ-39) scores. Assessments were done at baseline (T0), 12 weeks (T1), 24 weeks (T2), and 36 weeks (T3). Results: Generalized estimating equation analyses revealed that the PCG group had significantly better improvement in UPDRS-III score at T1, T2, and T3 [time-by-group interaction, T1: ß, -0.92 (95% CI, -1.59--0.25; p = 0.01); T2: ß, -2.08 (95% CI, -2.90--1.27; p < 0.001); T3: ß, -4.54 (95% CI, -5.37--3.71; p < 0.001))]. The PCG group showed a greater decrease (rate of disease change) in the total UPDRS score between T0 and T2 [-2.23 (95% CI, -2.72--1.73; p < 0.001) points per week vs. -0.21 (95% CI, -0.80-0.39; p = 0.50) points per week in the placebo group, p < 0.001]. Ameliorations of SCOPA-AUT, PDSS, HAM-D, HAM-A, UPDRS-II, and PDQ-39 scores were also observed. Conclusion: PCG had a long-lasting and extensive symptomatic efficacy for both motor and non-motor symptoms of PD with good tolerance. Trial registration: Chinese Clinical Trial Register, ChiCTR-INR-17011949.

Identification of ferroptosis-related gene signatures associated with multiple sclerosis using weighted gene co-expression network analysis.

Multiple sclerosis (MS) is a chronic inflammatory disease of central nervous system leading to demyelination followed by neurological symptoms. Ferroptosis is a newly discovered pathogenic hallmark important for the progression of MS. However, the gene markers of ferroptosis in MS are still uncertain. In this study, mRNA expression profiles and clinical data of MS samples were retrieved from Gene Expression Omnibus database. Weighted gene co-expression network analysis and receiver operating characteristic curve analysis were utilized to identify ferroptosis-related gene (FRG) signatures of MS. Gene set enrichment analysis and gene set variation analysis were performed to explore the biological functions of single FRG signature. HMOX1, LPCAT3 and RPL8 were firstly identified as FRG signatures of MS with the predictive capacity confirmed. Gene set enrichment analysis and gene set variation analyses revealed that metabolism-related, immune and inflammation-related, microglia-related, oxidation-related, and mitochondria-related biological functions were enriched, providing implications of the mechanisms underlying ferroptosis in MS. This study presented a systematic analysis of FRG in MS and explored the potential ferroptosis targets for new interventional strategies in MS.

Chinese herbal medicines for mild cognitive impairment: A protocol for meta-analysis and trial sequential analysis.

BACKGROUND: Mild cognitive impairment (MCI), as a common neurodegenerative aging disease representing an intermediate stage between normal cognitive functioning and dementia, poses an excessive burden on health care. The clinical benefit of Chinese herbal medicines (CHMs) for MCI remains inconclusive. This study is aimed at evaluating the efficacy and acceptability of CHMs through meta-analysis and trial sequential analysis (TSA). METHODS: We applied extensive strategies on preliminary literature screening to identify relevant randomized controlled trials which meticulously compare any of CHMs interventions with placebo groups as monotherapy for MCI. The primary outcome of this study is the change of global cognitive function, and the secondary outcomes include assessments of activities of daily living, mood, and adverse events. Data synthesis, risk of bias assessment, sensitivity and subgroup analyses, and TSA will be conducted with application of Review Manager, Stata, and TSA software. The quality of the evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation instrument. INPLASY registration number: INPLASY202190006 (https://inplasy.com/inplasy-2021-9-0006/). RESULTS: This study will confirm the clinical efficacy and safety of CHMs when used in the treatment of patients with MCI. CONCLUSION: This study will provide reliable evidence and references for the selection of CHMs in therapy and future clinical research of MCI.

Pingchan granule for depressive symptoms in parkinson's disease: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Depression in Parkinson's disease (dPD) is closely related to quality of life. Current studies have suggested that Pingchan Granule (PCG) might be effective for treating dPD. OBJECTIVE: This study determines the efficacy of PCG for depressive symptoms in Parkinson's disease (PD). DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This was a randomized, double-blind, placebo-controlled trial, conducted in Longhua Hospital, Shanghai, China. Patients diagnosed with idiopathic PD and clinically significant depressive symptoms (defined by a 24-item Hamilton Rating Scale for Depression [HAM-D] score ≥ 8) were included in this study, randomly assigned to PCG or placebo group in a 1:1 ratio and followed for 24 weeks. MAIN OUTCOME MEASURES: The primary outcome was the change from baseline to week 24 in HAM-D score among the set of patients who completed the study following the treatment protocol (per-protocol set). Secondary outcomes included changes in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) part 2 (UPDRS-II), UPDRS part 3 (UPDRS-III), Parkinson's Disease Sleep Scale (PDSS) and Hamilton Rating Scale for Anxiety (HAM-A), between baseline and week 24. RESULTS: Eighty-six patients were enrolled, and 85 patients were included in the per-protocol set. HAM-D scores decreased by an adjusted mean of 11.77 (standard error [SE] 0.25) in the PCG group and 3.86 (SE 0.25) in the placebo group (between-group difference = 7.91, 95% confidence interval [7.22, 8.80], P < 0.001), in the multivariable linear regression. Improvements in scores on the UPDRS-II, UPDRS-III, PDSS, and HAM-A scales were also observed. CONCLUSION: Treatment with PCG was well tolerated and improved depressive symptoms and motor and other non-motor symptoms in PD. TRIAL REGISTRATION: Chinese Clinical Trial Register: ChiCTR-INR-17011949.

Personalized prediction of depression in patients with newly diagnosed Parkinson's disease: A prospective cohort study.

BACKGROUND: Depressive disturbances in Parkinson's disease (dPD) have been identified as the most important determinant of quality of life in patients with Parkinson's disease (PD). Prediction models to triage patients at risk of depression early in the disease course are needed for prognosis and stratification of participants in clinical trials. METHODS: One machine learning algorithm called extreme gradient boosting (XGBoost) and the logistic regression technique were applied for the prediction of clinically significant depression (defined as The 15-item Geriatric Depression Scale [GDS-15] ≥ 5) using a prospective cohort study of 312 drug-naïve patients with newly diagnosed PD during 2-year follow-up from the Parkinson's Progression Markers Initiative (PPMI) database. Established models were assessed with out-of-sample validation and the whole sample was divided into training and testing samples by the ratio of 7:3. RESULTS: Both XGBoost model and logistic regression model achieved good discrimination and calibration. 2 PD-specific factors (age at onset, duration) and 4 nonspecific factors (baseline GDS-15 score, State Trait Anxiety Inventory [STAI] score, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire [RBDSQ] score, and history of depression) were identified as important predictors by two models. LIMITATIONS: Access to several variables was limited by database. CONCLUSIONS: In this longitudinal study, we developed promising tools to provide personalized estimates of depression in early PD and studied the relative contribution of PD-specific and nonspecific predictors, constituting a substantial addition to the current understanding of dPD.

Metabolic pattern analysis of 18F-FDG PET as a marker for Parkinson's disease: a systematic review and meta-analysis.

A large number of articles have assessed the diagnostic accuracy of the metabolic pattern analysis of [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in Parkinson's disease (PD); however, different studies involved small samples with various controls and methods, leading to discrepant conclusions. This study aims to consolidate the available observational studies and provide a comprehensive evaluation of the clinical utility of 18F-FDG PET for PD. The methods included a systematic literature search and a hierarchical summary receiver operating characteristic approach. Sensitivity analyses according to different pattern analysis methods (statistical parametric mapping versus scaled subprofile modeling/principal component analysis) and control population [healthy controls (HCs) versus atypical parkinsonian disorder (APD) patients] were performed to verify the consistency of the main results. Additional analyses for multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) were conducted. Fifteen studies comprising 1446 subjects (660 PD patients, 499 APD patients, and 287 HCs) were included. The overall diagnostic accuracy of 18F-FDG in differentiating PD from APDs and HCs was quite high, with a pooled sensitivity of 0.88 [95% confidence interval (95% CI), 0.85-0.91] and a pooled specificity of 0.92 (95% CI, 0.89-0.94), with sensitivity analyses indicating statistically consistent results. Additional analyses showed an overall sensitivity and specificity of 0.87 (95% CI, 0.76-0.94) and 0.93 (95% CI, 0.89-0.96) for MSA and 0.91 (95% CI, 0.78-0.95) and 0.96 (95% CI, 0.92-0.98) for PSP. Our study suggests that the metabolic pattern analysis of 18F-FDG PET has high diagnostic accuracy in the differential diagnosis of parkinsonian disorders.

Early Selective Serotonin Reuptake Inhibitors for Recovery after Stroke: A Meta-Analysis and Trial Sequential Analysis.

BACKGROUND: Potential benefits and risks of early (≤30 days from stroke onset) selective serotonin reuptake inhibitors (SSRIs) treatment for neurologic functional recovery after stroke are not fully understood. METHODS: We searched PubMed, Embase, and the Cochrane Library to identify randomized controlled trials that assessed SSRI medications during the initial ictus after stroke versus placebo. Primary outcome was decrease in National Institutes of Health Stroke Scale (NIHSS) score. Secondary outcomes included the improvement of Barthel index, functional independence (modified Rankin Scale score 0-2 at the end of follow-up), the incidence of depression, and adverse events including diarrhea, insomnia, hepatic enzyme disorders, seizure, and intracranial hemorrhage. We used fixed effects models or random effects models to estimate weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs) according to heterogeneity. RESULTS: Eight trials were included, with 1549 patients. Compared with placebo, decrease in NIHSS was greater in SSRI-treated patients (WMD, 0.82; 95% CI, 0.31-1.33; P = .002). Trial sequential analysis showed that the cumulative z curve crossed the trial sequential monitoring boundary for benefit, establishing sufficient and conclusive evidence. Early SSRI treatment also promoted Barthel index (WMD, 5.32; 95% CI, 1.65-8.99; P = .005) and functional independence (RR, 2.54; 95% CI, 1.82-3.55; P < .0001). There was no difference in the incidence of depression and adverse events between groups. No evidence of publication bias was detected. CONCLUSIONS: The early SSRIs treatment reduces the defective neurologic function in patients undergoing rehabilitation after stroke.