OBJECTIVE:This study aimed to investigate the characteristics and spectrum of cardiotoxicity induced by various antiparkinsonian drugs based on the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. METHODS:Data from the FAERS database from the first quarter of 2004 to the third quarter of 2025 were downloaded for disproportionality analysis. We employed validated disproportionality metrics including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS) to detect significant drug-event associations. RESULTS:After removing duplicates, a total of 42 583 cases of patients treated with antiparkinsonian drugs were included in the FAERS database. Dopamine receptor agonists exhibited the most extensive range of cardiac adverse events. Monoamine oxidase B inhibitors displayed the second broadest range of toxicity. As for catechol-O-methyltransferase inhibitors, a total of six signals were detected in entacapone. Four signals were detected for amantadine, while no signals were identified for levodopa. CONCLUSION:This study highlights the cardiovascular adverse reactions associated with Parkinson's treatment drugs. These findings underscore the importance of monitoring and evaluating the cardiovascular safety of antiparkinsonian medications.

BACKGROUND:Multiple sclerosis (MS) is a neuroimmunological disorder marked by demyelination and neuronal damage, significantly impacting young individuals' health and quality of life. Recent studies suggest a pivotal role of the gut microbiota and immune system in MS development, though the precise mechanisms remain unclear. METHODS:This study utilizes Mendelian randomization (MR) to explore the causal relationships between gut microbiota, immune traits, and MS. We conducted MR analysis using genetic data from 18,340 participants for gut microbiota, 3757 individuals for immune traits, and 47,429 MS cases alongside 68,374 controls. RESULTS:Our results suggested six microbial taxa with nominally significant associations to MS, with two taxa (Roseburia and Ruminococcus2) exhibiting putative mediating trends through specific immune cell phenotypes (CD28 on CD28+ CD4+ T cells and CD45 on HLA-DR+ CD8+ T cells). Mediation analysis demonstrated that 8.97% and 12.18% of the nominal effects of these taxa on MS were potentially mediated through the aforementioned immune traits, respectively. These results only represent exploratory trends and need to be interpreted with caution. CONCLUSION:These nominally significant exploratory findings provide hypothesis-generating clues that immune cell activation, particularly in CD4+ and CD8+ T cells, might be involved in the microbiota-MS relationship. These findings require validation in independent populations and experimental studies.

Background Progressive supranuclear palsy (PSP) is a rapidly advancing tauopathy, and amongst rapid eye movement (REM) sleep behavior disorder (RBD) has been observed. Prior studies were limited by small samples and inconsistent results; meanwhile, research is lacking since the updated criteria for PSP. This cross-sectional study aimed to assess RBD in a sizable PSP cohort. Methods Participants were consecutively recruited from the movement disorders specialty at West China Hospital between January 2019 and January 2021, adhering to established inclusion and exclusion criteria. We collected and analyzed clinical characteristics, scale assessments, and polysomnographic data to determine the prevalence and correlated factors of RBD in patients with PSP. Results The initial cohort comprised 153 PSP patients, with a median age of 68 years and 61.4 % male. Possible RBD (pRBD) was identified in 43 individuals (28.1 %; assessed by scale), who experienced more constipation, hyposmia, fatigue, drank less, and showed poorer cognition. Multivariate analysis indicated an inverse relationship between alcohol intake and pRBD, whereas constipation was positively linked to pRBD. Eighty-six PSP patients and 24 matched controls underwent polysomnography. Patients with PSP displayed more sleep disruption. Among them, 24 (27.9 %) were eventually diagnosed with RBD. No significant differences in sleep parameters, except for REM sleep without atonia, were found between the RBD and non-RBD groups. Patients with RBD reported increased constipation, fatigue, and overall non-motor symptoms. Similarly, constipation was positively associated with RBD. Conclusion Approximately 28 % of PSP patients have comorbid RBD, which correlates with various non-motor symptoms, particularly constipation. Further research is needed to elucidate the interaction of these disorders.

Background Observational studies indicate a complex relationship between coagulation factors and Alzheimer's disease (AD). However, the current findings are inconsistent, and it remains uncertain whether a causal relationship exists. Objective This study utilizes a Mendelian randomization analysis to investigate the causal relationships between blood levels of coagulation factors and AD risk. Methods Eleven coagulation factors with valid instrumental variables available were evaluated. Two independent cohorts of European ancestry with AD genome-wide association study (GWAS) summary statistics were used: UK Biobank (UKB, N = 472,868) and the International Genomics of Alzheimer's Project (IGAP, N = 63,926). We primarily conducted Mendelian randomization (MR) analyses using the Inverse variance weighted (IVW). Meanwhile, the MR-Egger intercept test is used to detect horizontal pleiotropy, the Residual Sum of Squares observed (RSSobs) is used to assess the model's goodness of fit, and the leave-one-out analysis is employed for sensitivity analysis. Results Using IVW analysis, the UKB database shows positive correlations of Protein C (PC, p = 0.002), Activated Partial Thromboplastin Time (aPTT, p = 0.019), and coagulation factor X (FX, p = 0.032) with AD, and a negative association for coagulation factor XI (FXI, p = 0.021). The IGAP database mirrors these findings for PC and FXI but not for the others. Leave-one-out analysis showed an anomaly after a single single nucleotide polymorphism (SNP) driving, yet the overall results remained stable. Conclusions This study demonstrates that elevated levels of PC, FX, and aPTT, along with reduced levels of FXI, are causally associated with an increased risk of AD. These findings might pave the way for the diagnosis and treatment of AD.

The correlation between asthma and frailty is increasingly garnering attention. The association between asthma and frailty remains inconclusive in observational studies, and the causality of this relationship still needs to be established. Therefore, we employed two-sample Mendelian randomization analyses using genetic instruments to determine the causal association of asthma on frailty. Two-sample Mendelian randomization (MR) analyses were performed to assess the causal effect of asthma on frailty. The genetic variants strongly associated with asthma (P < 5E-08) during the discovery and replication stages were derived from a recent meta-analysis of genome-wide association studies (GWAS) (N = 408,442) in the UK Biobank and a GWAS in the FinnGen Consortium (N = 217,421), respectively. Summary statistics of the frailty index (N = 175,226) are derived from the latest released GWAS dataset on frailty index. The inverse variance weighted (IVW) method was employed as the primary approach for calculating estimated values, with additional sensitivity analyses and heterogeneity analyses utilized to further validate the results. Using the IVW method, genetic susceptibility to asthma was associated with an increased risk of frailty in the discovery stage (odds ratio [OR] = 1.092, 95

: Fibrosis, caused by excessive production and deposition as well as reduction of the extracellular matrix, is a common occurrence during aging of many substantial organs. Under a pathological state, fibrosis can cause damage to organ structure and function, thereby resulting in organ failure in severe cases. Since 2012, advancement of high-throughput technology has led to exploration of many circular RNAs (circRNAs). These competitive endogenous RNAs play a complicated but crucial role in various processes of cell signal transduction and human diseases. To date, numerous researches have shown that circRNAs can either inhibit or promote fibrosis in many organs, including the heart, kidney, lung, and liver. In this review, we systematically review the current progress for the role of circRNA in fibrosis, with the aim of providing a theoretical basis for future development of targeted therapies against the disease.

PurposeA few observational studies have indicated that Parkinson’s disease (PD) risk may be higher in those with hearing loss, but the two’s causal relationship is yet unknown. Using Mendelian randomization (MR) methods, this study sought to explore the causal link between hearing loss and the risk of PD.MethodsWe identified single nucleotide polymorphisms (SNPs) linked to hearing loss (P-value<5E-08) in a genome-wide association study (GWAS) included 323,978 people from the UK Biobank. The summary data for PD in the discovery group came from a GWAS meta-analysis of 33,647 cases and 449,056 healthy participants of European descent. Using summary data from the aforementioned GWAS of PD (N=33,647) and hearing loss (N=323,978), we carried out a two-sample MR study. As validation groups, two separate PD GWAS studies were used. Inverse variance weighting (IVW) was utilized in the principal MR analysis. For our findings to be reliable, further analyses were carried out with the Cochran’s Q test, MR-Egger intercept, and leave-one-out analysis. In addition, we assessed the causal link between various forms of hearing loss and PD using the IVW approach.ResultsTwenty-two SNPs with genome-wide significance linked to hearing loss were used as instrumental factors. In the discovery dataset, we failed to detect a causal relationship between hearing loss and PD (OR=1.297; 95% CI=0.420-4.007; P-value=0.651). The findings of other methods agreed with the IVW method. The results were robust under sensitivity analyses. Furthermore, the above findings were confirmed in two validation PD datasets. Additionally, no causal correlation was found between genetic prediction of four different types of hearing loss and PD (conductive hearing loss, IVW: OR=1.058, 95%CI=0.988-1.133, P-value=0.108; sudden idiopathic hearing loss, IVW: OR=0.936, 95%CI=0.863-1.016, P-value=0.113; mixed conductive and sensorineural hearing loss, IVW: OR=0.963, 95%CI=0.878-1.058, P-value=0.436; sensorineural hearing loss, IVW: OR=1.050, 95%CI=0.948-1.161, P-value=0.354).ConclusionIn those of European heritage, our investigation revealed no causal link between hearing loss and PD risk.

This study aimed to identify potential markers that can predict Parkinson’s disease with mild cognitive impairment (PDMCI). We retrospectively collected general demographic data, clinically relevant scales, plasma samples, and neuroimaging data (T1-weighted magnetic resonance imaging (MRI) data as well as resting-state functional MRI [Rs-fMRI] data) from 173 individuals. Subsequently, based on the aforementioned multimodal indices, a support vector machine was employed to investigate the machine learning (ML) classification of PD patients with normal cognition (PDNC) and PDMCI. The performance of 29 classifiers was assessed based on various combinations of indicators. Results demonstrated that the optimal classifier in the validation set was composed by clinical + Rs-fMRI+ neurofilament light chain, exhibiting a mean Accuracy of 0.762, a mean area under curve of 0.840, a mean sensitivity of 0.745, along with a mean specificity of 0.783. The ML algorithm based on multimodal data demonstrated enhanced discriminative ability between PDNC and PDMCI patients.

The correlation between air pollution and neurodegenerative diseases has garnered growing attention. Although observational studies have indicated a potential link between air pollution and neurodegenerative disease, establishing a causal relationship remains uncertain. To address this gap, we performed a two-sample Mendelian randomization analysis utilizing genetic instruments. This analysis aimed to investigate the causal connections between PM2.5, PM10, NO2, and NOX exposure and the occurrence of Parkinson’s disease (PD) and Alzheimer’s disease (AD). We implemented a series of filtering steps to identify suitable genetic instruments that demonstrated significant associations (P < 5 × 10−8) with PM2.5, PM10, NO2, and NOX. These instruments were derived from a comprehensive genome-wide association study (GWAS) encompassing up to 456,380 participants in the UK Biobank. To obtain summary statistics for PD (N = 482,730) and AD risk (N = 63,926), we utilized the most recent GWAS datasets available. For our primary analysis, we employed the inverse-variance weighted approach for two-sample MR. A multivariable MR (MVMR) was also performed to verify the impact of air pollution exposure on the risk of PD and AD. To ensure the robustness of our findings, sensitivity analyses and heterogeneity assessments were performed. In two-sample MR, by employing the inverse-variance weighted method, our result suggested that genetically NO2 exposure showed a significant association with an elevated risk of PD (OR = 4.07, 95

Background:Diabetes mellitus (DM) is associated with different clinical complications. The aim of this study was to explore the prevalence of RLS in people with diabetes mellitus and compare the risk of restless leg syndrome (RLS) between diabetic and non-diabetic population. Methods:We searched for studies of RLS prevalence in DM through PubMed, Embase, and Web of Science. Two authors independently completed the literature screening, data extraction, and bias risk assessment of eligible studies. All observational studies that assessed the prevalence or risk of RLS in DM were included, where the diagnosis of RLS was based on the International Restless Legs Syndrome Study Group (IRLSSG). Percentages, odds ratio (OR) with 95% confidence intervals (CI) were used to assess pooled estimates of RLS prevalence and risk based on random-effects models. Newcastle-Ottawa-scale (NOS) or a modified NOS were used to evaluate the quality of studies. Findings:A total of 42 studies, including 835,986 participants, met the eligibility criteria for the meta-analysis. Among them, 30 studies were included in meta-analysis to analyze the prevalence of RLS. A second meta-analysis was conducted using 31 studies to determine RLS risk between diabetes and non-diabetes. The results indicate that between 25% (95% confidence interval 21%-29%) of people with diabetes showed signs of RLS, and people with diabetes had an increased risk of developing RLS compare to people without diabetes (OR 1.98, 95%CI 1.66- 2.34, p < 0.001). However, the available evidence was limited due to potential risk of bias and variability between studies (I2 >75%), all of observational design. Interpretation:Our study suggests that the prevalence and risk of RLS might be higher in DM patients than in non-diabetes population. However, given limitations in the analysis and study design, the findings need to be corroborated in future studies. Funding:This work was supported by the Basic Conditions Platform Construction Project of Sichuan Science and Technology Department (2019JDPT0015), and the "1・3・5 project for disciplines of excellence, West China Hospital, Sichuan University" (ZYJC18003).

Alzheimer's disease (AD) is the most common neurodegenerative disease, which results in dementia typically in the elderly. The disease is mainly characterized by the deposition of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. However, only few drugs are available for AD because of its unknown pathological mechanism which limits the development of new drugs. Therefore, it is urgent to identify potential therapeutic strategies for AD. Moreover, research have showed that there is a significant association between Type 2 diabetes mellites (T2DM) and AD, suggesting that the two diseases may share common pathophysiological mechanisms. Such mechanisms include impaired insulin signaling, altered glucose metabolism, inflammation, oxidative stress, and premature aging, which strongly affect cognitive function and increased risk of dementia. Consequently, as a widely used drug for T2DM, metformin also has therapeutic potential for AD in vivo. It has been confirmed that metformin is beneficial on the brain of AD animal models. The mechanisms underlying the effects of metformin in Alzheimer's disease are complex and multifaceted. Metformin may work through mechanisms involving homeostasis of glucose metabolism, decrease of amyloid plaque deposition, normalization of tau protein phosphorylation and enhancement of autophagy. However, in clinical trials, metformin had little effects on patients with mild cognitive impairment or mild AD. Pathological effects and negative clinical results of metformin on AD make the current topic quite controversial. By reviewing the latest progress of related research, this paper summarizes the possible role of metformin in AD. The purpose of this study is not only to determine the potential treatment of AD, but also other related neurodegenerative diseases.

Objective To investigate the prevalence of, and clinicodemographic factors associated with, frailty and sarcopenia in patients with multiple system atrophy or progressive supranuclear palsy. Methods A total of 264 participants were recruited in this study. Demographic and clinical data were collected through structured interviews. Frailty was assessed with the clinical frailty scale (CFS), and sarcopenia was assessed with the simple five-item scoring questionnaire (SARC-F). Results The prevalence of frailty and sarcopenia was 48.57% and 35.71% in multiple system atrophy, and 51.09% and 39.13% in progressive supranuclear palsy. Multiple system atrophy patients with frailty or sarcopenia were more likely to be female and have longer disease duration, greater motor impairment, greater non-motor burden, and lower life quality. In multiple system atrophy, frailty was associated with reduced motor function and sarcopenia was associated with female sex, reduced motor function, and orthostatic hypotension. Progressive supranuclear palsy patients with frailty or sarcopenia had more severe motor impairment and non-motor burden, longer disease duration, and lower life quality. In progressive supranuclear palsy, frailty was associated with mentation and gait/midline symptoms, while sarcopenia was associated with reduced daily activity and severe gait/midline symptoms. Conclusion Frailty and sarcopenia may be more common among patients with multiple system atrophy or progressive supranuclear palsy than among the general population, and they are associated with more severe forms of the two diseases. Prospective studies are necessary to clarify causal relationships between frailty/sarcopenia and clinical manifestations of multiple system atrophy and progressive supranuclear palsy.

Background: Parkinson’s disease (PD) is associated with coiled-coil-helix-coiled-coilhelix domain containing 2 (CHCHD2) downregulation, which has been linked to reduced cyclocytase activity and increased levels of oxygen free radicals, leading to mitochondrial fragmentation and apoptosis. Little is known about how CHCHD2 normally functions in the cell and, therefore, how its downregulation may contribute to PD. Objective: This study aimed to identify such target genes using chromatin immunoprecipitation sequencing from SH-SY5Y human neuroblastoma cells treated with neurotoxin 1-methyl-4- phenylpyridinium (MPP+) as a PD model. Methods: In this study, we established a MPP+ -related SH-SY5Y cell model and evaluated the effects of CHCHD2 overexpression on cell proliferation and apoptosis. At the same time, we used high-throughput chromatin immunoprecipitation sequencing to identify its downstream target gene in SH-SY5Y cells. In addition, we verified the possible downstream target genes and discussed their mechanisms. Results: The expression level of α-synuclein increased in SH-SY5Y cells treated with MPP+, while the protein expression level of CHCHD2 decreased significantly, especially after 24 h of treatment. Chip-IP results showed that CHCHD2 might regulate potential target genes such as HDX, ACP1, RAVER2, C1orf229, RN7SL130, GNPTG, erythroid 2 Like 2 (NFE2L2), required for cell differentiation 1 homologue (RQCD1), solute carrier family 5 member 7 (SLA5A7), and NAcetyltransferase 8 Like (NAT8L). NFE2L2 and RQCD1 were validated as targets using PCR and western blotting of immunoprecipitates, and these two genes together with SLA5A7 and NAT8L were upregulated in SH-SY5Y cells overexpressing CHCHD2. Downregulation of CHCHD2 may contribute to PD by leading to inadequate expression of NFE2L2 and RQCD1 as well as, potentially, SLA5A7 and NAT8L. Conclusion: Our results suggest that CHCHD2 plays a protective role by maintaining mitochondrial homeostasis and promoting proliferation in neurons. In this study, the changes of CHCHD2 and downstream target genes such as NFE2L2/RQCD1 may have potential application prospects in the future. These findings provide leads to explore PD pathogenesis and potential treatments.

Background: Recent studies have reported an association between PPP2R5D mutations and early-onset levodopa-responsive parkinsonism, but this gene has yet to be analyzed comprehensively in a large Parkinson's disease (PD) cohort. Objective: The aim of this study was to examine the frequency and spectrum of PPP2R5D mutations in a Han Chinese cohort with early- or late-onset PD. Methods: The 5'- and 3'-untranslated regions as well as coding sequence of the PPP2R5D gene were sequenced in 668 patients with sporadic PD. Novel variants were detected and validated based on genomic databases, as well as verified using genetic data from unrelated controls. Sanger sequencing was used to confirm rare mutations found by next-generation sequencing. Results: Two of the 145 EOPD patients carried two novel, unique PPP2R5D exonic variants (p.R91S,p.R523L), while none was detected in late-onset Parkinson's disease (LOPD). Two variants were predicted to be "disease-causing" by Mutation Taster, and both mutations were found to be highly conserved across species. Conclusion: Our study identified two rare PPP2R5D variants among Han Chinese EOPD patients, which broadens the spectrum of PPP2R5D mutations potentially associated with the disease.

BACKGROUND:As one of the widely used drugs for the management of type 2 diabetes mellites (T2DM), metformin is increasingly believed to delay cognitive deterioration and therapeutically for Alzheimer's disease (AD) patients especially those with T2DM. However, studies of the potential neuroprotective effects of metformin in AD patients have reported contradictory results.OBJECTIVE:This study aimed to evaluate the association between metformin and the risk of developing AD.METHODS:We systematically searched the PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases to identify clinical observational studies on the relationship between AD risk and metformin use published before December 20, 2021. Two investigators independently screened records, extracted data, and assessed the quality of the studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using random-effect models.RESULTS:After screening a total of 1,670 records, we included 10 studies involving 229,110 participants. The meta-analysis showed no significant association between AD incidence and metformin exposure (OR 1.17, 95% CI 0.88-1.56, p = 0.291). However, subgroup analysis showed that among Asians, the risk of AD was significantly higher among metformin users than those who did not (OR 1.71, 95% CI 1.24-2.37, p = 0.001).CONCLUSION:The available evidence does not support the idea that metformin reduces risk of AD, and it may, in fact, increase the risk in Asians. Further well-designed randomized controlled trials are required to understand the role played by metformin and other antidiabetic drugs in the prevention of AD and other neurodegenerative diseases.

Freezing of gait (FOG) is a common and complex disabling episodic gait disturbance in patients with Parkinson's disease (PD). Currently, the treatment of FOG remains a challenge for clinicians. The aim of our study was to develop a nomogram for FOG risk based on data collected from Chinese patients with PD. A total of 379 PD patients (197 with FOG) from Kunming Medical University were recruited as a training cohort. Additionally, 339 PD patients (166 with FOG) were recruited from West China Hospital of Sichuan University, to serve as the validation cohort. The least absolute shrinkage and selection operator regression model was used to select clinical and demographic characteristics as well as blood markers, which were incorporated into a predictive model using multivariate logistic regression to predict the risk of developing FOG. The model was validated using the validation dataset, and model performance was evaluated using the C-index, calibration plot, and decision curve analyses. The final predictive model included the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) score, Parkinson's Disease Questionnaire (PDQ39), H-Y stage, and visuospatial function. The model showed good calibration and good discrimination, with a C-index value of 0.772 against the training cohort and 0.766 against the validation cohort. Decision curve analysis demonstrated the clinical utility of the nomogram. A nomogram incorporating RBDSQ, PDQ39, H-Y stage, and visuospatial function may reliably predict the risk of FOG in PD patients.

Recent studies have reported an association between PPP2R5D mutations and early-onset levodopa-responsive parkinsonism. However, there was lack of comprehensive analysis of this gene in large Parkinson’s disease(PD) cohort.The aim of this study was to examine the frequency and spectrum of PPP2R5D mutations in a Han Chinese cohort with early- or late-onset PD. We sequenced all 17 exons of PPP2R5D and their flanking intron regions in 668 sporadic PD patients. Novel variants detected were validated based on genomic databases and verified using genetic data from unrelated controls. Three of the 668 PD patients carried three novel, unique PPP2R5D exonic variants(p.R91S,p.E8A,p.R523L).These variants were predicted to be “disease- causing” by mutation taster and all three mutations were found to be highly conserved across species. Our study identified three novel, rare PPP2R5D variants among Han Chinese PD patients, which broadens the spectrum of PPP2R5D mutations potentially associated with the disease.

Purpose Up to 20–30% of patients with Guillain-Barré syndrome (GBS) suffer serious clinical manifestations such as respiratory failure. We aim to determine whether two new prognostic biomarkers, the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), could reliably predict respiratory failure in GBS.we Materials and methods Data from 426 patients diagnosed at our center with GBS between January 2015 and July 2019 were retrospectively analyzed. Data were collected from the hospital database. Logistic regression and receiver operating characteristic curves were used to examine whether NLR alone, PLR alone or the combination, as measured at admission, could predict respiratory failure during hospitalization. Nomograms for predicting respiratory failure in GBS individuals were established, and predictive accuracy was evaluated using Harrell's concordance index (C-index). Results A total of 74 (17%) patients developed respiratory failure during hospitalization, and this was predicted independently by neutrophil count, NLR, PLR, and a combined "NLR-PLR" index, with the combined index performing best. The C-index of nomograms was 0.952 (95%CI 0.930–0.974) when NLR-PLR was included, or 0.933 (95%CI 0.911–0.955) when it was excluded. Conclusions The prognostic biomarkers NLR and PLR may be independent predictors of respiratory failure in GBS. Combining the two indices may be more effective than either one on its own.