Myasthenia gravis (MG) is an autoimmune disorder characterized by B cell dysfunction. Here, we designed B cell maturation antigen (BCMA)/CD19 chimeric antigen receptor T cell (CAR T cell) therapy for six refractory MGs, demonstrating favorable safety with grade 1 cytokine release syndrome observed. CAR T cell expansion induced profound B cell depletion, a sustained reduction in acetylcholine receptor (AChR) antibody titers, and symptom improvement. Five patients achieved drug-free remission with minimal manifestations by month 6, persisting through the 12-month follow-up despite B cell reconstitution. Reconstituted B cells showed naïve predominance with diminished AChR specificity and functional capacities. Olink proteomics revealed up-regulation of anti-inflammatory factors, along with down-regulation of proinflammatory molecules. Single-cell sequencing revealed that age-associated B cells (ABCs) were up-regulated in a relapsed patient, and differential gene analysis indicated that Fc receptor-like 5 (FCRL5) expression was elevated in ABCs, whereas CAR T cell responders exhibited a down-regulated trend. Notably, similar ABC expansion and FCRL5 up-regulation occurred in rituximab-relapsed patients. Our findings support BCMA/CD19 CAR T cell therapy as feasible, tolerable, and effective in MG, identifying FCRL5 as a previously unidentified target in relapse.

ObjectiveTo develop and validate a multimodal machine learning model to predict postoperative worsening of freezing of gait questionnaire (FOGQ) scores in patients with Parkinson’s disease (PD) undergoing subthalamic nucleus deep brain stimulation (STN-DBS).MethodsThis retrospective study analyzed data from 134 patients with PD who underwent bilateral STN-DBS. The model integrated four data modalities: clinical scale assessments, structural neuroimaging features derived from voxel-based morphometry (VBM), stereotactic electrode localization data via Lead-DBS analysis, and radiomics features extracted from preoperative MRI. Following standardization, feature selection was conducted using LASSO, Boruta and recursive feature elimination with cross-validation (RFECV) methods to identify the most relevant predictors. Multiple machine learning algorithms were evaluated. Model development and internal validation were conducted using a 5-fold nested cross-validation framework. Model performance was assessed using ROC curves, calibration curves, and decision curve analysis, and model interpretability was analyzed using SHAP values.ResultsThe LightGBM model achieved the highest AUC of 0.917 for predicting FOGQ deterioration. The analysis emphasized the importance of multimodal data integration, combining clinical, structural, and radiomic features to enhance predictive accuracy.ConclusionThis multimodal LightGBM model achieved robust discrimination between patients with and without postoperative FOGQ deterioration, highlighting the value of integrating clinical, structural, and radiomic features for preoperative risk stratification in PD patients undergoing STN-DBS. These findings may inform personalized patient selection, early identification of high-risk individuals, and treatment planning, though external validation in prospective multicenter cohorts remains a necessary next step.

Vascular parkinsonism (VP) and the postural instability and gait difficulty (PIGD) subtype of Parkinson’s disease (PD) exhibit similar gait characteristics. However, most research emphasizes lower-limb gait parameters, often neglecting the role of cognitive function in gait regulation. Therefore, this study investigates differences in cognitive-motor interactions between VP and PIGD to identifying specific gait biomarkers and develop a diagnostic model. We recruited 37 PIGD patients and 37 VP patients between year 2022 to 2024 and used wearable devices to record gait parameters during single-task and dual-task paradigms. Demographic and clinical data were collected from all participants. Statistical analysis was conducted using R software with P < 0.05 as statistically significance. Multiple gait parameters significantly difference between VP and PIGD groups under both single-task and dual-task paradigms. In both single-task and dual-task gait comparisons, significant differences were observed between VP and PIGD in walk speed, shank swing speed, gait speed, phase coordination index (PCI), and trunk sway maximum (P < 0.05). Corresponding dual-task costs (DTC) also showed significant differences (P < 0.05). ROC curve analysis indicated a good diagnostic performance when combining multiple gait parameters and their DTC with MoCA scores (AUC 0.838, 95

IntroductionFreezing of gait (FOG) in Parkinson’s disease (PD) patients is a critical determinant of motor impairment and fall risk. Rhythmic auditory stimulation (RAS) has been shown to ameliorate FOG symptoms, although the underlying neurophysiological mechanisms are not fully understood.ObjectivesThis research employed functional near-infrared spectroscopy (fNIRS) to analyze three RAS—two external auditory cueing strategies (beat perception and music therapy) and one internal cueing method (mental beat imagery)—to examine gait parameters and cortical activation patterns in Parkinson’s disease patients with freezing of gait (PD + FOG) compared to healthy controls (HC). The study also sought to evaluate the therapeutic effectiveness of these rhythm-based interventions in alleviating FOG episodes.MethodsTwenty-eight patients with PD + FOG and twenty-eight age-matched HC were enrolled in the study. Gait analysis was performed during narrow corridor ambulation, designed to induce freezing episodes, and during straight-line walking in an open environment. fNIRS was employed to measure fluctuations in oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (HHb) concentrations, serving as indicators of cortical activation. Regions of interest (ROIs) included the prefrontal cortex (PFC), premotor cortex (PMC), and temporal cortex (TLC). Intracortical functional connectivity during each locomotor task was evaluated through correlation analyses of HbO2 signals between the ROIs.ResultsPD + FOG patients exhibited gait disturbances characterized by reduced gait velocity and stride length, along with increased mediolateral postural sway during freezing episodes. Neuroimaging indicated significantly decreased activation in the primary somatosensory cortex (S1), PMC, and PFC compared to healthy controls, despite elevated intracortical connectivity involving indirect corticospinal pathways. Differential responses to RAS interventions were noted: rhythmic auditory cues enhanced connectivity between TLC and PMC; music therapy significantly improved PFC intrinsic connectivity; whereas imagined auditory cues potentially impaired sensorimotor integration due to excessive reliance on internal cognitive mechanisms.ConclusionVarious RAS pathways can ameliorate freezing of gait symptoms by selectively modulating functional connectivity between the prefrontal cortex and sensorimotor circuits. The underlying neural mechanisms may largely involve neural entrainment and reorganization of brain networks. These results offer vital empirical insights into the pathophysiology of gait freezing and provide a preliminary theoretical basis for designing precision neuromodulation interventions.

Ischemic stroke causes severe neurological disability, with some patients still presenting with residual neurological dysfunction. Aerobic exercise shows potential for post-stroke recovery. However, the mechanism behind its beneficial effects on the brain remains to be further explored. This study aimed to explore aerobic exercise’s role in the neurological recovery of ischemic stroke mice and to clarify the specific protective mechanisms involved. A mouse model of ischemic stroke was employed in this study. Mice were subjected to aerobic exercise intervention, with additional exogenous lactate administration and RNA-sequencing (RNA-seq) analysis conducted to explore the molecular mechanisms. Results demonstrated that aerobic exercise significantly elevated protein lactylation levels in ischemic stroke mice and facilitated neurological recovery. In addition, aerobic exercise attenuated neuroinflammation in the ischemic penumbra and promoted neural cell proliferation in the subventricular zone. Mechanistically, aerobic exercise-induced lactylation of α-tubulin may enhance the dynamic properties of microtubules, thereby facilitating neural repair. Exogenous lactate intervention was found to augment α-tubulin lactylation, promote hippocampal neurogenesis, and increase dendritic spine density as well as synaptic plasticity in both the ischemic penumbra and hippocampus. Consistent with these findings, exogenous lactate administration improved neurological function in ischemic stroke mice. RNA-seq analysis further revealed that elevated lactate levels exerted a promotive effect on neural repair. Aerobic exercise promotes post-ischemic stroke neurological recovery via elevating protein lactylation (α-tubulin lactylation), attenuating neuroinflammation, and enhancing neural repair. These findings highlight the potential of targeting lactate metabolism and protein lactylation as therapeutic strategies for facilitating neural repair and improving neurological outcomes following ischemic stroke.

Introduction:External cue interventions can effectively improve gait disturbances in patients with Parkinson's Disease (PD) and Freezing of Gait (FOG). However, the cortical mechanisms underlying cueing modulation of gait have rarely been investigated. Objectives:We aimed to compare gait performance and cerebral hemodynamic responses in patients with PD and FOG (PD-FOG) under different cueing interventions, and to further elucidate the neural mechanisms underlying the effects of different cues on gait by contrasting these findings with those of Healthy Controls (HCs). Methods:Twenty-eight PD-FOG patients and 28 HCs were enrolled. Gait parameters were measured during the walking experiment under Rhythmic Visual Cue (RVC) and Rhythmic Auditory Cue (RAC) to compare how these cues affect gait. Functional Near-infrared Spectroscopy (fNIRS) was employed to measure changes in oxyhemoglobin concentration (∆HbO2). Additionally, inter-channel connectivity strength was calculated to evaluate Functional Connectivity (FC) across various Regions of Interest (ROIs). Results:PD-FOG patients exhibit features including decreased gait velocity and stride length during freezing episodes. Both RVC and RAC enhance gait velocity and stride length. Conversely, the combined RVC and RAC (RVC + RAC) intervention did not produce meaningful changes in gait. Compared to HCs, PD-FOG patients show significantly lower ∆HbO2 in the Prefrontal Cortex (PFC) and Primary Somatosensory Cortex (S1). Both RVC and RAC interventions increase ∆HbO2 in the PFC and S1 in PD-FOG patients, whereas the RVC + RAC intervention decreases ∆HbO2 in the Premotor Cortex (PMC). Furthermore, compared with HCs, PD-FOG patients show increased FC between the S1-PFC and Primary Motor Cortex (M1)-PFC. The RVC intervention enhances FC within the PFC and between the PMC and the Visual Association Cortex (V2). The RAC intervention strengthens FC within the PFC and the PFC-Middle Temporal Gyrus (MTG). The RVC + RAC intervention increases FC within the PFC-MTG and PFC-PMC, partially compensating for functional deficits associated with cortical hypoactivation by enhancing connectivity among these ROIs. Conclusion:Single visual or auditory cues can improve FOG symptoms. RVC and RAC alleviate FOG by modulating cortical activation and enhancing FC between key ROIs. The heightened connectivity among these ROIs may represent the underlying neural pathway that mediates the cue-induced alleviation of FOG.

Recent studies have identified persistent immune inflammation as the third core pathological change in Alzheimer’s disease (AD). Progesterone receptor membrane component 2 (PGRMC2) is a member of the membrane-associated progesterone receptor family. This study aimed to investigate the effects of the expression of PGRMC2 in astrocytes in an AD mouse model. PGRMC2 overexpression in astrocytes was induced in male APPswe/PSEN1dE9 transgenic (AD) mice and C57BL/6J wild-type mice via an adeno-associated virus vector. The Morris water maze and Y-maze tests were used to evaluate spatial learning, spatial memory, and working memory. Cortical thickness and hippocampal volume were evaluated via brain MRI scans. Protein and mRNA levels were analyzed using Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques. PGRMC2 expression was significantly elevated in astrocytes in the AD mouse brain tissue. Learning and memory improved, brain atrophy was alleviated, and neuronal loss was reduced, but Aβ1–42 deposition was unaffected. These changes correlated with alterations in NF-κB signaling and shifts in astrocyte phenotypes, including reduced A1 activation and enhanced A2 polarization. PGRMC2 overexpression in astrocytes exerts neuroprotective effects on AD mice by altering astrocyte polarization and inflammatory responses; however, the present study does not establish causality in vivo.

Autoantibody- and complement-mediated cytotoxicity can cause autoimmune astrocytopathy that leads to CNS inflammatory demyelination. Formyl peptide receptor 2 (FPR2/ALX) governs the activation and propagation of immune response. However, the precise role of FPR2/ALX in neuroinflammation and the effect of FPR2/ALX stimulation on autoimmune astrocytopathy are poorly understood. Using a mouse model of autoimmune astrocytopathy induced by AQP4-IgG- and complement-mediated cytotoxicity, we found that the stimulation of FPR2/ALX with the small-molecule agonist Quin-C1 led to reduced brain lesion volume, astrocyte loss and demyelination. This was accompanied by enhanced anti-inflammatory activity of microglia and reduced infiltration of lymphocytes in the brain. FPR2/ALX stimulation also led to increased phosphorylation of SYK and AKT in mice with autoimmune astrocytopathy. Notably, the benefits of FPR2/ALX stimulation were attenuated in mice with autoimmune astrocytopathy after microglial depletion using the CSF1R inhibitor PLX5622 or natural killer (NK) cell depletion using an anti-NK1.1 monoclonal antibody. Additionally, the protective effects of FPR2/ALX stimulation were diminished in mice with autoimmune astrocytopathy that received the SYK inhibitor R406. Collectively, our findings demonstrate that FPR2/ALX stimulation may represent a promising therapeutic strategy to attenuate detrimental neuroinflammation in autoimmune astrocytopathy by modulating microglia and NK cells. FPR2/ALX stimulation suppresses autoimmune astrocytopathy: Using a mouse model of autoimmune astrocytopathy, we demonstrated that FPR2/ALX stimulation with the small molecule Quin-C1 reduces the CNS infiltration of lymphocytes and augments the anti-inflammatory activity of microglia, leading to attenuated astrocyte pathology induced by AQP4-IgG and complement-mediated attacks. Mechanistically, the benefits of FPR2/ALX stimulation using Quin-C1 involve microglia, natural killer (NK) cells, and SYK-AKT signaling.

Objective To investigate the differences in small nerve fiber damage between Parkinson's disease(PD)patients with and without rapid eye movement sleep behavior disorder(RBD),and to explore the correlation between corneal nerve parameters and the severity of RBD as well as clinical symptoms.Methods This study enrolled patients with PD who were admitted to The Affiliated Hospital of Xuzhou Medical University,from March to August 2022.Twenty-five age-and sex-matched healthy controls were also recruited during the same period as the healthy control group.Corneal confocal microscopy(CCM)was used to assess corneal small nerve fiber damage,including corneal nerve fiber density(CNFD),corneal nerve branch density(CNBD)and corneal nerve fiber length(CNFL).The Rapid Eye Movement Sleep Behavior Disorder Questionnaire-Hong Kong(RBDQ-HK)was employed to evaluate RBD symptom severity in PD patients.Autonomic function was assessed using the Scales for Outcomes in Parkinson's Disease-Autonomic(SCOPA-AUT),olfactory function using the 16-Item Sniffin Sticks Odor Identification Test(SS-16),and motor symptoms using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Ⅲ(MDS-UPDRS Ⅲ).Spearman rank correlation analysis and partial correlation analysis were performed to examine the associations between corneal nerve parameters and clinical scales.Multiple linear regression was used to evaluate the effects of CNFD and SCOPA-AUT score on RBDQ-HK score.Receiver operating characteristic(ROC)curves were constructed,the area under the curve(AUC)was calculated,and Delong test was used to assess the predictive performance of each indicator for PD with RBD.Results CCM showed statistically significant differences among the healthy control,PD-RBD,and PD-non RBD groups in CNFD(F=14.607,P=0.000),CNBD(H=17.749,P=0.000)and CNFL(F=11.988,P=0.000),respectively.Post-hoc pairwise comparisons revealed that the healthy control group had higher CNFD,CNBD,and CNFL values than both the PD-RBD group(t=5.397,P=0.000;Z=-4.123,P=0.000;t=4.873,P=0.000,respectively)and the PD-non RBD group(t=2.894,P=0.005;Z=-3.145,P=0.006;t=2.798,P=0.007,respectively).Moreover,the PD-non RBD group had significantly higher CNFD than the PD-RBD group(t=2.178,P=0.033).Partial correlation analysis showed that after controlling for SCOPA-AUT score,CNFD was negatively correlated with RBDQ-HK score(r=-0.291,P=0.045);after controlling for CNFD,SCOPA-AUT score was positively correlated with RBDQ-HK score(r=0.459,P=0.010).Multiple linear regression analysis showed that both CNFD(R2=0.284,P=0.045)andSCOPA-AUT score(R2=0.284,P=0.001)were associated with RBDQ-HK score.ROC curves analysis revealed that the AUC for CNFD alone was 0.689,for SCOPA-AUT alone was 0.701,and for the combined indicator(CNFD combined with SCOPA-AUT)was 0.766.Delong test indicated no statistically significant differences among the three AUCs(P>0.05,for all).Conclusions PD patients with RBD have more severe corneal small nerve fiber damage,and the degree of injury is positively correlated with the severity of RBD symptoms.PD with RBD may be a subtype with more prominent peripheral nerve involvement.

Parkinson’s disease (PD) is characterized by significant clinical heterogeneity, and there is an urgent need for biomarkers that can identify different progression subtypes. This paper utilizes a machine learning technique—Subtype and Stage Inference (SuStaIn)—which can reveal data-driven disease phenotypes with different temporal progression patterns from widely available cross-sectional patient studies. Corneal neuropathy is a promising peripheral biomarker for PD. Based on confocal microscopy of the cornea in PD patients, this study shows that the method can identify subgroups and their unique trajectories of regional neurodegeneration. SuStaIn can identify two subtypes merely through corneal data and uniquely characterize their temporal complexity. Further analysis revealed that these two subtypes correspond to different pathological protein transmission pathways respectively, and showed significant differences on key clinical symptom scales such as UPDRS-II, RBD-HK and FOGQ. The fine-grained patient stratification provided by SuStaIn has significantly enhanced the ability to predict the transformation between diagnostic categories, bringing new hope to the discovery of disease subtypes and precision medicine.

BackgroundThe role of histone deacetylase 6 (HDAC6) in neurodegenerative diseases, particularly Alzheimer's disease (AD), has attracted significant research interest. Peroxiredoxin 2 (Prx2), a key antioxidant enzyme and HDAC6 substrate, plays a neuroprotective role against oxidative stress-mediated apoptosis.ObjectiveThis study systematically investigates the neuroprotective mechanism of the HDAC6-Prx2 axis in both cellular and transgenic AD models.MethodsAn AD model was established by bilateral hippocampal microinjection of Aβ1-42 oligomers in mice. The assessments of mice or their brain samples were included behavioral tests, immunofluorescence, western blot, NADP+/NADPH ratio, and oxidative stress assays. HDAC6-mediated acetylation of Prx2 was confirmed via co-immunoprecipitation, and the specific site was identified.ResultsThe disruption of the HDAC6-Prx2 interaction can significantly alleviate the apoptosis of hippocampal neurons in AD mice and salvage learning/memory deficits. Inhibiting HDAC6 can increase the acetylation level of Prx2 K196, thereby enhancing its antioxidant activity. Acetylated Prx2 inhibits the excessive production of reactive oxygen species (ROS), which is mechanically linked to HDAC6-dependent neuronal apoptosis This pathway mechanistically links HDAC6 activity to oxidative stress-induced apoptosis. HDAC6-mediated deacetylation of Prx2 K196 was shown to exacerbate oxidative damage and cognitive decline.ConclusionsThe study identifies a novel pathway where HDAC6 inhibition elevates Prx2 K196 acetylation, breaking the vicious cycle of ROS and apoptosis. Dual targeting of HDAC6 activity and Prx2 acetylation status represents a promising therapeutic strategy for AD.

The pathogenicity of variants of uncertain significance in the LRRK2 gene remains underexplored. Investigating the LRRK2 variant spectrum in a large Chinese population cohort can provide deeper insights into its pathogenic mechanisms. This study examined the LRRK2 gene variants in 20,519 Chinese individuals, including 7,562 Parkinson’s disease (PD) patients, 3,077 Essential tremor (ET) patients, and 9880 healthy controls. We conducted a genetic analysis of low-frequency and common non-synonymous variants in the LRRK2 gene across the cohorts. A total of 287 low-frequency non-synonymous LRRK2 variants were identified in the PD and control cohorts. Among these, six reported pathogenic variants (p.R1325Q, p.R1441C, p.R1441H, p.V1447M, p.G2019S, p.I2020T) and three reported likely pathogenic variants (p.R1067Q, p.N1437D, p.R1728H) were enriched in PD cases, with a frequency of 0.71%. In contrast, only one pathogenic variant (p.R1325Q) and one likely pathogenic variant (p.R1067Q) were observed in healthy controls (0.11%), and the ET cohort exhibited similar variant distribution to controls (0.19%). Burden analysis and association analysis revealed novel likely pathogenic variants, including p.A312V, p.M968K, and p.R1320S as candidates. These novel variants were significantly more frequent in PD patients (0.79%) compared to healthy controls (0.20%) or ET patients (0.42%). Additionally, seven common missense variants of LRRK2 were identified, and significant associations with PD for p.A419V, p.R1628P, and p.G2385R were confirmed, but no common variants were linked to ET. This study provides the first comprehensive characterization of the LRRK2 variant spectrum in a large Chinese population, underscoring the pivotal role of LRRK2 in PD pathogenesis but not in ET. These findings advance the understanding of LRRK2 in neurodegenerative disorders and lay a foundation for personalized therapeutic strategies based on genetic profiling.

Introduction The optimal timing for direct oral anticoagulants (DOACs) initiation after acute ischaemic stroke in patients with atrial fibrillation (AF) remains unclear, particularly in those undergoing endovascular thrombectomy (EVT), who are at higher risk of both haemorrhagic transformation and early embolic recurrence. Patients undergoing thrombectomy have been under-represented in previous randomised trials, resulting in limited evidence for guiding management in this high-risk population. The TIMERS trial aims to evaluate the efficacy and safety of early versus delayed initiation of DOACs therapy after EVT in patients with large vessel occlusion stroke and AF. Methods and analysis This is a multicentre, prospective, randomised, open-label trial with a blinded outcome assessment. In total, 438 patients with acute ischaemic stroke and AF treated with EVT will be enrolled in this study. Patients will be randomised in a 1:1 ratio within 72 hours after stroke onset to early initiation (≤4 days) or delayed initiation (5–14 days). The primary outcome is a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage or all-cause death within 90 days. Secondary outcomes include individual components of the primary endpoint, venous thromboembolism, systemic embolism, myocardial infarction, functional outcome (modified Rankin Scale), health-related quality of life (EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L)) and major extracranial bleeding events. Ethics and dissemination The study is approved by the Ethics Committee of Xuanwu Hospital of Capital Medical University, the ethics approval document number is (2025)259-001. The trial findings will be disseminated through peer-reviewed publications and presentations at scientific conferences. Trial registration number NCT07139301 .

Dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) degenerate in Parkinson's disease (PD). Although pain is a common non-motor symptom in PD, it remains unclear whether and how degeneration of SNc DA neurons contributes to hyperalgesia. In the present study, we revealed a nigro-subthalamic DA circuit, composed of a subset of SNc DA neurons, the SNc DA projection to the subthalamic nucleus (STN), and the downstream STN neurons. These components regulate mechanical, but not thermal, pain threshold on the contralateral side, exhibiting distinct responses to mechanical and thermal stimuli which varied in neuropathic pain and Parkinsonian mice. D2-, but not D1-like, dopamine receptors in the STN were involved in these processes, and their activation mitigated mechanical hyperalgesia in both neuropathic pain and Parkinsonian mice. The GABAergic neurons in the substantia nigra pars reticulata (SNr) responded to pain stimulation and facilitated pain responses in SNc DA neurons. Thus, the SNrGABA-SNcDA-STN pathway is involved in the modulation and processing of pain in both physiological and chronic pain states and may be a potential therapeutic target for both neuropathic and Parkinsonian pain.

ObjectiveAs a common lifestyle habit, alcohol consumption has a controversial association with the onset of Parkinson’s disease (PD). To demonstrate the correlation between alcohol consumption and PD and to identify associated genes, we integrated findings from clinical surveys, genomics, transcriptomics, and animal experiments.MethodsWe investigated the alcohol consumption rates (including both before and after disease onset) among 244 PD patients in China and 177 PD patients from the U.S. NHANES database. Mendelian randomization (MR) analysis was performed using genome-wide association study (GWAS) data for three alcohol-related traits and seven PD-related datasets from the MRC IEU OpenGWAS database. Transcriptomic data from the substantia nigra of PD patients were obtained from three GEO datasets (GSE7621, GSE20141, and GSE49036) to analyze RIT2 gene transcription. Finally, three groups of animal experiments (water/20% ethanol/20% liquor, with 4 C57BL/6J mice per group) were conducted to examine changes in brain RIT2 gene expression and transcriptomic profiles following alcohol consumption.ResultsThe alcohol consumption rates among PD patients in China and the U.S. (9%-18.87%) were significantly lower than the general population rates of 15%-45% in their respective regions (P<0.001), suggesting a possible negative association between alcohol consumption and PD. Subsequently, in 21 bidirectional MR analyses using 3 alcohol-related GWAS datasets and 7 PD-related GWAS datasets, the forward MR analyses (alcohol intake as exposure, PD as outcome) yielded 12 negative associations (ORIVW<1) and 9 positive associations (ORIVW>1). Among these, only two negative associations reached statistical significance: alcohol intake frequency (ORIVW=0.75, 95% CI: 0.60-0.93, P=0.010) and alcohol consumption (ORIVW=0.20, 95% CI: 0.05-0.83, P=0.026). The forward MR analysis (alcohol intake→PD) identified 235 SNPs, annotated to 316 genes, while the reverse MR analyses (PD→alcohol intake) identified 37 SNPs, annotated to 53 genes. Notably, only the RIT2 gene appeared in both the forward and reverse MR analyses (alcohol intake→PD: rs28597806, rs8083110; PD→alcohol intake: rs4588066). RIT2 is selectively expressed in the human brain (FPKM: 5.259±2.103), with low or no expression in peripheral tissues (FPKM: <1). Analysis of three human substantia nigra transcriptomic datasets revealed a decreasing trend in RIT2 gene expression in PD patients (GSE20141 array signal: 3.49±1.23 vs. 2.33±0.87, P=0.044). Animal experiments demonstrated that administration of 20% ethanol or 20% liquor (approximately 8% ethanol) stimulated a >2-fold upregulation of RIT2 gene expression in the mouse brain. Furthermore, transcriptomic sequencing revealed that the two alcohol-treated groups exhibited 96 (20% ethanol vs. water control) and 4 (20% liquor vs. water control) differentially expressed genes, respectively, indicating that low-dose alcohol consumption can achieve RIT2 upregulation while minimizing impact on other brain genes. In addition to its anti-infective effects, low-dose alcohol consumption primarily influences signaling pathways related to neurodegenerative diseases such as PD and Prion diseases.ConclusionAlcohol consumption is generally considered as a harmful lifestyle habit. However, some studies have also shown a lower risk of mortality among individuals who consume low doses of alcohol (100 g/week of ethanol) or drink occasionally. Currently, one of the research focuses on alcohol consumption is whether the human body can benefit from low-dose alcohol intake. This study provides new evidence supporting a negative association between alcohol consumption and PD, and for the first time, through MR analysis, identifies the RIT2 gene as a potential mediator of the effect of alcohol consumption on PD. RIT2 is selectively expressed in the human brain. Building upon existing evidence indicating downregulated RIT2 gene expression in PD pathogenesis, our experiments confirm that low-dose alcohol consumption can upregulate RIT2 expression in the brain. In brief, alcohol consumption may suppress the pathogenesis of PD by upregulating RIT2 expression in the substantia nigra. China is facing a serious problem of population aging. This study offers important insights for long-term PD prevention and treatment strategies, with the aim of benefiting more potential PD patients through lifestyle modifications, thereby improving the quality of life of the aging population and reducing the economic burden on healthcare.

OBJECTIVE:Pain is one of the most prevalent and upsetting symptoms of Parkinson's disease (PD), possibly linked to small fiber neuropathy (SFN). We evaluated small nerve fiber damage in PD patients through corneal confocal microscopy (CCM) and investigated its relationship to pain. METHODS:68 PD patients and 31 healthy controls (HC) underwent CCM. Motor and non-motor symptom scales were used to evaluate the recruited PD patients. The patients were divided into two groups: PD with pain (PD-P) and PD with no pain (PD-NP). RESULTS:Compared to the HC and PD-NP group, PD-P exhibited significant reductions in corneal nerve fiber density (CNFD, P < 0.001), length (CNFL, P < 0.05), and fractal dimension (CNFrD, P < 0.01). Corneal parameters demonstrated significant negative correlations with pain severity, as well as measures of anxiety (HAMA) (all P < 0.05). Mediation analysis indicated that anxiety partially mediated the relationship between corneal nerve loss and pain. Principal component analysis condensed nerve parameters into one component explaining 81.58 % of variance, which strongly correlated with pain scores. Logistic regression identified low CNFD as an independent risk factor for PD-related pain (P < 0.01). Furthermore, corneal nerve parameters, particularly a combination of CNFD, CNFL, and CNFrD, effectively discriminated PD-P from PD-NP patients, achieving an area under the curve (AUC) of 0.80. CONCLUSIONS:Corneal nerve degeneration is significantly associated with pain in PD and may serve as an independent biomarker. SFN likely contributes to peripheral pain mechanisms in PD, involving complex peripheral and central interactions.

Background:An increasing body of research has identified a correlation between dysbiosis of the intestinal microbiota and the onset and progression of Parkinson's disease. Furthermore, aerobic exercise has been shown to positively influence the regulation of intestinal microbiota. This study aims to examine the effects of aerobic exercise on the clinical symptoms of people with Parkinson's disease and the underlying mechanisms. Methods:Twenty-six participants engaged in 8 weeks moderate-intensity aerobic exercise. The outcomes include the World Movement Disorder Society Unified Parkinson's Disease Comprehensive Rating Scale part III and so on. Concurrently, fecal and blood samples were collected from the subjects. Results:After aerobic exercise, the MDS-UPDRS part III score decreased. There was a statistically significant increase in the relative abundance of Clostridia (p = 0.043) and Roseburia (p = 0.015). Diversity analysis revealed a statistically significant increase in both the Chao1 index and the Beta diversity index among people with Parkinson's disease. Additionally, bile acid metabolic profiling indicated a significant reduction in fecal 7-ketolithocholic acid concentration in people with Parkinson's disease. Serum levels of Taurochenodeoxycholic acid and Taurodeoxycholic acid were also decreased. T-cell factor assays demonstrated that the levels of the pro-inflammatory cytokines interleukin-1β and interleukin-8 decreased, while the level of the anti-inflammatory cytokine interleukin-4 increased. Conclusion:Aerobic exercise has been shown to enhance both motor and non-motor functions in people with Parkinson's disease. The underlying mechanisms may involve the modulation of intestinal flora composition and diversity, bile acid metabolism, and inflammatory cytokine levels.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated neurological inflammatory disease. As a G protein-coupled receptor, formyl peptide receptor 2 (FPR2) orchestrates innate and adaptive immunity. Yet the precise role of FPR2 in neuroinflammation is poorly understood. Methods: Peripheral blood samples were collected from patients with NMOSD and healthy controls. Single-cell RNA sequencing (scRNA-seq) and flow cytometry were employed to assess the expression of FPR2 in immune cell subsets. We used a mouse model of NMOSD to examine the therapeutic potential and underlying immune mechanisms of an FPR2 antagonist Quin-C7. MRI and immunostaining were performed to quantify central nervous system injury. Results: ScRNA-seq and flow cytometry analyses revealed that FPR2 was expressed in various myeloid and lymphoid cell types in patients with NMOSD and a mouse model of NMOSD. In NMOSD mice, mouse formyl peptide receptor 2 (mFpr2) was mainly upregulated in microglia. Administration of Quin-C7 led to reduced brain lesion volume, astrocyte loss and demyelination in NMOSD mice. Further, FPR2 antagonism reduced the inflammatory activity of microglia and lymphocyte infiltration into the brain. Notably, depletion of microglia using a CSF1R inhibitor diminished the protective effects of FPR2 antagonism, suggesting that microglia contribute to the benefit of FPR2 antagonism in NMOSD. In contrast, genetic deficiency of T and B cells or antibody depletion of NK cells did not affect the benefit of FPR2 antagonism. Conclusion: Collectively, our findings revealed a previously unrecognized role of FPR2/mFpr2 in control of microglia activity during neuroinflammation, implying that FPR2 antagonism may serve as a viable therapeutic approach to restrict detrimental neuroinflammation and warrant further investigation.

Patients with Parkinson's disease (PD) with probable rapid eye movement sleep behavior disorder (RBD) (PD-RBD), a specific subtype of PD, are characterized by the presence of more severe motor and non-motor symptoms. This study aimed to elucidate the characteristics and interactions of gut microbiota and plasma metabolic characteristics of PD-RBD, thus screening for the disease mechanisms. A total of 100 PD patients, 50 healthy controls (HCs) and 16 probable idiopathic RBD (iRBD) patients were collected. There were 33 PD-RBD and 67 patients without probable RBD (PD-nRBD) in PD patients. DNA extraction, PCR amplification, and high-throughput sequencing were used for intestinal microbiota analysis, and ultra-high liquid chromatography tandem mass spectrometry was used for metabolome analysis. Spearman analysis was applied to investigate the correlation of fecal microbiota and plasma metabolome. Our findings revealed Lactobacillaceae (P = 0.017), Christensenellaceae (P = 0.017), Fusobacteriaceae (P = 0.018), Lactobacillus (P = 0.035), Christensenellaceae R-7 group (P = 0.035), and Fusobacterium (P = 0.035) were significantly different in PD-RBD, PD-nRBD, and HC. Moreover, the differential metabolites identified in both PD-nRBD and PD-RBD were 3-hydroxy-2-methylpyridine-4,5-dicarboxylate (VIP = 5.802) and 3-methoxy-4-hydroxyphenylglycol sulfate (VIP = 5.732). Furthermore, our analysis revealed that 3-methoxy-4-hydroxyphenylglycol sulfate showed a positive correlation with Lactobacillus (r = 0.197, P = 0.049). Finally, functional analysis indicated that these distinctive microbiota and metabolites were primarily associated with phenylalanine metabolism and vitamin B6 metabolism. We managed to show that the differential microbiota, differential metabolites, and their interactions in PD-RBD compared to PD-nRBD and HC. This furthers our understanding of disease pathogenesis, and offers fresh perspectives on its detection and treatment. IMPORTANCE:There are currently fewer investigations on the intestinal microbiota and metabolites of probable rapid eye movement sleep behavior disorder (PD-RBD) and idiopathic RBD (iRBD). Our findings indicate that PD-RBD exhibits an increase in Christensenellaceae and 3-methoxy-4-hydroxyphenethyleneglycol sulfate, and that iRBD exhibits a similar trend. This suggests that the PD prodromal stage may have seen this alteration. Furthermore, functional analysis indicated that these distinctive microbiota and metabolites were primarily associated with phenylalanine metabolism and vitamin B6 metabolism. Basic experiments and multi-center, large-cohort clinical researches are worth conducting to confirm this, since they may offer insights for treating individuals with PD-RBD.