The gut-brain axis is increasingly recognized as a critical contributor to Parkinson's disease (PD) pathogenesis, yet the therapeutic impact of microbiota modulation remains unclear due to lack of clinical trials in drug-naïve patients. We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the safety, tolerability, and efficacy of repeated donor fecal microbiota transplantation (dFMT) in de novo PD. FMT was administered for seven days (200 mL on days 1-3; 50 mL on days 4-7) per 4-week cycle. Seventy-two patients were randomized 1:1 to receive dFMT or autologous FMT (aFMT), and 66 completed the trial. At 35 weeks, the dFMT group showed significant improvement in motor symptoms (mean change in Unified Parkinson's Disease Rating Scale [UPDRS] III: -3.8 vs. +0.1; p = 0.0001) and a substantially greater reduction in constipation severity (dFMT vs. aFMT: -6.5 vs. -0.7; p < 0.0001), accompanied by improved quality-of-life scores. Microbiome profiling revealed greater similarity to donor composition and a marked reduction in Escherichia-Shigella, correlating with decreased colonic α-synuclein aggregation (r = 0.3775, p = 0.0277), supporting a gut-brain mechanistic link. Biochemical analyses showed elevated fecal dopamine and 3,4-dihydroxyphenylacetic acid levels, while histological assessments demonstrated strengthened epithelial barrier integrity with increased E-cadherin expression. All adverse events were mild and self-limited; no serious treatment-related events were observed. These findings demonstrate that repeated dFMT is safe, well tolerated, and yields clinically meaningful motor and gastrointestinal improvements in drug-naïve PD, providing integrated mechanistic and clinical evidence that microbiota-targeted modulation represents a promising nonpharmacologic therapeutic strategy for neurodegenerative disease. Trial registration: Chinese Clinical Trial Registry, ChiCTR2200064151.

BACKGROUND:Multiple system atrophy (MSA) shares clinical features with idiopathic Parkinson' s disease (iPD) and progressive supranuclear palsy (PSP), yet reliable biomarkers for differential diagnosis remain elusive. OBJECTIVES:This study aimed to evaluate Piezo1/2 expression in urinary exfoliated cells as a potential biomarker for MSA differentiation. METHODS:Piezo1/2 expression levels were quantified in urinary exfoliated cells from 76 MSA patients, 103 iPD patients, 59 PSP patients, and 126 healthy controls (HCs) across three independent cohorts using multiple analytical techniques. RESULTS:In the discovery cohort, Piezo1 expression was significantly reduced in MSA patients compared with HCs, iPD, and PSP (area under the curve: 0.9421, 0.8218, and 0.8036, respectively). These findings were validated in two independent cohorts, confirming consistently lower Piezo1 levels in MSA patients and their utility in distinguishing MSA from other groups. CONCLUSION:Reduced Piezo1 levels in urinary exfoliated cells show strong potential as a non-invasive biomarker for diagnosing MSA. © 2025 International Parkinson and Movement Disorder Society.

Taste impairment is a prevalent issue among individuals with idiopathic Parkinson’s disease (iPD). However, understanding taste disorders among different Parkinsonism remains incomplete. Our objective was to assess the incidence and severity of taste responses to sweet, salty, sour, bitter, and umami substances in patients with iPD, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Taste function was evaluated by assessing the intensity ratings of four concentrations of sweet, salty, sour, bitter, and umami in 221 healthy controls (HCs), 251 iPD patients, 156 PSP patients, and 60 MSA patients. The Kruskal–Wallis one-way analysis was employed to discern differences in taste function among groups. Logistic regression models were utilized to analyze the association between disease severity and taste function. Participants with iPD, PSP, and MSA exhibited lower total taste scores (TTS) compared to HCs (P < 0.0001, P < 0.0001, and P = 0.0002, respectively). The TTS was significantly lower in iPD patients compared to PSP and MSA patients (P = 0.0024 and P = 0.0464, respectively), with no discernible difference between PSP and MSA patients (P = 0.9998). Furthermore, in patients with iPD, both disease severity and gastrointestinal function exhibited a significant negative correlation with the TTS. However, the taste test lacked the potency to reliably distinguish iPD from PSP and MSA. These research findings suggest that taste impairment emerges as a phenotype of Parkinsonism, serving as a basis for differential diagnosis and guiding dietary adjustments for patients.

Variants in GBA1 represent the most prevalent genetic risk factors for Parkinson’s disease (PD), yet how environmental exposures interact with these mutations to drive disease remains unclear. Epidemiological evidence implicates high dairy consumption as a potential modifiable risk factor for PD, but the mechanistic basis remains elusive. Here, we identify hepatic deposition of phosphorylated α-synuclein (pα-syn) in two PD patients carrying the pathogenic GBA1 L444P variant with histories of excessive dairy intake. Using Gba1L444P/+ mice, we demonstrate that a dairy-rich diet enriched in calcium and casein could induce pathological α-syn aggregation within Kupffer cells (KCs) of the liver. Proteomic profiling reveals that this diet triggers mitochondrial oxidative stress and aggravates GBA1 mutation-induced autophagy defects in KCs, creating a permissive environment for α-synucleinopathy. Notably, hepatic pα-syn pathology propagates to discrete brain regions, including the dorsal nucleus of the vagus nerve, substantia nigra, striatum, and prefrontal cortex, leading to both motor and cognitive impairments. Surgical disruption of liver-brain communication via liver transplantation or hepatic denervation can postpone cerebral pα-syn deposition, confirming a neural conduit for disease transmission. These findings establish the liver as a novel origin site for α-syn pathology in a genetically susceptible context, and define a previously unrecognized liver-brain axis in PD pathogenesis. Our work highlights the interplay between environmental and genetic factors in shaping α-syn dynamics and uncovers potential targets for early intervention in PD.

Perivascular spaces (PVSs) as the anatomical basis of the glymphatic system, are increasingly recognized as potential imaging biomarkers of neurological conditions. However, it is not clear whether enlarged PVSs are associated with alcohol-related brain damage (ARBD). We aimed to investigate the effect of long-term alcohol exposure on dyslipidemia and the glymphatic system in ARBD. We found that patients with ARBD exhibited significantly enlargement of PVSs in the frontal cortex and basal ganglia, as well as a notable increased levels of total cholesterol (TC) and triglycerides (TG). The anatomical changes of the glymphatic drainage system mentioned above were positively associated with TC and TG. To further explore whether enlarged PVSs affects the function of the glymphatic system in ARBD, we constructed long alcohol exposure and high fat diet mice models. The mouse model of long alcohol exposure exhibited increased levels of TC and TG, enlarged PVSs, the loss of aquaporin-4 polarity caused by reactive astrocytes and impaired glymphatic drainage function which ultimately caused cognitive deficits, in a similar way as high fat diet leading to impairment in glymphatic drainage. Our study highlights the contribution of dyslipidemia due to long-term alcohol abuse in the impairment of the glymphatic drainage system.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the progressive loss of motor neurons. Recent insights into ALS pathogenesis underscore the pivotal role of the gut microbiome, prompting an investigation into the potential therapeutic impact of fecal microbiota transplantation (FMT) on sporadic ALS patients. Conducted as a double-blind, placebo-controlled, parallel-group, randomized clinical trial, the study enrolled 27 participants from October 2022 to April 2023. The participants were followed up for 6 months from February 2023 to October 2023, during in-person visits at baseline, week 15, week 23, and week 35. The participants, evenly randomized, received either healthy donor FMT (FMT, n = 14) or a mixture of 0.9

BackgroundSpinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no cure, nor effective treatment strategy.ObjectiveOur aim was to investigate the safety and efficacy of high-dose ganglioside GM1 (ganglioside-monosialic acid) pulse treatment in patients with SCA3.MethodsPatients were randomly allocated to receive either high-dose GM1 (400 mg on the first day followed by 200 mg/day), low-dose GM1 (40 mg/day), or placebo (normal saline) for 4 weeks. The primary outcome, assessed by measuring the change in the Scale for the Assessment and Rating of Ataxia (SARA) scores from baseline to 12 weeks post-treatment, is central to evaluating treatment efficacy. Secondary outcomes included changes in the International Cooperative Ataxia Rating Scale (ICARS) score, Barthel Index of Activities of Daily Living (ADL), and plasma and cerebrospinal fluid (CSF) GABA levels. Safety was assessed in all treated patients.ResultsA total of 48 patients with SCA3 were enrolled in this study. After 12 weeks, data from 43 patients were included in the efficacy analysis (intention-to-treat analysis). The least-squares mean change in the SARA score from baseline to 12 weeks post-treatment was -3.80 (standard error [SE], 0.39; 95% confidence interval [CI], -4.58 to -3.02) in the high-dose GM1 group, 0.34 (SE, 0.40; 95% CI, -0.46 to 1.13) in the low-dose GM1 group, and 0.73 (SE, 0.40; 95% CI, -0.07 to 1.52) in the placebo group, respectively. Secondary outcomes showed improvements in the ICARS score, Barthel Index of ADL, and plasma and CSF GABA levels in the high-dose GM1 group compared to the low-dose GM1 and placebo groups. All treatments were well-tolerated and safe.ConclusionsHigh-dose GM1 treatment significantly ameliorated ataxic symptoms in patients with SCA3. (c) 2024 International Parkinson and Movement Disorder Society.

Abstract Hypertrophic olivary degeneration (HOD) is a transsynaptic degeneration characterized by the disruption of dentato-rubro-olivary tract, a region also known as the Guillain-Mollaret triangle (GMT), which often occurs because of posterior fossa or brainstem lesions. Infratentorial cerebrovascular diseases (ICVD) has been linked to HOD in previous studies. The underlying mechanism of ICVD patients developed HOD, however, remains undetermined. In this study, we analyzed clinical features of 334 patients with ICVD and the results showed that brainstem hemorrhage was most likely to develop HOD (43.5%) among four types of ICVD. In addition, multivariate regression analysis revealed that PSP-RS was an independent risk factor (OR = 6.69, 95% CI: 1.58–28.32) for ICVD-HOD, and the presence of HOD was obviously higher in PSP-RS patients complicated by ICVD (43.5%) than that in PSP-RS patients uncomplicated by ICVD (4.2%). Furthermore, DTI study showed that the PSP-RS, HOD, PSP-RS with HOD, and PSP-RS with ICVD-HOD groups displayed the impaired microstructural integrity of the GMT compared to iPD and HCs groups. Moreover, some DTI parameters of the GMT showed correlation with the Progressive Supranuclear Palsy Rating Scale (PSPRS) score in PSP-RS patients. Taken together, our study demonstrated that PSP-RS was an independent etiological factor for ICVD-HOD which might due to impaired microstructural integrity of the GMT. More importantly, these findings suggest that PSP-RS patients should aim for the prevention of ICVD to reduce the occurrence of HOD.

Cerebral small vessel disease (CSVD) is a prominent cause of ischemic and hemorrhagic stroke and a leading cause of vascular dementia, affecting small penetrating vessels of the brain. Despite current advances in genetic susceptibility studies, challenges remain in defining the causative genes and the underlying pathophysiological mechanisms. Here, we reported that the ARHGEF15 gene was a causal gene linked to autosomal dominant inherited CSVD. We identified one heterozygous nonsynonymous mutation of the ARHGEF15 gene that cosegregated completely in two families with CSVD, and a heterozygous nonsynonymous mutation and a stop-gain mutation in two individuals with sporadic CSVD, respectively. Intriguingly, clinical imaging and pathological findings displayed severe osteoporosis and even osteoporotic fractures in all the ARHGEF15 mutation carriers. In vitro experiments indicated that ARHGEF15 mutations resulted in RhoA/ROCK2 inactivation-induced F-actin cytoskeleton disorganization in vascular smooth muscle cells and endothelial cells and osteoblast dysfunction by inhibiting the Wnt/β-catenin signaling pathway in osteoblast cells. Furthermore, Arhgef15-e(V368M)1 transgenic mice developed CSVD-like pathological and behavioral phenotypes, accompanied by severe osteoporosis. Taken together, our findings provide strong evidence that loss-of-function mutations of the ARHGEF15 gene cause CSVD accompanied by osteoporotic fracture.

Introduction Generalized anxiety disorder (GAD) is one of the most enduring anxiety disorders, being associated with increased systemic inflammation. However, the trigger and mechanisms underlying the activation of inflammatory cytokine responses in GAD remain poorly understood. Materials and methods We characterized the ear canal microbiome in GAD patients through 16S rRNA gene sequencing and metagenomic sequencing and identified the serum inflammatory markers in GAD patients. Spearman correlations were applied to test the relationship between the microbiota changes and systemic inflammation. Results Our findings showed the higher microbial diversity, accompanied with the significantly increased abundance of Proteobacteria, and decreased abundance of Firmicutes in the ear canal of GAD participants compared to that of the age- and sex-matched healthy controls (HC). Metagenomic sequencing showed that Pseudomonas aeruginosa were significantly increased at species-level in GAD patients. Furthermore, we observed the relative abundance of Pseudomonas aeruginosa was positively associated with elevated systemic inflammatory markers and the severity of disease, suggesting that these ear canal microbiota alterations might be correlated with GAD by activating the inflammatory response. Conclusions These findings indicate that microbiota-ear-brain interaction via upregulating inflammatory reaction involve in the development of GAD, as well as suggest that ear canal bacterial communities may be a target for therapeutic intervention.

Background Faecal microbiota transplantation (FMT) has demonstrated efficacy in treating gastrointestinal (GI) diseases, such as Clostridium difficile infection (CDI) and inflammatory bowel disease (IBD). GI dysfunction is a frequent and occasionally dominating symptom of progressive supranuclear palsy-Richardson's syndrome (PSP-RS). However, it is not known whether FMT has clinical efficacy for PSP-RS.Methods This 36-week, randomised, placebo-controlled, parallel-group, phase 2 clinical trial was performed at a university tertiary referral hospital in China. From August 15 2021 to December 31 2021, a total of 68 newly diagnosed patients with PSP-RS (male 40 [59%], female 28 [41%]) who had never received any antiparkinsonian medications were enrolled and randomly assigned to receive either healthy donor FMT (n = 34, FMT group) or a mixture of 0.9% saline and food colouring (E150c) as sham transplantation (n = 34, placebo group) through transendoscopic enteral tubing (TET). Two days after oral antibiotics, participants received 1 week of transplantation. After an interval of 4 weeks, retransplantation was performed. Then, the last transplantation was given after another interval of 4 weeks, and the participants were followed up for 24 weeks (week 36). Clinicaltrials.gov identifier: ChiCTR-2100045397.Findings Among 68 patients who were randomised (mean age, 67.2 (SD 5.1); 40 [59%] were male, 28 [41%] were female), 63 participants completed the trial. Efficacy analyses were performed on the intention-to-treat (ITT) analysis set. At week 16, the mean PSP Rating Scale (PSPRS) scores (the primary outcome) improved from 40.1 (SD 7.6) to 36.9 (SD 5.9) in the FMT group, whereas the scores changed from 40.1 (SD 6.9) to 41.7 (SD 6.2) in the placebo group, for a treatment benefit of 4.3 (95% CI, 3.2-5.4) (P < 0.0001). After 3-cycle intervention, symptoms of constipation, depression, and anxiety (the secondary outcome) improved significantly at week 16 in the FMT group compared with the placebo group, the majority of which were maintained at the 24-week follow-up (week 36). Interpretation Our findings suggest that, compared with placebo, FMT treatment significantly improved motor and nonmotor symptoms in patients with PSP-RS, as well as reduced intestinal inflammation and enhanced the intestinal barrier by regulating the intestinal microbiota composition.Funding The National Natural Science Foundation of China (No. 82122022, 82171248, 81873791, and 82230084), Natural Science Foundation of Henan Province for Excellent Young Scholars (no. 202300410357), and Henan Province Young and Middle-Aged Health Science and Technology Innovation Talent Project (YXKC2020033).Copyright (c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson’s disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (Pcombined = 1.47 × 10−9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10−8) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (rb) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14–0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (rg = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD.

Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) gene is a major-effect risk gene for sporadic PD (sPD). However, what environmental factors may trigger the formation of α-syn pathology in carriers of LRRK2 risk variants are still unknown. Here, we report that a markedly increased abundance of Escherichia coli (E. coli) in the intestinal microbiota was detected in LRRK2 risk variant(R1628P or G2385R) carriers with sPD compared with carriers without sPD. Animal experiments showed that E. coli administration triggered pathological α-syn accumulation in the colon and spread to the brain via the gut-brain axis in Lrrk2 R1628P mice, due to the co-occurrence of Lrrk2 variant-induced inhibition of α-syn autophagic degradation and increased phosphorylation of α-syn caused by curli in E. coli-derived extracellular vesicles. Fecal microbiota transplantation (FMT) effectively ameliorated motor deficits and α-syn pathology in Lrrk2 R1628P mice. Our findings elaborate on the mechanism that E. coli triggers α-syn pathology in Lrrk2 R1628P mice, and highlight a novel gene-environment interaction pattern in LRRK2 risk variants. Even more importantly, the findings reveal the interplay between the specific risk gene and the matched environmental factors triggers the initiation of α-syn pathology in sPD.

目的:研究单纯疱疹病毒脑炎(HSE)患者粪便和血清中炎症相关指标的变化,探讨肠道炎症在HSE中的作用.方法:使用ELISA法检测65例HSE患者及65例健康对照者粪便中粪钙卫蛋白(FC)、粪α-1-抗胰蛋白酶(FAT)、粪连蛋白(FZ)、粪乳铁蛋白(FLF)和血清中脂多糖(LPS)、脂多糖结合蛋白(LBP)水平.根据入院时改良Ranking量表评分将HSE患者分为轻度神经功能障碍组(A组,n=11)、中度神经功能障碍组(B组,n=15)和严重神经功能障碍组(C组,n=39).对6例(A组、B组、C组各2例)HSE患者及5例健康对照者进行肠黏膜活检.分别分析HSE组和健康对照组以及A组、B组、C组之间血清、肠道炎症指标之间的差异,进一步分析HSE患者血清炎症指标与肠道炎症指标的相关性.结果:HSE组FC、FAT、FZ、LPS和LBP水平高于健康对照组,差异有统计学意义(P<0.05),而两组间FLF差异无统计学意义(P>0.05);A、B、C 3组HSE患者FC、FAT、FZ、LPS和LBP水平比较差异有统计学意义(P<0.05),3组FLF水平比较差异无统计学意义(P>0.05);HSE患者血清炎症指标LPS、LBP水平与肠道炎症指标FC、FAT、FZ呈正相关(P<0.05),而与FLF无相关性(P>0.05);6例HSE患者肠黏膜活检均显示不同程度的肠道炎症.结论:肠道炎症可能参与HSE的发病及病情进展.

The meningeal lymphatic vessels (mLVs) in central nervous system (CNS) have been validated by rodent and human studies. The mLVs play a vital role in draining soluble molecules and trafficking lymphocytes, antigens and antibodies from CNS into cervical lymph nodes (CLNs). This indicates that mLVs may serve as a link between the CNS and peripheral immune system, perhaps involving in the neuroinflammatory disease. However, the morphology and drainage function of mLVs in patients with neuroinflammatory disease, such as neuromyelitis optica spectrum disorders (NMOSD), remains unexplored. Using the dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we found that slower flow through mLVs along superior sagittal sinus in NMOSD patients with acute attack instead of NMOSD patients in chronic phase. The reduced flow in mLVs correlated with the disease severity evaluated by expanded disability status scale (EDSS). The receiver operating characteristic curve (ROC) indicated DCE-MRI might provide objective evidence to predict the acute relapse of NMOSD through evaluating the function of mLVs. Promoting or restoring the function of mLVs might be a new target for the treatment of NMOSD relapse.

Objective:To report a Chinese family with a novel ABCD1 gene mutation at c.332T>G (p.V111G) site and discuss its clinical characteristics and molecular mechanism.Methods:The clinical data, laboratory examination, and imaging examination results were analyzed to make the clinical diagnosis of a middle-aged onset patient from the First Affiliated Hospital of Zhengzhou University in May 2017. High-throughput sequencing was used to discover a novel ABCD1 gene mutation. Sanger sequencing was used to find out whether other family members contain the same ABCD1 gene mutation. The pathogenicity of this mutation was explored by protein structure prediction and pathogenicity analysis. Adrenoleukodystrophy protein-green fluorescent protein (ALDP-GFP) and ALDP-GFP (V111G) plasmids were constructed and human embryonic kidney 293 cells were transfected, then immunofluorescence and Western blotting were used to explore the molecular mechanism of this mutation (completed in Henan Provincial People′s Hospital).Results:The proband (a 39-year-old male) was diagnosed as adrenomyeloneuropathy, a subset of X-linked adrenoleukodystrophy, with a novel heterozygous missense mutation in the ABCD1 gene at c.332T>G (p.V111G) site, and his mother and two daughters were all carriers. Protein structure prediction and pathogenicity results suggested that this mutation is pathogenic. Overexpression of ALDP-GFP (V111G) in the human embryonic kidney 293 cells resulted in a significant decrease in the expression levels of ALDP and the abnormal localization from the peroxisomal membrane to the cytoplasm, accompanied by significant down-regulation of LC3-Ⅱ/LC3-Ⅰ and beclin-1.Conclusion:c.332T>G (p.V111G) is a novel pathogenic mutation in the ABCD1 gene, which causes adrenomyeloneuropathy by impairing autophagy.

目的 探讨血脑屏障(blood-brain barrier,BBB)破坏对急性缺血性脑卒中患者血管内治疗预后的影响.方法 收集自2018年4月至2020年3月就诊于郑州大学第一附属医院的接受血管内治疗的急性缺血性脑卒中患者213例,其中血脑屏障破坏组130例(61.0％),血脑屏障未破坏组的83例(39.0％).血脑屏障破坏定义为血管内治疗后立即颅脑CT或CTA扫描上出现造影剂渗漏的高密度病变,24 h内颅脑CT扫描高密度区减低,而出血转化为持续高密度病变.结果 血脑屏障破坏(OR=3.245,P<0.001)、入院时的美国国立卫生研究院卒中量表评分(National Institute of Health Stroke Scale,NIHSS)(OR=1.101,P<0.001)、心源性栓塞(OR=2.039,P<0.001)和糖尿病(OR=1.404,P=0.001)是急性缺血性卒中患者血管内治疗预后的独立危险因素.与对照组相比,有血脑屏障破坏者血管内治疗后早期神经功能改善(47.7％,85.5％,P<0.001)和90 d预后差(16.9％,61.4％,P<0.001),90 d内死亡率(30.0％,1.2％,P<0.001)和出血性并发症(34.6％,4.8％,P<0.001)的风险高.结论 急性缺血性脑卒中患者血管内治疗后血脑屏障破坏患者的临床预后更差,并与卒中后死亡独立相关.

Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease (PD). However, there is no direct evidence in humans to support this role 1 – 5 . In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.

The neuropathological feature of multiple system atrophy (MSA), a fatal adult-onset disorder without effective therapy, is the accumulation of pathological α-synuclein (α-Syn) in the central nervous system (CNS). Here we show that pathological α-Syn exists in nerve terminals in detrusor and external urethral sphincter (EUS) of patients with MSA. Furthermore, α-Syn-preformed fibrils (PFFs) injected in the EUS or detrusor in TgM83+/− mice initiated the transmission of pathological α-Syn from the urogenital tract to brain via micturition reflex pathways, and these mice developed widespread phosphorylated α-Syn inclusion pathology together with phenotypes. In addition, urinary dysfunction and denervation-reinnervation of external anal sphincter were detected earlier in the mouse models with α-Syn PFFs inoculation before the behavioral manifestations. These results suggest that pathological α-Syn spreading through the micturition reflex pathways retrogradely from the urogenital tract to CNS may lead to urinary dysfunction in patients with MSA, which is different from the etiology of idiopathic Parkinson disease.

α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), α-synuclein (α-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83+/- mice, inoculation of α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction. Thus, we have generated a mouse model of pure autonomic dysfunction caused by α-Syn pathology. This model may help define the mechanistic link between transmission of pathological α-Syn and the cardinal features of autonomic dysfunction in α-synucleinopathy.