NPJ Parkinson's Disease最新文献

{"title":"Impact of α-synuclein fibril structure on seeding activity in experimental models of Parkinson's disease.","authors":"Junichiro Ohira,Masanori Sawamura,Kenichi Kawano,Risa Sato,Tomoyuki Taguchi,Tomoyuki Ishimoto,Jun Ueda,Masashi Ikuno,Shu-Ichi Matsuzawa,Katsumi Matsuzaki,Ryosuke Takahashi,Hodaka Yamakado","doi":"10.1038/s41531-025-01080-2","DOIUrl":"https://doi.org/10.1038/s41531-025-01080-2","url":null,"abstract":"The central pathogenesis of Parkinson's disease involves the misfolding and aggregation of α-synuclein (α-syn). There is a widespread belief that α-syn can propagate in a prion-like manner, and α-syn preformed fibrils (PFFs) have been widely used to establish α-syn propagation models. However, achieving standardized protocols for generating PFFs is challenging due to the influence of various factors on propagation efficiency, resulting in inter-laboratory and inter-experimental variability. Among these factors, the size of the PFFs is considered the most influential as unsonicated PFFs exhibit limited seeding and propagation abilities. Therefore, the objective of our research is to examine the impact of the size and conformation of sonicated PFFs on seeding activity. PFFs were sonicated under various conditions using a conventional water bath sonicator and a high-power sonicator, which is commonly used for DNA shearing in next-generation sequencing. Each sonicated PFF was analyzed for in vitro/in vivo seeding activities, after size confirmation by electron microscopy and a conformational analysis by Fourier Transform Infrared (FTIR) spectroscopy. Strong sonication for 30 min generated extremely short fibrils with the highest seeding activity, which is the optimal condition for the propagation model, whereas sonication for 60 minutes or more led to a reduction in seeding activity. FTIR spectroscopy suggested that sonication disrupted the aggregated strands and generated new fibril ends, thereby accounting for the increased seeding activity; however, prolonged sonication for 60 min or more released monomers with disrupted β-sheet structure from PFFs and reduced the seeding activity. In conclusion, the balance between size reduction and preservation of the β-sheet structure in PFFs plays a critical role in seeding activity. Optimizing these parameters of α-syn PFFs can help improve reproducible preclinical animal models based on α-syn propagation.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"14 1","pages":"224"},"PeriodicalIF":8.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Video analysis reveals early signs of Bradykinesia in REM sleep behavior disorder and Parkinson’s disease","authors":"Diego L. Guarín, Gabriela Acevedo, Carolina Calonge, Joshua K. Wong, Nikolaus R. McFarland, Adolfo Ramirez-Zamora, David E. Vaillancourt","doi":"10.1038/s41531-025-01082-0","DOIUrl":"https://doi.org/10.1038/s41531-025-01082-0","url":null,"abstract":"<p>Idiopathic REM sleep behavior disorder (iRBD) is a strong predictor of neurodegenerative diseases like Parkinson’s disease (PD). Early detection of motor impairments such as bradykinesia is critical for identifying at-risk populations. This study analyzed Finger Tapping Task videos from 66 participants, including healthy controls (HC) and individuals with iRBD and PD. Only videos that received a clinician score of zero on the MDS-UPDRS Part-III finger tapping item were analyzed. Movement amplitude, speed, and their decrements during the task were directly estimated from the videos using machine learning algorithms. Bradykinesia and hypokinesia were detectable in PD but not in iRBD, while decrement in movement amplitude and speed were observed in PD and iRBD. Classification models achieved 81.5% accuracy distinguishing PD from HC, 79.8% distinguishing iRBD from HC, and 81.7% differentiating iRBD from PD. Video-based assessments offer a low-cost, scalable solution for supporting the identification individuals at risk of developing neurodegenerative diseases.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"15 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of high, low, and asymmetric frequency subthalamic stimulation on speech and voice in Parkinson’s disease: a randomized trial","authors":"Zhitong Zeng, Mei Yang, Zhengyu Lin, Peng Huang, Yixin Pan, Chencheng Zhang, Bomin Sun, Dianyou Li","doi":"10.1038/s41531-025-01090-0","DOIUrl":"https://doi.org/10.1038/s41531-025-01090-0","url":null,"abstract":"<p>While bilateral high-frequency subthalamic nucleus stimulation (Bi-HFS) frequently worsens speech in Parkinson’s disease (PD), low-frequency stimulation (LFS) may alleviate gait deficits but lacks robust evidence for speech benefits. This randomized trial compared Bi-LFS (60 Hz) and Bi-HFS (130 Hz) in 33 PD patients with postural instability/gait difficulty (PIGD), and evaluated asymmetric frequency stimulation (AFS) in 20 patients. Bi-LFS significantly improved dysphonia severity index (DSI, FDR-<i>p</i> = 0.024), maximum phonation time (MPT, FDR- <i>p</i> = 0.025), and subjective speech ratings compared to Bi-HFS. Left-LFS/right-HFS (L-LFS/R-HFS) matched Bi-LFS efficacy and surpassed Bi-HFS in objective measures (FDR-p ≤ 0.021). Speech improvements correlated with motor/gait gains, independent of tremor. Findings suggest Bi-LFS mitigates speech dysfunction in PIGD-PD, with left-sided LFS potentially driving benefits, while AFS provides comparable outcomes. These data support tailored stimulation protocols to optimize speech in PD. The National Medical Research Registration and Information System of China (MR-31-23-036810).</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"10 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements in invasive and non-invasive neuromodulation for Parkinson’s disease: current findings and future directions","authors":"Nabin Koirala, Manuel Bange, Aparna Wagle Shukla, Muthuraman Muthuraman","doi":"10.1038/s41531-025-01071-3","DOIUrl":"https://doi.org/10.1038/s41531-025-01071-3","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"7 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oligomeric alpha-synuclein causes early synaptic dysfunction of the corticostriatal pathway associated with non-motor symptoms.","authors":"Laura Bellingacci,Miriam Sciaccaluga,Alfredo Megaro,Antonella Cardinale,Jacopo Canonichesi,Maria De Carluccio,Roberta Mastrantonio,Cinzia Costa,Massimiliano Di Filippo,Alessandro Usiello,Maria Teresa Viscomi,Paolo Calabresi,Alessandro Tozzi","doi":"10.1038/s41531-025-01075-z","DOIUrl":"https://doi.org/10.1038/s41531-025-01075-z","url":null,"abstract":"In synucleinopathies, α-synuclein oligomers (OSyn) appear to be associated with neurodegeneration, neurotoxicity, and proinflammatory responses, even at low concentrations, suggesting their pivotal role in the pathogenesis of Parkinson's disease (PD). We utilized a rat model of synucleinopathy induced by intrastriatal injection of OSyn, aiming to elucidate events preceding the formation of fibrillary α-syn aggregates. Electrophysiological assessments and behavioral assays revealed several early alterations in OSyn rats, evident as early as 12 weeks post-OSyn injection. These included mild and variable reduction of motor activity, anxiety-like behavior, impaired bidirectional striatal long-term synaptic plasticity, and diminished spontaneous excitatory neurotransmission in the striatum. Furthermore, p-α-syn aggregates were detected in the cortex but not in the substantia nigra (SN). Confocal microscopy analysis revealed reduced vesicular glutamate transporter 1 (VGluT1) expression at striatal glutamatergic terminals. Chronic administration of the ampakine Tulrampator to OSyn animals prevented impairment of long-term depression (LTD), spontaneous striatal neurotransmission, and VGluT1 levels. Tulrampator also ameliorated the anxiety-related behavioral phenotype, albeit without attenuating motor deficits, demonstrating its efficacy in mitigating early synaptic and emotional deficits induced by OSyn. These findings provide a basis for a novel drug treatment strategy aimed at mitigating or delaying early damage at cortico-striatal terminals induced by OSyn, thereby counteracting the pathophysiological processes underlying the onset of early non-motor symptoms in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"14 1","pages":"220"},"PeriodicalIF":8.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel approach to detecting plasma synuclein aggregates for Parkinson’s disease diagnosis","authors":"Hyo Rim Ko, Dawon Lee, Hyojung Park, Haemin Jeong, Taehwi Yoon, Sungmin Kang, Hye Lim Park, Soo Jin Kwon, SangYun Kim, Nayoung Ryoo, Ji Sun Ryu","doi":"10.1038/s41531-025-01083-z","DOIUrl":"https://doi.org/10.1038/s41531-025-01083-z","url":null,"abstract":"<p>Alpha-synuclein (αSyn) aggregates are pathognomonic of Parkinson’s disease (PD) and play a critical role in its pathogenesis. However, existing diagnostic approaches rely on invasive cerebrospinal fluid (CSF) sampling or tissue biopsies, limiting their accessibility and scalability in clinical practice. Here, we present the Constant Shake-Induced Conversion (CSIC) assay, a novel plasma-based technique for the detection of αSyn aggregates. A total of 102 participants, comprising 42 PD patients and 60 healthy controls (HCs), were enrolled. Plasma samples were subjected to CSIC and validated via αSyn depletion, enzyme-linked immunosorbent assay (ELISA), and Western blotting. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis, and clinical associations were examined using Spearman’s correlation. The CSIC assay achieved an area under the curve (AUC) of 0.91, with 81% sensitivity and 85% specificity in distinguishing PD from HCs. Assay specificity was confirmed through αSyn depletion, and reproducibility assessments yielded intra- and inter-assay coefficients of variation below 10% and ~20%, respectively. Notably, plasma αSyn aggregate levels correlated with Hoehn and Yahr (H&amp;Y) stage (<i>r</i> = 0.69), Unified Parkinson’s Disease Rating Scale (UPDRS) (<i>r</i> = 0.68), and Montreal Cognitive Assessment scores (<i>r</i> = −0.47). These findings establish CSIC as a robust, non-invasive diagnostic method with strong potential for clinical implementation in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"62 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in rotenone Parkinson’s model","authors":"Maria Tsalenchuk, Kyle Farmer, Sandra Castro, Abigail Scheirer, Yuqian Ye, J. Timothy Greenamyre, Emily M. Rocha, Sarah J. Marzi","doi":"10.1038/s41531-025-01049-1","DOIUrl":"https://doi.org/10.1038/s41531-025-01049-1","url":null,"abstract":"<p>Pesticide exposure is increasingly recognized as a potential environmental factor in idiopathic Parkinson’s disease, though the molecular mechanisms remain unclear. This study explores how pesticide exposure alters gene regulation in key brain regions using the rotenone rat model. We performed H3K27ac ChIP-sequencing to profile active regulatory elements in the substantia nigra and motor cortex. Despite uniform complex I inhibition across regions, we observed region-specific epigenomic changes associated with rotenone exposure. RNA-sequencing confirmed transcriptomic alterations. We identified a strong, rotenone-induced immune response in the substantia nigra, including increased activity in the C1q complement pathway, suggesting immune involvement driven by regulatory mechanisms. In contrast, the cortex showed dysregulation of synaptic function at the gene regulatory level. Our results highlight a role for gene regulatory mechanisms potentially mediating the effects of pesticide exposure, driving region-specific functional responses in the brain that may contribute to the pathology and selective vulnerability that characterise Parkinson’s disease.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"26 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diffusion–tensor MRI study of the relationship between glymphatic system asymmetry and onset lateralization in Parkinson’s disease","authors":"Zihan Li, Xinxin Miao, Qiumei Zhang, Jun Shen, Yongfeng Jia, Shaoyun Ge, Peixian Ji, Jianwei Wang, Kezhong Zhang, Min Wang","doi":"10.1038/s41531-025-01074-0","DOIUrl":"https://doi.org/10.1038/s41531-025-01074-0","url":null,"abstract":"<p>The characteristic asymmetric motor symptoms of Parkinson’s disease (PD) may be associated with asymmetric deposition of α-synuclein. The impaired glymphatic system may promote pathological deposition of α-synuclein, leading to disease progression. The aim of this study was to investigate the function of the glymphatic system in PD patients with unilateral motor symptom onset using diffusion tensor image analysis along the perivascular spaces (DTI-ALPS) method, and to elucidate the relationship between glymphatic system asymmetry and the side of motor symptom onset. We conducted diffusion tensor imaging scans on 36 left-onset PD (LPD) patients, 27 right-onset PD (RPD) patients, and 49 healthy controls (HCs). Bilateral hemispheric ALPS indices were calculated to assess glymphatic function, and an asymmetry index (AI) was derived to quantify interhemispheric asymmetry in glymphatic function. Compared to HCs, RPD patients exhibited a significant reduction in the left ALPS index, while both left and right ALPS indices were significantly reduced in LPD patients. In both LPD patients and HCs, the right ALPS index was lower than the left, suggesting a natural leftward asymmetry. However, this asymmetry was diminished in RPD patients, as indicated by a lower AI. Moreover, in RPD patients, the Unified Parkinson’s Disease Rating Scale Part III score showed a negative correlation with the left ALPS index and with AI. This study demonstrated that PD patients with lateralized motor symptom onset exhibit different patterns of glymphatic system function. The glymphatic system asymmetry may provide new insights into the mechanism underlying the lateralized onset of PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"115 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying individuals at-risk of developing Parkinson's disease using a population-based recruitment strategy: The Healthy Brain Ageing Kassel Study.","authors":"Sebastian Schade,Soumyabrata Ghosh,Alicia Garrido,Philipp Mahlknecht,Tainá M Marques,Corinne G C Horlings,Sonja R Jónsdóttir,Elisabeth Lang,Claire Pauly,Kavita Rege,Susana Schnell,Maritta Starke,Horst Hakelberg,Eduardo Tolosa,Claudia Trenkwalder,Tamara Wicke, ,Rejko Krüger,Maria J Marti,Werner Poewe,Venkata P Satagopam,Brit Mollenhauer","doi":"10.1038/s41531-025-01008-w","DOIUrl":"https://doi.org/10.1038/s41531-025-01008-w","url":null,"abstract":"Neurodegeneration in Parkinson's disease (PD) occurs before motor features develop: assessing risk factors and identifying prodromal markers is necessary to recruit prodromal cohorts, improve early diagnosis, and develop preventive therapies. As part of Healthy Brain Ageing (HeBA), we implemented a stepwise, population-based screening to identify people at high risk of developing PD. Residents (n = 158,818; 50-80 years) in and around Kassel, Germany were invited to complete an online survey with questions for prodromal symptoms and risk factors. An individual risk score was calculated (International Parkinson and Movement Disorder Society criteria). Selected individuals received a smell test. 8001 of 8774 survey responses were valid; the response rate to the smell test mailings (n = 3021) was 90%. Hyposmic participants (n = 1019) had more subjective hyposmia and subjective memory impairment (p < 0.01). Follow-up visits will validate the recruitment strategy and monitor conversion to manifest PD. Our recruitment strategy identifies people who might be at risk for PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"109 1","pages":"216"},"PeriodicalIF":8.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional network differences between unilateral and bilateral deep brain stimulation of the subthalamic nucleus","authors":"Brendan Santyr, Alexandre Boutet, Mohamad Abbass, Artur Vetkas, Jürgen Germann, Afis Ajala, Jianwei Qiu, Gavin J. B. Elias, Can Sarica, Andrew Z. Yang, Ibrahim Alhashyan, Suneil K. Kalia, Alfonso Fasano, Andres M. Lozano","doi":"10.1038/s41531-025-01064-2","DOIUrl":"https://doi.org/10.1038/s41531-025-01064-2","url":null,"abstract":"<p>Unilateral versus bilateral implantation is a critical surgical consideration for deep brain stimulation in Parkinson’s disease; however, the differing therapeutic effects remain incompletely understood. Using functional magnetic resonance imaging during active stimulation, we show that bilateral stimulation reinforces the recruitment of key motor hubs while reducing non-motor responses seen with unilateral stimulation and correlates with improved outcomes. This suggests a potential mechanistic basis for better motor function following bilateral stimulation.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"3 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}