NPJ Parkinson's Disease最新文献

{"title":"Human midbrain organoids: a powerful tool for advanced Parkinson’s disease modeling and therapy exploration","authors":"Xin Cui, Xinwei Li, Huimin Zheng, Yun Su, Shuyu Zhang, Mengjie Li, Xiaoyan Hao, Shuo Zhang, Zhengwei Hu, Zongping Xia, Changhe Shi, Yuming Xu, Chengyuan Mao","doi":"10.1038/s41531-024-00799-8","DOIUrl":"https://doi.org/10.1038/s41531-024-00799-8","url":null,"abstract":"<p>Parkinson’s disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra. Despite progress, the pathogenesis remains unclear. Human midbrain organoids (hMLOs) have emerged as a promising model for studying PD, drug screening, and potential treatments. This review discusses the development of hMLOs, their application in PD research, and current challenges in organoid construction, highlighting possible optimization strategies.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452140","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":"Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease","authors":"Clodagh Towns, Zih-Hua Fang, Manuela M. X. Tan, Simona Jasaityte, Theresa M. Schmaderer, Eleanor J. Stafford, Miriam Pollard, Russel Tilney, Megan Hodgson, Lesley Wu, Robyn Labrum, Jason Hehir, James Polke, Lara M. Lange, Anthony H. V. Schapira, Kailash P. Bhatia, Andrew B. Singleton, Cornelis Blauwendraat, Christine Klein, Henry Houlden, Nicholas W. Wood, Paul R. Jarman, Huw R. Morris, Raquel Real","doi":"10.1038/s41531-024-00778-z","DOIUrl":"https://doi.org/10.1038/s41531-024-00778-z","url":null,"abstract":"<p>The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset ≤35 years. We identified pathogenic variants in <i>LRRK2</i> in 4.2% of families, and biallelic pathogenic variants in <i>PRKN</i> in 3.6% of families. We also identified two families with <i>SNCA</i> duplications and three families with a pathogenic repeat expansion in <i>ATXN2</i>, as well as single families with pathogenic variants in <i>VCP</i>, <i>PINK1</i>, <i>PNPLA6</i>, <i>PLA2G6</i>, <i>SPG7</i>, <i>GCH1</i>, and <i>RAB32</i>. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk <i>GBA1</i> variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"1 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448249","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":"Machine learning model base on metabolomics and proteomics to predict cognitive impairment in Parkinson’s disease","authors":"Baiyuan Yang, Yongyun Zhu, Kelu Li, Fang Wang, Bin Liu, Qian Zhou, Yuchao Tai, Zhaochao Liu, Lin Yang, Ruiqiong Ba, Chunyan Lei, Hui Ren, Zhong Xu, Ailan Pang, Xinglong Yang","doi":"10.1038/s41531-024-00795-y","DOIUrl":"https://doi.org/10.1038/s41531-024-00795-y","url":null,"abstract":"<p>There is an urgent need to identify predictive biomarkers of Parkinson’s disease (PD) with cognitive impairment (PDCI) in order to individualize patient management, ensure timely intervention, and improve prognosis. The aim of this study was to screen for these biomarkers by comparing the plasma proteome and metabolome of PD patients with or without cognitive impairment. Proteomics and metabolomics analyses were performed on a discover cohort. A machine learning model was used to identify candidate protein and metabolite biomarkers of PDCI, which were validated in an independent cohort. The predictive ability of these biomarkers for PDCI was evaluated by plotting receiver operating characteristic curves and calculating the area under the curve (AUC). Moreover, we assessed the predictive ability of these proteins in combination with neuroimaging. In the discover cohort (<i>n</i> = 100), we identified 25 protein features with best results in the machine learning model, including top-ranked PSAP and H3C15. The two-proteins were used for model construction, achieving an Area under the curve (AUC) of 0.951 in the train set and AUC of 0.981 in the test set. Similarly, the model gives a rank list of endogenous metabolite features, Glycocholic Acid and 6-Methylnicotinamide were two top features. Combining these two markers further got the AUC of 0.969 in train set and 0.867 in the test set. To validate the performance of the protein biomarkers, we performed targeted analysis of selected proteins (H3C15 and PSAP) and proteins likely associated with PDCI (NCAM2 and LAMB2) using parallel reaction monitoring in validation cohort (<i>n</i> = 116). The AUC of the classifier built with H3C15 and PSAP is 0.813. Moreover, when combining H3C15, PSAP, NCAM2, and LAMB2, the model achieved AUC of 0.983 in the train set, AUC of 0.981 in the test set, and AUC of 0.839 in the validation set. Furthermore, we verified that these protein markers we discovered can improve the predictive effect of neuroimaging on PDCI: the classifier built with neuroimaging features had AUC of 0.833, which improved to 0.905 when combined with H3C15. Taken together, our integrated proteomics and metabolomics analysis successfully identified potential biomarkers for PDCI. Additionally, H3C15 showed promise in enhancing the predictive performance of neuroimaging for cognitive impairment.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"14 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405333","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":"MicroRNAs regulation in Parkinson’s disease, and their potential role as diagnostic and therapeutic targets","authors":"Nour Shaheen, Ahmed Shaheen, Mahmoud Osama, Abdulqadir J. Nashwan, Vishal Bharmauria, Oliver Flouty","doi":"10.1038/s41531-024-00791-2","DOIUrl":"https://doi.org/10.1038/s41531-024-00791-2","url":null,"abstract":"<p>MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by binding to target messenger RNA (mRNA) molecules and promoting their degradation or blocking their translation. Parkinson’s disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. There is increasing evidence to suggest that miRNAs play a role in the pathogenesis of PD. Studies have identified several miRNAs that are dysregulated in the brains of PD patients, and animal models of the disease. MiRNA expression dysregulation contributes to the onset and progression of PD by modulating neuroinflammation, oxidative stress, and protein aggregation genes. Moreover, miRNAs have emerged as potential therapeutic targets for PD. This review elucidates the changes in miRNA expression profiles associated with PD, emphasising their potential as diagnostic biomarkers and therapeutic targets, and detailing specific miRNAs implicated in PD and their downstream targets.</p><figure><p>Integrated Insights into miRNA Function, Microglial Activation, Diagnostic, and Treatment Prospects in PD Note: This figure is an original figure created by the authors.</p></figure>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"3 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377415","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":"Single-cell RNA sequencing reveals peripheral immunological features in Parkinson’s Disease","authors":"Liu-Lin Xiong, Ruo-Lan Du, Rui-Ze Niu, Lu-Lu Xue, Li Chen, Li-Ren Huangfu, Xiao-Xing Cai, Xiu-Ying He, Jin Huang, Xue-Yan Huang, Jia Liu, Chang-Yin Yu, Wen-Yuan Wang, Ting-Hua Wang","doi":"10.1038/s41531-024-00790-3","DOIUrl":"https://doi.org/10.1038/s41531-024-00790-3","url":null,"abstract":"<p>Although many researchers of Parkinson’s disease (PD) have shifted their focus from the central nervous system (CNS) to the peripheral blood, a significant knowledge gap remains between PD severity and the peripheral immune response. In the current study, we aimed to map the peripheral immunity atlas in peripheral blood mononuclear cells (PBMCs) from PD patients and healthy controls using single-cell RNA sequencing (scRNA-seq). Our study employed scRNA-seq analysis to map the peripheral immunity atlas in PD by profiling PBMCs from PD-Early, PD-Late patients and matched controls. By enlarging the blood sample size, we validated the roles of NK cells in numerous immune-related biological processes. We also detected the infiltration of NK cells into the cerebral motor cortex as the disease progressed, using human brain sections, and elucidated the communication between the periphery and CNS and its implications for PD. As a result, cell subpopulation atlases in PBMCs from PD patients and healthy controls along with differentially expressed genes in NK cells were identified by scRNA-seq analysis, representing 6 major immune cell subsets among which NK cells declined in the progression of PD. We further validated NK cell reduction in increasing samples and found that they participated in numerous immune-related biological processes and infiltration into the cerebral motor cortex as the disease proceeded, evidencingd the close communication between the peripheral immune response and CNS. Strikingly, XCL2 positively correlated with PD severity, with good predictive performance of PD and specific expression in subclusters C2 and C5 of NK cells. All these findings delineated the critical role of peripheral immune response mediated by NK cells in the pathogenesis of PD. NK cell-specific XCL2 could be used as a diagnostic marker for treating PD. The indispensable function of NK cells and NK cell-specific molecular biomarkers highlighted the implication of the peripheral immune response in PD progression. Trial registration: ChiCTR, ChiCTR1900023975. Registered 20 June 2019 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=31035.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374202","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":"Prospective study of bipolar disorder and neurodegenerative diseases","authors":"Xinming Xu, Yaqi Li, Hanyu Lu, Han Wang, Yi Guo, Alexandru Dregan, Liang Sun, Yun Shen, Tingting Geng, Xiang Gao","doi":"10.1038/s41531-024-00794-z","DOIUrl":"https://doi.org/10.1038/s41531-024-00794-z","url":null,"abstract":"<p>Bipolar disorder (BD) is linked to an increased risk of neurodegenerative diseases such as dementia and Parkinson disease (PD), yet several uncertainties still remain and the extent to which the associations could be explained by BD-related medications (antipsychotics, lithium, and antiepileptics) was unknown. This study included 501,233 UK Biobank participants (mean [standard deviation] age, 56.5 [8.10] years; 54.4% women), free of dementia and PD at baseline. After a median 13.8 year follow-up, 9422 cases of dementia and 3457 PD cases were identified. Participants with BD had a significantly higher risk of dementia (adjusted hazard ratio [HR] 2.52, 95% CI 2.00–3.19) and PD (adjusted HR 2.88, 95% CI 2.03-4.08). Findings suggest that up to two-thirds of the association of neurodegenerative diseases with BD may be mediated by BD-related medications. Further research is needed to confirm these findings and explore the underlying mechanisms.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"11 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369005","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 cerebrospinal dual-site magnetic stimulation on freezing of gait in Parkinson’s disease","authors":"Lina Wang, Huimin Sun, Heng Zhang, Min Ji, Caiting Gan, Aidi Shan, Xingyue Cao, Yongsheng Yuan, Kezhong Zhang","doi":"10.1038/s41531-024-00792-1","DOIUrl":"https://doi.org/10.1038/s41531-024-00792-1","url":null,"abstract":"<p>Addressing levodopa-unresponsive freezing of gait (FOG) in Parkinson’s disease (PD) presents a significant challenge. A randomized double-blinded trial evaluated the effects of repetitive transcranial magnetic stimulation (rTMS) in conjunction with transcutaneous magnetic spinal cord stimulation among 57 PD individuals experiencing levodopa-unresponsive FOG. Patients were randomized to receive dual-site stimulation involving bilateral primary motor cortex of the lower leg (M1-LL) and the lumbar spinal cord, single-site stimulation targeting bilateral M1-LL alone, or sham stimulation for 10 sessions. Low-frequency rTMS induced remarkable improvements in FOG, gait, and motor functions compared to sham at 1 day and 1 month postintervention. Notably, the dual-site protocol demonstrated superior efficacy in mitigating FOG and improving gait compared to the single-site approach, which correlated with a pronounced increase in short-interval intracortical inhibition of the abductor pollicis brevis. These findings underscore the potential of the cerebrospinal dual-site regimen as a promising approach for levodopa-unresponsive FOG and gait in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"37 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330331","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 systematic review and meta-analysis of the prevalence of Parkinson’s disease in lower to upper-middle-income countries","authors":"Gabriela Magalhães Pereira, Daniel Teixeira-dos-Santos, Nayron Medeiros Soares, Gabriel Alves Marconi, Deise Cristine Friedrich, Paula Saffie Awad, Bruno Lopes Santos-Lobato, Pedro Renato P. Brandão, Alastair J. Noyce, Connie Marras, Ignacio F. Mata, Carlos Roberto de Mello Rieder, Artur Francisco Schumacher Schuh","doi":"10.1038/s41531-024-00779-y","DOIUrl":"https://doi.org/10.1038/s41531-024-00779-y","url":null,"abstract":"<p>Parkinson’s disease (PD) is a common neurodegenerative disease that is a growing public health challenge. Estimates of the burden of PD have focused on data from high-income countries, with lower-income countries poorly described. We reviewed and examined the prevalence of PD reported by studies in low- to upper-middle-income countries. A systematic literature search was performed in the Medline/PubMed, Embase, LILACS, and Web of Science databases. Age group, sex, and geographic region were considered when analyzing the data. Of the 4327 assessed articles, 57 met the inclusion criteria for qualitative review, and 36 were included in the meta-analysis. Heterogeneity measures were high both as a whole and in each geographic region. Data analysis by geographic region showed that reported prevalence differed across regions, ranging from 49 per 100,000 (Sub-Saharan Africa) to 1081 per 100,000 (Latin America and the Caribbean). There was an increasing prevalence of PD with advancing age (per 100,000): 7 in 40–49 years, 158 in 50–59 years, 603 in 60–69 years, 1251 in 70–79 years, and 2181 in over the age of 80. The prevalence of PD in men and women was similar. There was a greater PD prevalence in populations with a higher 5-year GDP per capita and a higher life expectancy. Our findings suggest a higher prevalence of PD in lower and upper-middle-income countries than previously reported. Comparisons between regions are difficult, as the sociocultural differences and lack of methodological standardization hinder understanding key epidemiological data in varied populations.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"77 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330322","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":"TMS-evoked potentials unveil occipital network involvement in patients diagnosed with Parkinson’s disease within 5 years of inclusion","authors":"Noa Zifman, Ofri Levy-Lamdan, Tal Hiller, Avner Thaler, Iftach Dolev, Anat Mirelman, Hilla Fogel, Mark Hallett, Inbal Maidan","doi":"10.1038/s41531-024-00793-0","DOIUrl":"https://doi.org/10.1038/s41531-024-00793-0","url":null,"abstract":"<p>Distinguishing Parkinson’s disease (PD) subgroups may be achieved by observing network responses to external stimuli. We compared TMS-evoked potential (TEP) measures from stimulation of bilateral motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), and visual cortex (V1) between 62 PD patients (age: 69.9 ± 7.5) and 76 healthy controls (age: 69.2 ± 4.3) using a TMS–EEG protocol. TEP measures were analyzed using two-way ANCOVA adjusted for MOCA. PD patients were divided into tremor dominant (TD), non-tremor dominant (NTD) and rapid disease progression (RDP) subgroups. PD patients showed lower wide-waveform adherence (wWFA) (<i>p</i> = 0.025) and interhemispheric connectivity (IHC_CONN) (<i>p</i> &lt; 0.001) compared to healthy controls. Lower occipital IHC_CONN correlated with advanced disease stage (<i>r</i> = −0.37, <i>p</i> = 0.0039). The RDP and NTD groups showed lower wWFA in response to occipital stimulation than the TD group (<i>p</i> = 0.005). Occipital TEP measures identified RDP patients with 85% accuracy. These findings demonstrate occipital network involvement in early PD stages, suggesting that TEP measures offer insights into altered networks in PD subgroups.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"35 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330374","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":"Reduced subthalamic and subthalamic-cortical coherences associated with the therapeutic carryover effect of coordinated reset deep brain stimulation","authors":"Lvpiao Zheng, Ziling Luo, Biswaranjan Mohanty, Sana Amoozegar, Luke A. Johnson, Jerrold L. Vitek, Jing Wang","doi":"10.1038/s41531-024-00797-w","DOIUrl":"https://doi.org/10.1038/s41531-024-00797-w","url":null,"abstract":"<p>Coordinated reset deep brain stimulation (CR DBS), a promising treatment for Parkinson’s disease (PD), is hypothesized to desynchronize neuronal populations. However, little in vivo data probes this hypothesis. In a parkinsonian nonhuman primate, we found that subthalamic CR DBS suppressed subthalamic and cortical-subthalamic coherences in the beta band, correlating with motor improvements. Our results support the desynchronizing mechanism of CR DBS and propose potential biomarkers for closed-loop CR DBS.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"217 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328695","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}