NPJ Parkinson's Disease最新文献

{"title":"Circulating blood circular RNA in Parkinson’s Disease; from involvement in pathology to diagnostic tools in at-risk individuals","authors":"Aleksandra Beric, Yichen Sun, Santiago Sanchez, Charissa Martin, Tyler Powell, Ravindra Kumar, Jose Adrian Pardo, Gauri Darekar, Jessie Sanford, Devin Dikec, Bridget Phillips, Juan A. Botia, Carlos Cruchaga, Laura Ibanez","doi":"10.1038/s41531-024-00839-3","DOIUrl":"https://doi.org/10.1038/s41531-024-00839-3","url":null,"abstract":"<p>To identify circRNAs associated with Parkinson’s disease (PD) we leveraged two of the largest publicly available studies with longitudinal clinical and blood transcriptomic data. We performed a cross-sectional study utilizing the last visit of each participant (<i>N</i> = 1848), and a longitudinal analysis that included 1166 participants with at least two time points. We identified 192 differentially expressed circRNAs, with effects that were sustained during disease, in mutation carriers, and diverse ancestry. The 192 circRNAs were leveraged to distinguish between PD and healthy participants with a ROC AUC of 0.797. Further, 71 circRNAs were sufficient to distinguish between genetic PD (AUC₇₁ = 0.954) and, at-risk participants (AUC₇₁ = 0.929) and healthy controls, supporting that circRNAs have the potential to aid the diagnosis of PD. Finally, we identified five circRNAs highly correlated with symptom severity. Overall, we demonstrated that circRNAs play an important role in PD and can be clinically relevant to improve diagnostic and monitoring.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"8 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665365","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":"Occipital hypoperfusion and motor reserve in Parkinson’s disease: an early-phase 18F-FP-CIT PET study","authors":"Yeo Jun Yoon, Su Hong Kim, Seong Ho Jeong, Chan Wook Park, Hye Sun Lee, Phil Hyu Lee, Yun Joong Kim, Young H. Sohn, Yong Jeong, Seok Jong Chung","doi":"10.1038/s41531-024-00834-8","DOIUrl":"https://doi.org/10.1038/s41531-024-00834-8","url":null,"abstract":"<p>Individual variability exists in parkinsonian motor symptoms despite a similar degree of nigrostriatal dopamine depletion in Parkinson’s disease (PD), called motor reserve. We enrolled 397 patients newly diagnosed with PD who underwent dual-phase ¹⁸F-FP-CIT PET upon initial assessment. Individual motor reserve was estimated based on initial parkinsonian motor symptoms and striatal dopamine transporter availability using a residual model. Patients with low motor reserve (the lowest quartile group, <i>n</i> = 100) exhibited decreased uptake in the occipital region compared to those with high motor reserve (the highest quartile group, <i>n</i> = 100) on early-phase ¹⁸F-FP-CIT PET images. Patients with high motor reserve had a lower risk of conversion to dementia than the those with low motor reserve, whereas the effect of PD groups on the risk of dementia conversion was not mediated by occipital hypoperfusion. These findings suggest that cerebral hypoperfusion in the occipital region is associated with low motor reserve in patients with PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"34 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645851","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":"Cannabinoid regulation of angiotensin II-induced calcium signaling in striatal neurons","authors":"Rafael Rivas-Santisteban, Ana Muñoz, Jaume Lillo, Iu Raïch, Ana I. Rodríguez-Pérez, Gemma Navarro, José L. Labandeira-García, Rafael Franco","doi":"10.1038/s41531-024-00827-7","DOIUrl":"https://doi.org/10.1038/s41531-024-00827-7","url":null,"abstract":"<p>Calcium ion (Ca²⁺) homeostasis is crucial for neuron function and neurotransmission. This study focused on the actions mediated by the CB₁ receptor (CB₁R), the most abundant G protein-coupled receptor (GPCR) in central nervous system (CNS) neurons, over by the AT₁R, which is one of the few G protein-coupled CNS receptors able to regulate cytoplasmic Ca²⁺ levels. A functional interaction suggesting a direct association between these receptors was detected. AT₁-CB₁ receptor heteromers (AT₁CB₁Hets) were identified in HEK-293T cells by bioluminescence resonance energy transfer (BRET²). Functional interactions within the AT₁-CB₁ complex and their potential relevance in Parkinson’s disease (PD) were assessed. In situ proximity ligation assays (PLA) identified AT₁CB₁Hets in neurons, in which an important finding was that Ca²⁺ level increase upon AT₁R activation was reduced in the presence of cannabinoids acting on CB₁Rs. AT₁CB₁Het expression was quantified in samples from the 6-hydroxydopamine (6-OHDA) hemilesioned rat model of PD in which a lower expression of AT₁CB₁Hets was observed in striatal neurons from lesioned animals (versus non-lesioned). AT₁CB₁Het expression changed depending on both the lesion and the consequences of levodopa administration, i.e., dyskinesias versus lack of involuntary movements. A partial recovery in AT₁CB₁Het expression was detected in lesioned animals that developed levodopa-induced dyskinesias. These findings support the existence of a compensatory mechanism mediated by AT₁CB₁Hets that modulates susceptibility to levodopa-induced dyskinesias in PD. Therefore, cannabinoids may be useful in reducing calcium dyshomeostasis in dyskinesia.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637183","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":"Peripheral immune cell abundance differences link blood mitochondrial DNA copy number and Parkinson's disease.","authors":"Longfei Wang, Jiru Han, Liam G Fearnley, Michael Milton, Haloom Rafehi, Joshua Reid, Zachary F Gerring, Shashank Masaldan, Tali Lang, Terence P Speed, Melanie Bahlo","doi":"10.1038/s41531-024-00831-x","DOIUrl":"10.1038/s41531-024-00831-x","url":null,"abstract":"<p><p>Mitochondrial dysfunction plays an important role in Parkinson's disease (PD), with mitochondrial DNA copy number (mtDNA-CN) emerging as a potential marker for mitochondrial health. We investigated the links between blood mtDNA-CN and PD severity and risk using the Accelerating Medicines Partnership program for Parkinson's Disease dataset, replicating our results in the UK Biobank. Our findings reveal that reduced blood mtDNA-CN levels are associated with heightened PD risk and increased severity of motor symptoms and olfactory dysfunction. We estimated blood cell composition using complete blood cell profile when available or RNA-sequencing data as a surrogate. After adjusting for blood cell composition, the associations between mtDNA-CN and PD risk and clinical symptoms became non-significant. Bidirectional Mendelian randomization analysis also found no evidence of a direct causal relationship between blood mtDNA-CN and PD susceptibility. Hence peripheral inflammatory immune responses rather than mitochondrial dysfunction underpin these previously identified associations in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"10 1","pages":"219"},"PeriodicalIF":6.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal neuroimaging-based prediction of Parkinson’s disease with mild cognitive impairment using machine learning technique","authors":"Yongyun Zhu, Fang Wang, Pingping Ning, Yangfan Zhu, Lingfeng Zhang, Kelu Li, Bin Liu, Hui Ren, Zhong Xu, Ailan Pang, Xinglong Yang","doi":"10.1038/s41531-024-00828-6","DOIUrl":"https://doi.org/10.1038/s41531-024-00828-6","url":null,"abstract":"<p>This study aimed to identify potential markers that can predict Parkinson’s disease with mild cognitive impairment (PDMCI). We retrospectively collected general demographic data, clinically relevant scales, plasma samples, and neuroimaging data (T1-weighted magnetic resonance imaging (MRI) data as well as resting-state functional MRI [Rs-fMRI] data) from 173 individuals. Subsequently, based on the aforementioned multimodal indices, a support vector machine was employed to investigate the machine learning (ML) classification of PD patients with normal cognition (PDNC) and PDMCI. The performance of 29 classifiers was assessed based on various combinations of indicators. Results demonstrated that the optimal classifier in the validation set was composed by clinical + Rs-fMRI+ neurofilament light chain, exhibiting a mean Accuracy of 0.762, a mean area under curve of 0.840, a mean sensitivity of 0.745, along with a mean specificity of 0.783. The ML algorithm based on multimodal data demonstrated enhanced discriminative ability between PDNC and PDMCI patients.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"36 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597922","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 framework for translational therapy development in deep brain stimulation","authors":"Jia Zhi Chen, Jens Volkmann, Chi Wang Ip","doi":"10.1038/s41531-024-00829-5","DOIUrl":"https://doi.org/10.1038/s41531-024-00829-5","url":null,"abstract":"<p>Deep brain stimulation (DBS) is an established treatment for motor disorders like Parkinson’s disease, but its mechanisms and effects on neurons and networks are not fully understood, limiting research-driven progress. This review presents a framework that combines neurophysiological insights and translational research to enhance DBS therapy, emphasizing biomarkers, device technology, and symptom-specific neuromodulation. It also examines the role of animal research in improving DBS, while acknowledging challenges in clinical translation.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"9 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597087","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":"Novel tools to quantify total, phospho-Ser129 and aggregated alpha-synuclein in the mouse brain","authors":"Benjamin Guy Trist, Courtney Jade Wright, Alejandra Rangel, Louise Cottle, Asheeta Prasad, Nanna Møller Jensen, Hjalte Gram, Nicolas Dzamko, Poul Henning Jensen, Deniz Kirik","doi":"10.1038/s41531-024-00830-y","DOIUrl":"https://doi.org/10.1038/s41531-024-00830-y","url":null,"abstract":"<p>Assays for quantifying aggregated and phosphorylated (S129) human α-synuclein protein are widely used to evaluate pathological burden in patients suffering from synucleinopathy disorders. Many of these assays, however, do not cross-react with mouse α-synuclein or exhibit poor sensitivity for this target, which is problematic considering the preponderance of mouse models at the forefront of pre-clinical α-synuclein research. In this project, we addressed this unmet need by reformulating two existing AlphaLISA^® SureFire^® Ultra™ total and pS129 α-synuclein assay kits to yield robust and ultrasensitive (LLoQ ≤ 0.5 pg/mL) quantification of mouse and human wild-type and pS129 α-synuclein protein. We then employed these assays, together with the BioLegend α-synuclein aggregate ELISA, to assess α-synuclein S129 phosphorylation and aggregation in different mouse brain tissue preparations. Overall, we highlight the compatibility of these new immunoassays with rodent models and demonstrate their potential to advance knowledge surrounding α-synuclein phosphorylation and aggregation in synucleinopathies.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"18 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597085","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":"The p.Gly2019Ser is a common LRRK2 pathogenic variant among Egyptians with familial and sporadic Parkinson's disease.","authors":"Martina B William, Sharifa Hamed, Ali Shalash, Eman M Khedr, Mohamed H Yousef, Shaimaa El-Jaafary, Gharib Fawi, Asmaa Helmy, Eman Hamid, Mohamed Essam, Hamin Lee, Alina Jama, Mohamed Koraym, Doaa M Mahmoud, Sara Elfarrash, Yasmin Elsaid, Asmaa S Gabr, Nourhan Shebl, Nesreen Abdelwahhab, Tamer M Belal, Nehal A B Elsayed, Mohamed El-Gamal, Shimaa Elgamal, Salma Ragab, Jaidaa Mekky, Lobna Aly, Samir Nabhan, Gaafar Ragab, Mohamed A Hussein, Mohamed Tharwat Hegazy, Henry Houlden, Mohamed Salama, Mie Rizig","doi":"10.1038/s41531-024-00826-8","DOIUrl":"10.1038/s41531-024-00826-8","url":null,"abstract":"<p><p>The impact of LRRK2 variants on the risk of Parkinson's disease in Egyptians remains unknown. We examined 1210 Egyptians (611 PD patients and 599 controls) from 16 governorates across Egypt for 12 LRRK2 pathogenic variants. The p.Gly2019Ser was the only variant detected, with a prevalence of 4.1% in sporadic cases, 6.5% in familial cases, and 0.68% in controls. Among p.Gly2019Ser carriers, all were heterozygous bar one homozygous patient, and all shared the common haplotype 1. Demographics and UPDRS scores did not differ between carriers and non-carriers, with most patients being males and developed PD in their fifties. Young and Early-onset PD prevalence was 37.5% in carriers and 33% in non-carriers. Familial cases were 16.6% in carriers and 11.5% in non-carriers. This study affirms that like other Mediterranean populations, Egyptians with PD have a higher prevalence of the p.Gly2019Ser variant compared to the global average. LRRK2 inhibitors could be promising therapeutic options for further exploration in this population.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"10 1","pages":"215"},"PeriodicalIF":6.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcranial direct current stimulation for Parkinson’s disease: systematic review and meta-analysis of motor and cognitive effects","authors":"Zhuo Duan, Chencheng Zhang","doi":"10.1038/s41531-024-00821-z","DOIUrl":"https://doi.org/10.1038/s41531-024-00821-z","url":null,"abstract":"<p>Transcranial direct current stimulation (tDCS) is a promising noninvasive intervention for Parkinson’s disease (PD). However, studies of its motor and cognitive effect have produced mixed results. We conducted a systematic review including 38 studies and meta-analysis of 12 randomized sham-controlled trials with 263 PD patients. No significant differences were found between active and sham tDCS in motor function (UPDRS-III: SMD = –0.14, p = 0.74), gait (SMD = 0.10, p = 0.513), attention and working memory (SMD = 0.24, p = 0.13), executive function (SMD = 0.03, p = 0.854), and memory and learning (SMD: −0.07, p = 0.758). The prediction intervals indicated substantial heterogeneity among studies. Meta-regression showed small positive effects in younger PD patients with milder symptoms. These findings are preliminary but suggest tDCS may benefit some PD patients while being neutral or harmful to others.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"8 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588776","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":"Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson's disease overexpressing human alpha synuclein.","authors":"Mariangela Massaro Cenere, Marta Tiberi, Emanuela Paldino, Sebastian Luca D'Addario, Mauro Federici, Cecilia Giacomet, Debora Cutuli, Alessandro Matteocci, Francesca Cossa, Beatrice Zarrilli, Nicolas Casadei, Ada Ledonne, Laura Petrosini, Nicola Berretta, Francesca Romana Fusco, Valerio Chiurchiù, Nicola B Mercuri","doi":"10.1038/s41531-024-00824-w","DOIUrl":"10.1038/s41531-024-00824-w","url":null,"abstract":"<p><p>Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinson's disease (PD). In the present study, we assessed the development of symptoms on a genetic PD rat model that overexpresses human α-synuclein (Snca^+/+) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, constant potential amperometry, and behavioral analyses. A single injection of LPS into WT and Snca^+/+ rats triggered long-lasting increase in the activation of pro-inflammatory microglial markers, monocytes, and T lymphocytes. However, only LPS Snca^+/+ rats showed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction in the release of evoked dopamine in the striatum. No significant changes were observed in the behavioral domain. We propose our double-hit animal as a reliable model to investigate the mechanisms whereby α-synuclein and inflammation interact to promote neurodegeneration in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"10 1","pages":"213"},"PeriodicalIF":6.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}