Jacopo Gervasoni, Carmen Marino, Alberto Imarisio, Lavinia Santucci, Enza Napolitano, Tommaso Nuzzo, Isar Yahyavi, Micol Avenali, Michela Cicchinelli, Gabriele Buongarzone, Caterina Galandra, Marta Picascia, Manuela Grimaldi, Claudio Pacchetti, Francesco Errico, Anna Maria D'Ursi, Andrea Urbani, Enza Maria Valente, Alessandro Usiello
{"title":"Independent serum metabolomics approaches identify disrupted glutamic acid and serine metabolism in Parkinson's disease patients.","authors":"Jacopo Gervasoni, Carmen Marino, Alberto Imarisio, Lavinia Santucci, Enza Napolitano, Tommaso Nuzzo, Isar Yahyavi, Micol Avenali, Michela Cicchinelli, Gabriele Buongarzone, Caterina Galandra, Marta Picascia, Manuela Grimaldi, Claudio Pacchetti, Francesco Errico, Anna Maria D'Ursi, Andrea Urbani, Enza Maria Valente, Alessandro Usiello","doi":"10.1038/s41531-025-01126-5","DOIUrl":"10.1038/s41531-025-01126-5","url":null,"abstract":"<p><p>Whether distinct blood metabolomic profiles can distinguish Parkinson's disease (PD) patients from healthy controls (HC) is still a matter of debate. Here, we employed ¹H-NMR and UPLC/MS analyses on serum samples from a cohort of PD patients and HC. Compared to HC, PD patients showed: (1) higher glutamine, serine, pyruvate and lower α-ketoglutarate levels (<sup>1</sup>H-NMR); (2) higher glycine and lower glutamic acid concentrations (UPLC/MS). Several pathways associated with amino acids, mitochondrial and antioxidant metabolism emerged as dysregulated in PD. Our findings highlight a prominent disruption of cellular bioenergetic pathways and amino acid homeostasis in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"11 1","pages":"274"},"PeriodicalIF":8.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150359","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}
Yuri L Sosero, Karl Heilbron, Pierre Fontanillas, Lucy Norcliffe-Kaufmann, Eric Yu, Uladzislau Rudakou, Jennifer A Ruskey, Kathryn Freeman, Farnaz Asayesh, Kajsa A Brolin, Maria Swanberg, Huw R Morris, Lesley Wu, Raquel Real, Lasse Pihlstrøm, Manuela Tan, Thomas Gasser, Kathrin Brockmann, Hui Liu, Michele T M Hu, Donald G Grosset, Simon J G Lewis, John B Kwok, Pau Pastor, Ignacio Alvarez, Matej Skorvanek, Alexandra Lackova, Miriam Ostrozovicova, Mie Rizig, Lynne Krohn, Ziv Gan-Or
{"title":"Genome-wide association study of REM sleep behavior disorder in Parkinson's disease.","authors":"Yuri L Sosero, Karl Heilbron, Pierre Fontanillas, Lucy Norcliffe-Kaufmann, Eric Yu, Uladzislau Rudakou, Jennifer A Ruskey, Kathryn Freeman, Farnaz Asayesh, Kajsa A Brolin, Maria Swanberg, Huw R Morris, Lesley Wu, Raquel Real, Lasse Pihlstrøm, Manuela Tan, Thomas Gasser, Kathrin Brockmann, Hui Liu, Michele T M Hu, Donald G Grosset, Simon J G Lewis, John B Kwok, Pau Pastor, Ignacio Alvarez, Matej Skorvanek, Alexandra Lackova, Miriam Ostrozovicova, Mie Rizig, Lynne Krohn, Ziv Gan-Or","doi":"10.1038/s41531-025-01078-w","DOIUrl":"10.1038/s41531-025-01078-w","url":null,"abstract":"<p><p>REM sleep behavior disorder (RBD), is a prodromal synucleinopathy affecting a subset of Parkinson's disease (PD) patients and associated with neuropsychiatric symptoms. This study compared the genetic profiles of 13,020 PD patients with probable RBD (PD + RBD) and 5403 without (PD-RBD) using genome-wide association study (GWAS). RBD was assessed by questionnaires or self-reporting. Potential genetic correlations between neuropsychiatric traits and PD + RBD were assessed using linkage disequilibrium score regression. The top variant in the SNCA locus was associated with PD + RBD (rs10005233-T, OR = 1.21, 95% CI = 1.16-1.27, p = 1.81e-15). PD risk variants in SNCA (rs5019538-G, OR = 0.85, 95% CI = 0.81-0.89, p = 2.46e-10; rs356182-G, OR = 0.89, 95% CI = 0.84-0.95, p = 0.0001) and LRRK2 loci (rs34637584, OR = 0.41, 95% CI = 0.28-0.61, p = 1.04e-5) were associated with reduced PD + RBD risk. A suggestive genetic correlation between attention deficit hyperactivity disorder and PD + RBD was observed but was not statistically significant after correction. These findings highlight genetic distinctions between PD + RBD and PD-RBD, offering insights into PD stratification and potential subtype-specific treatments.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"11 1","pages":"272"},"PeriodicalIF":8.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150337","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":"Predicting Parkinson's disease and its progression based on radiomics in T1-weight images and α‑synuclein in cerebrospinal fluid.","authors":"Xu Zhang,Hui Li,Xiaona Xia,Jiaojiao Wu,Feng Shi,Cuiping Zhao,Xiangshui Meng,Qingguo Ren","doi":"10.1038/s41531-025-01097-7","DOIUrl":"https://doi.org/10.1038/s41531-025-01097-7","url":null,"abstract":"This study aimed to develop a radiomics model that can predict Parkinson's disease (PD) and its progression of using T1-weighted images (T1WI), and to evaluate the prediction performance of a multimodal model incorporating clinical factors. We selected all participants from the Parkinson's Progression Markers Initiative (PPMI) (n = 205) database and Qilu Hospital of Shandong University (Qingdao) (n = 60). The patients were tracked over 4-5 years via Hoehn-Yahr Scale (HYS) and categorized into stable PD (SPD: HYS unchanged) and progression PD (PPD: HYS increase). Participants from the PPMI database were randomly divided into a training dataset and an internal testing dataset to construct radiomics models, which were validated by the Qilu Hospital database as an independent testing dataset. Only participants from the PPMI database had cerebrospinal fluid (CSF) α‑synuclein (α-syn) data, which were used to establish a combined model. The radiomics-based classifier for healthy controls (HC) and PD achieved areas under the receiver operating characteristic curves (AUROCs) of 0.787 and 0.746 in the internal and independent testing datasets, respectively, while the AUROCs were 0.857 and 0.802 in predicting SPD and PPD, respectively. Moreover, integrating CSF total α-syn in the combined model enhanced the predictive performance, with AUROC of 0.890, sensitivity of 0.846 and specificity of 0.857 for HC vs. PD, and AUROC of 0.939, sensitivity of 0.917 and specificity of 0.933 for SPD vs. PPD in the internal testing dataset. The current research presented evidence that radiomics utilizing conventional T1WI can predict the clinical stages of PD and that the efficacy of the multimodal model can be boosted by combining radiomics with CSF total α‑syn.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"29 1","pages":"273"},"PeriodicalIF":8.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140305","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}
Marc Sevenich, Ian Gering, Bettina Kass, Madita Vollmer, Selma Aghabashlou Saisan, Markus Tusche, Tatsiana Kupreichyk, Thomas Pauly, Matthias Stoldt, Wolfgang Hoyer, Antje Willuweit, Janine Kutzsche, Nils-Alexander Lakomek, Luitgard Nagel-Steger, Lothar Gremer, Gültekin Tamgüney, Jeannine Mohrlüder, Dieter Willbold
{"title":"Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide.","authors":"Marc Sevenich, Ian Gering, Bettina Kass, Madita Vollmer, Selma Aghabashlou Saisan, Markus Tusche, Tatsiana Kupreichyk, Thomas Pauly, Matthias Stoldt, Wolfgang Hoyer, Antje Willuweit, Janine Kutzsche, Nils-Alexander Lakomek, Luitgard Nagel-Steger, Lothar Gremer, Gültekin Tamgüney, Jeannine Mohrlüder, Dieter Willbold","doi":"10.1038/s41531-025-01132-7","DOIUrl":"10.1038/s41531-025-01132-7","url":null,"abstract":"<p><p>A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration associated with soluble oligomeric and fibrillar forms of misfolded α-synuclein (α-syn). In this study, all-D-enantiomeric peptide ligands are presented that bind monomeric α-syn with high affinity, stabilize its physiological monomeric status, prevent aggregation and dissolve existing aggregates. This \"antiprionic\" mode of action directly targets pathogenic aggregated particles. Using mirror-image phage display on D-enantiomeric full-length α-syn, SVD-1 and SVD-1a were identified, showing a delay of aggregation and reduction of aggregate formation in both de novo and seeded models. Picomolar KDs were confirmed by SPR, where a highly dynamic interaction mode was verified by PRE-NMR. SVD-1a also reduced the toxicity and intracellular seeding of α-syn fibrils in cell culture by disassembling them into monomers, as confirmed by atomic force microscopy and dynamic light scattering. These results support SVD-1a as a promising lead compound for the treatment of Parkinson's disease.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"11 1","pages":"271"},"PeriodicalIF":8.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125697","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}
Layla Drwesh, Giuseppe Arena, Daniel J. Merk, Daniele Ferrante, Vyron Gorgogietas, Thomas Gasser, Anne Grünewald, Patrick May, Kathrin Brockmann, Rejko Krüger, Richard Wüst, Christian Johannes Gloeckner, Julia C. Fitzgerald
{"title":"Methodological validation of Miro1 retention as a candidate Parkinson’s disease biomarker","authors":"Layla Drwesh, Giuseppe Arena, Daniel J. Merk, Daniele Ferrante, Vyron Gorgogietas, Thomas Gasser, Anne Grünewald, Patrick May, Kathrin Brockmann, Rejko Krüger, Richard Wüst, Christian Johannes Gloeckner, Julia C. Fitzgerald","doi":"10.1038/s41531-025-01115-8","DOIUrl":"https://doi.org/10.1038/s41531-025-01115-8","url":null,"abstract":"<p>Mitochondrial markers help stratify Parkinson’s disease (PD) patients. We use high-throughput blotting to quantify Miro1, Mfn2, and VDAC levels in fibroblasts, blood cells, and iPSC-derived neurons. Miro1 is specifically retained in PD cells but degraded in healthy ones after mitochondrial depolarization. We correlate Miro1 retention scores with pathogenic mutations, genetic background, age, and clinical data. This scalable assay and quantifiable score for mitochondrial-PD support biomarker development and pharmacological screening.</p><figure></figure>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"71 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068060","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}
Luisa Franck, Lisa Hahnefeld, Lucie Valek, Katharina Klatt-Schreiner, Annett Wilken-Schmitz, Mohamad Wessam Alnouri, Sandra Trautmann, Marc-Philipp Weyer, Dominique Thomas, Robert Gurke, Stefan Offermanns, Gerd Geisslinger, Irmgard Tegeder
{"title":"Elevated hexosylceramides in Parkinson’s disease cause gene upregulations in neurons mimicking responses to pathogens","authors":"Luisa Franck, Lisa Hahnefeld, Lucie Valek, Katharina Klatt-Schreiner, Annett Wilken-Schmitz, Mohamad Wessam Alnouri, Sandra Trautmann, Marc-Philipp Weyer, Dominique Thomas, Robert Gurke, Stefan Offermanns, Gerd Geisslinger, Irmgard Tegeder","doi":"10.1038/s41531-025-01114-9","DOIUrl":"https://doi.org/10.1038/s41531-025-01114-9","url":null,"abstract":"<p>Parkinson’s Disease (PD) is driven by pathological aggregates of alpha-synuclein (αSyn), whose formation is facilitated by impaired glycosphingolipid metabolism via acidic glucocerebrosidase (GCase). We investigated glucosylceramide (GlcCer) accumulation in human, mouse, and cellular PD models. Lipidomic analyses revealed elevated plasma GlcCer, especially GlcCer24:1, and a shift in phosphatidylcholine (PC) species in PD patients. PD patient skin fibroblasts accumulated more GlcCer under lysosomal stress. GlcCer and sulfatides (SHexCer) were increased in Pink1<sup>−/−</sup>SNCA<sup>A53T</sup> PD mouse brains, and HT22 neurons exposed to preformed αSyn fibrils accumulated GlcCer and ceramides. GlcCer24:1 enhanced fibril toxicity, but had no direct or indirect effect on G-protein coupled receptors. RNAseq of GlcCer24:1-treated dorsal root ganglion neurons showed upregulation of glycolipid response genes, similar to pathogen-related signaling. These data indicate extracellular GlcCer is elevated in PD and triggers innate immune responses in sensory neurons.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"93 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919173","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}
Jessica Pei, Nathalia L. Oliveira, Sherilyn J. Recinto, Alexandra Kazanova, Celso M. Queiroz-Junior, Ziyi Li, Katalina Couto, Susan Westfall, Ahmed M. Fahmy, Camila Tiefensee-Ribeiro, Irah L. King, Austen J. Milnerwood, Michel Desjardins, Ajitha Thanabalasuriar, Jo Anne Stratton, Samantha Gruenheid
{"title":"Lrrk2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis","authors":"Jessica Pei, Nathalia L. Oliveira, Sherilyn J. Recinto, Alexandra Kazanova, Celso M. Queiroz-Junior, Ziyi Li, Katalina Couto, Susan Westfall, Ahmed M. Fahmy, Camila Tiefensee-Ribeiro, Irah L. King, Austen J. Milnerwood, Michel Desjardins, Ajitha Thanabalasuriar, Jo Anne Stratton, Samantha Gruenheid","doi":"10.1038/s41531-025-01077-x","DOIUrl":"https://doi.org/10.1038/s41531-025-01077-x","url":null,"abstract":"<p>Parkinson’s Disease (PD) is a neurodegenerative disorder often preceded by gastrointestinal dysfunction. Mutations in leucine-rich repeat kinase 2 (<i>LRRK2</i>) are known risk factors for both PD and inflammatory bowel disease (IBD), suggesting a link between PD and the gastrointestinal tract. Using single-cell RNA-sequencing and spectral flow cytometry, we demonstrated that the <i>Lrrk2</i> Gly2019Ser (G2019S) mutation is associated with an increased neutrophil presence in the colonic lamina propria during <i>Citrobacter rodentium</i> infection. This concurred with a Th17 skewing, upregulated <i>Il17a</i>, and greater colonic pathology during infection. In vitro experiments showed enhanced kinase-dependent neutrophil chemotaxis and neutrophil extracellular trap (NET) formation in <i>Lrrk2</i> G2019S mice compared to wild-type counterparts. Our results add to the understanding of LRRK2-driven immune cell dysregulation and its contribution to PD, offering insights into potential biomarkers for early diagnosis and intervention in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"11 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919116","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}
Johannes L. Busch, Jonathan Kaplan, Jennifer K. Behnke, Victoria S. Witzig, Luisa Drescher, Jeroen G. V. Habets, Andrea A. Kühn
{"title":"Chronic adaptive deep brain stimulation for Parkinson’s disease: clinical outcomes and programming strategies","authors":"Johannes L. Busch, Jonathan Kaplan, Jennifer K. Behnke, Victoria S. Witzig, Luisa Drescher, Jeroen G. V. Habets, Andrea A. Kühn","doi":"10.1038/s41531-025-01124-7","DOIUrl":"https://doi.org/10.1038/s41531-025-01124-7","url":null,"abstract":"<p>Adaptive deep brain stimulation (DBS) dynamically adjusts stimulation amplitude based on neurophysiological feedback and may alleviate residual motor fluctuations in patients with Parkinson’s disease. However, potential clinical benefits and programming strategies remain poorly understood. We programmed eight patients with Parkinson’s disease on commercially available Dual Threshold adaptive DBS based on subthalamic beta power. Symptom severity was evaluated at home using ecological momentary assessments during two weeks of both continuous and adaptive DBS. Patients were not blinded to the stimulation mode. On the group level, overall well-being significantly improved with adaptive DBS (<i>p</i> = 0.007), and there was a non-significant trend toward enhanced general movement (<i>p</i> = 0.058). Within-subject analysis showed a significant improvement in overall well-being and general movement in three of eight patients. Six of eight patients chose to remain on adaptive DBS. Programming challenges included biomarker selection, threshold definition, and artifact-related maladaptation, for which targeted strategies are reported. Our findings support adaptive DBS as a potential option for selected Parkinson’s disease patients with persistent motor symptoms on continuous DBS. We propose a three-step programming approach to guide clinical implementation of adaptive DBS.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"55 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915366","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}
Yan Li, Millie McDonald-Webb, David J. McLernon, Carl E. Counsell, Angus D. Macleod
{"title":"Systematic review of prognostic models in Parkinson’s disease","authors":"Yan Li, Millie McDonald-Webb, David J. McLernon, Carl E. Counsell, Angus D. Macleod","doi":"10.1038/s41531-025-01112-x","DOIUrl":"https://doi.org/10.1038/s41531-025-01112-x","url":null,"abstract":"<p>Predicting outcomes for people with Parkinson’s (PwP) can enable better information provision, personalised treatments, and enhanced trial design. It is unclear what prognostic models are optimal for use. We systematically reviewed previously published prognostic models for PwP, assessed quality, and made recommendations. We searched MEDLINE and EMBASE for studies developing/validating models predicting clinical outcomes in PwP. We assessed risk of bias and applicability using the PROBAST tool. We screened 1024 references and identified 25 studies (41 prognostic models). The most common outcomes were falls (11 studies), dementia (7) and motor complications (4). Most models made short-term predictions (60% ≤2 years). All studies had concerns about bias, e.g., inadequate population details (<i>n</i> = 16), suboptimal methods for missing data (<i>n</i> = 21), and no external validation (<i>n</i> = 22). 13 models had sufficient information to be used in practice. Further development and validation of prognostic models is needed which follows existing guidelines to reduce risk of bias.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"10 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915365","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}