Application of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteins
Abstract The challenge of early detection and stratification in Parkinson’s disease (PD) is urgent due to the current emergence of mechanism-based disease-modifying treatments. In here, metabolomic and lipidomic parameters obtained by a standardized and targeted in vitro diagnostic research (IVDr) p...
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2025-05-01
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| author | Georgy Berezhnoy Gyuntae Bae Leonie Wüst Claudia Schulte Claire Cannet Isabel Wurster Milan Zimmermann Alexander Jäck Eike Jakob Spruth Julian Hellmann-Regen Sandra Roeske Dominik Pürner Wenzel Glanz Fabian Maass Felix Hufschmidt Ingo Kilimann Elisabeth Dinter Okka Kimmich Anna Gamez Johannes Levin Josef Priller Oliver Peters Michael Wagner Alexander Storch Paul Lingor Emrah Düzel Christoph van Riesen Ullrich Wüllner Stefan Teipel Björn Falkenburger Mathias Bähr Inga Zerr Gabor C. Petzold Annika Spottke Patricia Rizzu Frederic Brosseron Hartmut Schäfer Thomas Gasser Christoph Trautwein |
| author_facet | Georgy Berezhnoy Gyuntae Bae Leonie Wüst Claudia Schulte Claire Cannet Isabel Wurster Milan Zimmermann Alexander Jäck Eike Jakob Spruth Julian Hellmann-Regen Sandra Roeske Dominik Pürner Wenzel Glanz Fabian Maass Felix Hufschmidt Ingo Kilimann Elisabeth Dinter Okka Kimmich Anna Gamez Johannes Levin Josef Priller Oliver Peters Michael Wagner Alexander Storch Paul Lingor Emrah Düzel Christoph van Riesen Ullrich Wüllner Stefan Teipel Björn Falkenburger Mathias Bähr Inga Zerr Gabor C. Petzold Annika Spottke Patricia Rizzu Frederic Brosseron Hartmut Schäfer Thomas Gasser Christoph Trautwein |
| author_sort | Georgy Berezhnoy |
| collection | DOAJ |
| description | Abstract The challenge of early detection and stratification in Parkinson’s disease (PD) is urgent due to the current emergence of mechanism-based disease-modifying treatments. In here, metabolomic and lipidomic parameters obtained by a standardized and targeted in vitro diagnostic research (IVDr) platform have a significant potential to address therapy-related questions and generate improved biomarker panels. Our study aimed to use IVDr nuclear magnetic resonance (NMR) spectroscopy to quantify metabolites and lipoproteins in PD blood serum from different cohorts to stratify metabolically driven subtypes of idiopathic and genetic PD. Serum aliquots from three neurodegeneration biobank cohorts (287 samples in total, including 62 PD patient samples with GBA mutation, 98/43 PD patient samples of early/late stages of disease duration, 20 PD samples from patients with mutations in recessive PD genes and some smaller subgroups of mitochondrial and double mutation cases) were prepared and analyzed with IVDr NMR spectroscopy, covering 39 blood serum metabolites and 112 lipoprotein parameters. Uni- and multivariate statistics were used to identify metabolism-driven changes under consideration of typical confounders such as age, sex and disease duration and set into context with clinical biomarkers such as CSF concentrations of alpha-synuclein, neurofilament light chain, and tau protein. Based on the different PD subgroups we performed a total of eight different comparisons. Highlights from these comparisons include increased citrate and dimethylglycine with a decrease of creatinine and methionine in healthy controls and early PD group compared to GBA, PD late and recessive PD. We furthermore identified decreased HDL-3 free cholesterol in genetic PD cases compared to sporadic subject samples (sum of the PD early and PD late groups). Considering medication, we found that the levodopa equivalent daily dose (LEDD) is mostly positively correlated with tyrosine and citrate in sporadic PD compared to pyruvate and phenylalanine in genetic PD. Cerebrospinal fluid levels of alpha-synuclein were negatively correlated with alanine. Further metabolites and lipoproteins with discriminatory power for double mutation PD cases involved ornithine, 2-aminobutyrate and 2-hydroxybutyrate as well as for mitochondrial phenotypes via LDL phospholipid, apolipoprotein and cholesterol subfractions. Quantitative IVDr NMR serum spectroscopy is able to stratify PD patient samples of different etiology and can contribute to a wider understanding of the underlying metabolism-driven alterations e.g. in energy, amino acid, and lipoprotein metabolism. Though our overall cohort was large, major confounders such as age, sex and medication have a strong impact. That is why absolute quantification and detailed patient knowledge about metabolic confounders, is a premise for future translation of NMR serum spectroscopy to routine PD diagnostics. |
| format | Article |
| id | doaj-art-090a91ccf0504f0f98c10d62617fca73 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-090a91ccf0504f0f98c10d62617fca732025-08-20T02:34:17ZengNature PortfolioScientific Reports2045-23222025-05-0115112010.1038/s41598-025-01352-0Application of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteinsGeorgy Berezhnoy0Gyuntae Bae1Leonie Wüst2Claudia Schulte3Claire Cannet4Isabel Wurster5Milan Zimmermann6Alexander Jäck7Eike Jakob Spruth8Julian Hellmann-Regen9Sandra Roeske10Dominik Pürner11Wenzel Glanz12Fabian Maass13Felix Hufschmidt14Ingo Kilimann15Elisabeth Dinter16Okka Kimmich17Anna Gamez18Johannes Levin19Josef Priller20Oliver Peters21Michael Wagner22Alexander Storch23Paul Lingor24Emrah Düzel25Christoph van Riesen26Ullrich Wüllner27Stefan Teipel28Björn Falkenburger29Mathias Bähr30Inga Zerr31Gabor C. Petzold32Annika Spottke33Patricia Rizzu34Frederic Brosseron35Hartmut Schäfer36Thomas Gasser37Christoph Trautwein38Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of TübingenWerner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of TübingenWerner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of TübingenHertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of TübingenBruker BioSpin GmbH & Co. KG (AIC Division)Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of TübingenHertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of TübingenGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Department of Neurology, School of Medicine, University Hospital München rechts der Isar, Technical University of MunichGerman Center for Neurodegenerative Diseases (DZNE)Department of Neurology, University Medical Center, Georg August UniversityGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Department of Neurology, University Medical Center, Georg August UniversityGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Department of Neurology, University Medical Center, Georg August UniversityDepartment of Neurology, University Medical Center, Georg August UniversityGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Bruker BioSpin GmbH & Co. KG (AIC Division)Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of TübingenWerner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of TübingenAbstract The challenge of early detection and stratification in Parkinson’s disease (PD) is urgent due to the current emergence of mechanism-based disease-modifying treatments. In here, metabolomic and lipidomic parameters obtained by a standardized and targeted in vitro diagnostic research (IVDr) platform have a significant potential to address therapy-related questions and generate improved biomarker panels. Our study aimed to use IVDr nuclear magnetic resonance (NMR) spectroscopy to quantify metabolites and lipoproteins in PD blood serum from different cohorts to stratify metabolically driven subtypes of idiopathic and genetic PD. Serum aliquots from three neurodegeneration biobank cohorts (287 samples in total, including 62 PD patient samples with GBA mutation, 98/43 PD patient samples of early/late stages of disease duration, 20 PD samples from patients with mutations in recessive PD genes and some smaller subgroups of mitochondrial and double mutation cases) were prepared and analyzed with IVDr NMR spectroscopy, covering 39 blood serum metabolites and 112 lipoprotein parameters. Uni- and multivariate statistics were used to identify metabolism-driven changes under consideration of typical confounders such as age, sex and disease duration and set into context with clinical biomarkers such as CSF concentrations of alpha-synuclein, neurofilament light chain, and tau protein. Based on the different PD subgroups we performed a total of eight different comparisons. Highlights from these comparisons include increased citrate and dimethylglycine with a decrease of creatinine and methionine in healthy controls and early PD group compared to GBA, PD late and recessive PD. We furthermore identified decreased HDL-3 free cholesterol in genetic PD cases compared to sporadic subject samples (sum of the PD early and PD late groups). Considering medication, we found that the levodopa equivalent daily dose (LEDD) is mostly positively correlated with tyrosine and citrate in sporadic PD compared to pyruvate and phenylalanine in genetic PD. Cerebrospinal fluid levels of alpha-synuclein were negatively correlated with alanine. Further metabolites and lipoproteins with discriminatory power for double mutation PD cases involved ornithine, 2-aminobutyrate and 2-hydroxybutyrate as well as for mitochondrial phenotypes via LDL phospholipid, apolipoprotein and cholesterol subfractions. Quantitative IVDr NMR serum spectroscopy is able to stratify PD patient samples of different etiology and can contribute to a wider understanding of the underlying metabolism-driven alterations e.g. in energy, amino acid, and lipoprotein metabolism. Though our overall cohort was large, major confounders such as age, sex and medication have a strong impact. That is why absolute quantification and detailed patient knowledge about metabolic confounders, is a premise for future translation of NMR serum spectroscopy to routine PD diagnostics.https://doi.org/10.1038/s41598-025-01352-0Parkinson’s diseaseGBARecessive inheritanceBloodDementiaBiomarkers |
| spellingShingle | Georgy Berezhnoy Gyuntae Bae Leonie Wüst Claudia Schulte Claire Cannet Isabel Wurster Milan Zimmermann Alexander Jäck Eike Jakob Spruth Julian Hellmann-Regen Sandra Roeske Dominik Pürner Wenzel Glanz Fabian Maass Felix Hufschmidt Ingo Kilimann Elisabeth Dinter Okka Kimmich Anna Gamez Johannes Levin Josef Priller Oliver Peters Michael Wagner Alexander Storch Paul Lingor Emrah Düzel Christoph van Riesen Ullrich Wüllner Stefan Teipel Björn Falkenburger Mathias Bähr Inga Zerr Gabor C. Petzold Annika Spottke Patricia Rizzu Frederic Brosseron Hartmut Schäfer Thomas Gasser Christoph Trautwein Application of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteins Scientific Reports Parkinson’s disease GBA Recessive inheritance Blood Dementia Biomarkers |
| title | Application of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteins |
| title_full | Application of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteins |
| title_fullStr | Application of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteins |
| title_full_unstemmed | Application of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteins |
| title_short | Application of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteins |
| title_sort | application of ivdr nmr spectroscopy to stratify parkinson s disease with absolute quantitation of blood serum metabolites and lipoproteins |
| topic | Parkinson’s disease GBA Recessive inheritance Blood Dementia Biomarkers |
| url | https://doi.org/10.1038/s41598-025-01352-0 |
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