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@ARTICLE{Berezhnoy:278919,
      author       = {Berezhnoy, Georgy and Bae, Gyuntae and Wüst, Leonie and
                      Schulte, Claudia and Cannet, Claire and Wurster, Isabel and
                      Zimmermann, Milan and Jäck, Alexander and Spruth, Eike
                      Jakob and Hellmann-Regen, Julian and Roeske, Sandra and
                      Pürner, Dominik and Glanz, Wenzel and Maass, Fabian and
                      Hufschmidt, Felix and Kilimann, Ingo and Dinter, Elisabeth
                      and Kimmich, Okka and Gamez, Anna and Levin, Johannes and
                      Priller, Josef and Peters, Oliver and Wagner, Michael and
                      Storch, Alexander and Lingor, Paul and Düzel, Emrah and van
                      Riesen, Christoph and Wüllner, Ullrich and Teipel, Stefan
                      and Falkenburger, Björn and Bähr, Mathias and Zerr, Inga
                      and Petzold, Gabor C and Spottke, Annika and Rizzu, Patricia
                      and Brosseron, Frederic and Schäfer, Hartmut and Gasser,
                      Thomas and Trautwein, Christoph},
      title        = {{A}pplication of {IVD}r {NMR} spectroscopy to stratify
                      {P}arkinson's disease with absolute quantitation of blood
                      serum metabolites and lipoproteins.},
      journal      = {Scientific reports},
      volume       = {15},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2025-00645},
      pages        = {17738},
      year         = {2025},
      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.},
      keywords     = {Humans / Parkinson Disease: blood / Parkinson Disease:
                      diagnosis / Parkinson Disease: genetics / Male / Female /
                      Lipoproteins: blood / Magnetic Resonance Spectroscopy:
                      methods / Biomarkers: blood / Middle Aged / Aged /
                      Metabolomics: methods / Mutation / GBA (Other) / Biomarkers
                      (Other) / Blood (Other) / Dementia (Other) / Parkinson’s
                      disease (Other) / Recessive inheritance (Other) /
                      Lipoproteins (NLM Chemicals) / Biomarkers (NLM Chemicals)},
      cin          = {AG Gasser / Clinical Research (Munich) / AG Endres / AG
                      Wagner / AG Düzel / AG Spottke / Clinical Research Platform
                      (CRP) / AG Teipel / AG Falkenburger / Clinical Research
                      (Bonn) / AG Priller / AG Peters / AG Storch / AG Fischer /
                      AG Wüllner / Clinical Dementia Research (Göttingen) / AG
                      Zerr / AG Petzold / AG Heneka},
      ddc          = {600},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)1111015 /
                      I:(DE-2719)1811005 / I:(DE-2719)1011201 / I:(DE-2719)5000006
                      / I:(DE-2719)1011103 / I:(DE-2719)1011401 /
                      I:(DE-2719)1510100 / I:(DE-2719)1710012 / I:(DE-2719)1011001
                      / I:(DE-2719)5000007 / I:(DE-2719)5000000 /
                      I:(DE-2719)5000014 / I:(DE-2719)1410002 / I:(DE-2719)1011302
                      / I:(DE-2719)1440015 / I:(DE-2719)1440011-1 /
                      I:(DE-2719)1013020 / I:(DE-2719)1011303},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40404791},
      pmc          = {pmc:PMC12098827},
      doi          = {10.1038/s41598-025-01352-0},
      url          = {https://pub.dzne.de/record/278919},
}