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@ARTICLE{Yan:1027035,
      author       = {Yan, Shijun and Jiang, Cheng and Janzen, Annette and
                      Barber, Thomas R. and Seger, Aline and Sommerauer, Michael
                      and Davis, Jason J. and Marek, Kenneth and Hu, Michele T.
                      and Oertel, Wolfgang H. and Tofaris, George K.},
      title        = {{N}euronally {D}erived {E}xtracellular {V}esicle
                      α-{S}ynuclein as a {S}erum {B}iomarker for {I}ndividuals at
                      {R}isk of {D}eveloping {P}arkinson {D}isease},
      journal      = {JAMA neurology},
      volume       = {81},
      number       = {1},
      issn         = {2168-6149},
      address      = {Chicago, Ill.},
      publisher    = {American Medical Association},
      reportid     = {FZJ-2024-03601},
      pages        = {59 -},
      year         = {2024},
      abstract     = {IMPORTANCE Nonmotor symptoms of Parkinson disease (PD)
                      often predate the movement disorder by decades. Currently,
                      there is no blood biomarker to define this prodromal
                      phase.OBJECTIVE To investigate whether a-synuclein in
                      neuronally derived serum-extracellular vesicles identifies
                      individuals at risk of developing PD and related
                      dementia.DESIGN, SETTING, AND PARTICIPANTS This
                      retrospective, cross-sectional multicenter study of serum
                      samples included the Oxford Discovery, Marburg, Cologne, and
                      Parkinson·s Progression Markers Initiative cohorts.
                      Participants were recruited from July 2013 through August
                      2023 and samples were analyzed from April 2022 through
                      September 2023. The derivation group (n = 170) included
                      participants with isolated rapid eye movement sleep behavior
                      disorder (iRBD) and controls. Two validation groups were
                      used: the first (n = 122)included participants with iRBD and
                      controls and the second (n = 263) included nonmanifestGBAN/
                      o4 s9 gene carriers, participants with iRBD or hyposmia, and
                      available dopamine transporter single-photon emission
                      computed tomography, healthy controls, and patients with
                      sporadic PD. Overall the study included 199 participants
                      with iRBD, 20 hyposmic participants with available dopamine
                      transporter single-photon emission computed tomography, 146
                      nonmanifest GBAIN 4095 gene carriers, 21 GBAIN 4095 gene
                      carrier patients with PD, 50 patients with sporadic PD, and
                      140 healthy controls. In the derivation group and validation
                      group 1. participants with polysomnographically confirmed
                      iRBD were included. In the validation group 2, at-risk
                      participants with available Movement Disorder Society
                      prodromal markers and serum samples were included. Among 580
                      potential participants,4 were excluded due to alternative
                      diagnoses.EXPOSURES Clinical assessments, imaging, and serum
                      collection.MAIN OUTCOME AND MEASURES LlCAM-positive
                      extracellular vesicles (LlEV) were immunocaptured from
                      serum. a-Synuclein and syntenin-1 were measured by
                      electrochemiluminescence. Area under the receiver operating
                      characteristic (ROC) curve (AUC) with $95\%$ Cis evaluated
                      biomarker performance. Probable prodromal PD was determined
                      using the updated Movement Disorder Society research
                      criteria. Multiple linear regression models assessed the
                      association between LlEV a-synuclein and prodromal
                      markers.RESULTS Among 576 participants included, the mean
                      (SD) age was 64.30 (8.27) years, 394 were male (68 $.4\%),$
                      and 182 were female $(31.6\%).$ A derived threshold of serum
                      LlEV a-synuclein distinguished participants with iRBD from
                      controls (AUC = 0.91; $95\%$ Cl, 0.86-0.96) and those with
                      more than $80\%$ probability of having prodromal PD from
                      participants with less than $5\%$ probability (AUC = 0.80;
                      $95\%$ Cl. 0.71-0.89) . Subgroup analyses revealed that
                      specific combinations of prodromal markers were associated
                      with increased LlEV a-synuclein levels. Across all cohorts,
                      LlEV a-synuclein differentiated participants with more than
                      $80\%$ probability of having prodromal PD from current
                      andhistoric healthy control populations (AUC = 0.90; $95\%$
                      Cl, 0 .87-0 .93), irrespective of initialdiagnosis. LlEV
                      a-synuclein was increased in at-risk participants with a
                      positive cerebrospinal fluid seed amplification assay and
                      was above the identified threshold in $80\%$ of cases(n =
                      40) that phenoconverted to PD or related
                      dementia.CONCLUSIONS AND RELEVANCE LlEVa-synuclein in
                      combination with prodromal markers should be considered in
                      the stratification of those at high risk of developing PD
                      and related Lewy body diseases.},
      cin          = {INM-3},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-3-20090406},
      pnm          = {5252 - Brain Dysfunction and Plasticity (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5252},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {38048087},
      UT           = {WOS:001117758100002},
      doi          = {10.1001/jamaneurol.2023.4398},
      url          = {https://juser.fz-juelich.de/record/1027035},
}