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@ARTICLE{Siderowf:257678,
      author       = {Siderowf, Andrew and Concha-Marambio, Luis and Lafontant,
                      David-Erick and Farris, Carly M and Ma, Yihua and Urenia,
                      Paula A and Nguyen, Hieu and Alcalay, Roy N and Chahine,
                      Lana M and Foroud, Tatiana and Galasko, Douglas and
                      Kieburtz, Karl and Merchant, Kalpana and Mollenhauer, Brit
                      and Poston, Kathleen L and Seibyl, John and Simuni, Tanya
                      and Tanner, Caroline M and Weintraub, Daniel and Videnovic,
                      Aleksandar and Choi, Seung Ho and Kurth, Ryan and
                      Caspell-Garcia, Chelsea and Coffey, Christopher S and
                      Frasier, Mark and Oliveira, Luis M A and Hutten, Samantha J
                      and Sherer, Todd and Marek, Kenneth and Soto, Claudio},
      collaboration = {Initiative, Parkinson's Progression Markers},
      title        = {{A}ssessment of heterogeneity among participants in the
                      {P}arkinson's {P}rogression {M}arkers {I}nitiative cohort
                      using α-synuclein seed amplification: a cross-sectional
                      study.},
      journal      = {The lancet / Neurology},
      volume       = {22},
      number       = {5},
      issn         = {1474-4422},
      address      = {London},
      publisher    = {Lancet Publ. Group},
      reportid     = {DZNE-2023-00475},
      pages        = {407 - 417},
      year         = {2023},
      abstract     = {Emerging evidence shows that α-synuclein seed
                      amplification assays (SAAs) have the potential to
                      differentiate people with Parkinson's disease from healthy
                      controls. We used the well characterised, multicentre
                      Parkinson's Progression Markers Initiative (PPMI) cohort to
                      further assess the diagnostic performance of the
                      α-synuclein SAA and to examine whether the assay identifies
                      heterogeneity among patients and enables the early
                      identification of at-risk groups.This cross-sectional
                      analysis is based on assessments done at enrolment for PPMI
                      participants (including people with sporadic Parkinson's
                      disease from LRRK2 and GBA variants, healthy controls,
                      prodromal individuals with either rapid eye movement sleep
                      behaviour disorder (RBD) or hyposmia, and non-manifesting
                      carriers of LRRK2 and GBA variants) from 33 participating
                      academic neurology outpatient practices worldwide (in
                      Austria, Canada, France, Germany, Greece, Israel, Italy, the
                      Netherlands, Norway, Spain, the UK, and the USA).
                      α-synuclein SAA analysis of CSF was performed using
                      previously described methods. We assessed the sensitivity
                      and specificity of the α-synuclein SAA in participants with
                      Parkinson's disease and healthy controls, including
                      subgroups based on genetic and clinical features. We
                      established the frequency of positive α-synuclein SAA
                      results in prodromal participants (RBD and hyposmia) and
                      non-manifesting carriers of genetic variants associated with
                      Parkinson's disease, and compared α-synuclein SAA to
                      clinical measures and other biomarkers. We used odds ratio
                      estimates with $95\%$ CIs to measure the association between
                      α-synuclein SAA status and categorical measures, and
                      two-sample $95\%$ CIs from the resampling method to assess
                      differences in medians between α-synuclein SAA positive and
                      negative participants for continuous measures. A linear
                      regression model was used to control for potential
                      confounders such as age and sex.This analysis included 1123
                      participants who were enrolled between July 7, 2010, and
                      July 4, 2019. Of these, 545 had Parkinson's disease, 163
                      were healthy controls, 54 were participants with scans
                      without evidence of dopaminergic deficit, 51 were prodromal
                      participants, and 310 were non-manifesting carriers.
                      Sensitivity for Parkinson's disease was $87·7\%$ $(95\%$ CI
                      84·9-90·5), and specificity for healthy controls was
                      $96·3\%$ (93·4-99·2). The sensitivity of the α-synuclein
                      SAA in sporadic Parkinson's disease with the typical
                      olfactory deficit was $98·6\%$ (96·4-99·4). The
                      proportion of positive α-synuclein SAA was lower than this
                      figure in subgroups including LRRK2 Parkinson's disease
                      $(67·5\%$ [59·2-75·8]) and participants with sporadic
                      Parkinson's disease without olfactory deficit $(78·3\%$
                      [69·8-86·7]). Participants with LRRK2 variant and normal
                      olfaction had an even lower α-synuclein SAA positivity rate
                      $(34·7\%$ [21·4-48·0]). Among prodromal and at-risk
                      groups, 44 $(86\%)$ of 51 of participants with RBD or
                      hyposmia had positive α-synuclein SAA (16 of 18 with
                      hyposmia, and 28 of 33 with RBD). 25 $(8\%)$ of 310
                      non-manifesting carriers (14 of 159 $[9\%]$ LRRK2 and 11 of
                      151 $[7\%]$ GBA) were positive.This study represents the
                      largest analysis so far of the α-synuclein SAA for the
                      biochemical diagnosis of Parkinson's disease. Our results
                      show that the assay classifies people with Parkinson's
                      disease with high sensitivity and specificity, provides
                      information about molecular heterogeneity, and detects
                      prodromal individuals before diagnosis. These findings
                      suggest a crucial role for the α-synuclein SAA in
                      therapeutic development, both to identify pathologically
                      defined subgroups of people with Parkinson's disease and to
                      establish biomarker-defined at-risk cohorts.PPMI is funded
                      by the Michael J Fox Foundation for Parkinson's Research and
                      funding partners, including: Abbvie, AcureX, Aligning
                      Science Across Parkinson's, Amathus Therapeutics, Avid
                      Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen,
                      BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene,
                      Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali,
                      Edmond J Safra Foundation, Eli Lilly, GE Healthcare,
                      Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen
                      Neuroscience, Lundbeck, Merck, Meso Scale Discovery,
                      Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi
                      Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily,
                      Voyager Therapeutics, and Yumanity.},
      keywords     = {Humans / alpha-Synuclein: genetics / Parkinson Disease:
                      diagnosis / Parkinson Disease: genetics / Cross-Sectional
                      Studies / Anosmia / REM Sleep Behavior Disorder / Biomarkers
                      / alpha-Synuclein (NLM Chemicals) / Biomarkers (NLM
                      Chemicals)},
      cin          = {AG Fischer},
      ddc          = {610},
      cid          = {I:(DE-2719)1410002},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC10627170},
      pubmed       = {pmid:37059509},
      doi          = {10.1016/S1474-4422(23)00109-6},
      url          = {https://pub.dzne.de/record/257678},
}