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@ARTICLE{Brockmann:162639,
      author       = {Brockmann, Kathrin and Quadalti, Corinne and Lerche,
                      Stefanie and Rossi, Marcello and Wurster, Isabel and
                      Baiardi, Simone and Röben, Benjamin and Mammana, Angela and
                      Zimmermann, Milan and Hauser, Ann-Kathrin and Deuschle,
                      Christian and Schulte, Claudia and Waniek, Katharina and
                      Lachmann, Ingolf and Sjödin, Simon and Brinkmalm, Ann and
                      Blennow, Kaj and Zetterberg, Henrik and Gasser, Thomas and
                      Parchi, Piero},
      title        = {{A}ssociation between {CSF} alpha-synuclein seeding
                      activity and genetic status in {P}arkinson's disease and
                      dementia with {L}ewy bodies.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {9},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2021-01335},
      pages        = {175},
      year         = {2021},
      note         = {CC BY},
      abstract     = {The clinicopathological heterogeneity in Lewy-body diseases
                      (LBD) highlights the need for pathology-driven
                      biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a
                      lead candidate based on its crucial role in disease
                      pathophysiology. Real-time quaking-induced conversion
                      (RT-QuIC) analysis of CSF has recently shown high
                      sensitivity and specificity for the detection of misfolded
                      α-Syn in patients with Parkinson's disease (PD) and
                      dementia with Lewy bodies (DLB). In this study we performed
                      the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched
                      for different genetic forms with mutations
                      in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of
                      100 PD patients was also analysed longitudinally. We
                      correlated kinetic seeding parameters of RT-QuIC with
                      genetic status and CSF protein levels of molecular pathways
                      linked to α-Syn proteostasis. Overall, $85\%$ of PD and
                      $86\%$ of DLB patients showed positive RT-QuIC α-Syn
                      seeding activity. Seeding profiles were significantly
                      associated with mutation status across the spectrum of
                      genetic LBD. In PD patients, we detected positive α-Syn
                      seeding in $93\%$ of patients carrying
                      severe GBA mutations, in $78\%$ with LRRK2 mutations, in
                      $59\%$ carrying heterozygous mutations in recessive genes,
                      and in none of those with bi-allelic mutations in recessive
                      genes. Among PD patients, those with severe GBA mutations
                      showed the highest seeding activity based on RT-QuIC kinetic
                      parameters and the highest proportion of samples with 4 out
                      of 4 positive replicates. In DLB patients, $100\%$
                      with GBA mutations showed positive α-Syn seeding compared
                      to $79\%$ of wildtype DLB. Moreover, we found an association
                      between α-Syn seeding activity and reduced CSF levels of
                      proteins linked to α-Syn proteostasis, specifically
                      lysosome-associated membrane glycoprotein 2 and
                      neurosecretory protein VGF.These findings highlight the
                      value of α-Syn seeding activity as an in-vivo marker of
                      Lewy-body pathology and support its use for patient
                      stratification in clinical trials targeting α-Syn.},
      keywords     = {Biomarkers: cerebrospinal fluid / Humans / Lewy Body
                      Disease: cerebrospinal fluid / Lewy Body Disease: genetics /
                      Lewy Body Disease: pathology / Parkinson Disease:
                      cerebrospinal fluid / Parkinson Disease: genetics /
                      Parkinson Disease: pathology / alpha-Synuclein:
                      cerebrospinal fluid / CSF (Other) / GBA (Other) / PD (Other)
                      / Parkin (Other) / RT-QuIC (Other) / α-Syn seeding (Other)},
      cin          = {AG Gasser / Core ICRU / Biobanking Facility Tübingen / AG
                      Berg},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)1240005 /
                      I:(DE-2719)1240004 / I:(DE-2719)5000055},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34717775},
      pmc          = {pmc:PMC8556894},
      doi          = {10.1186/s40478-021-01276-6},
      url          = {https://pub.dzne.de/record/162639},
}