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@ARTICLE{Wilke:164658,
      author       = {Wilke, Carlo and Mengel, David and Schöls, Ludger and
                      Hengel, Holger and Rakowicz, Maria and Klockgether, Thomas
                      and Dürr, Alexandra and Filla, Alessandro and Melegh, Bela
                      and Schüle, Rebecca and Reetz, Kathrin and Jacobi, Heike
                      and Synofzik, Matthis},
      title        = {{L}evels of {N}eurofilament {L}ight at the {P}reataxic and
                      {A}taxic {S}tages of {S}pinocerebellar {A}taxia {T}ype 1},
      journal      = {Neurology},
      volume       = {98},
      number       = {20},
      issn         = {0028-3878},
      address      = {[S.l.]},
      publisher    = {Ovid},
      reportid     = {DZNE-2022-01188},
      pages        = {e1985 - e1996},
      year         = {2022},
      abstract     = {Neurofilament light (NfL) appears to be a promising fluid
                      biomarker in repeat-expansion spinocerebellar ataxias
                      (SCAs), with piloting studies in mixed SCA cohorts
                      suggesting that NfL might be increased at the ataxic stage
                      of SCA type 1 (SCA1). We here hypothesized that NfL is
                      increased not only at the ataxic stage of SCA1, but also at
                      its (likely most treatment-relevant) preataxic stage.Methods
                      We assessed serum NfL (sNfL) and CSF NfL (cNfL) levels in
                      both preataxic and ataxic SCA1, leveraging a multicentric
                      cohort recruited at 6 European university centers, and
                      clinical follow-up data, including actually observed (rather
                      than only predicted) conversion to the ataxic stage. Levels
                      of sNfL and cNfL were assessed by single-molecule array and
                      ELISA technique, respectively.Results Forty individuals with
                      SCA1 (23 preataxic, 17 ataxic) and 89 controls were
                      enrolled, including 11 preataxic individuals converting to
                      the ataxic stage. sNfL levels were increased at the
                      preataxic (median 15.5 pg/mL [interquartile range
                      10.5–21.1 pg/mL]) and ataxic stage (31.6 pg/mL
                      [26.2–37.7 pg/mL]) compared to controls (6.0 pg/mL
                      [4.7–8.6 pg/mL]), yielding high age-corrected effect sizes
                      (preataxic: r = 0.62, ataxic: r = 0.63). sNfL increases were
                      paralleled by increases of cNfL at both the preataxic and
                      ataxic stage. In preataxic individuals, sNfL levels
                      increased with proximity to predicted ataxia onset, with
                      significant sNfL elevations already 5 years before onset,
                      and confirmed in preataxic individuals with actually
                      observed ataxia onset. sNfL increases were detected already
                      in preataxic individuals with SCA1 without volumetric
                      atrophy of cerebellum or pons, suggesting that sNfL might be
                      more sensitive to early preataxic neurodegeneration than the
                      currently known most change-sensitive regions in volumetric
                      MRI. Using longitudinal sNfL measurements, we estimated
                      sample sizes for clinical trials with the reduction of sNfL
                      as the endpoint.Discussion sNfL levels might provide easily
                      accessible peripheral biomarkers in both preataxic and
                      ataxic SCA1, allowing stratification of preataxic
                      individuals regarding proximity to onset, early detection of
                      neurodegeneration even before volumetric MRI alterations,
                      and potentially capture of treatment response in clinical
                      trials.Trial Registration Information ClinicalTrials.gov
                      Identifier: NCT01037777.Classification of Evidence This
                      study provides Class III evidence that NfL levels are
                      increased in both ataxic and preataxic SCA1 and are
                      associated with ataxia onset.},
      keywords     = {Atrophy: pathology / Biomarkers / Cerebellar Ataxia:
                      pathology / Cerebellum: pathology / Humans / Intermediate
                      Filaments / Neurofilament Proteins / Spinocerebellar
                      Ataxias: diagnosis},
      cin          = {Core ICRU / AG Gasser 1 / AG Klockgether / AG Maetzler /
                      Patient studies, Bonn},
      ddc          = {610},
      cid          = {I:(DE-2719)1240005 / I:(DE-2719)1210000 /
                      I:(DE-2719)1011001 / I:(DE-2719)5000024 /
                      I:(DE-2719)1011101},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9162044},
      pubmed       = {pmid:35264424},
      doi          = {10.1212/WNL.0000000000200257},
      url          = {https://pub.dzne.de/record/164658},
}