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@ARTICLE{Landt:283072,
      author       = {Landt, Carolin and Held, Friederike and Kolotourou,
                      Konstantina and Guranda, Mihaela and Vakrakou, Aigli G and
                      Franz, Jonas and Thomas, Carolina and Schmiedeknecht, Max
                      Ulrich Heiner and Bergann, Klaus and Wrzos, Claudia and
                      Endmayr, Verena and Tsaktanis, Thanos and Zechel, Sabrina
                      and Ancău, Mihai and Misgeld, Thomas and Hakroush, Samy and
                      Hametner, Simon and Rothhammer, Veit and Höftberger, Romana
                      and Hemmer, Bernhard and Stadelmann, Christine and Nessler,
                      Stefan},
      title        = {{C}omplement {C}4d {I}nforms the {D}ifferential {D}iagnosis
                      of {I}nflammatory {D}emyelinating {CNS} {D}iseases.},
      journal      = {Neurology: Neuroimmunology $\&$ Neuroinflammation ;
                      official journal of the American Academy of Neurology},
      volume       = {13},
      number       = {2},
      issn         = {2332-7812},
      address      = {Philadelphia, Pa.},
      publisher    = {Wolters Kluwer},
      reportid     = {DZNE-2025-01479},
      pages        = {e200528},
      year         = {2026},
      abstract     = {Complement-targeting therapies are pivotal in managing
                      neuromyelitis optica spectrum disorder (NMOSD), calling for
                      a deeper understanding of complement activation across
                      idiopathic inflammatory demyelinating diseases (IIDDs) of
                      the CNS. C4d, a covalently bound complement split product,
                      offers prolonged detectability at activation sites. This
                      study explores whether C4d immunohistochemistry (IHC)
                      extends the detection window for complement activation in
                      CNS biopsies of IIDDs and evaluates its usefulness as a
                      fluid biomarker.Forty-four IIDD biopsies with active
                      demyelination were analyzed for complement deposition using
                      IHC for C9neo and C4d. C4d levels were also quantified in
                      blood and CSF of patients with IIDDs. The persistence of C4d
                      in CNS tissue was further evaluated in an in vivo NMOSD
                      model.C4d IHC enhanced the sensitivity to detect complement
                      activation, surpassing C9neo by twofold in NMOSD and by
                      sixfold in ADEM, while remaining undetectable in MS
                      biopsies. Exclusive C4d immunopositivity at the glia
                      limitans distinguished NMOSD from ADEM. Furthermore, CSF C4d
                      levels were significantly elevated in both seronegative and
                      seropositive NMOSD compared with MS.C4d detection extends
                      the window for identifying complement activation in CNS
                      biopsies of IIDDs and emerges as a valuable CSF biomarker,
                      enhancing diagnostic precision, autoantibody target
                      identification, and patient stratification for
                      complement-targeting therapies.},
      keywords     = {Humans / Complement C4b: cerebrospinal fluid / Complement
                      C4b: metabolism / Complement C4b: analysis / Female / Male /
                      Middle Aged / Adult / Neuromyelitis Optica: diagnosis /
                      Diagnosis, Differential / Biomarkers: cerebrospinal fluid /
                      Biomarkers: blood / Peptide Fragments: cerebrospinal fluid /
                      Aged / Demyelinating Autoimmune Diseases, CNS: diagnosis /
                      Complement Activation / Young Adult / Animals / Multiple
                      Sclerosis: diagnosis / Complement C4b (NLM Chemicals) /
                      complement C4d (NLM Chemicals) / Biomarkers (NLM Chemicals)
                      / Peptide Fragments (NLM Chemicals)},
      cin          = {AG Misgeld},
      ddc          = {610},
      cid          = {I:(DE-2719)1110000-4},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41435221},
      pmc          = {pmc:PMC12735299},
      doi          = {10.1212/NXI.0000000000200528},
      url          = {https://pub.dzne.de/record/283072},
}