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@ARTICLE{Cebulla:299825,
      author       = {G. M. Cebulla$^*$ and L. Hai$^*$ and U. Warnken$^*$ and C.
                      Güngör and D. C. Hoffmann$^*$ and M. Korporal-Kuhnke and
                      B. Wildemann and W. Wick$^*$ and T. Kessler$^*$ and M.
                      Weiler},
      title        = {{L}ong-term {CSF} responses in adult patients with spinal
                      muscular atrophy type 2 or 3 on treatment with nusinersen.},
      journal      = {Journal of neurology},
      volume       = {272},
      number       = {4},
      issn         = {0367-004X},
      address      = {[Darmstadt]},
      publisher    = {Steinkopff},
      reportid     = {DKFZ-2025-00562},
      pages        = {270},
      year         = {2025},
      note         = {#EA:B320#LA:B320#},
      abstract     = {5q-associated spinal muscular atrophy (SMA) is a monogenic
                      disease causing progressive alpha motor neuron degeneration,
                      muscle atrophy, and weakness. Intrathecal therapy with the
                      antisense oligonucleotide nusinersen modifies the disease
                      course. However, biomarkers for understanding underlying
                      molecular pathomechanisms and monitoring therapy are not yet
                      known.A total of 130 cerebrospinal fluid (CSF) samples from
                      24 adult patients with SMA type 2 or 3 were collected over
                      3.5 years, and CSF proteome was analyzed using mass
                      spectrometry (MS). By applying two complementary MS protein
                      quantification methods, label-free quantification (LFQ) and
                      tandem mass tag (TMT) isotopic labeling, specific protein
                      patterns reflecting changes in the CSF in response to
                      nusinersen therapy were identified. These results were
                      combined with cellular and metabolic profiles.Nusinersen
                      therapy led to a median motor function improvement of 2.2
                      Hammersmith Functional Motor Scale-Expanded points after 10
                      months and 2.6 points after 34 months. CSF macrophages
                      increased in number and showed an altered morphology.
                      Albumin quotient (qAlb), glucose, and lactate concentrations
                      were inversely correlated with clinical improvement. MS
                      analysis of CSF identified 1,674 (TMT) and 441 (LFQ)
                      proteins. Protein profiles reflected reduced inhibition of
                      'nervous system development' and 'axogenesis' pathways under
                      therapy. In addition, clinical improvement was associated
                      with upregulation of the interacting proteins
                      α-dystroglycan and beta-1,4-glucuronyltransferase 1,
                      reduction of complement factors, negative correlation in
                      immunoglobulin- and B cell-related pathways, and reduction
                      of cellular mediators such as lymphocytes.The present
                      multi-proteomic analysis contributes to the understanding of
                      the molecular mechanisms underlying nusinersen's therapeutic
                      effects and offers potential biomarkers for monitoring
                      treatment response in SMA.},
      keywords     = {Humans / Adult / Oligonucleotides: pharmacology /
                      Oligonucleotides: administration $\&$ dosage / Male / Female
                      / Spinal Muscular Atrophies of Childhood: drug therapy /
                      Spinal Muscular Atrophies of Childhood: cerebrospinal fluid
                      / Middle Aged / Young Adult / Biomarkers: cerebrospinal
                      fluid / Adolescent / Treatment Outcome / Antisense
                      oligonucleotide (ASO) (Other) / Cerebrospinal fluid (CSF)
                      (Other) / Mass spectrometry (MS) (Other) / Nusinersen
                      (Other) / Proteomics (Other) / Spinal muscular atrophy (SMA)
                      (Other) / nusinersen (NLM Chemicals) / Oligonucleotides (NLM
                      Chemicals) / Biomarkers (NLM Chemicals)},
      cin          = {B320 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B320-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40085221},
      pmc          = {pmc:PMC11909034},
      doi          = {10.1007/s00415-025-12984-7},
      url          = {https://inrepo02.dkfz.de/record/299825},
}