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@ARTICLE{Grut:285259,
      author       = {V. Grut and M. Biström and J. Salzer and P. Stridh and D.
                      Jons and R. Gustafsson and A. Fogdell-Hahn and J. Huang and
                      J. A. Butt$^*$ and A. Lindam and L. Alonso-Magdalena and T.
                      Bergström and I. Kockum and T. Waterboer$^*$ and T. Olsson
                      and H. Zetterberg and K. Blennow and O. Andersen and S.
                      Nilsson and P. Sundström},
      title        = {{H}uman herpesvirus 6{A} and axonal injury before the
                      clinical onset of multiple sclerosis.},
      journal      = {Brain},
      volume       = {147},
      number       = {1},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2023-02294},
      pages        = {177-185},
      year         = {2024},
      note         = {2024 Jan 4;147(1):177-185},
      abstract     = {Recent research indicates that multiple sclerosis is
                      preceded by a prodromal phase with elevated levels of serum
                      neurofilament light chain (sNfL), a marker of axonal injury.
                      The effect of environmental risk factors on the extent of
                      axonal injury during this prodrome is unknown. Human
                      herpesvirus 6A (HHV-6A) is associated with an increased risk
                      of developing multiple sclerosis. The objective of this
                      study was to determine if HHV-6A serostatus is associated
                      with the level of sNfL in the multiple sclerosis prodrome,
                      which would support a causative role of HHV-6A. A nested
                      case-control study was performed by crosslinking multiple
                      sclerosis registries with Swedish biobanks. Individuals with
                      biobank samples collected before the clinical onset of
                      multiple sclerosis were included as cases. Controls without
                      multiple sclerosis were randomly selected, matched for
                      biobank, sex, sampling date and age. Serostatus of HHV-6A
                      and Epstein-Barr virus (EBV) was analysed with a bead-based
                      multiplex assay. The concentration of sNfL was analysed with
                      Single molecule array technology. The association between
                      HHV-6A serology and sNfL was assessed by stratified t-tests
                      and linear regressions, adjusted for EBV serostatus and
                      sampling age. Within-pair ratios of HHV-6A seroreactivity
                      and sNfL were calculated for each case and its matched
                      control. To assess the temporal relationship between HHV-6A
                      antibodies and sNfL, these ratios were plotted against the
                      time to the clinical onset of multiple sclerosis and
                      compared using locally estimated scatterplot smoothing
                      regressions with $95\%$ confidence intervals (CI). Samples
                      from 519 matched case-control pairs were included. In cases,
                      seropositivity of HHV-6A was significantly associated with
                      the level of sNfL $(+11\%,$ $95\%$ CI $0.2-24\%,$ P =
                      0.045), and most pronounced in the younger half of the cases
                      $(+24\%,$ $95\%$ CI $6-45\%,$ P = 0.007). No such
                      associations were observed among the controls. Increasing
                      seroreactivity against HHV-6A was detectable before the rise
                      of sNfL (significant within-pair ratios from 13.6 years vs
                      6.6 years before the clinical onset of multiple sclerosis).
                      In this study, we describe the association between HHV-6A
                      antibodies and the degree of axonal injury in the multiple
                      sclerosis prodrome. The findings indicate that elevated
                      HHV-6A antibodies both precede and are associated with a
                      higher degree of axonal injury, supporting the hypothesis
                      that HHV-6A infection may contribute to multiple sclerosis
                      development in a proportion of cases.},
      keywords     = {Epstein-Barr virus (Other) / axonal injury (Other) / human
                      herpesvirus 6-A (Other) / multiple sclerosis (Other) /
                      neurofilament light chain (Other)},
      cin          = {F020},
      ddc          = {610},
      cid          = {I:(DE-He78)F020-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37930324},
      doi          = {10.1093/brain/awad374},
      url          = {https://inrepo02.dkfz.de/record/285259},
}