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@ARTICLE{Bouzigues:280021,
      author       = {Bouzigues, Arabella and Du, Vincent Le and Joulot, Matthieu
                      and Peysson, Ninon and Houot, Marion and Béranger, Benoît
                      and Russell, Lucy L and Foster, Phoebe H and Ferry-Bolder,
                      Eve and van Swieten, John C and Jiskoot, Lize and Seelaar,
                      Harro and Sanchez-Valle, Raquel and Laforce, Robert and
                      Graff, Caroline and Galimberti, Daniela and Vandenberghe,
                      Rik and de Mendonça, Alexandre and Tiraboschi, Pietro and
                      Santana, Isabel and Gerhard, Alexander and Levin, Johannes
                      and Sorbi, Sandro and Otto, Markus and Bertoux, Maxime and
                      Lebouvier, Thibaud and Ducharme, Simon and Butler, Chris R
                      and Ber, Isabelle Le and Finger, Elizabeth and Tartaglia,
                      Maria Carmela and Masellis, Mario and Rowe, James B and
                      Synofzik, Matthis and Moreno, Fermin and Borroni, Barbara
                      and Rohrer, Jonathan D and Migliaccio, Raffaella},
      collaboration = {Initiative, GENetic Frontotemporal dementia},
      title        = {{S}tructural and functional connectivity in tau mutation
                      carriers: from presymptomatic to symptomatic frontotemporal
                      dementia.},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {7},
      issn         = {1552-5260},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {DZNE-2025-00865},
      pages        = {e70367},
      year         = {2025},
      abstract     = {Microtubule-associated protein tau (MAPT) mutations cause
                      frontotemporal dementia (FTD), characterised by behavioural,
                      language, and motor impairments due to brain connectivity
                      disruptions. We investigated structural and functional
                      connectivity in 86 mutation carriers and 272 controls to map
                      connectivity changes at different disease stages.The CDR
                      Dementia Staging Instrument plus National Alzheimer's
                      Coordinating Center (NACC) Behaviour and Language domains
                      (CDR plus NACC FTLD) stratified carriers into three groups:
                      asymptomatic, prodromal, and symptomatic. We extracted
                      measures of cortical thickness, white matter integrity, and
                      functional connectivity, which were compared between each
                      carrier group and controls using linear mixed models.Early
                      isolated functional disruptions in salience/visual networks
                      were present in asymptomatic carriers, along with anterior
                      cingulate gray matter reductions. In prodromal carriers,
                      functional changes extended to other networks, with
                      additional structural damage in temporal
                      poles/cingulate.This study shows that functional networks
                      likely drive lifelong compensation for a genetically
                      determined disease, manifesting clinically when structural
                      damage reaches a critical threshold. This supports
                      connectivity measures as potential biomarkers for
                      MAPT-related neurodegeneration.Our findings reveal the
                      progressive and staged nature of structural and functional
                      connectivity alterations in MAPT mutation carriers, with
                      distinct patterns at each disease stage. In asymptomatic
                      carriers, we identified early functional connectivity
                      alterations in salience and visual networks, despite
                      preserved white matter and only subtle gray matter atrophy.
                      These appear to represent both response to pathology and
                      possible compensatory mechanisms. In prodromal carriers,
                      functional connectivity alterations were accompanied by
                      structural damage, including cortical atrophy and white
                      matter tract disruptions, in regions directly connected to
                      early-affected networks. The sequential progression, from
                      functional connectivity changes to structural degeneration,
                      aligns with the hypothesis that tau propagates along axonal
                      connections, disrupting neural network integrity before
                      measurable atrophy occurs. We propose a theoretical
                      data-driven model of biomarker evolution in MAPT mutation
                      carriers, highlighting functional disruptions as early
                      indicators and structural damage as a later-stage hallmark.
                      These connectivity biomarkers have the potential to inform
                      therapeutic strategies and clinical trial design.},
      keywords     = {Humans / Frontotemporal Dementia: genetics / Frontotemporal
                      Dementia: pathology / Frontotemporal Dementia:
                      physiopathology / Frontotemporal Dementia: diagnostic
                      imaging / tau Proteins: genetics / Male / Female / Middle
                      Aged / Mutation: genetics / Magnetic Resonance Imaging /
                      Aged / White Matter: pathology / White Matter: diagnostic
                      imaging / Heterozygote / Brain: pathology / Brain:
                      physiopathology / Brain: diagnostic imaging / Prodromal
                      Symptoms / MAPT (Other) / functional connectivity (Other) /
                      genetic frontotemporal dementia (Other) / graph analysis
                      (Other) / gray matter (Other) / macroscale organization
                      (Other) / mutation (Other) / neurodegeneration (Other) / tau
                      (Other) / tau pathology (Other) / white matter (Other) / tau
                      Proteins (NLM Chemicals) / MAPT protein, human (NLM
                      Chemicals)},
      cin          = {AG Levin / Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1111016 / I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40673371},
      doi          = {10.1002/alz.70367},
      url          = {https://pub.dzne.de/record/280021},
}