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@ARTICLE{Zatcepin:271973,
      author       = {Zatcepin, Artem and Gnörich, Johannes and Rauchmann, Boris
                      Stephan and Bartos, Laura M and Wagner, Stephan and
                      Franzmeier, Nicolai and Malpetti, Maura and Xiang, Xianyuan
                      and Shi, Yuan and Parhizkar, Samira and Grosch, Maximilian
                      and Wind-Mark, Karin and Kunte, Sebastian T and Beyer,
                      Leonie and Klaus, Carolin and Brösamle, Desirée and
                      Wendeln, Ann-Christin and Osei-Sarpong, Collins and Heindl,
                      Steffanie and Liesz, Arthur and Stoecklein, Sophia and
                      Biechele, Gloria and Finze, Anika and Eckenweber, Florian
                      and Lindner, Simon and Rominger, Axel and Bartenstein, Peter
                      and Willem, Michael and Tahirovic, Sabina and Herms, Jochen
                      and Buerger, Katharina and Simons, Mikael and Haass,
                      Christian and Rupprecht, Rainer and Riemenschneider, Markus
                      J and Albert, Nathalie L and Beyer, Marc and Neher, Jonas J
                      and Paeger, Lars and Levin, Johannes and Höglinger, Günter
                      U and Perneczky, Robert and Ziegler, Sibylle I and Brendel,
                      Matthias},
      title        = {{R}egional desynchronization of microglial activity is
                      associated with cognitive decline in {A}lzheimer's disease.},
      journal      = {Molecular neurodegeneration},
      volume       = {19},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2024-01115},
      pages        = {64},
      year         = {2024},
      abstract     = {Microglial activation is one hallmark of Alzheimer disease
                      (AD) neuropathology but the impact of the regional interplay
                      of microglia cells in the brain is poorly understood. We
                      hypothesized that microglial activation is regionally
                      synchronized in the healthy brain but experiences regional
                      desynchronization with ongoing neurodegenerative disease. We
                      addressed the existence of a microglia connectome and
                      investigated microglial desynchronization as an AD
                      biomarker.To validate the concept, we performed microglia
                      depletion in mice to test whether interregional correlation
                      coefficients (ICCs) of 18 kDa translocator protein
                      (TSPO)-PET change when microglia are cleared. Next, we
                      evaluated the influence of dysfunctional microglia and AD
                      pathophysiology on TSPO-PET ICCs in the mouse brain,
                      followed by translation to a human AD-continuum dataset. We
                      correlated a personalized microglia desynchronization index
                      with cognitive performance. Finally, we performed
                      single-cell radiotracing (scRadiotracing) in mice to ensure
                      the microglial source of the measured
                      desynchronization.Microglia-depleted mice showed a strong
                      ICC reduction in all brain compartments, indicating
                      microglia-specific desynchronization. AD mouse models
                      demonstrated significant reductions of microglial
                      synchronicity, associated with increasing variability of
                      cellular radiotracer uptake in pathologically altered brain
                      regions. Humans within the AD-continuum indicated a
                      stage-depended reduction of microglia synchronicity
                      associated with cognitive decline. scRadiotracing in mice
                      showed that the increased TSPO signal was attributed to
                      microglia.Using TSPO-PET imaging of mice with depleted
                      microglia and scRadiotracing in an amyloid model, we provide
                      first evidence that a microglia connectome can be assessed
                      in the mouse brain. Microglia synchronicity is closely
                      associated with cognitive decline in AD and could serve as
                      an independent personalized biomarker for disease
                      progression.},
      keywords     = {Animals / Microglia: metabolism / Alzheimer Disease:
                      metabolism / Alzheimer Disease: pathology / Mice / Cognitive
                      Dysfunction: metabolism / Humans / Brain: metabolism /
                      Brain: pathology / Disease Models, Animal /
                      Positron-Emission Tomography / Receptors, GABA: metabolism /
                      Male / Mice, Transgenic / Connectome: methods / Female /
                      Alzheimer’s disease (Other) / Brain connectivity (Other) /
                      Dementia (Other) / Microglia (Other) / Microglia
                      desynchronization (Other) / Microglia synchronicity (Other)
                      / Neuroinflammation (Other) / PET (Other) / TSPO (Other) /
                      Receptors, GABA (NLM Chemicals)},
      cin          = {AG Haass / AG Herms / AG Dichgans / AG Beyer / AG Neher
                      (Tübingen) / AG Tahirovic / Clinical Research (Munich) /
                      PRECISE},
      ddc          = {570},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1110001 /
                      I:(DE-2719)5000022 / I:(DE-2719)1013035 / I:(DE-2719)1210012
                      / I:(DE-2719)1140003 / I:(DE-2719)1111015 /
                      I:(DE-2719)1013031},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353 /
                      G:(DE-HGF)POF4-351},
      experiment   = {EXP:(DE-2719)PRECISE-20190321},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11375924},
      pubmed       = {pmid:39238030},
      doi          = {10.1186/s13024-024-00752-6},
      url          = {https://pub.dzne.de/record/271973},
}