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@ARTICLE{Biechele:164000,
      author       = {Biechele, Gloria and Sebastian Monasor, Laura and Wind,
                      Karin and Blume, Tanja and Parhizkar, Samira and Arzberger,
                      Thomas and Sacher, Christian and Beyer, Leonie and
                      Eckenweber, Florian and Gildehaus, Franz-Josef and von
                      Ungern-Sternberg, Barbara and Willem, Michael and
                      Bartenstein, Peter and Cumming, Paul and Rominger, Axel and
                      Herms, Jochen and Lichtenthaler, Stefan F and Haass,
                      Christian and Tahirovic, Sabina and Brendel, Matthias},
      title        = {{G}litter in the {D}arkness? {N}onfibrillar β-{A}myloid
                      {P}laque {C}omponents {S}ignificantly {I}mpact the
                      β-{A}myloid {PET} {S}ignal in {M}ouse {M}odels of
                      {A}lzheimer {D}isease.},
      journal      = {Journal of nuclear medicine},
      volume       = {63},
      number       = {1},
      issn         = {0022-3123},
      address      = {New York, NY},
      publisher    = {Soc.},
      reportid     = {DZNE-2022-00669},
      pages        = {117 - 124},
      year         = {2022},
      abstract     = {β-amyloid (Aβ) PET is an important tool for
                      quantification of amyloidosis in the brain of suspected
                      Alzheimer disease (AD) patients and transgenic AD mouse
                      models. Despite the excellent correlation of Aβ PET with
                      gold standard immunohistochemical assessments, the relative
                      contributions of fibrillar and nonfibrillar Aβ components
                      to the in vivo Aβ PET signal remain unclear. Thus, we
                      obtained 2 murine cerebral amyloidosis models that present
                      with distinct Aβ plaque compositions and performed
                      regression analysis between immunohistochemistry and Aβ PET
                      to determine the biochemical contributions to Aβ PET signal
                      in vivo. Methods: We investigated groups of AppNL-G-F and
                      APPPS1 mice at 3, 6, and 12 mo of age by longitudinal
                      18F-florbetaben Aβ PET and with immunohistochemical
                      analysis of the fibrillar and total Aβ burdens. We then
                      applied group-level intermodality regression models using
                      age- and genotype-matched sets of fibrillar and nonfibrillar
                      Aβ data (predictors) and Aβ PET results (outcome) for both
                      Aβ mouse models. An independent group of double-hit APPPS1
                      mice with dysfunctional microglia due to knockout of
                      triggering receptor expression on myeloid cells 2 (Trem2-/-)
                      served for validation and evaluation of translational
                      impact. Results: Neither fibrillar nor nonfibrillar Aβ
                      content alone sufficed to explain the Aβ PET findings in
                      either AD model. However, a regression model compiling
                      fibrillar and nonfibrillar Aβ together with the estimate of
                      individual heterogeneity and age at scanning could explain a
                      $93\%$ of variance of the Aβ PET signal (P < 0.001).
                      Fibrillar Aβ burden had a 16-fold higher contribution to
                      the Aβ PET signal than nonfibrillar Aβ. However, given the
                      relatively greater abundance of nonfibrillar Aβ, we
                      estimate that nonfibrillar Aβ produced $79\%$ ± $25\%$ of
                      the net in vivo Aβ PET signal in AppNL-G-F mice and $25\%$
                      ± $12\%$ in APPPS1 mice. Corresponding results in separate
                      groups of APPPS1/Trem2-/- and APPPS1/Trem2+/+ mice validated
                      the calculated regression factors and revealed that the
                      altered fibrillarity due to Trem2 knockout impacts the Aβ
                      PET signal. Conclusion: Taken together, the in vivo Aβ PET
                      signal derives from the composite of fibrillar and
                      nonfibrillar Aβ plaque components. Although fibrillar Aβ
                      has inherently higher PET tracer binding, the greater
                      abundance of nonfibrillar Aβ plaque in AD-model mice
                      contributes importantly to the PET signal.},
      keywords     = {Plaque, Amyloid / PET signal (Other) / amyloid (Other) /
                      fibrillar (Other) / mouse (Other) / nonfibrillar (Other)},
      cin          = {AG Tahirovic / AG Herms / Neuropathology / Brainbank / AG
                      Lichtenthaler / AG Haass},
      ddc          = {610},
      cid          = {I:(DE-2719)1140003 / I:(DE-2719)1110001 /
                      I:(DE-2719)1140013 / I:(DE-2719)1110006 /
                      I:(DE-2719)1110007},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34016733},
      pmc          = {pmc:PMC8717179},
      doi          = {10.2967/jnumed.120.261858},
      url          = {https://pub.dzne.de/record/164000},
}