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@ARTICLE{Khan:903186,
      author       = {Khan, Ahmed Faraz and Adewale, Quadri and Baumeister,
                      Tobias R and Carbonell, Felix and Zilles, Karl and
                      Palomero-Gallagher, Nicola and Iturria-Medina, Yasser},
      title        = {{P}ersonalized brain models identify neurotransmitter
                      receptor changes in {A}lzheimer’s disease},
      journal      = {Brain},
      volume       = {145},
      number       = {5},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {FZJ-2021-04906},
      pages        = {1785–1804},
      year         = {2022},
      abstract     = {Alzheimer’s disease involves many neurobiological
                      alterations from molecular to macroscopic spatial scales,
                      but we currently lack integrative, mechanistic brain models
                      characterizing how factors across different biological
                      scales interact to cause clinical deterioration in a way
                      that is subject-specific or personalized. As important
                      signalling molecules and mediators of many neurobiological
                      interactions, neurotransmitter receptors are promising
                      candidates for identifying molecular mechanisms and drug
                      targets in Alzheimer's disease.We present a neurotransmitter
                      receptor-enriched multifactorial brain model, which
                      integrates spatial distribution patterns of 15
                      neurotransmitter receptors from post-mortem autoradiography
                      with multiple in vivo neuroimaging modalities (tau,
                      amyloid-β and glucose PET, and structural, functional and
                      arterial spin labelling MRI) in a personalized, generative,
                      whole-brain formulation.In a heterogeneous aged population
                      (n = 423, ADNI data), models with personalized
                      receptor-neuroimaging interactions showed a significant
                      improvement over neuroimaging-only models, explaining about
                      $70\%$ $(±20\%)$ of the variance in longitudinal changes to
                      the six neuroimaging modalities. In Alzheimer's disease
                      patients (n = 25, ADNI data), receptor-imaging interactions
                      explained up to $39.7\%$ (P < 0.003, family-wise
                      error-rate-corrected) of inter-individual variability in
                      cognitive deterioration, via an axis primarily affecting
                      executive function. Notably, based on their contribution to
                      the clinical severity in Alzheimer’s disease, we found
                      significant functional alterations to glutamatergic
                      interactions affecting tau accumulation and neural activity
                      dysfunction and GABAergic interactions concurrently
                      affecting neural activity dysfunction, amyloid and tau
                      distributions, as well as significant cholinergic receptor
                      effects on tau accumulation. Overall, GABAergic alterations
                      had the largest effect on cognitive impairment (particularly
                      executive function) in our Alzheimer’s disease cohort (n =
                      25). Furthermore, we demonstrate the clinical applicability
                      of this approach by characterizing subjects based on
                      individualized ‘fingerprints’ of receptor
                      alterations.This study introduces the first robust,
                      data-driven framework for integrating several
                      neurotransmitter receptors, multimodal neuroimaging and
                      clinical data in a flexible and interpretable brain model.
                      It enables further understanding of the mechanistic
                      neuropathological basis of neurodegenerative progression and
                      heterogeneity, and constitutes a promising step towards
                      implementing personalized, neurotransmitter-based
                      treatments.},
      cin          = {INM-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-1-20090406},
      pnm          = {5251 - Multilevel Brain Organization and Variability
                      (POF4-525) / HBP SGA3 - Human Brain Project Specific Grant
                      Agreement 3 (945539) / HBP SGA2 - Human Brain Project
                      Specific Grant Agreement 2 (785907)},
      pid          = {G:(DE-HGF)POF4-5251 / G:(EU-Grant)945539 /
                      G:(EU-Grant)785907},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34605898},
      UT           = {WOS:000788204200001},
      doi          = {10.1093/brain/awab375},
      url          = {https://juser.fz-juelich.de/record/903186},
}