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@ARTICLE{Pescoller:282585,
      author       = {Pescoller, Julia and Dewenter, Anna and Dehsarvi, Amir and
                      Steward, Anna and Frontzkowski, Lukas and Zhu, Zeyu and
                      Roemer-Cassiano, Sebastian N and Palleis, Carla and Hirsch,
                      Fabian and Wagner, Fabian and de Bruin, Hannah and
                      Rauchmann, Boris Stephan and Perneczky, Robert and Gnoerich,
                      Johannes and Malpetti, Maura and Ossenkoppele, Rik and
                      Schöll, Michael and Levin, Johannes and Höglinger, Günter
                      U and Brendel, Matthias and Franzmeier, Nicolai},
      title        = {{C}ortical tau deposition promotes atrophy in connected
                      white matter regions in {A}lzheimer's disease.},
      journal      = {Brain},
      volume       = {148},
      number       = {12},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2025-01345},
      pages        = {4359 - 4371},
      year         = {2025},
      abstract     = {In Alzheimer's disease (AD), fibrillar tau pathology is a
                      key driver of neurodegeneration and cortical atrophy. Yet,
                      emerging evidence suggests that tau aggregates also
                      contribute to white matter (WM) damage. Specifically,
                      physiological tau stabilizes intra-axonal microtubules,
                      whereas hyperphosphorylated tau disrupts microtubule
                      integrity, with ensuing intraneuronal tau aggregation,
                      neuronal disconnection and axonal degeneration. Therefore,
                      we investigated whether cortical tau promotes atrophy in
                      connected WM regions in AD. To this end, we included 186
                      amyloid-positive (Aβ+) patients across the AD spectrum and
                      102 cognitively normal (CN) amyloid-negative (Aβ-)
                      participants from the Alzheimer's Disease Neuroimaging
                      Initiative (ADNI) with baseline amyloid-PET, tau-PET and
                      T1-weighted MRI. Longitudinal tau-PET and MRI (∼2 years)
                      were available for a subset of 138 participants to assess
                      the relationship between tau accumulation and WM atrophy
                      over time. For replication, we included 378/60 CN Aβ+/Aβ-
                      participants from the A4/LEARN cohort with baseline
                      amyloid-PET, tau-PET and T1-weighted MRI, where a subset of
                      141/4 CN Aβ+/Aβ- subjects had ∼5-year longitudinal
                      tau-PET and MRI. Cortical tau-PET standardized uptake value
                      ratios were extracted from 210 cortical regions of the
                      Brainnetome Atlas. In addition, we used a diffusion
                      MRI-based tractography template to determine WM volumes of
                      fibre tracts connected to cortical regions using segmented
                      T1-weighted MRI. Using linear regression, we tested whether
                      higher cortical tau-PET at baseline was associated with (i)
                      lower baseline WM volume and (ii) faster WM volume loss over
                      time, and (iii) whether faster longitudinal tau-PET
                      increases paralleled faster WM loss. Testing the reverse
                      model examined whether baseline WM atrophy predicted faster
                      subsequent tau-PET increase in connected regions. Models
                      were adjusted for age, sex, intracranial volume, WM
                      hyperintensity volume, ApoE4 status and global amyloid-PET.
                      In ADNI participants, elevated baseline cortical tau-PET in
                      temporal regions was associated with lower baseline WM
                      volume in adjacent regions, with more pronounced effects in
                      patients across the AD spectrum and with weaker associations
                      in the preclinical A4/LEARN sample. In both samples, higher
                      baseline temporo-parietal tau-PET and faster tau-PET
                      increase over time were significantly linked to accelerated
                      volume loss in connected WM regions, which was especially
                      pronounced in individuals on the AD spectrum. Importantly,
                      baseline WM volume did not predict subsequent tau-PET rates
                      of change in adjacent cortical regions, suggesting a
                      unidirectional relationship between fibrillar tau and
                      subsequent WM degeneration. Together, our findings suggest
                      that cortical tau accumulation promotes atrophy in adjacent
                      WM regions in AD, highlighting that tau-induced axonal
                      degeneration and, potentially, neuronal disconnection might
                      play a pivotal role in disease progression.},
      keywords     = {Humans / Alzheimer Disease: pathology / Alzheimer Disease:
                      metabolism / Alzheimer Disease: diagnostic imaging / tau
                      Proteins: metabolism / Male / Female / Aged / White Matter:
                      pathology / White Matter: metabolism / White Matter:
                      diagnostic imaging / Atrophy: pathology / Atrophy:
                      metabolism / Positron-Emission Tomography / Aged, 80 and
                      over / Magnetic Resonance Imaging / Cerebral Cortex:
                      pathology / Cerebral Cortex: metabolism / Cerebral Cortex:
                      diagnostic imaging / Middle Aged / Longitudinal Studies /
                      Amyloid beta-Peptides: metabolism / Alzheimer’s disease
                      (Other) / neuroimaging (Other) / progressive white matter
                      degeneration (Other) / tau pathology (Other) / tau Proteins
                      (NLM Chemicals) / Amyloid beta-Peptides (NLM Chemicals) /
                      MAPT protein, human (NLM Chemicals)},
      cin          = {Clinical Research (Munich) / AG Dichgans / AG Levin / AG
                      Haass},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015 / I:(DE-2719)5000022 /
                      I:(DE-2719)1111016 / I:(DE-2719)1110007},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40966722},
      doi          = {10.1093/brain/awaf339},
      url          = {https://pub.dzne.de/record/282585},
}