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@ARTICLE{Richter:1040638,
      author       = {Richter, Nils and Breidenbach, Laura and Schmieschek,
                      Maximilian HT and Heiss, Wolf-Dieter and Fink, Gereon Rudolf
                      and Onur, Özgür},
      title        = {{A}lzheimer-typical temporo-parietal atrophy and
                      hypoperfusion are associated with a more significant
                      cholinergic impairment in amnestic neurodegenerative
                      syndromes},
      journal      = {Journal of Alzheimer's disease},
      volume       = {104(4)},
      issn         = {1387-2877},
      address      = {Amsterdam},
      publisher    = {IOS Press},
      reportid     = {FZJ-2025-01978},
      year         = {2025},
      note         = {J Alzheimers Dis 2025 Apr;104(4):1290-1300. The authors
                      disclosed receipt of the following financial support for the
                      research, authorship, and/or publication of this article:
                      This work was supported by a grant from the Marga and Walter
                      Boll Foundation (Nr. 210-08-13), Kerpen, Germany, to GRF and
                      OO.},
      abstract     = {BackgroundTo date, cholinomimetics remain central in the
                      pharmacotherapy of Alzheimer's disease (AD) dementia.
                      However, postmortem investigations indicate that the
                      AD-typical progressive amnestic syndrome may also result
                      from predominantly limbic non-AD neuropathology such as
                      TDP-43 proteinopathy and argyrophilic grain disease.
                      Experimental evidence links a beneficial response to
                      cholinomimetics in early AD to reduced markers of
                      cholinergic neurotransmission. However, the cholinergic
                      impairment varies among patients with a clinical AD
                      presentation, likely due to non-AD
                      (co)-pathologies.ObjectiveThis study examines whether
                      AD-typical atrophy and hypoperfusion can provide information
                      about the cholinergic system in clinically diagnosed
                      AD.MethodsThirty-two patients with amnestic mild cognitive
                      impairment or mild dementia due to AD underwent positron
                      emission tomography (PET) with the tracer
                      N-methyl-4-piperidyl-acetate (MP4A) to estimate
                      acetylcholinesterase (AChE) activity, neurological
                      examinations, cerebral magnetic resonance imaging (MRI) and
                      neuropsychological assessment. The ‘cholinergic deficit’
                      was computed as the deviation of AChE activity from
                      cognitively normal controls across the cerebral cortex and
                      correlated gray matter (GM) and perfusion of
                      temporo-parietal cortices typically affected by AD and basal
                      forebrain (BF) GM.ResultsTemporo-parietal perfusion and GM,
                      as well as the inferior temporal to medial temporal ratio of
                      perfusion correlated negatively with the ‘cholinergic
                      deficit’. A smaller Ch4p area of the BF was associated
                      with a more significant ‘cholinergic deficit’, albeit to
                      a lesser degree than cortical measures.ConclusionsIn
                      clinically diagnosed AD, temporo-parietal GM and perfusion
                      are more closely associated with the ‘cholinergic
                      deficit’ than BF volumes, making them possible markers for
                      cholinergic treatment response in amnestic
                      neurodegeneration.IntroductionAlzheimer's disease (AD),
                      biologically characterized by the accumulation of amyloid
                      and tau pathologies and subsequent neurodegeneration,1
                      typically first presents with slowly progressive memory
                      impairment. The observation of particularly severe
                      degeneration of the cholinergic basal forebrain in AD led to
                      the use of cholinomimetics, which to date are central to AD
                      pharmacotherapy.2,3 However, the effects of these
                      medications are limited and vary considerably across
                      patients, while side-effects often limit their use.
                      Nonetheless, cholinergic pharmacotherapy is likely to remain
                      relevant despite the introduction of anti-amyloid
                      medications, given the moderate effects, side-effects, and
                      contraindications of current anti-amyloid therapies and the
                      lack of alternatives.4 Given the enormous burden of AD and
                      other amnestic neurodegenerative syndromes on patients and
                      caregivers and the risk of side-effects in the often
                      geriatric patients, it is therefore crucial to identify
                      factors that will allow a targeted use of cholinergic
                      medications and ensure an appropriate risk-benefit balance
                      for each patient.An explanation for the variable treatment
                      response and limited group level effects of cholinomimetics
                      may be, that a relevant ‘cholinergic deficit’ is
                      required for patients to benefit from these medications and
                      that the degree of cholinergic degeneration varies
                      considerably across patients. Supporting this idea, we
                      previously observed that even patients with mild cognitive
                      impairment (MCI) due to AD may benefit from cholinergic
                      stimulation, but the treatment response depended on the
                      degree of cholinergic impairment.5 Interestingly, even in
                      this relatively homogenous group, the cortical levels of
                      acetylcholinesterase (AChE), a critical enzyme of
                      cholinergic neurotransmission, varied substantially between
                      patients.6 There is also evidence for more severe
                      cholinergic impairment in patients with early-onset than
                      late-onset AD.6–8A cause of the variability in cholinergic
                      degeneration and, consequently, response to cholinergic
                      treatment could be the heterogeneity of underlying
                      neuropathology. Trials examining the efficacy of cholinergic
                      medications recruited patients based purely on a clinical AD
                      diagnosis.9–11 However, it has become clear, that the
                      AD-typical amnestic syndrome may also be caused by non-AD
                      pathologies.12 Non-AD pathological change is common and can
                      be observed as co-pathology in up to half of the patients
                      with molecular evidence of AD-pathology, especially with
                      increasing age.12–14 It remains unclear, how limbic
                      predominant non-AD pathologies, such as limbic-predominant
                      age-associated TDP-43 encephalopathy (LATE) and argyrophilic
                      grain disease, affect the cholinergic system. Basal
                      forebrain atrophy has been linked to amyloid and Lewy-body
                      pathology rather than LATE.15 Furthermore, the basal
                      forebrain does not appear particularly susceptible to the
                      TDP-43 pathology observed in frontotemporal lobar
                      degeneration,16 and total basal forebrain volumes measured
                      using MRI did not differ between patients with pure-AD and
                      pure LATE neuropathological change.17Specific molecular
                      markers of cholinergic neurotransmission, such as the
                      activity of critical enzymes, transporters, and receptors,
                      can be quantified in vivo using positron emission tomography
                      (PET).18–20 However, these techniques are
                      resource-intensive, and their use, hence, remains restricted
                      to specialized centers, limiting their utility in
                      large-scale studies of treatment response. However, AD and
                      non-AD (co)-pathologies are associated with specific
                      hypometabolism and atrophy patterns:13,21–25 The common
                      non-AD pathologies predominantly affect the medial temporal
                      lobe, whereas AD also affects lateral temporal and parietal
                      cortices. Furthermore, the volume of basal forebrain
                      structures, which are the source of cholinergic input to the
                      cerebral cortex, can be assessed with MRI methods similar to
                      those routinely used in the clinical setting.6,26,27
                      Therefore, these markers, thought to reflect different
                      underlying pathologies, might be suitable for indirectly
                      assessing the degree of cholinergic dysfunction in
                      vivo.Hence, we here examined putative structural (MRI) and
                      metabolic (PET) imaging markers that could provide insights
                      regarding the integrity of the cortical cholinergic system
                      in patients with a clinical diagnosis of AD. Specifically,
                      based on our prior work, we hypothesized (1) that the volume
                      of the posterior basal forebrain (Ch4p region) would be more
                      closely correlated with levels of cortical AChE activity
                      than that of the whole basal forebrain. Furthermore, we
                      hypothesized (2) that the inferior temporal gyrus to medial
                      temporal (ITM) ratio of cerebral perfusion, which contrasts
                      perfusion in areas of AD- and non-AD-degeneration,13,21 and
                      perfusion of temporo-parietal cortices, serving as markers
                      of AD-specific degeneration, would also be correlated with
                      cortical AChE activity.},
      cin          = {INM-3},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-3-20090406},
      pnm          = {5251 - Multilevel Brain Organization and Variability
                      (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5251},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1177/13872877251324080},
      url          = {https://juser.fz-juelich.de/record/1040638},
}