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@ARTICLE{Cai:283050,
      author       = {Cai, Mengfei and Li, Hao and Nemy, Milan and Jacob, Mina A
                      and Norris, David G and Duering, Marco and Zhang, Yuhu and
                      Kessels, Roy P C and Vyslouzilova, Lenka and Teipel, Stefan
                      J and Ferreira, Daniel and de Leeuw, Frank-Erik and
                      Tuladhar, Anil M},
      title        = {{C}holinergic {D}isruption {C}ontributes to {M}otoric
                      {C}ognitive {D}ysfunction in {C}erebral {S}mall {V}essel
                      {D}isease.},
      journal      = {Stroke},
      volume       = {57},
      number       = {1},
      issn         = {0039-2499},
      address      = {New York, NY},
      publisher    = {Association},
      reportid     = {DZNE-2025-01457},
      pages        = {169 - 181},
      year         = {2026},
      abstract     = {Cognitive decline and gait disturbance are often observed
                      simultaneously in patients with small vessel disease (SVD),
                      also known as motoric cognitive dysfunction. However, it
                      remains unknown whether cholinergic system disruption
                      contributes to motoric cognitive dysfunction.In this
                      cross-sectional, single-center study conducted in the
                      Netherlands, we included 213 patients with SVD between 2020
                      and 2021, all of whom had multimodal magnetic resonance
                      imaging scans, gait assessments using the 6-meter walk test,
                      and cognitive test battery data available. Cholinergic
                      cortical (through external capsule and cingulum) and
                      thalamic projections (pedunculopontine nucleus to thalamus)
                      were reconstructed using probabilistic tractography on
                      diffusion images, followed by the quantification of the
                      disruption in these tracts with diffusion metrics derived
                      from neurite orientation dispersion and density imaging
                      model. Conventional magnetic resonance imaging markers for
                      SVD were assessed.Covariates, including neurite orientation
                      dispersion and density imaging metrics in the white matter
                      control mask and SVD markers, were adjusted in linear
                      regression.A total of 213 patients with SVD were included,
                      with a mean (SD) age of 74.6 (6.8) years, of whom 96
                      $(45.1\%)$ were women. Conventional SVD markers are
                      differentially associated with disrupted cholinergic
                      pathways, with white matter hyperintensities (WMH) being the
                      main contributor (R² highest for neurite density index,
                      0.38). WMH within the external capsule cholinergic pathway
                      is more strongly associated with the neurite orientation
                      dispersion and density imaging metrics in this tract
                      compared with total WMH volume or WMH outside cholinergic
                      projections. In contrast, WMH within the cingulum pathway
                      contributes less to neurite orientation dispersion and
                      density imaging variability (R²=0.18-0.33 versus
                      0.22-0.38). Disruption in cholinergic cortical pathways was
                      associated with concurrent decline in performance of
                      cognition and gait (external capsule pathway cerebrospinal
                      fluid isotropic volume fraction, β=-10.77; P=0.004;
                      cingulum pathway cerebrospinal fluid isotropic volume
                      fraction, β=-13.38; P=0.011), adjusted for the
                      covariates.Taken together, our findings suggest that
                      disruption in cholinergic cortical pathways attributable to
                      SVD, rather than cholinergic thalamic pathways, contributes
                      to the motoric cognitive dysfunction in patients with SVD.},
      keywords     = {Humans / Cerebral Small Vessel Diseases: diagnostic imaging
                      / Cerebral Small Vessel Diseases: complications / Cerebral
                      Small Vessel Diseases: physiopathology / Female / Male /
                      Aged / Cognitive Dysfunction: diagnostic imaging / Cognitive
                      Dysfunction: etiology / Cognitive Dysfunction:
                      physiopathology / Cross-Sectional Studies / Aged, 80 and
                      over / White Matter: diagnostic imaging / Middle Aged /
                      Magnetic Resonance Imaging / Diffusion Tensor Imaging /
                      cerebral small vessel diseases (Other) / cognition (Other) /
                      cognitive dysfunction (Other) / gait (Other) / neuroimaging
                      (Other)},
      cin          = {AG Teipel},
      ddc          = {610},
      cid          = {I:(DE-2719)1510100},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41164858},
      doi          = {10.1161/STROKEAHA.125.052256},
      url          = {https://pub.dzne.de/record/283050},
}