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@ARTICLE{Doppler:163310,
      author       = {Doppler, Christopher E J and Kinnerup, Martin B and Brune,
                      Corinna and Farrher, Ezequiel and Betts, Matthew and
                      Fedorova, Tatyana D and Schaldemose, Jeppe L and Knudsen,
                      Karoline and Ismail, Rola and Seger, Aline D and Hansen,
                      Allan K and Stær, Kristian and Fink, Gereon R and Brooks,
                      David J and Nahimi, Adjmal and Borghammer, Per and
                      Sommerauer, Michael},
      title        = {{R}egional locus coeruleus degeneration is uncoupled from
                      noradrenergic terminal loss in {P}arkinson's disease.},
      journal      = {Brain},
      volume       = {144},
      number       = {9},
      issn         = {1460-2156},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2022-00090},
      pages        = {2732 - 2744},
      year         = {2021},
      abstract     = {Previous studies have reported substantial involvement of
                      the noradrenergic system in Parkinson's disease.
                      Neuromelanin-sensitive MRI sequences and PET tracers have
                      become available to visualize the cell bodies in the locus
                      coeruleus and the density of noradrenergic terminal
                      transporters. Combining these methods, we investigated the
                      relationship of neurodegeneration in these distinct
                      compartments in Parkinson's disease. We examined 93 subjects
                      (40 healthy controls and 53 Parkinson's disease patients)
                      with neuromelanin-sensitive turbo spin-echo MRI and
                      calculated locus coeruleus-to-pons signal contrasts. Voxels
                      with the highest intensities were extracted from published
                      locus coeruleus coordinates transformed to individual MRI.
                      To also investigate a potential spatial pattern of locus
                      coeruleus degeneration, we extracted the highest signal
                      intensities from the rostral, middle, and caudal third of
                      the locus coeruleus. Additionally, a study-specific
                      probabilistic map of the locus coeruleus was created and
                      used to extract mean MRI contrast from the entire locus
                      coeruleus and each rostro-caudal subdivision. Locus
                      coeruleus volumes were measured using manual segmentations.
                      A subset of 73 subjects had 11C-MeNER PET to determine
                      noradrenaline transporter density, and distribution volume
                      ratios of noradrenaline transporter-rich regions were
                      computed. Patients with Parkinson's disease showed reduced
                      locus coeruleus MRI contrast independently of the selected
                      method (voxel approaches: P < 0.0001, P < 0.001;
                      probabilistic map: P < 0.05), specifically on the
                      clinically-defined most affected side (P < 0.05), and
                      reduced locus coeruleus volume (P < 0.0001). Reduced MRI
                      contrast was confined to the middle and caudal locus
                      coeruleus (voxel approach, rostral: P = 0.48, middle: P <
                      0.0001, and caudal: P < 0.05; probabilistic map, rostral: P
                      = 0.90, middle: P < 0.01, and caudal: P < 0.05). The
                      noradrenaline transporter density was lower in patients with
                      Parkinson's diseasein all examined regions (group effect P <
                      0.0001). No significant correlation was observed between
                      locus coeruleus MRI contrast and noradrenaline transporter
                      density. In contrast, the individual ratios of noradrenaline
                      transporter density and locus coeruleus MRI contrast were
                      lower in Parkinson's disease patients in all examined
                      regions (group effect P < 0.001). Our multimodal imaging
                      approach revealed pronounced noradrenergic terminal loss
                      relative to cellular locus coeruleus degeneration in
                      Parkinson's disease; the latter followed a distinct spatial
                      pattern with the middle-caudal portion being more affected
                      than the rostral part. The data shed first light on the
                      interaction between the axonal and cell body compartments
                      and their differential susceptibility to neurodegeneration
                      in Parkinson's disease, which may eventually direct research
                      towards potential novel treatment approaches.},
      keywords     = {Aged / Aged, 80 and over / Female / Humans / Locus
                      Coeruleus: diagnostic imaging / Locus Coeruleus: metabolism
                      / Magnetic Resonance Imaging: methods / Male / Middle Aged /
                      Multimodal Imaging: methods / Norepinephrine Plasma Membrane
                      Transport Proteins: metabolism / Parkinson Disease:
                      diagnostic imaging / Parkinson Disease: metabolism /
                      Positron-Emission Tomography: methods / MeNER (Other) /
                      Parkinson’s disease (Other) / neuromelanin (Other) /
                      noradrenaline (Other) / positron emission tomography (Other)
                      / Norepinephrine Plasma Membrane Transport Proteins (NLM
                      Chemicals) / SLC6A2 protein, human (NLM Chemicals)},
      cin          = {AG Düzel},
      ddc          = {610},
      cid          = {I:(DE-2719)5000006},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34196700},
      doi          = {10.1093/brain/awab236},
      url          = {https://pub.dzne.de/record/163310},
}