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Peer-reviewedCC BYBrain communications

Tegmental atrophy in isolated REM sleep behaviour disorder: ex vivo MRI-informed in vivo imaging.

  • Masakazu Hirose1,2
  • Kenji Yoshinaga1
  • Yoshifumi Mori1,3
  • Atsushi Shima2,4,5
  • Nobukatsu Sawamoto5
  • Noritaka Wakasugi6
  • Hirohiko Imai7
  • Masahiko Watanabe8
  • Goichi Beck9
  • Yuta Kajiyama9
  • Ujiakira Nishiike9
  • Hideki Mochizuki9
14 more authors
  • Kazuya Kawabata10,11
  • Keita Hiraga12
  • Tomohiko Nakamura12,13
  • Masahisa Katsuno12
  • Hirohisa Watanabe10
  • Taku Hatano14
  • Koji Kamagata15
  • Nobutaka Hattori14
  • Akira Nishida2,16
  • Yohei Mukai17
  • Eiko N Minakawa18
  • Yuji Takahashi17
  • Ryosuke Takahashi2
  • Takashi Hanakawa1,4,6
18 affiliations
  1. 1Department of Integrated Neuroanatomy and Neuroimaging, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
  2. 2Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
  3. 3Computational Cognitive Neuroscience & Neuroimaging, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, the Netherlands.
  4. 4Human Brain Research Centre, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
  5. 5Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
  6. 6Department of Advanced Neuroimaging, Integrative Brain Imaging Center, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
  7. 7Innovation Research Centre for Quantum Medicine, Gifu University School of Medicine, Gifu 501-1194, Japan.
  8. 8Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan.
  9. 9Department of Neurology, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
  10. 10Department of Neurology, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
  11. 11Division of BrainTheraInformatics, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
  12. 12Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
  13. 13Department of Neurology, Hamamatsu University Hospital, Hamamatsu, Shizuoka 431-3192, Japan.
  14. 14Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo 113-8421, Japan.
  15. 15Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
  16. 16Department of Neurology, Kurashiki Central Hospital, Kurashiki, Okayama 710-8602, Japan.
  17. 17Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan.
  18. 18Department of Neurophysiology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
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Abstract

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is an early-stage synucleinopathy characterized by brainstem pathology. In rodents, the pontine tegmentum contains a REM sleep centre, the sublaterodorsal nucleus, which expresses corticotropin-releasing hormone binding protein (CRHBP). While the involvement of brainstem pathophysiology is thus implicated in iRBD, its solid evidence remains scarce in humans due to the difficulty in identifying small brainstem nuclei with conventional MRI technology alone. Here, we aimed to detect tegmental atrophy in iRBD with voxel-based morphometry (VBM) analysis combined with a novel human brainstem atlas. Structural MRIs from 98 patients with iRBD and 114 controls were analysed to investigate grey matter volume using VBM. Our unique approach involved detailed assessments of the VBM results, guided by a high-resolution MRI-based atlas of the human brainstem. This brainstem atlas was founded on ex vivo MRI of 10 post-mortem human specimens. We validated it with CRHBP immunostaining, which aided in identifying putative REM sleep-regulating nuclei in humans. We applied this brainstem atlas to identify atrophy in specific brainstem regions in iRBD and correlate their volumes with clinical and polysomnographic measures. Voxel-based morphometry revealed a focal cluster of grey matter atrophy in the dorsal pontine tegmentum of iRBD patients, including the laterodorsal tegmental nucleus, ventral part (LDTgV) and the pedunculopontine tegmental nucleus (PTg). Our atlas-based analysis confirmed the LDTgV as the site of most conspicuous atrophy, revealing a significant volume reduction in iRBD patients compared with controls with a moderate effect size (Cohen's d = 0.44, Bonferroni-corrected P = 0.019). Furthermore, greater atrophy in the LDTgV and the PTg was associated with more severe autonomic dysfunction as measured by Scales for Outcomes in Parkinson's Disease-Autonomic dysfunction scores (partial r = -0.237, P = 0.021 and partial r = -0.236, P = 0.021, respectively). In 23 patients from whom quantitative polysomnographic data were available, LDTgV atrophy was correlated with the percentage ratio of REM sleep without atonia (partial r = -0.491, P = 0.028). Histological analysis confirmed that the LDTgV is selectively enriched with CRHBP-positive neurons, a putative marker for REM sleep-on neurons. We provided novel evidence for the involvement of LDTgV, the putative human homologue of the murine sublaterodorsal nucleus, in iRBD. The present findings advance our understanding of the neuroanatomical basis of iRBD and will contribute to the development of early biomarkers for α-synucleinopathies.

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Cite

BibTeXRIS
BibTeX
@article{hirose2026tegmental,
  title = {{Tegmental atrophy in isolated REM sleep behaviour disorder: ex vivo MRI-informed in vivo imaging.}},
  author = {Masakazu Hirose and Kenji Yoshinaga and Yoshifumi Mori and Atsushi Shima and Nobukatsu Sawamoto and Noritaka Wakasugi and Hirohiko Imai and Masahiko Watanabe and Goichi Beck and Yuta Kajiyama and Ujiakira Nishiike and Hideki Mochizuki and Kazuya Kawabata and Keita Hiraga and Tomohiko Nakamura and Masahisa Katsuno and Hirohisa Watanabe and Taku Hatano and Koji Kamagata and Nobutaka Hattori and Akira Nishida and Yohei Mukai and Eiko N Minakawa and Yuji Takahashi and Ryosuke Takahashi and Takashi Hanakawa},
  journal = {Brain communications},
  year = {2026},
  month = oct,
  doi = {10.1093/braincomms/fcag379},
  url = {https://europepmc.org/article/MED/42921079},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Tegmental atrophy in isolated REM sleep behaviour disorder: ex vivo MRI-informed in vivo imaging.
AU  - Masakazu Hirose
AU  - Kenji Yoshinaga
AU  - Yoshifumi Mori
AU  - Atsushi Shima
AU  - Nobukatsu Sawamoto
AU  - Noritaka Wakasugi
AU  - Hirohiko Imai
AU  - Masahiko Watanabe
AU  - Goichi Beck
AU  - Yuta Kajiyama
AU  - Ujiakira Nishiike
AU  - Hideki Mochizuki
AU  - Kazuya Kawabata
AU  - Keita Hiraga
AU  - Tomohiko Nakamura
AU  - Masahisa Katsuno
AU  - Hirohisa Watanabe
AU  - Taku Hatano
AU  - Koji Kamagata
AU  - Nobutaka Hattori
AU  - Akira Nishida
AU  - Yohei Mukai
AU  - Eiko N Minakawa
AU  - Yuji Takahashi
AU  - Ryosuke Takahashi
AU  - Takashi Hanakawa
PY  - 2026
DA  - 2026/10/08
JO  - Brain communications
DO  - 10.1093/braincomms/fcag379
UR  - https://europepmc.org/article/MED/42921079
AB  - Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is an early-stage synucleinopathy characterized by brainstem pathology. In rodents, the pontine tegmentum contains a REM sleep centre, the sublaterodorsal nucleus, which expresses corticotropin-releasing hormone binding protein (CRHBP). While the involvement of brainstem pathophysiology is thus implicated in iRBD, its solid evidence remains scarce in humans due to the difficulty in identifying small brainstem nuclei with conventional MRI technology alone. Here, we aimed to detect tegmental atrophy in iRBD with voxel-based morphometry (VBM) analysis combined with a novel human brainstem atlas. Structural MRIs from 98 patients with iRBD and 114 controls were analysed to investigate grey matter volume using VBM. Our unique approach involved detailed assessments of the VBM results, guided by a high-resolution MRI-based atlas of the human brainstem. This brainstem atlas was founded on ex vivo MRI of 10 post-mortem human specimens. We validated it with CRHBP immunostaining, which aided in identifying putative REM sleep-regulating nuclei in humans. We applied this brainstem atlas to identify atrophy in specific brainstem regions in iRBD and correlate their volumes with clinical and polysomnographic measures. Voxel-based morphometry revealed a focal cluster of grey matter atrophy in the dorsal pontine tegmentum of iRBD patients, including the laterodorsal tegmental nucleus, ventral part (LDTgV) and the pedunculopontine tegmental nucleus (PTg). Our atlas-based analysis confirmed the LDTgV as the site of most conspicuous atrophy, revealing a significant volume reduction in iRBD patients compared with controls with a moderate effect size (Cohen's d = 0.44, Bonferroni-corrected P = 0.019). Furthermore, greater atrophy in the LDTgV and the PTg was associated with more severe autonomic dysfunction as measured by Scales for Outcomes in Parkinson's Disease-Autonomic dysfunction scores (partial r = -0.237, P = 0.021 and partial r = -0.236, P = 0.021, respectively). In 23 patients from whom quantitative polysomnographic data were available, LDTgV atrophy was correlated with the percentage ratio of REM sleep without atonia (partial r = -0.491, P = 0.028). Histological analysis confirmed that the LDTgV is selectively enriched with CRHBP-positive neurons, a putative marker for REM sleep-on neurons. We provided novel evidence for the involvement of LDTgV, the putative human homologue of the murine sublaterodorsal nucleus, in iRBD. The present findings advance our understanding of the neuroanatomical basis of iRBD and will contribute to the development of early biomarkers for α-synucleinopathies.
SN  - 2632-1297
ER  -