{ "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.", "abstract_shown": true, "affiliations": [ "Department of Integrated Neuroanatomy and Neuroimaging, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.", "Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.", "Computational Cognitive Neuroscience & Neuroimaging, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, the Netherlands.", "Human Brain Research Centre, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.", "Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.", "Department of Advanced Neuroimaging, Integrative Brain Imaging Center, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.", "Innovation Research Centre for Quantum Medicine, Gifu University School of Medicine, Gifu 501-1194, Japan.", "Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan.", "Department of Neurology, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.", "Department of Neurology, Fujita Health University, Toyoake, Aichi 470-1192, Japan.", "Division of BrainTheraInformatics, International Center for Brain Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.", "Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.", "Department of Neurology, Hamamatsu University Hospital, Hamamatsu, Shizuoka 431-3192, Japan.", "Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo 113-8421, Japan.", "Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.", "Department of Neurology, Kurashiki Central Hospital, Kurashiki, Okayama 710-8602, Japan.", "Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan.", "Department of Neurophysiology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan." ], "article_type": "research article", "arxiv": null, "author_total": 26, "authors": [ { "affs": [ 0, 1 ], "name": "Masakazu Hirose", "orcid": "0000-0002-0479-7841" }, { "affs": [ 0 ], "name": "Kenji Yoshinaga" }, { "affs": [ 0, 2 ], "name": "Yoshifumi Mori" }, { "affs": [ 1, 3, 4 ], "name": "Atsushi Shima", "orcid": "0000-0002-3068-4621" }, { "affs": [ 4 ], "name": "Nobukatsu Sawamoto", "orcid": "0000-0001-8695-0223" }, { "affs": [ 5 ], "name": "Noritaka Wakasugi" }, { "affs": [ 6 ], "name": "Hirohiko Imai" }, { "affs": [ 7 ], "name": "Masahiko Watanabe" }, { "affs": [ 8 ], "name": "Goichi Beck" }, { "affs": [ 8 ], "name": "Yuta Kajiyama" }, { "affs": [ 8 ], "name": "Ujiakira Nishiike" }, { "affs": [ 8 ], "name": "Hideki Mochizuki", "orcid": "0000-0002-0874-7542" }, { "affs": [ 9, 10 ], "name": "Kazuya Kawabata" }, { "affs": [ 11 ], "name": "Keita Hiraga", "orcid": "0000-0002-0134-2956" }, { "affs": [ 11, 12 ], "name": "Tomohiko Nakamura" }, { "affs": [ 11 ], "name": "Masahisa Katsuno", "orcid": "0000-0001-9453-9311" }, { "affs": [ 9 ], "name": "Hirohisa Watanabe" }, { "affs": [ 13 ], "name": "Taku Hatano", "orcid": "0000-0002-6808-0444" }, { "affs": [ 14 ], "name": "Koji Kamagata", "orcid": "0000-0001-5028-218X" }, { "affs": [ 13 ], "name": "Nobutaka Hattori", "orcid": "0000-0002-2034-2556" }, { "affs": [ 1, 15 ], "name": "Akira Nishida" }, { "affs": [ 16 ], "name": "Yohei Mukai" }, { "affs": [ 17 ], "name": "Eiko N Minakawa" }, { "affs": [ 16 ], "name": "Yuji Takahashi" }, { "affs": [ 1 ], "name": "Ryosuke Takahashi", "orcid": "0000-0002-1407-9640" }, { "affs": [ 0, 3, 5 ], "name": "Takashi Hanakawa" } ], "bibtex": "https://research.draconitic.com/paper/fmbyqeksd7zht.bib", "cited_by": 0, "doi": "10.1093/braincomms/fcag379", "fulltext_url": "https://europepmc.org/articles/PMC13691600", "id": "fmbyqeksd7zht", "issns": [ "2632-1297" ], "landing_url": "https://europepmc.org/article/MED/42921079", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2728|Parkinson's Disease Mechanisms and Treatments" ] ], "openalex": "W7220997575", "pdf_url": "https://europepmc.org/articles/PMC13691600?pdf=render", "pmcid": "PMC13691600", "pmid": "42921079", "published": "2026-10-08", "publisher": null, "ris": "https://research.draconitic.com/paper/fmbyqeksd7zht.ris", "sources": [ { "first_seen": "2026-10-30T12:20:33Z", "native_id": "MED:42921079", "source": "europepmc", "url": "https://europepmc.org/article/MED/42921079" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2728|Parkinson's Disease Mechanisms and Treatments", "subfield": "neurology" } ], "title": "Tegmental atrophy in isolated REM sleep behaviour disorder: ex vivo MRI-informed in vivo imaging.", "title_text": "Tegmental atrophy in isolated REM sleep behaviour disorder: ex vivo MRI-informed in vivo imaging.", "type": "peer-reviewed", "updated_at": "2026-10-30T12:20:33Z", "url": "https://research.draconitic.com/paper/fmbyqeksd7zht", "venue": "Brain communications", "versions": [] }