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  3. Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases

Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases

  • Neuron. 2024 Aug 7;112(15):2540-2557.e8. doi: 10.1016/j.neuron.2024.05.006.
Hironobu Endo 1,  Maiko Ono 2,  Yuhei Takado 2,  Kiwamu Matsuoka 3,  Manami Takahashi 4,  Kenji Tagai 5,  Yuko Kataoka 6,  Kosei Hirata 7,  Keisuke Takahata 8,  Chie Seki 6,  Naomi Kokubo 6,  Masayuki Fujinaga 9,  Wakana Mori 9,  Yuji Nagai 6,  Koki Mimura 10,  Katsushi Kumata 9,  Tatsuya Kikuchi 9,  Aki Shimozawa 11,  Sushil K Mishra 12,  Yoshiki Yamaguchi 13,  Hiroshi Shimizu 14,  Akiyoshi Kakita 14,  Hiroyuki Takuwa 15,  Hitoshi Shinotoh 16,  Hitoshi Shimada 17,  Yasuyuki Kimura 18,  Masanori Ichise 6,  Tetsuya Suhara 19,  Takafumi Minamimoto 6,  Naruhiko Sahara 6,  Kazunori Kawamura 9,  Ming-Rong Zhang 9,  Masato Hasegawa 11,  Makoto Higuchi 20
Affiliations

Affiliations

  • 1 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan. Electronic address: [email protected].
  • 2 Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 3 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Nara Medical University, Nara 634-8522, Japan.
  • 4 Quantum Neuromapping and Neuromodulation Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 5 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
  • 6 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 7 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
  • 8 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Keio University School of Medicine, Tokyo 160-0016, Japan.
  • 9 Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 10 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Research Center for Medical and Health Data Science, The Institute of Statistical Mathematics, Tokyo 190-8562, Japan.
  • 11 Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
  • 12 Department of BioMolecular Sciences, The University of Mississippi, Oxford, MS 38677, USA.
  • 13 Division of Structural Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Miyagi Japan.
  • 14 Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
  • 15 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Quantum Neuromapping and Neuromodulation Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 16 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Neurology Clinic, Chiba 260-0045, Chiba Japan.
  • 17 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Department of Functional Neurology & Neurosurgery, Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
  • 18 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu 474-8511, Aichi, Japan.
  • 19 National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 20 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Department of Neuroetiology and Diagnostic Science, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan.
PMID: 38843838 DOI: 10.1016/j.neuron.2024.05.006
Abstract

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.

Keywords

PET; Parkinson’s disease; dementia with Lewy bodies; intravital two-photon microscopy; in vivo; marmoset model; mouse model; multiple system atrophy; propagation; α-synuclein.

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