Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases PMID: 38843838

ADC Targets in Oncology

2026-04-10

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

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.

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.