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

• Published in: Neuron (Cambridge, Mass.) Vol. 112; no. 15; pp. 2540 - 2557.e8
• Main Authors: Endo, Hironobu, Ono, Maiko, Takado, Yuhei, Matsuoka, Kiwamu, Takahashi, Manami, Tagai, Kenji, Kataoka, Yuko, Hirata, Kosei, Takahata, Keisuke, Seki, Chie, Kokubo, Naomi, Fujinaga, Masayuki, Mori, Wakana, Nagai, Yuji, Mimura, Koki, Kumata, Katsushi, Kikuchi, Tatsuya, Shimozawa, Aki, Mishra, Sushil K., Yamaguchi, Yoshiki, Shimizu, Hiroshi, Kakita, Akiyoshi, Takuwa, Hiroyuki, Shinotoh, Hitoshi, Shimada, Hitoshi, Kimura, Yasuyuki, Ichise, Masanori, Suhara, Tetsuya, Minamimoto, Takafumi, Sahara, Naruhiko, Kawamura, Kazunori, Zhang, Ming-Rong, Hasegawa, Masato, Higuchi, Makoto
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.08.2024
• Subjects: dementia with Lewy bodies; intravital two-photon microscopy; in vivo; marmoset model; mouse model; multiple system atrophy; Parkinson’s disease; PET; propagation; α-synuclein; dementia with Lewy bodies; propagation; mouse model; marmoset model; intravital two-photon microscopy; multiple system atrophy; α-synuclein; PET; in vivo; Parkinson’s disease
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2024.05.006

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. [Display omitted] •A novel imaging agent for α-synuclein pathologies, C05-05, was developed•C05-05 enabled visualization of α-synuclein depositions in Parkinson’s disease•C05-05 retentions in the midbrain correlated with the severity of motor symptoms•C05-05 offered microscopic and macroscopic α-synuclein imaging in animal models Endo et al. developed a positron emission tomography agent, 18F-C05-05, for α-synuclein pathologies in animal models and provided the first demonstration of α-synuclein imaging in patients with Parkinson’s disease and dementia with Lewy bodies. This technology offers neuropathology-based translational assessments for diagnostic and therapeutic purposes.