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

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.