Objective: This study aimed to determine the potential of ¹⁸F-FD4 PET to serve as an in vivo pathology mapping tool for MSA, providing initial proof-of-concept for its use in patient stratification and as an objective biomarker for monitoring disease progression.

Background: Multiple system atrophy (MSA) is a progressive synucleinopathy characterized by dysautonomia, parkinsonism, and cerebellar ataxia. In vivo imaging of α-synuclein pathology remains a critical unmet need for improving diagnosis and monitoring.

Method: Forty-five patients with clinically diagnosed MSA and 9 healthy controls underwent ¹⁸F-FD4 PET at Huashan Hospital, Fudan University. Images were analyzed visually and semi-quantitatively. Spatiotemporal progression patterns (via event-based modeling) were assessed. Seven patients completed one-year follow-up scans.

Results: ¹⁸F-FD4 uptake in patients mirrored the known distribution of α-synuclein pathology, primarily in the basal ganglia, cerebellum, and supplementary motor area. A remarkably high consistency (97.8%, 44/45) is observed between the ¹⁸F-FD4 binding patterns and clinical symptoms. Notably,¹⁸F-FD4 PET demonstrates potential for detecting pathological aggregates preceding the manifestation of full clinical symptoms. Furthermore, a data-driven subtyping of MSA based on ¹⁸F-FD4 PET reveals three pathological subtypes (Cerebellar-Origin, Striatal-Origin, Multi-Regional Synchronous-Origin) with distinct progression patterns, explaining clinical heterogeneity. Thus, a novel biological-clinical framework that moves beyond clinical symptom origin is established, enabling pathological stratification. Longitudinal data confirm its utility in tracking disease progression, with increasing SUVR correlating with clinical decline.

Conclusion: This study provides initial proof-of-concept for ¹⁸F-FD4 PET as an in vivo biomarker of α-synuclein pathology in MSA, and position it as a promising tool for prognostic stratification and objective monitoring in future clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/18f-fd4-pet-reveals-%ce%b1-synuclein-deposition-and-clinical-correlations-in-multiple-system-atrophy/