Synaptic Density Reductions in MSA: A Potential Biomarker Identified Through [18F]SynVesT-1 PET Imaging
Jian Li1, Daji Chen2, Yongxiang Tang1
1Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
Objective:
The objective of this study was to delineate synaptic density alterations in multiple system atrophy (MSA) and explore its potential role as a biomarker for MSA diagnosis and disease severity monitoring using [18F]SynVesT-1 positron emission tomography / computed tomography (PET CT).
Methods:
In this prospective study, 60 patients with MSA (30 patients with MSA-parkinsonian [MSA-P] subtype and 30 patients with MSA-cerebellar [MSA-C] subtype), 30 patients with Parkinson's disease (PD), and 30 age-matched healthy controls (HCs) underwent [18F]SynVesT-1 PET/CT for synaptic density assessment. Visual, voxel, and volumetric region of interest (VOI) analyses were used to elucidate synaptic density patterns in the MSA brain and establish diagnostic criteria. The diagnostic performances of both visual and VOI-based diagnostics were evaluated using receiver operating characteristic (ROC) analysis. Spearman correlation analyses were conducted to investigate the relationship between brain synaptic density and disease severity RESULTS: Patients with MSA displayed extensive reductions in synaptic density throughout the brain, notably affecting both primary VOIs (the cerebellum and putamen) and secondary VOIs including the medulla oblongata, ventral tegmental area, and pons. Notably, patients with MSA-C exhibited a remarkable decrease in cerebellar synaptic density, whereas patients with MSA-P demonstrated significant synaptic loss within the posterior putamen. Compared with patients with PD, the patients with MSA show a more pronounced reduction in synaptic density in infratentorial brain regions. VOI-based diagnosis significantly outperformed visual analysis in diagnosing and differentiating MSA and its subtypes. Synaptic density in primary and multiple secondary VOIs correlated significantly with motor scales in patients with MSA.
Interpretation:
Our study identified widespread synaptic density reductions in MSA, particularly in the basal ganglia and infratentorial region, suggesting [18F]SynVesT-1 PET as a potential biomarker for diagnosing and evaluating the disease, and guiding synaptic restoration trials. ANN NEUROL 2025;97:879-893.
Insights
Multiple system atrophy (MSA) shows widespread synaptic density loss, especially in the basal ganglia and infratentorial regions. [18F]SynVesT-1 PET imaging can help diagnose MSA and monitor disease severity.
Area of Science:
- Neuroscience
- Radiology
- Biomarker Discovery
Background:
- Multiple system atrophy (MSA) is a progressive neurodegenerative disorder.
- Accurate diagnosis and monitoring of disease severity in MSA remain challenging.
- Synaptic dysfunction is a key pathological feature in MSA.
Purpose of the Study:
- To assess synaptic density alterations in patients with MSA using [18F]SynVesT-1 positron emission tomography/computed tomography (PET/CT).
- To evaluate the potential of [18F]SynVesT-1 PET/CT as a biomarker for MSA diagnosis and disease severity.
- To differentiate between MSA subtypes (MSA-P and MSA-C) and Parkinson's disease (PD) based on synaptic density patterns.
Main Methods:
- Prospective study involving 60 MSA patients (30 MSA-P, 30 MSA-C), 30 PD patients, and 30 healthy controls (HCs).
- All participants underwent [18F]SynVesT-1 PET/CT imaging for synaptic density assessment.
- Visual, voxel, and region of interest (VOI) analyses were performed, with diagnostic performance evaluated by receiver operating characteristic (ROC) analysis. Spearman correlation assessed the relationship between synaptic density and disease severity.
Main Results:
- Patients with MSA exhibited significant reductions in synaptic density across multiple brain regions, including the cerebellum, putamen, medulla oblongata, ventral tegmental area, and pons.
- MSA-C patients showed marked cerebellar synaptic loss, while MSA-P patients had significant synaptic loss in the posterior putamen.
- MSA patients displayed more pronounced infratentorial synaptic density reduction compared to PD patients. VOI-based analysis significantly outperformed visual assessment for MSA diagnosis and subtype differentiation.
- Brain synaptic density correlated significantly with motor function scales in MSA patients.
Conclusions:
- Widespread synaptic density reductions are characteristic of MSA, particularly in the basal ganglia and infratentorial areas.
- [18F]SynVesT-1 PET/CT shows promise as a biomarker for diagnosing MSA and assessing disease progression.
- This imaging technique could guide future synaptic restoration therapies in MSA.
