Synaptic Density Reductions in MSA: A Potential Biomarker Identified Through [F]SynVesT-1 PET Imaging.

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 [F]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 [F]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 [F]SynVesT-1 PET as a potential biomarker for diagnosing and evaluating the disease, and guiding synaptic restoration trials. ANN NEUROL 2025;97:879-893.