PET Imaging of Synaptic Density Loss in Patients with Multiple Sclerosis

Synaptic loss is increasingly recognized as a key pathological feature in multiple sclerosis (MS), contributing to disease progression and cognitive dysfunction. Synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging has emerged as a promising tool for non-invasively quantifying synaptic density in vivo. Here, we evaluated the potential of SV2A PET imaging in an experimental autoimmune encephalomyelitis (EAE) mouse model and translated the findings to MS patients. In EAE mice, dynamic [18F]SynVesT-1 PET imaging revealed a significant global reduction in tracer uptake, with a nearly 30% decrease in regional distribution volume (VT) across all analyzed brain regions (p < 0.0001). Correspondingly, in vitro autoradiography on rodent EAE brains corroborated the preclinical PET imaging results. We also investigated potential synaptic loss in the spinal cord of EAE mice and observed a significant decrease in SV2A levels in both the cervical and lumbar sections. In a clinical PET research study, [11C]UCB-J was used to image in MS patients (n=5) and age-matched healthy controls (n=6), and MS patients revealed a 16.6% reduction in cortical SV2A binding (p = 0.043), with significant regional reductions in the caudate (25.6%, p = 0.026), hippocampus (18.5%, p = 0.04), and frontal cortex (16.3%, p = 0.048). These findings demonstrate the application of SV2A PET imaging as a sensitive and quantitative biomarker of synaptic pathology in MS. The consistent reductions in SV2A binding observed in both preclinical and clinical research highlight the role of synaptic degeneration in MS and underscore the utility of SV2A PET imaging in MS research.