SV2A PET reveals synaptic density loss in experimental autoimmune encephalomyelitis and in a pilot multiple sclerosis study

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 quantifying synaptic density in vivo. Here, we used the clinically translatable tracer [¹⁸F]SynVesT-1 to comprehensively characterize synaptic density across the brain and spinal cord in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. In parallel, we performed SV2A PET in patients with MS using the first clinically implemented SV2A radiotracer, [¹¹C]UCB-J, providing cross-species validation of SV2A PET imaging as a biomarker of synaptic pathology. In EAE mice, dynamic [¹⁸F]SynVesT-1 PET imaging revealed a significant global reduction in tracer uptake, with nearly 30% decrease in regional distribution volume (<i>V_T</i>) across all analyzed brain regions (<i>P</i> < 0.0001). Correspondingly, autoradiography (ARG) corroborated the PET findings, and additional analyses demonstrated reduced SV2A levels in the cervical and lumbar spinal cord. In a clinical PET research study, [¹¹C]UCB-J imaging in MS patients (n = 6) versus age-matched healthy controls (n = 6) showed a 16.4% reduction in global cortical SV2A binding (<i>P</i> = 0.026), with significant regional reductions of 16 to 26% in several cortical and subcortical subregions. Together, these findings demonstrate that SV2A PET imaging provides 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.