What is it about?
Multiple sclerosis (MS) is often thought of as a disease of inflammation and myelin damage, but growing evidence suggests that loss of synapses, the connections between nerve cells, may also play an important role in disability and cognitive decline. In this study, we used PET imaging to measure synaptic density in vivo by targeting SV2A, a protein found in synaptic vesicles. We first used the clinically translatable tracer [18F]SynVesT-1 to examine the brain and spinal cord in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We then performed SV2A PET imaging in a pilot group of people with MS using [11C]UCB-J, the first clinically implemented SV2A radiotracer. Across both the mouse model and human study, we observed reduced SV2A signal, consistent with synaptic loss. These findings support SV2A PET as a sensitive and quantitative imaging biomarker for studying synaptic pathology in MS.
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Why is it important?
This work is important because it provides cross-species evidence that synaptic loss can be detected noninvasively in MS using PET imaging. In the EAE model, we found a broad reduction in SV2A PET signal across the brain, together with evidence of reduced SV2A in the spinal cord. In the pilot human study, MS participants also showed lower SV2A binding than healthy controls, including in cortical and subcortical regions. Together, these results strengthen the idea that synaptic degeneration is a meaningful component of MS pathology, beyond demyelination alone. They also highlight the translational potential of SV2A PET for understanding disease mechanisms, tracking progression, and supporting future therapeutic studies aimed at protecting synapses in neuroinflammatory disease.
Perspectives
Our goal was to bridge preclinical and clinical imaging to better understand how synaptic pathology contributes to multiple sclerosis. By combining SV2A PET studies in an EAE mouse model with a pilot study in patients, we aimed to test whether a shared imaging approach could reveal synaptic loss across the translational pipeline. We hope this work will help expand the use of PET imaging beyond traditional inflammatory readouts and encourage greater attention to synaptic injury as a potentially important therapeutic target in MS. More broadly, this study highlights how clinically relevant molecular imaging tools can connect animal models and human disease in a way that may accelerate translational neuroscience research.
Chao Zheng
University of Toronto
Read the Original
This page is a summary of: SV2A PET reveals synaptic density loss in experimental autoimmune encephalomyelitis and in a pilot multiple sclerosis study, Proceedings of the National Academy of Sciences, March 2026, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2517709123.
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