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SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis
Emily M Ullrich Gavilanes1,2, Laura M Bartos1,2,3, Jonathan A Gernert1,2
1Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.
Science Translational Medicine
|October 1, 2025
Summary
Positron emission tomography (PET) imaging with [18F]UCB-H can detect synapse loss in multiple sclerosis (MS) gray matter. This novel PET imaging tool reveals widespread cortical pathology, aiding in monitoring MS progression and patient disability.
Area of Science:
- Neuroscience
- Radiochemistry
- Neurology
Background:
- Gray matter pathology, including cortical lesions, is a key predictor of multiple sclerosis (MS) progression.
- Synapse loss is an early feature of gray matter pathology in MS, but its detection and monitoring remain challenging.
- Synaptic vesicle protein 2A (SV2A) is a marker of synapse density.
Purpose of the Study:
- To investigate the utility of positron emission tomography (PET) imaging targeting SV2A with the radioligand [18F]UCB-H for detecting and monitoring synapse loss in MS.
- To validate SV2A as a marker of synapse density in MS gray matter.
- To assess the potential of SV2A-PET imaging in revealing clinically relevant cortical pathology in people with MS (PwMS).
Main Methods:
- SV2A mRNA and protein expression analysis in cortical gray matter of MS patients.
- SV2A-PET imaging in a mouse model of cortical MS pathology to assess synapse loss detection and correlate PET findings with genetic and immunohistochemical synapse density.
- In vivo SV2A-PET imaging in 31 PwMS at various disease stages.
Main Results:
- SV2A is confirmed as a suitable marker for synapse density in MS gray matter.
- SV2A-PET imaging successfully detected synapse loss in cortical lesions in a mouse model, with PET-measured densities correlating with labeled synapses.
- In vivo SV2A-PET imaging revealed synapse loss in cortical MS lesions in PwMS.
- Interhemispheric asymmetries in SV2A-PET uptake identified cortical alterations significantly larger than MRI-detected lesions.
- The extent of PET-defined cortical synapse pathology was greater in progressive MS and correlated with disability and cognitive impairment.
Conclusions:
- SV2A-PET imaging with [18F]UCB-H is a promising tool for detecting and monitoring synapse loss and widespread cortical pathology in MS.
- This imaging technique can unmask clinically relevant pathology in MS, potentially aiding in disease progression assessment.
- SV2A-PET imaging offers a novel in vivo method to evaluate synaptic integrity and cortical alterations in MS.
