SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis

Article Article scientifique Article SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis eng 2025-10-01 2025-10 author Ullrich Gavilanes Emily M 0009-0009-9811-1019 Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany. author Bartos Laura M 0009-0007-6158-319X Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany.,Department of Nuclear Medicine, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Gernert Jonathan A 0000-0002-6655-5557 Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany. author Carral Carla Ares 0009-0007-9605-4992 Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany. author Ruiz Navarro Diego 0009-0007-4825-8624 Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany. author Havla Joachim 0000-0002-4386-1340 Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany. author Gerdes Lisa-Ann 0000-0002-7053-3924 Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany.,Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany. author Gnörich Johannes S 0000-0003-1554-7765 Department of Nuclear Medicine, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Kunze Lea H 0000-0003-4669-2113 Department of Nuclear Medicine, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Dorneich Julia S Department of Nuclear Medicine, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Pakula Vanessa Department of Nuclear Medicine, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Tagnin Lisa 0009-0000-9116-4497 Department of Nuclear Medicine, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Zimmermann Hanna 0000-0002-1476-3477 Institute of Neuroradiology, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Seelos Klaus 0009-0009-0350-1293 Institute of Neuroradiology, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Franzmeier Nicolai 0000-0001-9736-2283 Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany.,Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Department of Psychiatry and Neurochemistry, University of Gothenburg, Sahlgrenska Academy, Institute of Neuroscience and Physiology, 43133 Mölndal and 41345 Gothenburg, Sweden. author Frontzkowski Lukas Department of Nuclear Medicine, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Pedrosa de Barros Nuno 0000-0003-2403-6705 Icometrix, 3012 Leuven, Belgium. author Ribbens Annemie 0000-0002-5732-5389 Icometrix, 3012 Leuven, Belgium. author Zwergal Rachel Maria 0009-0006-5083-6182 Department of Neurology, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Zwergal Andreas 0000-0002-3839-8398 Department of Neurology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,German Center for Vertigo and Balance Disorders (DSGZ), LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Vollmar Christian 0000-0002-4630-7484 Department of Neurology, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Remi Jan Department of Neurology, LMU University Hospital, LMU Munich, 81377 Munich, Germany. author Picon Munoz Carmen Division of Clinical Pathology, Geneva University Hospital, 1205 Geneva, Switzerland.,Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 969332 Département de pathologie et immunologie (PATIM) author Reynolds Richard 0000-0003-4622-4694 Department of Brain Sciences, UK Multiple Sclerosis Society Tissue Bank, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, W12 0NN London, UK. author Merkler Doron 0000-0002-0247-2007 Division of Clinical Pathology, Geneva University Hospital, 1205 Geneva, Switzerland.,Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 735735 Département de pathologie et immunologie (PATIM) author Wattjes Mike P Department of Neuroradiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 12203 Berlin, Germany. author Kümpfel Tania 0000-0001-7509-5268 Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany. author Brendel Matthias 0000-0002-9247-2843 Department of Nuclear Medicine, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany.,German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany. author Kerschensteiner Martin 0000-0003-4898-9383 Institute of Clinical Neuroimmunology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.,Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Martinsried, Germany.,Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany. eadt5585 10.1126/scitranslmed.adt5585 41032626 1946-6234 https://www.science.org/doi/10.1126/scitranslmed.adt5585 Gray matter pathology, including the formation of cortical lesions, predicts progression in people with multiple sclerosis (PwMS). Here, we investigated whether positron emission tomography (PET) imaging using the synaptic vesicle protein 2A (SV2A)-targeting radioligand [<sup>18</sup> F]UCB-H could help to detect and monitor synapse loss, an early feature of gray matter pathology in MS. First, we confirmed that SV2A is a suitable marker of synapse density in MS by analyzing SV2A mRNA and protein expression in cortical gray matter. We then used a mouse model of cortical MS pathology to demonstrate that SV2A-PET imaging can detect synapse loss in cortical lesions and that synapse densities measured by PET imaging correspond to the densities of genetically and immunohistochemically labeled synapses in the same lesions. Last, we performed SV2A-PET imaging in a total of 31 PwMS at different stages of the disease process, showing that PET imaging can detect synapse loss in cortical MS lesions in vivo. Moreover, we found that interhemispheric asymmetries in SV2A-PET tracer uptake can be leveraged to uncover further cortical alterations, the volume of which was more than 20-fold larger than the cortical lesion area detected by MRI. The extent of these PET-defined areas of cortical synapse pathology was larger in the progressive stage of the disease and correlated with the disability and cognitive performance of the same individuals. SV2A-PET imaging thus unmasked clinically relevant cortical pathology in MS thereby providing a promising tool to detect and monitor disease progression. Positron-Emission Tomography / methods Multiple Sclerosis / diagnostic imaging Multiple Sclerosis / pathology Multiple Sclerosis / metabolism Animals Synapses / pathology Synapses / metabolism Humans Membrane Glycoproteins / metabolism Membrane Glycoproteins / genetics Nerve Tissue Proteins / metabolism Nerve Tissue Proteins / genetics Male Female Middle Aged Adult Mice Cerebral Cortex / pathology Cerebral Cortex / diagnostic imaging Gray Matter / pathology Gray Matter / diagnostic imaging Mice, Inbred C57BL Dewey 616.07 Swiss National Science Foundation Regulators of long-term dyshomeostasis in chronic neuroinflammation 215050 CH Swiss National Science Foundation Deciphering transcriptional regulators of T cell fate decisions in CNS autoimmunity 201271 CH European Commission Molecular pathology of anti-viral T cell responses in the central nervous system 865026 PATHOCODE EU H2020 137 Département de pathologie et immunologie 21F false 565 La Sclérose en plaques 908 Science translational medicine 17 818 1e73051c-8dc9-4bf0-b4f0-97635fb6099b Article (Published version) Public Article.pdf 19076616 application/pdf OA OTHER 4ad72d413b4dfa3fab26a3633c77114e148685a13cf890df8f2950df5834311f openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

Title	Published in	Year	Views	Downloads

Dysregulation of the endosomal sorting complex III is linked to neurodegeneration in progressive multiple sclerosis	Brain pathology	2026	14	8
SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis	Science translational medicine	2025	8	10
The circadian clock time tunes axonal regeneration	Cell metabolism	2023	82	0

Archive ouverte UNIGE

Picon Munoz, Carmen