TY  - JOUR
AU  - Ullrich Gavilanes, Emily
AU  - Bartos, Laura M
AU  - Gernert, Jonathan A
AU  - Carral, Carla Ares
AU  - Ruiz Navarro, Diego
AU  - Havla, Joachim
AU  - Gerdes, Lisa-Ann
AU  - Gnoerich, Johannes
AU  - Kunze, Lea
AU  - Dorneich, Julia S
AU  - Pakula, Vanessa
AU  - Tagnin, Lisa
AU  - Zimmermann, Hanna
AU  - Seelos, Klaus
AU  - Franzmeier, Nicolai
AU  - Frontzkowski, Lukas
AU  - Pedrosa de Barros, Nuno
AU  - Ribbens, Annemie
AU  - Zwergal, Rachel Maria
AU  - Zwergal, Andreas
AU  - Vollmar, Horst Christian
AU  - Remi, Jan
AU  - Picon, Carmen
AU  - Reynolds, Richard
AU  - Merkler, Doron
AU  - Wattjes, Mike P
AU  - Kümpfel, Tania
AU  - Brendel, Matthias
AU  - Kerschensteiner, Martin
TI  - SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis.
JO  - Science translational medicine
VL  - 17
IS  - 818
SN  - 1946-6234
CY  - Washington, DC
PB  - AAAS
M1  - DZNE-2025-01147
SP  - eadt5585
PY  - 2025
AB  - 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 [18F]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.
KW  - Positron-Emission Tomography: methods
KW  - Multiple Sclerosis: diagnostic imaging
KW  - Multiple Sclerosis: pathology
KW  - Multiple Sclerosis: metabolism
KW  - Animals
KW  - Synapses: pathology
KW  - Synapses: metabolism
KW  - Humans
KW  - Membrane Glycoproteins: metabolism
KW  - Membrane Glycoproteins: genetics
KW  - Nerve Tissue Proteins: metabolism
KW  - Nerve Tissue Proteins: genetics
KW  - Male
KW  - Female
KW  - Middle Aged
KW  - Adult
KW  - Mice
KW  - Cerebral Cortex: pathology
KW  - Cerebral Cortex: diagnostic imaging
KW  - Gray Matter: pathology
KW  - Gray Matter: diagnostic imaging
KW  - Mice, Inbred C57BL
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
KW  - SV2A protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41032626
DO  - DOI:10.1126/scitranslmed.adt5585
UR  - https://pub.dzne.de/record/281529
ER  -