Journal Article

DZNE-2025-01147

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis.

Ullrich Gavilanes, E. ; Bartos, L. M. ; Gernert, J. A. ; Carral, C. A. ; Ruiz Navarro, D. ; Havla, J. ; Gerdes, L.-A. ; Gnoerich, J.Extern* ; Kunze, L.Extern* ; Dorneich, J. S. ; Pakula, V. ; Tagnin, L. ; Zimmermann, H. ; Seelos, K. ; Franzmeier, N. ; Frontzkowski, L. ; Pedrosa de Barros, N. ; Ribbens, A. ; Zwergal, R. M. ; Zwergal, A. ; Vollmar, H. C. ; Remi, J. ; Picon, C. ; Reynolds, R. ; Merkler, D. ; Wattjes, M. P. ; Kümpfel, T. ; Brendel, M.DZNE* ; Kerschensteiner, M.

2025
AAAS Washington, DC

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Please use a persistent id in citations: doi:10.1126/scitranslmed.adt5585

Abstract: 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.

Keyword(s): Positron-Emission Tomography: methods (MeSH) ; Multiple Sclerosis: diagnostic imaging (MeSH) ; Multiple Sclerosis: pathology (MeSH) ; Multiple Sclerosis: metabolism (MeSH) ; Animals (MeSH) ; Synapses: pathology (MeSH) ; Synapses: metabolism (MeSH) ; Humans (MeSH) ; Membrane Glycoproteins: metabolism (MeSH) ; Membrane Glycoproteins: genetics (MeSH) ; Nerve Tissue Proteins: metabolism (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; Middle Aged (MeSH) ; Adult (MeSH) ; Mice (MeSH) ; Cerebral Cortex: pathology (MeSH) ; Cerebral Cortex: diagnostic imaging (MeSH) ; Gray Matter: pathology (MeSH) ; Gray Matter: diagnostic imaging (MeSH) ; Mice, Inbred C57BL (MeSH) ; Membrane Glycoproteins ; Nerve Tissue Proteins ; SV2A protein, human

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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