SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-10-01 DOI:10.1126/scitranslmed.adt5585

Emily M. Ullrich Gavilanes, Laura M. Bartos, Jonathan A. Gernert, Carla Ares Carral, Diego Ruiz Navarro, Joachim Havla, Lisa-Ann Gerdes, Johannes S. Gnörich, Lea H. Kunze, Julia S. Dorneich, Vanessa Pakula, Lisa Tagnin, Hanna Zimmermann, Klaus Seelos, Nicolai Franzmeier, Lukas Frontzkowski, Nuno Pedrosa de Barros, Annemie Ribbens, Rachel Maria Zwergal, Andreas Zwergal, Christian Vollmar, Jan Remi, Carmen Picon, Richard Reynolds, Doron Merkler, Mike P. Wattjes, Tania Kümpfel, Matthias Brendel, Martin Kerschensteiner

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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.

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SV2A-PET成像揭示多发性硬化症皮质突触丢失

灰质病理学，包括皮层病变的形成，预测多发性硬化症（PwMS）患者的进展。在这里，我们研究了使用突触囊泡蛋白2A （SV2A）靶向放射配体UCB-H的正电子发射断层扫描（PET）成像是否有助于检测和监测突触丢失，这是MS灰质病理的早期特征。首先，我们通过分析皮层灰质中SV2A mRNA和蛋白的表达证实SV2A是MS突触密度的合适标记。然后，我们使用小鼠皮质MS病理模型来证明SV2A-PET成像可以检测皮质病变中的突触丢失，并且PET成像测量的突触密度与同一病变中遗传和免疫组织化学标记的突触密度相对应。最后，我们对31例处于疾病过程不同阶段的PwMS进行了SV2A-PET成像，表明PET成像可以检测体内皮质MS病变中的突触丢失。此外，我们发现SV2A-PET示踪剂摄取的半球间不对称可以用来揭示进一步的皮质改变，其体积比MRI检测到的皮质病变面积大20倍以上。在疾病的进展阶段，这些pet定义的皮质突触病理区域的范围更大，并且与同一个体的残疾和认知表现相关。因此，SV2A-PET成像揭示了MS临床相关的皮质病理，从而提供了一种有希望的检测和监测疾病进展的工具。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.