Comprehensive mapping of synaptic vesicle protein 2A (SV2A) in health and neurodegenerative diseases: a comparative analysis with synaptophysin and ground truth for PET-imaging interpretation

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-10-30 DOI:10.1007/s00401-024-02816-9
Mahsa Shanaki Bavarsad, Salvatore Spina, Abby Oehler, Isabel E. Allen, Claudia K. Suemoto, Renata E. P. Leite, William S. Seeley, Ari Green, William Jagust, Gil D. Rabinovici, Lea T. Grinberg
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Abstract

Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer’s disease (EOAD), late-onset Alzheimer’s disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN). We identified region in SV2A density among controls and observed disease- and region-specific reductions, with the most severe in FTLD-GRN (up to 59.5%) and EOAD. EOAD showed a 49% reduction in the middle frontal gyrus (MFG), while LOAD had over 30% declines in the inferior frontal gyrus (IFG) and hippocampus (CA1). In PSP, smaller but significant reductions were noted in the hippocampal formation, with the inferior temporal gyrus (ITG) relatively unaffected. A strong positive correlation between SV2A and SYP densities confirmed SV2A’s reliability as a synaptic integrity marker. This study supports the use of SV2A PET imaging for early diagnosis and monitoring of neurodegenerative diseases, providing essential data for interpreting in vivo PET results. Further research should explore SV2A as a therapeutic target and validate these findings in larger, longitudinal studies.

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健康和神经退行性疾病中突触囊泡蛋白 2A (SV2A) 的综合图谱:与突触素和 PET 成像解读地面实况的比较分析
突触功能障碍和丧失是神经退行性疾病的核心,并与认知能力下降相关。突触小泡蛋白 2A(SV2A)是评估体内突触密度的一个很有前景的 PET 成像靶点,但需要在人脑中绘制全面的图谱来验证其生物标记物的潜力。本研究采用定量免疫组化和 Western 印迹法绘制了健康对照组和早发性阿尔茨海默病(EOAD)、晚发性阿尔茨海默病(LOAD)、进行性核上性麻痹(PSP)和前颞叶变性伴 TDP-43 包涵体(FTLD-GRN)患者六个皮质区域的 SV2A 和突触素(SYP)密度图。我们确定了对照组中 SV2A 密度的区域,并观察到了疾病和区域特异性降低,其中 FTLD-GRN (高达 59.5%)和 EOAD 最为严重。EOAD 的额叶中回(MFG)下降了 49%,而 LOAD 的额叶下回(IFG)和海马(CA1)下降了 30% 以上。在帕金森病患者中,海马形成的下降幅度较小,但也很明显,而颞下回(ITG)则相对不受影响。SV2A 和 SYP 密度之间的强正相关性证实了 SV2A 作为突触完整性标记物的可靠性。这项研究支持将 SV2A PET 成像用于神经退行性疾病的早期诊断和监测,为解释体内 PET 结果提供了重要数据。进一步的研究应探索将 SV2A 作为治疗靶点,并在更大规模的纵向研究中验证这些发现。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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