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.

突触功能障碍和丧失是神经退行性疾病的核心，与认知能力下降相关。突触囊泡蛋白 2A （SV2A） 是一种很有前途的 PET 成像靶标，用于评估体内突触密度，但需要在人脑中进行全面标测以验证其生物标志物的潜力。本研究使用定量免疫组织化学和蛋白质印迹来绘制健康对照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） 和额颞叶变性伴 TDP-43 包涵体 （FTLD-GRN） 患者六个皮层区域的 SV2A 和突触素 （SYP） 密度。我们在对照中确定了 SV2A 密度的区域，并观察到疾病和区域特异性降低，其中 FTLD-GRN （高达 59.5%） 和 EOAD 最严重。EOAD 显示额中回 （MFG） 减少 49%，而 LOAD 额下回 （IFG） 和海马 （CA1） 下降超过 30%。在 PSP 中，海马形成中观察到较小但显着的减少，而颞下回 （ITG） 相对不受影响。SV2A 和 SYP 密度之间的强正相关证实了 SV2A 作为突触完整性标志物的可靠性。本研究支持使用 SV2A PET 成像进行神经退行性疾病的早期诊断和监测，为解释体内 PET 结果提供重要数据。进一步的研究应探索 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。