评估突触小泡蛋白 VAMP-2 在散发性阿尔茨海默病连续体中的脑脊液水平。
Evaluation of cerebrospinal fluid levels of synaptic vesicle protein, VAMP-2, across the sporadic Alzheimer's disease continuum.
机构信息
ADx NeuroSciences NV, Zwijnaarde, Ghent, Belgium.
Sant Pau Memory Unit, Neurology Department and IIB-Sant Pau, Hospital de La Santa Creu I Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
出版信息
Alzheimers Res Ther. 2023 Oct 28;15(1):186. doi: 10.1186/s13195-023-01336-0.
BACKGROUND
Synapse loss is an early event that precedes neuronal death and symptom onset and is considered the best neuropathological correlate of cognitive decline in Alzheimer's disease (AD). Vesicle-associated membrane protein 2 (VAMP-2) has emerged as a promising biomarker of AD-related synapse degeneration in cerebrospinal fluid (CSF). The aim of this study was to explore the CSF profile of VAMP-2 across the AD continuum in relation to core AD biomarkers, other synaptic proteins, neurogranin (Ng) and synaptosomal-associated Protein-25 kDa (SNAP-25) and cognitive performance.
METHODS
We developed a digital immunoassay on the Single Molecule Array platform to quantify VAMP-2 in CSF and used existing immunoassays to quantify Ng, SNAP-25 and core CSF AD biomarkers. The clinical study included 62 cognitively unimpaired AD biomarker-negative subjects and 152 participants across the AD continuum from the SPIN cohort (Sant Pau Initiative on Neurodegeneration). Cognitive measures of episodic, semantic, executive and visuospatial domains and global cognition were included. Statistical methods included χ tests, spearman correlation, and ANCOVA analyses.
RESULTS
The VAMP-2 assay had a good analytical performance (repeatability 8.9%, intermediate precision 10.3%). Assay antibodies detected native VAMP-2 protein in human brain homogenates. CSF concentrations of VAMP-2, neurogranin and SNAP-25 were lower in preclinical AD stage 1 compared to controls and higher at later AD stages compared to AD stage 1 and were associated with core AD biomarkers, particularly total tau (adj. r = 0.62 to 0.78, p < 0.001). All three synaptic proteins were associated with all cognitive domains in individuals on the AD continuum (adj. r = 0.04 to 0.19, p < 0.05).
CONCLUSIONS
Our novel digital immunoassay accurately measures VAMP-2 changes in CSF, which reflect AD biomarkers and cognitive performance across multiple domains.
背景
突触丧失是发生在神经元死亡和症状出现之前的早期事件，被认为是阿尔茨海默病（AD）认知能力下降的最佳神经病理学相关物。囊泡相关膜蛋白 2（VAMP-2）已成为脑脊液（CSF）中 AD 相关突触退化的有前途的生物标志物。本研究旨在探索 AD 连续体中 VAMP-2 的 CSF 特征与核心 AD 生物标志物、其他突触蛋白、神经颗粒蛋白（Ng）和突触相关蛋白 25kDa（SNAP-25）以及认知表现的关系。
方法
我们在单分子阵列平台上开发了一种数字免疫测定法来定量 CSF 中的 VAMP-2，并使用现有的免疫测定法来定量 Ng、SNAP-25 和核心 CSF AD 生物标志物。该临床研究包括 62 名认知正常 AD 生物标志物阴性受试者和来自 SPIN 队列（Sant Pau 神经退行性变倡议）的 AD 连续体的 152 名参与者。包括情景、语义、执行和视空间领域以及整体认知的认知测量。统计方法包括 χ 检验、Spearman 相关和 ANCOVA 分析。
结果
VAMP-2 测定法具有良好的分析性能（重复性 8.9%，中间精密度 10.3%）。测定法抗体检测到人脑匀浆中的天然 VAMP-2 蛋白。与对照组相比，临床前 AD 阶段 1 患者的 CSF 中 VAMP-2、神经颗粒蛋白和 SNAP-25 浓度较低，而在 AD 后期阶段则较高，与核心 AD 生物标志物（尤其是总 tau）相关（调整后 r 值为 0.62 至 0.78，p 值均<0.001）。在 AD 连续体上的个体中，所有三种突触蛋白均与所有认知领域相关（调整后 r 值为 0.04 至 0.19，p 值均<0.05）。
结论
我们的新型数字免疫测定法准确测量 CSF 中 VAMP-2 的变化，反映了 AD 生物标志物和多个领域的认知表现。
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