Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, c/Sant Quintí, 77-79, 08025, Barcelona, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain.
Alzheimers Res Ther. 2021 Jun 28;13(1):119. doi: 10.1186/s13195-021-00861-0.
There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment.
We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ ratio, CSF Aβ, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing.
In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002).
These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.
唐氏综合征（DS）患者急需客观的阿尔茨海默病（AD）相关认知障碍标志物，以改善诊断、监测疾病进展并评估疾病修饰疗法的效果。此前，GluA4 和神经元五联素 2（NPTX2）在 DS 成人患者中作为脑脊液（CSF）认知障碍标志物的潜力有限。在这里，我们比较了一个突触蛋白（Calsyntenin-1、神经粘连蛋白 2、神经连接蛋白 2A、神经连接蛋白 3A、突触素 1B、Thy-1、VAMP-2）的 CSF 图谱与 NPTX2 和 GluA4 在跨越临床前和临床 AD 连续体的大量 DS 受试者中的图谱，并探讨了它们与认知障碍的相关性。
我们通过选定的反应监测在 20 名非三体型认知正常对照者（平均年龄 44 岁）和 80 名按临床 AD 诊断分组的 DS 成人患者的 CSF 中定量测定突触蛋白组。我们使用回归分析来确定 AD 连续体中的 CSF 变化，并探讨与年龄、整体认知表现（CAMCOG）、情景记忆（改良提示回忆测试；mCRT）和 CSF 生物标志物、CSF Aβ 比、CSF Aβ、CSF p-tau 和 CSF NFL 的相关性。P 值为多重检验调整。
在 DS 成人中，VAMP-2 是唯一与情景记忆（延迟回忆，调整后 p =.04）和年龄（调整后 p =.0008）相关的突触蛋白，也是 CSF Aβ（调整后 p =.0001）、p-tau（调整后 p <.0001）和 NFL（调整后 p <.0001）的最佳相关物。与对照组相比，仅无症状 DS 成人的 VAMP-2 水平较低（调整后 p =.02）。Neurexin-3A、Thy-1、Neurexin-2A、Calsyntenin-1、神经粘连蛋白 2、GluA4 和突触素 1B 的 CSF 水平均与 NPTX2 强烈相关（p <.0001），NPTX2 是唯一在所有 AD 阶段 CSF 水平均低于对照组的突触蛋白（调整后 p <.002）。
这些数据证明 CSF VAMP-2 作为突触退化的潜在标志物具有概念验证，它与 CSF AD 和轴突退化标志物以及认知表现相关。
