Jiarui Ao, Cynthia Picard, Daniel Auld, Henrik Zetterberg, Ann Brinkmalm, Kaj Blennow, Sylvia Villeneuve, John C. S. Breitner, Judes Poirier
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Observed correlations with CSF levels of Alzheimer amyloid-β (Aβ42) were somewhat weaker. In longitudinal data, baseline levels of ADAM22 and ADAM23 robustly predicted increase over time in both total- and P-<i>tau</i>. CSF SYT1 levels also correlated with PET image uptake of <i>tau</i> and (at a trend level) Aβ in areas of interest for early AD pathology. CSF SYT1 and SNAP25 levels correlated inversely with a global psychometric score and several of its domain subscales. In quantitative trait loci analyses, all four synaptic markers were associated with at least one AD genetic risk locus. Upon “staging” participants by their evidence of amyloid and <i>tau</i> pathology (A/T/N framework), the CSF synaptic markers were unexpectedly reduced in participants with CSF evidence of amyloid but not <i>tau</i> pathology. They were clearly elevated, however, in the CSF of persons with indications of both <i>tau</i> and amyloid pathology. 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引用次数: 0
摘要
阿尔茨海默病(AD)的认知功能障碍与神经元微管相关蛋白 tau 的病理变化密切相关。Tau病变可能通过神经突触扩散。在一群认知功能未受损但罹患 AD 风险较高的老年人中,我们研究了突触功能障碍和退化的四种脑脊液(CSF)标记物。其中三个(SYT1、SNAP25 和 ADAM23)来自突触前结构,而 ADAM22 则反映突触后变化。所有这四种标记物都与 tau 蛋白的测量结果密切相关。在统计模型中,SYT1占总tau和P(181)-tau水平总方差的一半以上。观察到的与 CSF 阿尔茨海默淀粉样蛋白-β(Aβ42)水平的相关性稍弱。在纵向数据中,ADAM22和ADAM23的基线水平可以有力地预测总tau和P-tau随时间推移而增加的情况。CSF SYT1水平还与PET图像中tau和(趋势水平上的)Aβ在早期AD病理相关区域的摄取相关。CSF SYT1和SNAP25水平与总体心理测量评分及其若干领域分量表呈反向相关。在定量性状位点分析中,所有四个突触标记都与至少一个AD遗传风险位点相关。根据淀粉样蛋白和tau病理学证据(A/T/N框架)对参与者进行 "分期 "后,在CSF中有淀粉样蛋白证据但无tau病理学证据的参与者中,CSF突触标记物出乎意料地减少了。然而,在脑脊液中同时存在 tau 和淀粉样蛋白病理迹象的人群中,突触标记物明显升高。这些观察结果提供了证据,表明在认知功能未受损但有早期注意力缺失症病理生物标志物证据的人群中,突触前退化十分明显。
Novel synaptic markers predict early tau pathology and cognitive deficit in an asymptomatic population at risk of Alzheimer’s disease
Cognitive dysfunction in Alzheimer’s disease (AD) correlates closely with pathology in the neuronal microtubule-associated protein tau. Tau pathology may spread via neural synapses. In a population of cognitively unimpaired elderly at elevated risk of AD, we investigated four cerebrospinal (CSF) markers of synaptic dysfunction and degeneration. Three of these (SYT1, SNAP25, and ADAM23) are derived from pre-synaptic structures, while ADAM22 reflects post-synaptic changes. All four markers correlated strongly with tau protein measures. In statistical models, SYT1 accounted for more than half the total variance in both total- and P(181)-tau levels. Observed correlations with CSF levels of Alzheimer amyloid-β (Aβ42) were somewhat weaker. In longitudinal data, baseline levels of ADAM22 and ADAM23 robustly predicted increase over time in both total- and P-tau. CSF SYT1 levels also correlated with PET image uptake of tau and (at a trend level) Aβ in areas of interest for early AD pathology. CSF SYT1 and SNAP25 levels correlated inversely with a global psychometric score and several of its domain subscales. In quantitative trait loci analyses, all four synaptic markers were associated with at least one AD genetic risk locus. Upon “staging” participants by their evidence of amyloid and tau pathology (A/T/N framework), the CSF synaptic markers were unexpectedly reduced in participants with CSF evidence of amyloid but not tau pathology. They were clearly elevated, however, in the CSF of persons with indications of both tau and amyloid pathology. These observations provide evidence for clear pre-synaptic degeneration in cognitively unimpaired persons with biomarker evidence of early AD pathology.
期刊介绍:
Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.