RELATING CSF MARKERS NEUROGRANIN, NEUROFILAMENT-LIGHT AND YKL-40 TO Aβ, APOE ε4 AND COGNITION: RESULTS FROM THE EMIF-AD MULTIMODAL BIOMARKER DISCOVERY STUDY
RELATING CSF MARKERS NEUROGRANIN, NEUROFILAMENT-LIGHT AND YKL-40 TO Aβ, APOE ε4 AND COGNITION: RESULTS FROM THE EMIF-AD MULTIMODAL BIOMARKER DISCOVERY STUDY
复制标题
将 CSF 标志物 NEUROGRANIN、NEUROFILAMENT-LIGHT 和 YKL-40 与 Aβ、APOE ε4 和认知相关：EMIF-AD 多模式生物标志物发现研究的结果
DOI：
10.1016/j.jalz.2018.06.2307
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
H. Zetterberg
中科院分区：
文献类型：
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作者：
I. Bos;S. Vos;F. Verhey;P. Scheltens;S. Engelborghs;G. Frisoni;O. Blin;J. Richardson;R. Bordet;M. Tsolaki;J. Popp;P. Martínez;A. Lleó;P. Johannsen;Y. Freund;L. Frölich;R. Vandenberghe;A. Baird;F. Barkhof;C. Legido;L. Bertram;S. Lovestone;J. Streffer;U. Andreasson;K. Blennow;P. Visser;H. Zetterberg
背景β淀粉样蛋白（Aβ）是阿尔茨海默病（AD）最早的标志物之一，载脂蛋白E（APOE）ε4携带是最强的遗传性AD危险因素。在整个临床 AD 谱系中，Aβ、APOE-ε4 与认知以及新兴脑脊液 (CSF) 标记物 YKL-40、神经粒蛋白 (Ng) 和神经丝光 (NFL) 之间的关系仍不确定。方法我们纳入了来自 EMIF-AD 多模式生物标记物发现研究的 770 名个体（该队列由 3 项多中心和 8 项单中心欧洲研究整理而来），对他们进行了集中的 CSF 分析。 140 人认知正常 (CN)，450 人患有轻度认知障碍 (MCI)，180 人患有 AD 痴呆。 CSF Aβ 42/40 比率（具有队列特定截止值 (0.061)）用于确定 Aβ 状态。我们使用方差分析和卡方根据 Aβ 状态比较了诊断组内的特征。使用线性混合模型根据 APOE-ε4 状态比较 NFL、Ng 和 YKL-40 浓度，并测试这些标记物对认知的影响，所有标记物均按 Aβ 状态分层，并根据人口统计和研究进行调整。 结果与 Aβ 个体相比，整个 AD 谱系中 Aβ+ 个体的 Ng 水平升高，而 NFL 和 YKL 水平仅在 Aβ+ CN 和 MCI 个体中升高。在患有 MCI 或 AD 型痴呆的 Aβ 个体中，APOE ε4+ 与 NFL 和 Ng 水平降低相关。无论 Aβ 状态如何，高 NFL 与基线认知能力较低和下降速度较快相关（图 1）。无论 Aβ 值如何，高 Ng 还与更快的衰退速度相关，但仅限于痴呆阶段。仅在 Aβ 个体中，高 YKL-40 与较低的基线分数和较快的下降速度相关（图 1）。结论 NFL 是一种早期诊断和预后神经退行性标记物，但对 AD 不具有特异性。 Ng 是一种有价值的 AD 诊断标志物，因为它与所有认知阶段的 Aβ 相关。由于 YKL-40 先前已被确定为炎症标志物，因此我们的研究结果表明 Aβ 病理学与痴呆前期的炎症有关，这可能会影响 Aβ 缺失时的认知。这些发现对于临床实践、试验招募和研究具有重要价值。
BackgroundAmyloid-beta (Aβ) is one of the earliest markers for Alzheimer's disease (AD) and apolipoprotein E (APOE) ε4 carriership is the strongest genetic AD risk factor. The relationship between Aβ, APOE-ε4 and cognition, with emerging cerebrospinal fluid (CSF) markers YKL-40, neurogranin (Ng) and neurofilament light (NFL), across the clinical AD spectrum, remains uncertain.MethodsWe included 770 individuals from the EMIF-AD Multimodal Biomarker Discovery study-a cohort collated from 3 multicenter and 8 single center European studies-for whom CSF analyses were conducted centrally. 140 individuals were cognitively normal (CN), 450 had mild cognitive impairment (MCI) and 180 had AD dementia. The CSF Aβ 42/40 ratio, with a cohort specific cut-off (0.061), was used to determine Aβ status. We compared characteristics within diagnostic group by Aβ status using ANOVA and Chi-square. Linear mixed modeling was used to compare NFL, Ng and YKL-40 concentrations by APOE-ε4 status and to test the influence of these markers on cognition, all stratified by Aβ status and adjusted for demographics and study.ResultsCompared to Aβ-individuals, Ng levels were elevated in Aβ+ individuals across the AD spectrum, while NFL and YKL levels were only elevated in Aβ+ CN and MCI individuals. In Aβ-individuals with MCI or AD-type dementia, APOE ε4+ was associated with decreased levels of NFL and Ng. High NFL was associated with lower cognitive performance at baseline and a faster rate of decline, regardless of Aβ status (Figure 1). High Ng was also associated with a faster rate of decline, regardless of Aβ, but only in the dementia stage. High YKL-40 was associated with lower baseline scores and a faster rate of decline only in Aβ-individuals (Figure 1).ConclusionsNFL is an early diagnostic and prognostic neurodegenerative marker, but non-specific for AD. Ng is a valuable diagnostic AD marker as it is associated with Aβ in all cognitive stages. As YKL-40 has been indentified as inflammation marker previously, our findings suggest that Aβ pathology is associated with inflammation in the pre-dementia stages and this may influence cognition in absence of Aβ. These findings are of value in clinical practice, trial recruitment and research.