YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer's disease.
YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer's disease.
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YKL-40：一种用于临床前阿尔茨海默病的新型预后液体生物标志物。
DOI：
10.1016/j.biopsych.2010.08.025
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发表时间：
2010-11-15
影响因子：
10.6
通讯作者：
Holtzman, David M.
中科院分区：
文献类型：
--
作者：
Craig-Schapiro, Rebecca;Perrin, Richard J.;Roe, Catherine M.;Xiong, Chengjie;Carter, Deborah;Cairns, Nigel J.;Mintun, Mark A.;Peskind, Elaine R.;Li, Ge;Galasko, Douglas R.;Clark, Christopher M.;Quinn, Joseph F.;D'Angelo, Gina;Malone, James P.;Townsend, R. Reid;Morris, John C.;Fagan, Anne M.;Holtzman, David M.
阿尔茨海默病（AD）的疾病修饰疗法如果在显著神经元损失发生之前的“临床前”阶段（存在认知完整的病理学）期间应用将是最有益的。因此，可以在早期阶段检测AD病理并预测痴呆发作和进展的生物标志物对于患者护理和有效的临床试验设计将是非常宝贵的。采用二维差示凝胶电泳和液相色谱串联质谱法检测脑脊液（CSF）中AD相关变化。通过酶联免疫吸附测定法进一步评价发现队列（N=47）、具有配对血浆样本（N=237）、额颞叶变性（N=9）和进行性核上性麻痹（PSP，N=6）的独立样本集（N=292）中CSF YKL-40的浓度。用化学方法研究人类AD脑以鉴定YKL-40的潜在来源。在发现和验证队列中，极轻度和轻度AD型痴呆（临床痴呆评分[CDR] 0.5和1）的平均CSF YKL-40高于对照组（CDR 0）和PSP。重要的是，CSF YKL-40/Aβ42比值可预测发生认知功能障碍（CDR 0至CDR>0转换）的风险，以及迄今为止确定的最佳CSF生物标志物tau/Aβ42和p-tau 181/Aβ42。CDR 0.5和1组的平均血浆YKL-40高于CDR 0组，并与CSF水平相关。在淀粉样斑块亚群附近的星形胶质细胞内观察到YKL-40免疫反应性，表明YKL-40参与了Aβ沉积的神经炎症反应。这些数据表明，YKL-40（一种假定的神经炎症指标）在AD中升高，并且与Aβ42一起作为临床前AD的生物标志物具有潜在的预后效用。
Disease-modifying therapies for Alzheimer’s disease (AD) would be most beneficial if applied during the ‘preclinical’ stage (pathology present with cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design. 2D–difference gel electrophoresis and liquid chromatography tandem mass spectrometry were used to measure AD-associated changes in cerebrospinal fluid (CSF). Concentrations of CSF YKL-40 were further evaluated by enzyme-linked immunosorbent assay in the discovery cohort (N=47), an independent sample set (N=292) with paired plasma samples (N=237), frontotemporal lobar degeneration (N=9), and progressive supranuclear palsy (PSP, N=6). Human AD brain was studied immunohistochemically to identify potential source(s) of YKL-40. In the discovery and validation cohorts, mean CSF YKL-40 was higher in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) vs. controls (CDR 0) and PSP. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 vs. CDR 0 groups, and correlated with CSF levels. YKL-40 immunoreactivity was observed within astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition. These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD, and that, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.
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