Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Lancet Neurol. 2016 Jun;15(7):673-684. doi: 10.1016/S1474-4422(16)00070-3. Epub 2016 Apr 8.
Alzheimer's disease biomarkers are important for early diagnosis in routine clinical practice and research. Three core CSF biomarkers for the diagnosis of Alzheimer's disease (Aβ42, T-tau, and P-tau) have been assessed in numerous studies, and several other Alzheimer's disease markers are emerging in the literature. However, there have been no comprehensive meta-analyses of their diagnostic performance. We systematically reviewed the literature for 15 biomarkers in both CSF and blood to assess which of these were most altered in Alzheimer's disease.
In this systematic review and meta-analysis, we screened PubMed and Web of Science for articles published between July 1, 1984, and June 30, 2014, about CSF and blood biomarkers reflecting neurodegeneration (T-tau, NFL, NSE, VLP-1, and HFABP), APP metabolism (Aβ42, Aβ40, Aβ38, sAPPα, and sAPPβ), tangle pathology (P-tau), blood-brain-barrier function (albumin ratio), and glial activation (YKL-40, MCP-1, and GFAP). Data were taken from cross-sectional cohort studies as well as from baseline measurements in longitudinal studies with clinical follow-up. Articles were excluded if they did not contain a cohort with Alzheimer's disease and a control cohort, or a cohort with mild cognitive impairment due to Alzheimer's disease and a stable mild cognitive impairment cohort. Data were extracted by ten authors and checked by two for accuracy. For quality assessment, modified QUADAS criteria were used. Biomarker performance was rated by random-effects meta-analysis based on the ratio between biomarker concentration in patients with Alzheimer's disease and controls (fold change) or the ratio between biomarker concentration in those with mild cognitive impariment due to Alzheimer's disease and those with stable mild cognitive impairment who had a follow-up time of at least 2 years and no further cognitive decline.
Of 4521 records identified from PubMed and 624 from Web of Science, 231 articles comprising 15 699 patients with Alzheimer's disease and 13 018 controls were included in this analysis. The core biomarkers differentiated Alzheimer's disease from controls with good performance: CSF T-tau (average ratio 2·54, 95% CI 2·44-2·64, p<0·0001), P-tau (1·88, 1·79-1·97, p<0·0001), and Aβ42 (0·56, 0·55-0·58, p<0·0001). Differentiation between cohorts with mild cognitive impairment due to Alzheimer's disease and those with stable mild cognitive impairment was also strong (average ratio 0·67 for CSF Aβ42, 1·72 for P-tau, and 1·76 for T-tau). Furthermore, CSF NFL (2·35, 1·90-2·91, p<0·0001) and plasma T-tau (1·95, 1·12-3·38, p=0·02) had large effect sizes when differentiating between controls and patients with Alzheimer's disease, whereas those of CSF NSE, VLP-1, HFABP, and YKL-40 were moderate (average ratios 1·28-1·47). Other assessed biomarkers had only marginal effect sizes or did not differentiate between control and patient samples.
The core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Emerging CSF biomarkers NSE, VLP-1, HFABP, and YKL-40 were moderately associated with Alzheimer's disease, whereas plasma Aβ42 and Aβ40 were not. Due to their consistency, T-tau, P-tau, Aβ42, and NFL in CSF should be used in clinical practice and clinical research.
Swedish Research Council, Swedish State Support for Clinical Research, Alzheimer's Association, Knut and Alice Wallenberg Foundation, Torsten Söderberg Foundation, Alzheimer Foundation (Sweden), European Research Council, and Biomedical Research Forum.
阿尔茨海默病生物标志物对于常规临床实践和研究中的早期诊断非常重要。已有大量研究评估了用于阿尔茨海默病诊断的三种核心 CSF 生物标志物（Aβ42、T-tau 和 P-tau），并且文献中也出现了其他一些阿尔茨海默病标志物。然而，目前尚无这些生物标志物诊断性能的综合荟萃分析。我们系统性地检索了 1984 年 7 月 1 日至 2014 年 6 月 30 日之间在 PubMed 和 Web of Science 上发表的有关 CSF 和血液中反映神经退行性变的 15 种生物标志物（T-tau、NFL、NSE、VLP-1 和 HFABP）、APP 代谢（Aβ42、Aβ40、Aβ38、sAPPα 和 sAPPβ）、缠结病理（P-tau）、血脑屏障功能（白蛋白比）和神经胶质激活（YKL-40、MCP-1 和 GFAP）的文献，以评估哪些标志物在阿尔茨海默病中改变最明显。
在这项系统性综述和荟萃分析中，我们筛查了 1984 年 7 月 1 日至 2014 年 6 月 30 日之间在 PubMed 和 Web of Science 上发表的有关 CSF 和血液中反映神经退行性变的 15 种生物标志物（T-tau、NFL、NSE、VLP-1 和 HFABP）、APP 代谢（Aβ42、Aβ40、Aβ38、sAPPα 和 sAPPβ）、缠结病理（P-tau）、血脑屏障功能（白蛋白比）和神经胶质激活（YKL-40、MCP-1 和 GFAP）的文献，以评估哪些标志物在阿尔茨海默病中改变最明显。我们从横断面队列研究以及有临床随访的纵向研究的基线测量中提取数据。如果文章没有包含阿尔茨海默病患者和对照组，或包含阿尔茨海默病轻度认知障碍患者和稳定轻度认知障碍患者的队列（后者的随访时间至少为 2 年且没有进一步认知下降），则将其排除在外。由 10 位作者提取数据，由两位作者核对准确性。使用改良的 QUADAS 标准进行质量评估。基于阿尔茨海默病患者与对照组之间的生物标志物浓度比（倍数变化）或阿尔茨海默病轻度认知障碍患者与稳定轻度认知障碍患者且随访时间至少为 2 年且没有进一步认知下降患者之间的生物标志物浓度比，采用随机效应荟萃分析来评估生物标志物的性能。
从 PubMed 检索到 4521 条记录，从 Web of Science 检索到 624 条记录，共纳入了 231 篇文章，包括 15699 例阿尔茨海默病患者和 13018 例对照组。核心生物标志物对阿尔茨海默病患者与对照组的区分具有良好的性能：CSF T-tau（平均比值 2.54，95%CI 2.44-2.64，p<0.0001）、P-tau（1.88，1.79-1.97，p<0.0001）和 Aβ42（0.56，0.55-0.58，p<0.0001）。阿尔茨海默病轻度认知障碍患者与稳定轻度认知障碍患者之间的区分也很强（CSF Aβ42 的平均比值为 0.67，P-tau 为 1.72，T-tau 为 1.76）。此外，CSF NFL（2.35，1.90-2.91，p<0.0001）和血浆 T-tau（1.95，1.12-3.38，p=0.02）在区分对照组和阿尔茨海默病患者时具有较大的效应量，而 CSF NSE、VLP-1、HFABP 和 YKL-40 的效应量适中（平均比值为 1.28-1.47）。其他评估的生物标志物的效应量较小或不能区分对照组和患者样本。
神经退行性变的核心 CSF 生物标志物（T-tau、P-tau 和 Aβ42）、CSF NFL 和血浆 T-tau 与阿尔茨海默病强烈相关，并且核心生物标志物与阿尔茨海默病轻度认知障碍密切相关。新兴的 CSF 生物标志物 NSE、VLP-1、HFABP 和 YKL-40 与阿尔茨海默病中度相关，而血浆 Aβ42 和 Aβ40 则不然。由于其一致性，CSF 中的 T-tau、P-tau、Aβ42 和 NFL 应该在临床实践和临床研究中使用。
瑞典研究委员会、瑞典国家临床研究支持、阿尔茨海默病协会、Knut 和 Alice Wallenberg 基金会、Torsten Söderberg 基金会、阿尔茨海默病基金会（瑞典）、欧洲研究理事会和生物医学研究论坛。
