BACKGROUND AND OBJECTIVES There is a clear need to characterize and validate molecular biomarkers of cerebral amyloid angiopathy (CAA), in an effort to improve diagnostics, especially in the context of patients with Alzheimer disease (AD) receiving immunotherapies (for whom underlying CAA is the driver of amyloid-related imaging abnormalities). We performed an updated meta-analysis of 5 core CSF biomarkers (Aβ42, Aβ40, Aβ438, total tau [T-tau], and phosphorylated tau [P-tau]) to assess which of these are most altered in sporadic CAA. METHODS We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting APP metabolism (Aβ42, Aβ40, Aβ38), neurodegeneration (T-tau), and tangle pathology (P-tau), in symptomatic sporadic CAA cohorts (based on the Boston criteria) vs control groups and/or vs patients with AD. Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations in (1) patients with CAA to controls and (2) CAA to patients with AD. RoM >1 indicates higher biomarker concentration in CAA vs comparison population, and RoM <1 indicates higher concentration in comparison groups. RESULTS 8 studies met inclusion criteria: a total of 11 CAA cohorts (n = 289), 9 control cohorts (n = 310), and 8 AD cohorts (n = 339). Overall included studies were of medium quality based on our assessment tools. CAA to controls had lower mean level of all amyloid markers with CSF Aβ42, Aβ40, and Aβ38 RoMs of 0.46 (95% CI 0.38-0.55, p < 0.0001), 0.70 (95% CI 0.63-0.78, p < 0.0001), and 0.71 (95% CI 0.56-0.89, p = 0.003), respectively. CSF T-tau and P-tau RoMs of patients with CAA to controls were both greater than 1: 1.56 (95% CI 1.32-1.84, p < 0.0001) and 1.31 (95% CI 1.13-1.51, p < 0.0001), respectively. Differentiation between CAA and AD was strong for CSF Aβ40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001) and Aβ38 (RoM 0.55, 95% CI 0.38-0.81, p < 0.0001), but not Aβ42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For T-tau and P-tau, average CSF ratios in patients with CAA vs AD were 0.64 (95% CI 0.58-0.71, p < 0.0001) and 0.64 (95% CI 0.58-0.71, p < 0.0001), respectively. DISCUSSION Specific CSF patterns of Aβ42, Aβ40, Aβ38, T-tau, and P-tau might serve as molecular biomarkers of CAA, in research and clinical settings, offering the potential to improve the clinical diagnostic approach pathway in specific scenarios.

中文翻译：

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脑淀粉样血管病的核心 CSF 生物标志物概况：更新的荟萃分析。


背景和目标 显然需要表征和验证脑淀粉样血管病 (CAA) 的分子生物标志物，以努力改进诊断，特别是在接受免疫治疗的阿尔茨海默病 (AD) 患者的背景下（对于他们来说，潜在的 CAA 是淀粉样蛋白相关成像异常的驱动因素）。我们对 5 个核心 CSF 生物标志物（Aβ42、Aβ40、Aβ438、总 tau [T-tau] 和磷酸化 tau [P-tau]）进行了更新的荟萃分析，以评估其中哪些在散发性 CAA 中变化最大。方法 我们系统地检索了 PubMed，寻找报告有症状散发性 CAA 队列中反映 APP 代谢（Aβ42、Aβ40、Aβ38）、神经变性（T-tau）和缠结病理学（P-tau）的 CSF 生物标志物数据的合格研究（基于 Boston标准）与对照组和/或 AD 患者相比。在随机效应荟萃分析中，根据 (1) CAA 患者与对照组以及 (2) CAA 与 AD 患者的平均 (RoM) 生物标志物浓度比率来评估生物标志物性能。 RoM >1 表明 CAA 中生物标志物浓度高于对照组，RoM <1 表明对照组中生物标志物浓度更高。结果 8 项研究符合纳入标准：总共 11 个 CAA 队列（n = 289）、9 个对照队列（n = 310）和 8 个 AD 队列（n = 339）。根据我们的评估工具，纳入的研究总体质量中等。 CAA 的所有淀粉样蛋白标记物平均水平低于对照组，其中 CSF Aβ42、Aβ40 和 Aβ38 RoM 分别为 0.46 (95% CI 0.38-0.55，p < 0.0001)、0.70 (95% CI 0.63-0.78，p < 0.0001)和 0.71（95% CI 0.56-0.89，p = 0.003）。 CAA 患者的 CSF T-tau 和 P-tau RoM 与对照组均大于 1：1.56（95% CI 1.32-1.84，p < 0.0001）和 1.31（95% CI 1.13-1.51，p < 0.31）。0001），分别。 CSF Aβ40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001) 和 Aβ38 (RoM 0.55, 95% CI 0.38-0.81, p < 0.0001) 之间 CAA 和 AD 之间的差异很大，但 Aβ42 (RoM 1.00；95% CI 0.81-1.23，p = 0.970）。对于 T-tau 和 P-tau，CAA 与 AD 患者的平均 CSF 比率分别为 0.64 (95% CI 0.58-0.71，p < 0.0001) 和 0.64 (95% CI 0.58-0.71，p < 0.0001)。 。讨论 Aβ42、Aβ40、Aβ38、T-tau 和 P-tau 的特定 CSF 模式可能在研究和临床环境中作为 CAA 的分子生物标志物，为改善特定情况下的临床诊断方法提供了潜力。