BACKGROUND AND OBJECTIVES CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP). METHODS This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4, and interval between LP and death. RESULTS The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs. DISCUSSION This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.

中文翻译：

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用于阿尔茨海默病早期检测的 Lumipulse 测量的脑脊液生物标志物。


背景和目的 Aβ42 和磷酸化 tau （p-tau181） 的 CSF 生物标志物在临床上用于检测生活中阿尔茨海默病 （AD） 的病理。CSF 生物标志物验证研究主要使用临床诊断和/或淀粉样蛋白 PET 成像作为参考标准。少数现有的 CSF 到尸检研究仅限于晚期 AD。这项 CSF 到尸检研究调查了 AD 的 CSF 生物标志物与腰椎穿刺 （LP） 时认知正常的脑供体的 AD 神经病理学变化之间的关联。方法 这是一项回顾性研究，对象为来自国家阿尔茨海默病协调中心的脑捐献者，这些捐献者在 LP 时认知正常，并且使用 Lumipulse 测定进行了 CSF Aβ42 和 p-tau181 测量。所有大脑捐献者均来自华盛顿大学奈特 ADRC。AD 神经病理学变化 （ADNC） 的分期是根据美国国家老龄化研究所-阿尔茨海默病协会的标准进行的。在本研究中，参与者分为 2 类：“AD-”（无 AD/低 ADNC）和“AD+”（中/高 ADNC）。使用曲线下面积 （AUC） 统计数据评估区分 AD 状态的每种生物标志物的准确性，该统计数据使用控制年龄、性别、APOE ε4 和 LP 与死亡间隔的二元 logistic 回归的预测概率生成。结果 LP 的平均年龄为 79.3 岁 （SD = 5.6），平均死亡年龄为 87.1 岁 （SD = 6.5）。在 49 名大脑捐献者中，24 名 （49%） 为男性，47 名 （95.9%） 为白人。20 例 （40.8%） 经尸检证实为 AD。从 LP 到死亡的平均间隔为 7.76 年 （SD = 4.31）。CSF p-tau181/Aβ42 是 AD 的最佳预测因子，具有出色的鉴别准确性 （AUC = 0.97,95% CI 0.94-1.00，p = 0.003）。 单独的 CSF p-tau181 具有第二好的鉴别准确性 （AUC = 0.92,95% CI 0.84-1.00，p = 0.001），其次是单独的 CSF Aβ42 （AUC = 0.92,95% CI 0.85-1.00，p = 0.007），而 CSF t-tau 的辨别准确性在数值上最低 （AUC = 0.87,95% CI 0.76-0.97，p = 0.005）。在控制了普遍的共病神经病理学后，效果仍然存在。CSF p-tau181/Aβ42 与神经炎淀粉样蛋白斑块评分的 CERAD 评级和 NFT 的 Braak 分期密切相关。讨论 本研究支持 Lumipulse 测量的 CSF Aβ42 和 p-tau181，特别是 p-tau181 与 Aβ42 的比率，用于 AD 病理生理过程的早期检测。证据分类 本研究提供了 II 类证据，表明 CSF 中 p-tau181/Aβ42 的 Lumipulse 测量准确区分了认知正常的参与者，有和没有阿尔茨海默病神经病理变化。