From the Boston University Alzheimer's Disease Research Center (M.S., J.R.G., J.W., W.W.Q.Q., A.C.M., T.D.S., J.M., M.L.A.), Boston University CTE Center, Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, MA; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Institut du Cerveau et de la Moelle épinière (ICM) (K.B.), Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France; University of Science and Technology of China and First Affiliated Hospital of USTC (K.B.), Hefei, Anhui, P.R. China; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology; UK Dementia Research Institute at UCL (H.Z.), UCL Institute of Neurology, University College London, United Kingdom; Department of Biostatistics (Y.T.); Biostatistics and Epidemiology Data Analytics Center (BEDAC) (B.M.), Boston University School of Public Health, MA; University of Florida (B.M.A.), Gainesville, FL; Memory & Aging Center (G.D.R.), Department of Neurology, Weill Institute for Neurosciences; Department of Radiology and Biomedical Imaging (G.D.R.), University of California, San Francisco; Department of Psychiatry (W.W.Q.Q.); Department of Pharmacology and Experimental Therapeutics (W.W.Q.Q.), Boston University Chobanian & Avedisian School of Medicine, MA; VA Boston Healthcare System (A.C.M., T.D.S.), US Department of Veteran Affairs, Jamaica Plain, MA; Department of Pathology and Laboratory Medicine (A.C.M., T.D.S.), Boston University Chobanian & Avedisian School of Medicine; VA Bedford Healthcare System (A.C.M., T.D.S.), US Department of Veteran Affairs, Bedford; Framingham Heart Study (J.M.), Framingham, MA; Department of Neurology (R.L.H., J.L., J.C.M., R.J.P., S.E.S.), Knight Alzheimer's Disease Research Center, Washington University School of Medicine; Department of Neurology (M.L.A.), Boston Medical Center; and Department of Anatomy & Neurobiology (M.L.A.), Boston University Chobanian & Avedisian School of Medicine, MA.
Neurology. 2024 Dec 10;103(11):e209866. doi: 10.1212/WNL.0000000000209866. Epub 2024 Nov 4.
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).
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, , and interval between LP and death.
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, = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, = 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.
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.
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.
脑脊液 Aβ42 和磷酸化 tau（p-tau181）生物标志物用于临床检测生前阿尔茨海默病（AD）的病理。脑脊液生物标志物验证研究主要使用临床诊断和/或淀粉样 PET 成像作为参考标准。少数现有的脑脊液到尸检研究仅限于晚期 AD。本项脑脊液到尸检研究调查了在腰椎穿刺（LP）时认知正常的脑捐献者中 AD 脑脊液生物标志物与 AD 神经病理变化之间的关联。
这是一项对国家老龄化阿尔茨海默病协调中心脑捐献者的回顾性研究，这些脑捐献者在 LP 时认知正常，并且使用 Lumipulse 检测进行了 CSF Aβ42 和 p-tau181 的测量。所有脑捐献者均来自华盛顿大学 Knight ADRC。根据国家老龄化研究所-阿尔茨海默病协会的标准进行 AD 神经病理变化（ADNC）分期。在本研究中，参与者分为 2 类：“AD-”（无 AD/低 ADNC）和“AD+”（中/高 ADNC）。使用二项逻辑回归产生的预测概率控制年龄、性别、种族和 LP 与死亡之间的间隔，使用曲线下面积（AUC）统计来评估每个生物标志物对 AD 状态的区分准确性。
LP 的平均年龄为 79.3 岁（SD=5.6），死亡的平均年龄为 87.1 岁（SD=6.5）。在 49 名脑捐献者中，24 名（49%）为男性，47 名（95.9%）为白人。20 名（40.8%）有尸检证实的 AD。LP 到死亡的平均间隔为 7.76 年（SD=4.31）。CSF p-tau181/Aβ42 是 AD 的最佳预测指标，具有出色的区分准确性（AUC=0.97，95%CI 0.94-1.00， =0.003）。单独的 CSF p-tau181 具有第二佳的区分准确性（AUC=0.92，95%CI 0.84-1.00， =0.001），其次是单独的 CSF Aβ42（AUC=0.92，95%CI 0.85-1.00， =0.007），而 CSF t-tau 的区分准确性最低（AUC=0.87，95%CI 0.76-0.97， =0.005）。在控制常见共病神经病理学后，效果仍然存在。CSF p-tau181/Aβ42 与 CERAD 评分的神经原纤维缠结评分和 Braak 分期的 NFT 强烈相关。
本研究支持 Lumipulse 测量的 CSF Aβ42 和 p-tau181，特别是 p-tau181 与 Aβ42 的比值，用于早期检测 AD 病理生理过程。
本研究提供了 II 级证据，表明 Lumipulse 测量的 CSF 中 p-tau181/Aβ42 可准确区分认知正常的伴有和不伴有阿尔茨海默病神经病理改变的参与者。
