From the Departments of Neurology (K.A.Q.C., S.A., S.S., D.O., M.G., D.W., C.T.M., A.C.-P., D.J.I.), Pathology and Laboratory Medicine (L.M.S., E.L., J.Q.T.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Psychiatry and Neurochemistry (H.Z., K.B.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden; and Department of Neurodegenerative Disease (H.Z.), Institute of Neurology, University College London, UK.
Neurology. 2022 Nov 14;99(20):e2303-e2312. doi: 10.1212/WNL.0000000000201202.
CSF biomarkers β-amyloid 1-42 (Aβ), phosphorylated tau 181 (p-tau), total tau (t-tau), and neurogranin (Ng) can diagnose Alzheimer disease (AD) in life. However, it is unknown whether CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as α-synuclein (αSyn). Our primary goal was to test whether biomarkers in patients with AD are altered by concomitant αSyn. We compared CSF Aβ, p-tau, t-tau, and Ng levels across autopsy-confirmed AD and concomitant AD and αSyn (AD + αSyn). Antemortem CSF levels were related to postmortem accumulations of αSyn. Finally, we tested how concommitant AD + αSyn affected the diagnostic accuracy of 2 CSF-based strategies: the amyloid/tau/neurodegeneration (ATN) framework and the t-tau/Aβ ratio.
Inclusion criteria were neuropathologic diagnoses of AD, mixed AD + αSyn, and αSyn. A convenience sample of nonimpaired controls was selected with available CSF and a Mini-Mental State Examination (MMSE) ≥ 27. αSyn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF Aβ, p-tau, t-tau, and Ng differences across AD and AD + αSyn. Linear models tested how biomarkers were altered by αSyn accumulation in AD, accounting for pathologic β-amyloid and tau. Receiver operating characteristic and area under the curve (AUC), including 95% CI, evaluated diagnostic accuracy.
Participants were 61 patients with AD, 39 patients with mixed AD + αSyn, 20 patients with αSyn, and 61 controls. AD had similar median age (73 [interquartile range {IQR} = 12] years), MMSE (23 [IQR = 9]), and sex distribution (male = 49%) compared with AD + αSyn age (70 [IQR = 13] years; = 0.3), MMSE (25 [IQR = 9.5]; = 0.19), and sex distribution (male = 69%; = 0.077). ANCOVAs showed that AD + αSyn had lower p-tau (F(1,94) = 17, < 2.6e-16), t-tau (F(1,93) = 11, = 0.0004), and Ng levels (F(1,50) = 12, = 0.0004) than AD; there was no difference in Aβ ( = 0.44). Models showed increasing αSyn related to lower p-tau (β = -0.26, SE = 0.092, = 0.0065), t-tau (β = -0.19, SE = 0.092, = 0.041), and Ng levels (β = -0.2, SE = 0.066, = 0.0046); αSyn was not a significant factor for Aβ ( = 1). T-tau/Aβ had the highest accuracy when detecting AD, including mixed AD + αSyn cases (AUC = 0.95; CI 0.92-0.98).
Findings demonstrate that concomitant αSyn pathology in AD is associated with lower CSF p-tau, t-tau, and Ng levels and can affect diagnostic accuracy in patients with AD.
脑脊液生物标志物β-淀粉样蛋白 1-42（Aβ）、磷酸化 tau181（p-tau）、总 tau（t-tau）和神经颗粒蛋白（Ng）可在生前诊断阿尔茨海默病（AD）。然而，尚不清楚伴随 AD 常见的共病病理，如α-突触核蛋白（αSyn）是否会影响 CSF 浓度及其准确性。我们的主要目标是检验 AD 患者的生物标志物是否会受到共病αSyn 的影响。我们比较了经尸检证实的 AD 和同时伴有 AD 和 αSyn（AD + αSyn）患者的 CSF Aβ、p-tau、t-tau 和 Ng 水平。在生前的 CSF 水平与死后αSyn 的积累相关。最后，我们测试了共病 AD + αSyn 如何影响两种基于 CSF 的策略的诊断准确性：淀粉样蛋白/tau/神经退行性变（ATN）框架和 t-tau/Aβ 比值。
纳入标准为 AD 的神经病理学诊断、混合 AD + αSyn 和αSyn。选择了非认知障碍的对照作为便利样本，他们有可用的 CSF 和 Mini-Mental State Examination（MMSE）≥27。无 AD 和对照的αSyn 被纳入参考组。协方差分析（ANCOVAs）测试了 CSF Aβ、p-tau、t-tau 和 Ng 在 AD 和 AD + αSyn 之间差异的计划比较。线性模型测试了生物标志物在 AD 中如何因αSyn 积累而发生变化，同时考虑了病理β-淀粉样蛋白和 tau。接收者操作特征和曲线下面积（AUC），包括 95%置信区间，用于评估诊断准确性。
参与者包括 61 例 AD 患者、39 例混合 AD + αSyn 患者、20 例αSyn 患者和 61 例对照。AD 的中位年龄（73[四分位间距{IQR}=12]岁）、MMSE（23[IQR=9]）和性别分布（男性=49%）与 AD + αSyn 相似（年龄=70[IQR=13]岁； =0.3）、MMSE（25[IQR=9.5]； =0.19）和性别分布（男性=69%； =0.077）。ANCOVAs 显示 AD + αSyn 的 p-tau（F（1,94）=17， < 2.6e-16）、t-tau（F（1,93）=11， =0.0004）和 Ng 水平（F（1,50）=12， =0.0004）低于 AD；Aβ无差异（ =0.44）。模型显示，随着αSyn 的增加，p-tau（β=-0.26，SE=0.092， =0.0065）、t-tau（β=-0.19，SE=0.092， =0.041）和 Ng 水平（β=-0.2，SE=0.066， =0.0046）降低；αSyn 不是 Aβ的显著因素（ =1）。t-tau/Aβ 在检测 AD 时具有最高的准确性，包括混合 AD + αSyn 病例（AUC=0.95；CI 0.92-0.98）。
研究结果表明，AD 中同时存在的αSyn 病理与 CSF p-tau、t-tau 和 Ng 水平降低有关，并可能影响 AD 患者的诊断准确性。
