Visinin-like protein-1 (VILIP-1) and chitinase-3-like protein 1 (CHI3L1 or YKL-40) in cerebrospinal fluid (CSF) are newly discovered markers indicating neuronal damage and microglial activation, respectively. Phosphorylated tau (p-tau) reflects the neuropathology of Alzheimer’s disease (AD) and is useful as diagnostic markers for AD. However, it is unknown whether these biomarkers have similar or complementary information in AD. We stratified 121 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN), stable mild cognitive impairment (sMCI), progressive MCI (pMCI), and dementia due to AD. Analysis of covariance (ANOVA) and chi-square analyses, Spearman correlation, and logistic regression models were performed to test the demographic, associations between biomarkers, and diagnostic accuracies, respectively. Linear mixed-effects models were used to evaluate the effects of CSF amyloid-β (Aβ) on above biomarkers within diagnostic groups, the combination of diagnostic group and Aβ status as predictor, and CSF biomarkers as predictors of AD features, including cognition measured by Mini–Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI). P-tau, VILIP-1, and YKL-40 were all predictors of AD diagnosis, but combinations of biomarkers did not improve the diagnostic accuracy (AUC 0.924 for p-tau, VILIP-1, and YKL-40) compared to p-tau (AUC 0.922). P-tau and VILIP-1 were highly correlated (r = 0.639, p < 0.001) and strongly associated with Aβ pathology across clinical stages of AD, while YKL-40 was correlated with Aβ pathology in CN and AD groups. VILIP-1 was associated with acceleration of cognitive decline, hippocampal atrophy, and expansion of ventricles in longitudinal analyses. YKL-40 was associated with hippocampal atrophy at baseline and follow-up, while p-tau was only associated with worsening WMH at baseline. CSF levels of p-tau, VILIP-1, and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD. Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration. These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD.

中文翻译：

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轻度认知障碍和阿尔茨海默病的脑脊液磷酸化 tau、visinin 样蛋白 1 和几丁质酶 3 样蛋白 1

脑脊液 (CSF) 中的 Visinin 样蛋白 1 (VILIP-1) 和几丁质酶 3 样蛋白 1 (CHI3L1 或 YKL-40) 是新发现的分别指示神经元损伤和小胶质细胞活化的标志物。磷酸化 tau (p-tau) 反映了阿尔茨海默病 (AD) 的神经病理学，可用作 AD 的诊断标志物。然而，尚不清楚这些生物标志物在 AD 中是否具有相似或互补的信息。我们将阿尔茨海默病神经影像学倡议 (ADNI) 数据库中的 121 名参与者分层为认知正常 (CN)、稳定的轻度认知障碍 (sMCI)、进行性 MCI (pMCI) 和 AD 引起的痴呆。进行协方差分析 (ANOVA) 和卡方分析、Spearman 相关性和逻辑回归模型，以测试人口统计学、生物标志物之间的关联和诊断准确性，分别。线性混合效应模型用于评估CSF淀粉样蛋白-β（Aβ）对诊断组内上述生物标志物的影响，诊断组和Aβ状态的组合作为预测因子，CSF生物标志物作为AD特征的预测因子，包括通过测量的认知通过磁共振成像 (MRI) 测量的简易精神状态检查 (MMSE) 和脑结构和白质高信号 (WMH)。P-tau、VILIP-1 和 YKL-40 都是 AD 诊断的预测因子，但与 p-tau、VILIP-1 和 YKL-40 相比，生物标志物的组合并未提高诊断准确性（p-tau、VILIP-1 和 YKL-40 的 AUC 为 0.924） tau (AUC 0.922)。P-tau 和 VILIP-1 高度相关 (r = 0.639, p < 0.001) 并与 AD 临床阶段的 Aβ 病理学密切相关，而 YKL-40 与 CN 和 AD 组的 Aβ 病理学相关。在纵向分析中，VILIP-1 与加速认知衰退、海马萎缩和脑室扩张有关。YKL-40 与基线和随访时的海马萎缩相关，而 p-tau 仅与基线时 WMH 恶化相关。p-tau、VILIP-1 和 YKL-40 的 CSF 水平可能有助于区分认知正常的受试者和 AD 患者。VILIP-1 和 YKL-40 水平升高可能与疾病退化有关。这些 CSF 生物标志物应考虑用于未来评估 AD 自然史的特征。而 p-tau 仅与基线时 WMH 恶化有关。p-tau、VILIP-1 和 YKL-40 的 CSF 水平可能有助于区分认知正常的受试者和 AD 患者。VILIP-1 和 YKL-40 水平升高可能与疾病退化有关。这些 CSF 生物标志物应考虑用于未来评估 AD 自然史的特征。而 p-tau 仅与基线时 WMH 恶化有关。p-tau、VILIP-1 和 YKL-40 的 CSF 水平可能有助于区分认知正常的受试者和 AD 患者。VILIP-1 和 YKL-40 水平升高可能与疾病退化有关。这些 CSF 生物标志物应考虑用于未来评估 AD 自然史的特征。