From the Department of Neurology (G.S.D., A.S.L.-C., N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Departments of Pathology and Immunology (M.Y.Y., E.M.H., J.H.L.) and Neurology (R.C.B., R.L.H., E.M.H., J.H.L., J.C.M., A.F.) and The Charles F. and Joanne Knight Alzheimer Disease Research Center (R.L.H., J.C.M., A.F.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (P.M.D.K.), University of Magdeburg; Department of Neurology and Experimental Neurology (P.M.D.K., H.P.) Charité, Universitätmedizin Berlin, Germany; Department of Medicine (M.J.F.), Cumming School of Medicine, University of Calgary; Department of Medicine (W.M., D.F.T.-W., J.H.), Division of Neurology, University of Toronto, Canada; and NYU Langone Comprehensive Epilepsy Center (C.S.), NYU Langone Health, New York, NY.
Neurology. 2021 May 18;96(20):e2546-e2557. doi: 10.1212/WNL.0000000000011937. Epub 2021 Apr 1.
To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.
Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or / (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients.
Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = -0.56; = 0.01), lower VILIP-1 (ρ = -0.60; < 0.01) and SNAP-25 (ρ = -0.54; = 0.01), and higher log(YKL-40/SNAP-25) (ρ = 0.48; = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; = 0.02) and neurogranin (ρ = 0.55; = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge.
CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.
为了确定神经元和神经轴突损伤、神经炎症和突触功能障碍是否与抗体介导性脑炎（AME）的临床病程和结局相关，我们测量了来自表现为 AME 和认知正常个体的 CSF 中这些过程的生物标志物。
在 NMDA 受体（n = 34）或 /（n = 11）AME 诊断时，从 45 名患者中获得 CSF，测量了神经元（总 tau，VILIP-1）和神经轴突损伤（神经丝轻链 [NfL]）、炎症（YKL-40）和突触功能（神经颗粒蛋白，SNAP-25）的生物标志物。在一组（n = 20）进行了纵向随访的患者中评估了生物标志物与改良 Rankin 量表（mRS）评分之间的相关性。
在 AME 患者就诊时，神经轴突损伤（NfL）和神经炎症（YKL-40）的生物标志物升高，而神经元损伤和突触功能的标志物稳定（总 tau）或降低（VILIP-1、SNAP-25、神经颗粒蛋白）。YKL-40/SNAP-25 的对数比最佳地区分了患者与认知正常个体（受试者工作特征曲线下面积 0.99；95%置信区间 0.97，>0.99）。年龄较小（ρ = -0.56； = 0.01）、VILIP-1 较低（ρ = -0.60； < 0.01）和 SNAP-25（ρ = -0.54； = 0.01）以及较高的 log(YKL-40/SNAP-25)（ρ = 0.48； = 0.04）与前瞻性随访患者的疾病严重程度（较高的 mRS 评分）相关。较高的 YKL-40（ρ = 0.60； = 0.02）和神经颗粒蛋白（ρ = 0.55； = 0.03）在入院时与出院后 12 个月的 mRS 评分较高相关。
CSF 生物标志物表明，尽管存在神经轴突损伤，但 AME 中的神经元完整性仍会急性维持。突触功能生物标志物水平较低可能反映了抗体介导的细胞表面受体内化，并且可能代表了抗体介导的突触功能障碍的急性相关因素，具有提供疾病严重程度和结局信息的潜力。
