Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease.
Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease.
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DOI：
10.1111/jnc.14330
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发表时间：
2018-06
影响因子：
4.7
通讯作者：
Lee VM
中科院分区：
文献类型：
--
作者：
Akhtar RS;Licata JP;Luk KC;Shaw LM;Trojanowski JQ;Lee VM
帕金森病 (PD) 的诊断和预后需要 α-突触核蛋白的生物标志物。 α-突触核蛋白的内源性自身抗体可以作为潜在突触核蛋白病的生物标志物，但之前对自身抗体的评估已显示出变异性和不一致的临床相关性。我们假设 α-突触核蛋白自身抗体可以诊断 PD 并解释其临床异质性。为了检验这一假设，我们开发了一种酶联免疫吸附测定法，用于测量人类样本中的 α-突触核蛋白自身抗体。我们评估了我们机构的 69 份血清样本（16 份健康对照 (HC) 和 53 份 PD 患者）和 145 份脑脊液样本（52 份 HC 和 93 份 PD 患者）。 24 名参与者均可获得血清和脑脊液。两种液体中男性的自身抗体水平均高于女性。与 HC 相比，PD 患者的 CSF 自身抗体水平显着较高，而血清水平没有显着差异。脑脊液自身抗体水平与淀粉样蛋白-β1-42、总 tau 蛋白或磷酸化 tau 蛋白无关。脑脊液自身抗体水平与蒙特利尔认知评估的表现相关，即使在控制脑脊液淀粉样蛋白β1-42时也是如此。脑脊液血红蛋白水平作为腰椎穿刺过程中血液污染脑脊液的指标，并不影响这些观察结果。使用 N 端和 C 端截短的重组 α-突触核蛋白，我们发现 CSF 自身抗体靶向 α-突触核蛋白的 100 至 120 个氨基酸。我们得出的结论是，与 HC 患者相比，PD 患者的内源性 CSF 自身抗体显着较高，这表明它们可能表明潜在的突触核蛋白病的存在。这些自身抗体与认知能力差相关，与 CSF 淀粉样蛋白 β1-42 无关，并且靶向 α-突触核蛋白的选定 C 末端区域。 α-突触核蛋白的内源性自身抗体可能是帕金森病 (PD) 的有用生物标志物，但之前测量自身抗体的尝试尚未得出结论。我们开发了一种可靠的方法来测量生物流体样品中的 α-突触核蛋白自身抗体。我们发现 PD 患者脑脊液 (CSF) 中的自身抗体水平明显高于健康对照者。在血清中，两组的自身抗体水平相似。根据蒙特利尔认知评估的测量，脑脊液自身抗体水平较高的参与者往往认知能力较差。这些自身抗体识别 α-突触核蛋白中的 C 末端结构域。这项研究表明，α-突触核蛋白自身抗体可能是诊断 PD 的有用生物标志物，并且可能与临床疾病特征相关。
Biomarkers for α-synuclein are needed for diagnosis and prognosis in Parkinson’s disease (PD). Endogenous auto-antibodies to α-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to α-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring α-synuclein auto-antibodies in human samples. We evaluated 69 serum samples (16 healthy controls (HC) and 53 PD patients) and 145 CSF samples (52 HC and 93 PD patients) from our Institution. Both serum and CSF were available for 24 participants. Males had higher auto-antibody levels than females in both fluids. CSF auto-antibody levels were significantly higher in PD patients as compared to HC, whereas serum levels were not significantly different. CSF auto-antibody levels did not associate with amyloid-β1–42, total tau, or phosphorylated tau. CSF auto-antibody levels correlated with performance on the Montreal Cognitive Assessment, even when controlled for CSF amyloidβ1–42. CSF hemoglobin levels, as a proxy for contamination of CSF by blood during lumbar puncture, did not influence these observations. Using recombinant α-synuclein with N- and C-terminal truncations, we found that CSF auto-antibodies target amino acids 100 through 120 of α-synuclein. We conclude that endogenous CSF auto-antibodies are significantly higher in PD patients as compared to HC, suggesting that they could indicate the presence of underlying synucleinopathy. These auto-antibodies associate with poor cognition, independently of CSF amyloidβ1–42., and target a select C-terminal region of α-synuclein. Endogenous auto-antibodies to α-synuclein could be useful biomarkers in Parkinson’s disease (PD), but previous attempts to measure auto-antibodies have been inconclusive. We developed a reliable method to measure α-synuclein auto-antibodies in biofluid samples. We found significantly higher levels of auto-antibodies in the cerebrospinal fluid (CSF) of PD patients than in healthy controls. In the serum, levels of auto-antibodies were similar in both groups. Participants with higher levels of CSF auto-antibodies tended to have worse cognitive performance, as measured by the Montreal Cognitive Assessment. These auto-antibodies recognized the C-terminal domain in α-synuclein. This study suggests that auto-antibodies to α-synuclein could be useful biomarkers for diagnosis in PD and may correlate with clinical disease features.
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