Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
Lancet Neurol. 2021 Mar;20(3):203-212. doi: 10.1016/S1474-4422(20)30449-X.
Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy.
In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations.
52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4-95·8) and a specificity of 90·0% (95% CI 76·9-96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019-1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0·0001; hazard ratio 0·024, 95% CI 0·003-0·177).
In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein.
Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.
孤立性快速眼动（REM）睡眠行为障碍（IRBD）可能是α-突触核蛋白病帕金森病和路易体痴呆的前驱期的一部分。实时震颤诱导转化（RT-QuIC）分析脑脊液对帕金森病和路易体痴呆患者中错误折叠的α-突触核蛋白的检测具有高灵敏度和特异性。我们研究了 RT-QuIC 是否可以检测到 IRBD 患者的 CSF 中的 α-突触核蛋白，并作为 α-突触核蛋白病前驱期的生物标志物。
在这项纵向观察性研究中，从西班牙巴塞罗那一家专门的睡眠障碍中心招募的经视频多导睡眠图证实的 IRBD 患者和无神经系统疾病的对照者通过腰椎穿刺获得 CSF 样本。CSF 样本在进行 RT-QuIC 分析前储存。腰椎穿刺后，每隔 3-12 个月对参与者进行临床评估神经状态。使用 Kaplan-Meier 法估计无神经疾病的生存概率。无神经疾病生存的概率从腰椎穿刺的日期开始计算，直到任何神经退行性疾病的诊断日期，或对已删除的观察结果进行最后一次随访。
2008 年 3 月 23 日至 2017 年 7 月 16 日期间，52 名 IRBD 患者和 40 名健康对照者（年龄匹配，p=0.20；性别匹配，p=0.15；随访时间匹配，p=0.27）接受了腰椎穿刺。CSF α-突触核蛋白 RT-QuIC 检测在 47 名（90%）IRBD 患者和 4 名（10%）对照者中呈阳性，敏感性为 90.4%（95%CI 79.4-95.8），特异性为 90.0%（95%CI 76.9-96.0）。IRBD 患者从腰椎穿刺到研究结束（2020 年 7 月 31 日）的平均随访时间为 7.1 年（SD 2.8），对照组为 7.7 年（2.9）。在随访期间，32 名（62%）患者在腰椎穿刺后平均 3.4 年（SD 2.6）被诊断为帕金森病或路易体痴呆，其中 31 名（97%）在基线时为 α-突触核蛋白阳性。Kaplan-Meier 分析表明，IRBD 患者中 α-突触核蛋白阴性患者的帕金森病或路易体痴呆发病风险较低，在 2、4、6、8 和 10 年的随访中，α-突触核蛋白阳性患者的发病风险较低（对数秩检验，p=0.028；风险比 0.143，95%CI 0.019-1.063）。在随访期间，没有对照者发生 α-突触核蛋白病。Kaplan-Meier 分析表明，α-突触核蛋白阴性的参与者（即 5 名 IRBD 患者加 36 名对照者）在腰椎穿刺后 2、4、6、8 和 10 年的帕金森病或路易体痴呆发病风险低于 α-突触核蛋白阳性的参与者（即 47 名 IRBD 患者加 4 名对照者；对数秩检验，p<0.0001；风险比 0.024，95%CI 0.003-0.177）。
在 IRBD 患者中，RT-QuIC 以 90%的灵敏度和特异性检测 CSF 中的错误折叠的 α-突触核蛋白，α-突触核蛋白阳性与随后诊断为帕金森病或路易体痴呆的风险增加相关。CSF 中 α-突触核蛋白的检测代表了帕金森病和路易体痴呆的潜在前驱期生物标志物。如果这些发现在其他队列中得到复制，那么通过 RT-QuIC 检测 CSF 中的 α-突触核蛋白可能会用于在神经保护试验中富集 IRBD 队列，特别是在评估针对 α-突触核蛋白的干预措施时。
英国卫生部和社会保健部政策研究计划、苏格兰政府和韦斯顿脑研究所。
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