Orrú Christina D, Vaughan David P, Vijiaratnam Nirosen, Real Raquel, Martinez-Carrasco Alejandro, Fumi Riona, Jensen Marte Theilmann, Hodgson Megan, Girges Christine, Gil-Martinez Ana-Luisa, Stafford Eleanor J, Wu Lesley, Lerche Stefanie, Wurster Isabel, Groveman Bradley R, Hughson Andrew G, Ansorge Olaf, Quaegebeur Annelies, Allinson Kieren S J, Warner Thomas T, Jaunmuktane Zane, Misbahuddin Anjum, Leigh P Nigel, Ghosh Boyd C P, Bhatia Kailash P, Church Alistair, Kobylecki Christopher, Hu Michele T M, Rowe James B, Parchi Piero, Brockmann Kathrin, Foltynie Thomas, Morris Huw R, Caughey Byron, Jabbari Edwin
Laboratory of Neurological Infections and Immunity, Division of Intramural Research, NIH/NIAID Rocky Mountain Laboratories, Hamilton, MT, USA.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK.
Lancet Neurol. 2025 Jul;24(7):580-590. doi: 10.1016/S1474-4422(25)00157-7.
BACKGROUND: α-synuclein seed amplification assay (SAA) positivity has been proposed as a diagnostic biomarker for Parkinson's disease. However, studies of the prognostic value of this biomarker have been limited to small, single-centre studies over short follow-up periods. We aimed to assess the diagnostic and prognostic value of quantitative CSF α-synuclein SAA kinetic measures in Parkinson's disease. METHODS: In this longitudinal cohort study, we collected and analysed data from participants with Parkinson's disease, progressive supranuclear palsy, and healthy controls enrolled in three cohorts: the UK parkinsonism cohort, the Parkinson's Progression Markers Initiative (PPMI) international observational study, and the Tübingen Parkinson's disease cohort. Baseline CSF α-synuclein SAA data and longitudinal clinical data were collected between Jan 1, 2005, and Nov 1, 2023. The following seeding kinetic measures were calculated from the α-synuclein SAA curve for each SAA-positive sample: time to threshold (TTT) for a positive SAA result; maximum Thioflavin T fluorescence during the reaction time (MaxThT); and area under the fluorescence curve during the reaction time (AUC). We compared seeding kinetic measures between sporadic Parkinson's disease and progressive supranuclear palsy, and between sporadic Parkinson's disease and monogenic Parkinson's disease. We used time-to-event analyses to assess the ability of α-synuclein SAA kinetic measures to predict an unfavourable outcome in Parkinson's disease, adjusting for sex, age, and disease duration at SAA testing. FINDINGS: We analysed data from 1631 participants: newly generated data from the UK parkinsonism cohort (Parkinson's disease, n=66; progressive supranuclear palsy, n=52; controls, n=9) and previously generated data from the PPMI (Parkinson's disease, n=1036; controls, n=239) and Tübingen (Parkinson's disease, n=229) cohorts. In the UK parkinsonism cohort, α-synuclein SAA was positive in 63 (96%) of 66 Parkinson's disease samples and eight (15%) of 52 progressive supranuclear palsy samples, with six (75%) of eight positive progressive supranuclear palsy samples having distinct low and slow seeding kinetics (low MaxThT and high TTT) as a marker of Lewy body co-pathology. TTT was faster in GBA1-associated Parkinson's disease compared with sporadic Parkinson's disease in both the PPMI (p=0·04) and Tübingen (p=0·01) cohorts. In the PPMI cohort, after excluding individuals who had an unfavourable outcome at the time of baseline SAA testing, an unfavourable outcome was observed in 593 (73%) of 810 participants with α-synuclein SAA-positive Parkinson's disease during a median follow-up period of 4·5 years (IQR 2-9). TTT at baseline predicted only cognitive decline (Montreal Cognitive Assessment score ≤21) as a component of an unfavourable outcome in Parkinson's disease in both the PPMI (n=824, hazard ratio [HR] 2·36 [95% CI 1·60-3·46], p=0·001) and Tübingen (n=135, 2·17 [1·07-4·41], p=0·03) cohorts. TTT also predicted cognitive decline in a subgroup of participants with Parkinson's disease in the PPMI cohort who were Alzheimer's disease biomarker negative (n=355, HR 1·80 [95% CI 1·03-3·18], p=0·04). INTERPRETATION: Assessing α-synuclein SAA kinetic measures might aid in the diagnostic differentiation of Parkinson's disease from progressive supranuclear palsy with Lewy body co-pathology. Furthermore, faster seeding kinetics are found in GBA1-Parkinson's disease and predict cognitive decline in Parkinson's disease independently of Alzheimer's disease co-pathology. FUNDING: Medical Research Council, PSP Association. COPYRIGHT: © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
背景：α-突触核蛋白种子扩增分析（SAA）阳性已被提议作为帕金森病的一种诊断生物标志物。然而，关于这种生物标志物预后价值的研究仅限于小型单中心研究，且随访期较短。我们旨在评估帕金森病中脑脊液α-突触核蛋白SAA定量动力学指标的诊断和预后价值。
方法：在这项纵向队列研究中，我们收集并分析了来自三个队列的帕金森病、进行性核上性麻痹患者及健康对照的数据：英国帕金森综合征队列、帕金森病进展标志物倡议（PPMI）国际观察性研究以及图宾根帕金森病队列。在2005年1月1日至2023年11月1日期间收集了基线脑脊液α-突触核蛋白SAA数据和纵向临床数据。对于每个SAA阳性样本，从α-突触核蛋白SAA曲线计算以下种子动力学指标：SAA结果呈阳性的阈值时间（TTT）；反应时间内硫黄素T荧光的最大值（MaxThT）；以及反应时间内荧光曲线下的面积（AUC）。我们比较了散发性帕金森病与进行性核上性麻痹之间以及散发性帕金森病与单基因帕金森病之间的种子动力学指标。我们使用生存分析来评估α-突触核蛋白SAA动力学指标预测帕金森病不良结局的能力，并对SAA检测时的性别、年龄和病程进行了校正。
结果：我们分析了1631名参与者的数据：英国帕金森综合征队列的新生成数据（帕金森病，n = 66；进行性核上性麻痹，n = 52；对照，n = 9）以及PPMI（帕金森病，n = 1036；对照，n = 239）和图宾根（帕金森病，n = 229）队列先前生成的数据。在英国帕金森综合征队列中，66个帕金森病样本中的63个（96%）和52个进行性核上性麻痹样本中的8个（15%）α-突触核蛋白SAA呈阳性，8个阳性进行性核上性麻痹样本中的6个（75%）具有明显低且慢的种子动力学（低MaxThT和高TTT），作为路易小体合并病理的标志物。在PPMI队列（p = 0·04）和图宾根队列（p = 0·01）中，与散发性帕金森病相比，GBA1相关帕金森病的TTT更快。在PPMI队列中，排除基线SAA检测时已有不良结局的个体后，在中位随访期4·5年（IQR 2 - 9）内，810名α-突触核蛋白SAA阳性帕金森病参与者中有593名（73%）出现了不良结局。基线时的TTT仅预测了帕金森病不良结局中的认知下降（蒙特利尔认知评估评分≤21），在PPMI队列（n = 824，风险比[HR] 2·36 [95% CI 1·60 - 3·46]，p = 0·001）和图宾根队列（n = 135，2·17 [1·07 - 4·41]，p = 0·03）中均如此。TTT还预测了PPMI队列中阿尔茨海默病生物标志物阴性的帕金森病参与者亚组中的认知下降（n = 355，HR 1·80 [95% CI 1·03 - 3·18]，p = 0·04）。
解读：评估α-突触核蛋白SAA动力学指标可能有助于帕金森病与伴有路易小体合并病理的进行性核上性麻痹的诊断鉴别。此外，在GBA1帕金森病中发现更快的种子动力学，且独立于阿尔茨海默病合并病理预测帕金森病的认知下降。
资助：医学研究委员会、PSP协会。 版权：© 2025作者。由爱思唯尔有限公司出版。这是一篇根据CC BY 4.0许可的开放获取文章。
J Parkinsons Dis. 2024
Cochrane Database Syst Rev. 2017-11-22
Cochrane Database Syst Rev. 2021-4-19
Cochrane Database Syst Rev. 2017-11-22
Cochrane Database Syst Rev. 2022-5-20
Zotero 插件