α-突触核蛋白种子扩增测定动力学指标在帕金森病中的诊断和预后价值：一项纵向队列研究

The Lancet Neurology Pub Date : 2025-06-18 DOI:10.1016/s1474-4422(25)00157-7

Christina D Orrú, David P Vaughan, Nirosen Vijiaratnam, Raquel Real, Alejandro Martinez-Carrasco, Riona Fumi, Marte Theilmann Jensen, Megan Hodgson, Christine Girges, Ana-Luisa Gil-Martinez, Eleanor J Stafford, Lesley Wu, Stefanie Lerche, Isabel Wurster, Bradley R Groveman, Andrew G Hughson, Olaf Ansorge, Annelies Quaegebeur, Kieren S J Allinson, Thomas T Warner, Edwin Jabbari

{"title":"α-突触核蛋白种子扩增测定动力学指标在帕金森病中的诊断和预后价值：一项纵向队列研究","authors":"Christina D Orrú, David P Vaughan, Nirosen Vijiaratnam, Raquel Real, Alejandro Martinez-Carrasco, Riona Fumi, Marte Theilmann Jensen, Megan Hodgson, Christine Girges, Ana-Luisa Gil-Martinez, Eleanor J Stafford, Lesley Wu, Stefanie Lerche, Isabel Wurster, Bradley R Groveman, Andrew G Hughson, Olaf Ansorge, Annelies Quaegebeur, Kieren S J Allinson, Thomas T Warner, Edwin Jabbari","doi":"10.1016/s1474-4422(25)00157-7","DOIUrl":null,"url":null,"abstract":"<h3>Background</h3>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.<h3>Methods</h3>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.<h3>Findings</h3>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 <em>GBA1</em>-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).<h3>Interpretation</h3>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 <em>GBA1</em>-Parkinson's disease and predict cognitive decline in Parkinson's disease independently of Alzheimer's disease co-pathology.<h3>Funding</h3>Medical Research Council, PSP Association.<h3>Copyright</h3>© 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"29 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study\",\"authors\":\"Christina D Orrú, David P Vaughan, Nirosen Vijiaratnam, Raquel Real, Alejandro Martinez-Carrasco, Riona Fumi, Marte Theilmann Jensen, Megan Hodgson, Christine Girges, Ana-Luisa Gil-Martinez, Eleanor J Stafford, Lesley Wu, Stefanie Lerche, Isabel Wurster, Bradley R Groveman, Andrew G Hughson, Olaf Ansorge, Annelies Quaegebeur, Kieren S J Allinson, Thomas T Warner, Edwin Jabbari\",\"doi\":\"10.1016/s1474-4422(25)00157-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3>Background</h3>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.<h3>Methods</h3>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.<h3>Findings</h3>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 <em>GBA1</em>-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).<h3>Interpretation</h3>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 <em>GBA1</em>-Parkinson's disease and predict cognitive decline in Parkinson's disease independently of Alzheimer's disease co-pathology.<h3>Funding</h3>Medical Research Council, PSP Association.<h3>Copyright</h3>© 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.\",\"PeriodicalId\":22676,\"journal\":{\"name\":\"The Lancet Neurology\",\"volume\":\"29 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-06-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Lancet Neurology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/s1474-4422(25)00157-7\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Lancet Neurology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/s1474-4422(25)00157-7","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}

引用次数: 0

摘要

α-突触核蛋白种子扩增试验（SAA）阳性已被提出作为帕金森病的诊断生物标志物。然而，对这种生物标志物的预后价值的研究仅限于小型、单中心、短随访期的研究。目的探讨脑脊液α-突触核蛋白SAA动力学定量测定对帕金森病的诊断和预后价值。方法在这项纵向队列研究中，我们收集并分析了帕金森病、进行性核上性麻痹和健康对照患者的数据，这些患者分为三个队列：英国帕金森病队列、帕金森进展标志物倡议（PPMI）国际观察性研究和宾根帕金森病队列。基线脑脊液α-突触核蛋白SAA数据和纵向临床数据收集于2005年1月1日至2023年11月1日。根据α-synuclein SAA曲线计算每个SAA阳性样品的播种动力学指标：SAA阳性的阈值时间（TTT）；反应时间内最大硫黄素T荧光（MaxThT）；和反应时间内荧光曲线下面积（AUC）。我们比较了散发性帕金森病和进行性核上性麻痹之间以及散发性帕金森病和单基因帕金森病之间的播种动力学指标。我们使用时间-事件分析来评估α-突触核蛋白SAA动力学测量预测帕金森病不利结果的能力，在SAA测试中调整性别、年龄和疾病持续时间。研究结果：我们分析了1631名参与者的数据：新生成的数据来自英国帕金森病队列(帕金森病，n=66；进行性核上性麻痹，n=52；对照，n=9)和先前PPMI生成的数据(帕金森病，n=1036；对照组，n=239)和t bingen（帕金森病，n=229）队列。在英国帕金森队列中，66例帕金森病患者中有63例(96%)α-synuclein SAA阳性，52例进行性核上麻痹患者中有8例(15%)α-synuclein SAA阳性，8例进行性核上麻痹患者中有6例（75%）具有明显的低和慢种子动力学（低MaxThT和高TTT），这是路易体共病理的标志。在PPMI组（p= 0.04）和t bingen组（p= 0.01）中，gba1相关帕金森病的TTT比散发性帕金森病更快。在PPMI队列中，在排除基线SAA检测时出现不良结果的个体后，在中位随访期4.5年（IQR 2-9）期间，810名α-突触核蛋白SAA阳性帕金森病患者中有593人（73%）出现不良结果。在PPMI （n=824，风险比[HR] 2.36 [95% CI 1.60 - 3.46], p= 0.001）和t bingen （n=135, 2.17 [1.07 - 4.41], p= 0.03）两组中，TTT基线时仅预测认知能力下降（蒙特利尔认知评估评分≤21）是帕金森病不良结局的一个组成部分。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患者亚组的认知能力下降（n=355, HR 1.80 [95% CI 1.03 - 3·18],p= 0.04）。评价α-突触核蛋白SAA动力学指标可能有助于帕金森病与伴路易体病理的进行性核上性麻痹的诊断鉴别。此外，在gba1 -帕金森病中发现了更快的播种动力学，并独立于阿尔茨海默病的共病理预测帕金森病的认知衰退。资助医学研究理事会，PSP协会。版权所有©2025作者。Elsevier Ltd.出版。这是一篇基于CC BY 4.0许可的开放获取文章。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study

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

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

The Lancet Neurology

自引率

0.00%

发文量