Evidence from neuropathological cohorts indicates that a CSF α-synuclein (α-syn) seed amplification assay (SAA) may provide quantitative kinetic parameters correlating with α-syn pathology burden in patients with Lewy body disease (LBD). Studies are needed to assess their longitudinal trend during the pre-symptomatic and clinical disease phases and their correlation with measures of disease progression. We aimed to assess the baseline α-syn CSF SAA kinetic parameters, their longitudinal variations and associations with clinical outcomes in a cohort of longitudinally repeatedly sampled Lewy Body disease patients, including clinically unimpaired (asymptomatic LBD) and neurologically impaired individuals. Participants from the prospective BioFINDER-1 study with longitudinal CSF collections (n=718) were screened by α-syn SAA. CSF samples were tested in four replicates blinded to clinical diagnoses. The number of positive replicates (Nrep), the time needed by the fluorescence signal to reach the threshold (Lag) and the highest intensity of the fluorescent signal (Imax). were analysed at baseline (time of first positive SAA) in all participants and longitudinally in those with at least two α-syn positive CSF samples available. One hundred ninety-six individuals (whole cohort) showing α-syn seeding activity were included. Of those, 170 participants tested positive by SAA in all available samples, while 26 converted from a negative to a positive test result during follow-up (LBD-converters), suggesting an early LBD stage. At baseline, LBD-converters showed lower Nrep (p=0.001) and a longer Lag (p=0.001) than subjects displaying α-syn seeding activity from the first available sample. Nrep increased longitudinally in the whole cohort (β=0.09, 95% confidence interval (95%CI) 0.06-0.12, p<0.001), in asymptomatic LBD (β=0.15, 95%CI 0.09-0.21, p<0.001) and Parkinson’s disease individuals without dementia (β=0.07, 95%CI 0.02-0.12, p=0.01). The Lag decreased longitudinally in asymptomatic LBD (β=-0.24, 95%CI -0.42 - -0.06, p=0.008). Baseline Nrep predicted the subsequent appearance of dementia in the whole cohort (Hazard ratio (HR) 1.57, 95%CI 1.19-2.07, p=0.001) and the Parkinson’s disease subgroup (HR 1.83, 95%CI 1.17-2.85, p=0.008). The difference between the Lag at each sampling and that at baseline was negatively associated with the appearance of dementia in the whole cohort (HR 0.76, 95%CI 0.59–0.99, p=0.04) and Parkinson’s disease subgroup (HR 0.69, 95%CI 0.50-0.95, p=0.02). α-syn SAA parameters Nrep and Lag showed associations with the LBD stage and the development of dementia. Furthermore, their longitudinal variation is coherent with pathology progression over time. These data support the use of SAA kinetic parameters to monitor disease progression and therapeutic response.

中文翻译：

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Alpha-突触核蛋白种子扩增测定路易体疾病谱的纵向结果


来自神经病理学队列的证据表明，CSF α-突触核蛋白 （α-syn） 种子扩增测定 （SAA） 可能提供与路易体病 （LBD） 患者 α-syn 病理负担相关的定量动力学参数。需要研究来评估它们在症状前和临床疾病阶段的纵向趋势以及它们与疾病进展指标的相关性。我们旨在评估纵向重复采样的路易体病患者队列的基线 α-syn CSF SAA 动力学参数、它们的纵向变化以及与临床结果的关联，包括临床上未受损 （无症状 LBD） 和神经受损的个体。来自 BioFINDER-1 纵向 CSF 收集 （n=718） 的前瞻性研究的参与者通过 α-syn SAA 进行筛选。对 CSF 样本进行了 4 次重复测试，对临床诊断不知情。阳性重复数 （Nrep）、荧光信号达到阈值所需的时间 （Lag） 和荧光信号的最高强度 （Imax）。在所有参与者的基线 （首次 SAA 阳性的时间） 和至少有两个 α-syn 阳性 CSF 样本的参与者进行纵向分析。纳入 196 例显示 α-syn 接种活性的个体 （整个队列）。其中，170 名参与者在所有可用样本中经 SAA 检测呈阳性，而 26 名参与者在随访期间从阴性检测结果转化为阳性（LBD 转换者），表明 LBD 处于早期阶段。在基线时，LBD 转换器显示出较低的 Nrep （p=0.001） 和更长的 Lag （p=0.001），而不是从第一个可用样本中显示 α-syn 接种活性的受试者。Nrep 在整个队列中纵向增加 （β=0.09,95% 置信区间 （95%CI） 0。06-0.12，p<0.001），在无症状 LBD （β=0.15,95% CI 0.09-0.21，p<0.001） 和无 痴呆的帕金森病个体 （β=0.07,95% CI 0.02-0.12，p=0.01）。无症状 LBD 的 Lag 纵向降低 （β=-0.24,95% CI -0.42 - -0.06，p=0.008）。基线 Nrep 预测了整个队列 （风险比 （HR） 1.57,95% CI 1.19-2.07，p=0.001） 和帕金森病亚组 （HR 1.83,95%CI 1.17-2.85，p=0.008） 痴呆的后续出现。每个样本的滞后与基线时的滞后差异与整个队列 （HR 0.76,95% CI 0.59-0.99，p=0.04） 和帕金森病亚组 （HR 0.69,95%CI 0.50-0.95，p=0.02） 的痴呆外观呈负相关。α-syn SAA 参数 Nrep 和 Lag 显示与 LBD 分期和 痴呆 发展相关。此外，它们的纵向变化与病理学随时间的进展是一致的。这些数据支持使用 SAA 动力学参数来监测疾病进展和治疗反应。