Baseline α-synuclein seeding activity and disease progression in sporadic and genetic Parkinson's disease in the PPMI cohort.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-09-01 Epub Date: 2025-08-06 DOI:10.1016/j.ebiom.2025.105866

Jackson G Schumacher, Xinyuan Zhang, Eric A Macklin, Jian Wang, Armin Bayati, Johannes M Dijkstra, Hirohisa Watanabe, Michael A Schwarzschild, Marianna Cortese, Xuehong Zhang, Xiqun Chen

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引用次数: 0

Abstract

Background: α-Synuclein (α-syn) seed amplification assays (SAAs) have shown remarkable potential in diagnosing Parkinson's disease (PD). Using data from the Parkinson's Progression Markers Initiative (PPMI) cohort, we aimed to test whether baseline α-syn seeding activity and α-syn SAA kinetic parameters are associated with disease progression in sporadic PD, LRRK2-associated PD (LRRK2 PD), and GBA-associated PD (GBA PD).

Methods: We analysed 7 years of motor, non-motor, and cognitive assessments and 5 years of dopamine transporter imaging along with baseline α-syn SAA results from 564 PPMI participants (n = 332 sporadic PD, 162 LRRK2 PD, and 70 GBA PD) using linear mixed-effects models, adjusted for potential confounders, to test whether baseline α-syn SAA positivity (n = 315 sporadic PD, 111 LRRK2 PD, and 66 GBA PD) and α-syn SAA kinetic parameters are associated with PD progression.

Findings: While non-statistically significant, there was a trend towards faster motor decline in participants with α-syn SAA positive LRRK2 PD compared to those with α-syn SAA negative LRRK2 PD (MDS-UPDRS III points per year: 2.39 (95% confidence interval: 1.86-2.92) vs. 1.76 (0.93-2.60); difference = 0.63 (-0.29 to 1.55, p = 0.18). This trend appeared to be driven by R1441C/G + M1646T carriers (3.89 (1.22-6.55) vs. 0.31 (-1.32 to 1.93); difference = 3.58 (0.56-6.60, p = 0.02) and excluding them eliminated any trend (2.33 (1.79-2.86) vs. 2.26 (1.34-3.18); difference = 0.07 (-0.93 to 1.07, p = 0.89). Based on a clinically meaningful difference of 4.63 points we found no statistically significant or clinically meaningful difference in motor decline between α-syn SAA positive and α-syn SAA negative participants with sporadic PD (2.46 (2.20-2.72) vs. 2.39 (1.36-3.42); difference = 0.07 (-0.99 to 1.12), p = 0.90) or GBA PD (2.67 (1.91-3.44) vs. 2.40 (-0.18 to 4.99); difference = 0.27 (-2.42 to 2.96), p = 0.84). No statistically significant or clinically meaningful differences were seen in the progression of non-motor symptoms, cognition, or DAT imaging. Additionally, we found no clinically meaningful association between α-syn SAA kinetic parameters and PD progression.

Interpretation: We found no statistically significant associations between baseline α-syn seeding activity, α-syn SAA kinetic parameters, and PD progression among manifest patients in the PPMI cohort. Future studies are needed to further investigate relationships among α-syn seeding activity, disease heterogeneity, disease stage, and PD progression.

Funding: This research was funded by Aligning Science Across Parkinson's grant ASAP-237603 through the Michael J. Fox Foundation for Parkinson's Research and by the National Institutes of Health through the National Institute of Neurological Disorders and Stroke grants R01NS102735 and 5R01NS126260.

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PPMI队列中散发性和遗传性帕金森病的基线α-突触核蛋白播种活性和疾病进展

背景：α-突触核蛋白（α-syn）种子扩增试验（SAAs）在帕金森病（PD）的诊断中显示出显著的潜力。使用来自帕金森进展标志物倡议（PPMI）队列的数据，我们旨在测试α-syn种子的基线活性和α-syn SAA动力学参数是否与散发性PD、LRRK2相关PD （LRRK2 PD）和GBA相关PD （GBA PD）的疾病进展相关。方法：我们分析了564名PPMI参与者（n = 332例散发性PD、162例LRRK2 PD和70例GBA PD） 7年的运动、非运动和认知评估，以及5年的多巴胺转运体成像和基线α-syn SAA结果，采用线性混合效应模型，调整了潜在的混杂因素，以检验基线α-syn SAA阳性（n = 315例散发性PD、111例LRRK2 PD和66例GBA PD）和α-syn SAA动力学参数是否与PD进展相关。研究结果：与α-syn SAA阴性LRRK2 PD患者相比，α-syn SAA阳性LRRK2 PD患者有更快的运动功能下降趋势(MDS-UPDRS III分/年：2.39（95%置信区间：1.86-2.92）比1.76 (0.93-2.60)；差异= 0.63（-0.29至1.55,p = 0.18）。这一趋势似乎是由R1441C/G + M1646T携带者推动的(3.89 (1.22-6.55)vs. 0.31 (-1.32 - 1.93)；差异= 3.58 (0.56-6.60,p = 0.02)，排除它们可以消除任何趋势(2.33 (1.79-2.86)vs. 2.26 (1.34-3.18)；差异= 0.07（-0.93至1.07,p = 0.89）。基于4.63分的临床意义差异，我们发现α-syn SAA阳性和α-syn SAA阴性的散发性PD患者的运动能力下降无统计学意义或临床意义差异(2.46（2.20-2.72）比2.39 (1.36-3.42)；差异= 0.07(-0.99至1.12),p = 0.90)或GBA PD(2.67(1.91至3.44)vs. 2.40(-0.18至4.99)；差异= 0.27(-2.42至2.96),p = 0.84)。在非运动症状的进展、认知或DAT成像方面没有统计学意义或临床意义的差异。此外，我们发现α-syn SAA动力学参数与PD进展之间没有临床意义的关联。解释：我们发现基线α-syn种子活性、α-syn SAA动力学参数与PPMI队列中显性患者PD进展之间无统计学意义的关联。需要进一步研究α-syn种子活性、疾病异质性、疾病分期和PD进展之间的关系。资助：本研究由Michael J. Fox帕金森病研究基金会的帕金森病基金ASAP-237603和美国国立卫生研究院通过国家神经疾病和中风研究所的R01NS102735和5R01NS126260资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.