Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China.
Alzheimers Res Ther. 2024 May 10;16(1):103. doi: 10.1186/s13195-024-01463-2.
The role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood.
A total of 331 non-demented individuals were included in the study from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition.
Higher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1.
These findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.
α-突触核蛋白在痴呆中的作用已得到认可，但它对认知能力下降的具体影响在非痴呆老年人中仍未完全明确。
本研究共纳入来自阿尔茨海默病神经影像学倡议（ADNI）的 331 名非痴呆个体。根据α-突触核蛋白水平，将参与者分为两组：一组水平较低（α-突触核蛋白-L），另一组水平较高（α-突触核蛋白-H）。评估指标包括神经精神量表、脑脊液（CSF）生物标志物和血液转录组学。采用线性混合效应模型探究认知的纵向变化。采用 Kaplan-Meier 生存分析和 Cox 比例风险模型评估不同水平的α-突触核蛋白对痴呆的影响。采用基因集富集分析（GSEA）探究与认知障碍相关的生物学途径。采用 Pearson 相关分析、多元线性回归模型和中介分析探究α-突触核蛋白与神经退行性生物标志物的关系及其影响认知的潜在机制。
较高的 CSF α-突触核蛋白水平与认知下降和向痴呆进展的风险增加相关。富集分析突出了α-突触核蛋白-H 组中 tau 相关和免疫反应途径的激活。进一步的相关和回归分析表明，CSF α-突触核蛋白水平与 CSF 总 tau（t-tau）、磷酸化 tau（p-tau）181、肿瘤坏死因子受体 1（TNFR1）和细胞间黏附分子-1（ICAM-1）呈正相关。中介分析进一步表明，CSF α-突触核蛋白对认知的不良影响主要通过 CSF t-tau 和 p-tau 介导。此外，还观察到 CSF α-突触核蛋白通过 CSF TNFR1 和 ICAM-1 参与的炎症途径影响 CSF t-tau 和 p-tau181 水平。
这些发现阐明了 CSF α-突触核蛋白水平升高与认知下降进展之间的显著关联，突出了激活的炎症途径和 tau 病理在这一关联中的关键作用。它们强调了监测 CSF α-突触核蛋白水平作为识别认知恶化风险增加和发生痴呆个体的有前途的生物标志物的重要性。
