PDF(Pubmed)
Abstract：
BACKGROUND: Aging represents a significant risk factor for the occurrence of cerebral small vessel disease, associated with white matter (WM) lesions, and to age-related cognitive alterations, though the precise mechanisms remain largely unknown. This study aimed to investigate the impact of polygenic risk scores (PRS) for WM integrity, together with age-related DNA methylation, and gene expression alterations, on cognitive aging in a cross-sectional healthy aging cohort. The PRSs were calculated using genome-wide association study (GWAS) summary statistics for magnetic resonance imaging (MRI) markers of WM integrity, including WM hyperintensities, fractional anisotropy (FA), and mean diffusivity (MD). These scores were utilized to predict age-related cognitive changes and evaluate their correlation with structural brain changes, which distinguish individuals with higher and lower cognitive scores. To reduce the dimensionality of the data and identify age-related DNA methylation and transcriptomic alterations, Sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) was used. Subsequently, a canonical correlation algorithm was used to integrate the three types of omics data (PRS, DNA methylation, and gene expression data) and identify an individual \"omics\" signature that distinguishes subjects with varying cognitive profiles.
RESULTS: We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging.
CONCLUSIONS: These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.
RESULTS: We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging.
CONCLUSIONS: These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.
摘要：
背景：衰老是脑小血管病发生的重要危险因素，与白质（WM）病变相关，以及与年龄相关的认知改变，尽管确切的机制在很大程度上仍然未知。本研究旨在调查多基因风险评分(PRS)对WM完整性的影响。与年龄相关的DNA甲基化，和基因表达改变，关于横断面健康老龄化队列中的认知衰老。使用全基因组关联研究（GWAS）汇总统计来计算WM完整性的磁共振成像（MRI）标记，包括WM超强度，分数各向异性（FA），和平均扩散系数(MD)。这些分数用于预测与年龄相关的认知变化，并评估其与大脑结构变化的相关性。区分认知分数较高和较低的个体。为了减少数据的维度并识别与年龄相关的DNA甲基化和转录组改变，使用稀疏偏最小二乘判别分析(sPLS-DA)。随后，使用典型相关算法来整合三种类型的组学数据(PRS，DNA甲基化，和基因表达数据），并确定一个个体“组学”签名，以区分具有不同认知特征的受试者。
结果：我们发现MD-PRS与长期记忆呈正相关，以及MD-PRS与大脑结构变化之间的相关性，有效区分记忆得分较低和较高的个体。此外，我们观察到与血管和非血管因子相关的基因中多基因信号的富集。DNA甲基化和基因表达的年龄相关改变表明参与衰老和寿命调节的关键分子特征和信号通路的失调。多组数据的整合强调了突触功能障碍的参与，轴突变性,微管组织，和认知衰老过程中的糖基化。
结论：这些发现为WM相干性与认知老化之间关联的生物学机制提供了有价值的见解。此外,他们强调了与年龄相关的DNA甲基化和基因表达变化如何导致认知衰老.
结果：我们发现MD-PRS与长期记忆呈正相关，以及MD-PRS与大脑结构变化之间的相关性，有效区分记忆得分较低和较高的个体。此外，我们观察到与血管和非血管因子相关的基因中多基因信号的富集。DNA甲基化和基因表达的年龄相关改变表明参与衰老和寿命调节的关键分子特征和信号通路的失调。多组数据的整合强调了突触功能障碍的参与，轴突变性,微管组织，和认知衰老过程中的糖基化。
结论：这些发现为WM相干性与认知老化之间关联的生物学机制提供了有价值的见解。此外,他们强调了与年龄相关的DNA甲基化和基因表达变化如何导致认知衰老.
