Powell Jada, Hugenschmidt Christina E, Hsu Fang-Chi, Flashman Laura A, Xu Jianzhao, Bowden Donald W, Freedman Barry I, Palmer Nicholette D
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Section on Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Sci Rep. 2025 Apr 26;15(1):14688. doi: 10.1038/s41598-025-99606-4.
To understand the relationship between type 2 diabetes (T2D) and risk for developing cognitive impairment, this study is the first to examine association between metabolites measured at mid-life and cognitive performance assessed later in life (8-10 years) in a T2D-enriched cohort. The discovery set included metabolomics from European Americans (EAs; n = 137) and African Americans (AAs; n = 134) from the Diabetes Heart Study (DHS) and the African American-DHS (AA-DHS). The cognitive testing battery included measures of executive function, memory, attention, language, and global cognition. Ancestry-specific linear regression analyses were performed and a false discovery rate (FDR)-corrected p-value was used to assess significance. Overall, fewer significant metabolites were associated with cognitive performance in AAs (n = 19) as compared to EAs (n = 118) suggesting racial differences. There was a positive association between sphingomyelins and cognitive performance, consistent with prior reports. Novel findings implicated partially characterized metabolites linked to oxidative breakdown of bilirubin to multiple cognitive domains suggesting further exploration of this class of metabolites towards improving pathophysiologic understanding and early intervention. Cross-ancestry replication identified four metabolites that generalized to both populations. Replication was performed among additional study participants, i.e. 421 EAs and 167 AAs, followed by a formal meta-analysis. Replication bolstered the association of multiple metabolites with cognitive function. Among these, cortisol was associated in AAs suggesting a link between stress and risk for reduced cognitive function. Further work is needed to provide insight into the pathophysiologic mechanisms and highlight metabolites for inclusion in risk stratification models of cognitive performance.
为了解2型糖尿病（T2D）与发生认知障碍风险之间的关系，本研究首次在一个富含T2D的队列中，考察中年时测量的代谢物与晚年（8 - 10年）评估的认知表现之间的关联。发现集包括来自糖尿病心脏研究（DHS）和非裔美国人 - DHS（AA - DHS）的欧裔美国人（EA；n = 137）和非裔美国人（AA；n = 134）的代谢组学数据。认知测试组合包括执行功能、记忆、注意力、语言和整体认知的测量。进行了特定血统的线性回归分析，并使用错误发现率（FDR）校正的p值来评估显著性。总体而言，与EA（n = 118）相比，AA（n = 19）中与认知表现相关的显著代谢物较少，表明存在种族差异。鞘磷脂与认知表现呈正相关，与先前报道一致。新发现涉及与胆红素氧化分解相关的部分特征化代谢物与多个认知领域的关联，表明对这类代谢物进行进一步探索以改善病理生理理解和早期干预。跨血统复制确定了四种在两个群体中都具有普遍性的代谢物。在另外的研究参与者中进行了复制，即421名EA和167名AA，随后进行了正式的荟萃分析。复制加强了多种代谢物与认知功能的关联。其中，皮质醇在AA中存在关联，表明压力与认知功能降低风险之间存在联系。需要进一步开展工作，以深入了解病理生理机制，并突出可纳入认知表现风险分层模型的代谢物。
