Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY 10032, USA.
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Aging (Albany NY). 2022 Sep 6;14(17):6859-6886. doi: 10.18632/aging.204268.
Aging-related cognitive decline is an early symptom of Alzheimer's disease and other dementias, and on its own can have substantial consequences on an individual's ability to perform important everyday functions. Despite increasing interest in the potential roles of extracellular microRNAs (miRNAs) in central nervous system (CNS) pathologies, there has been little research on extracellular miRNAs in early stages of cognitive decline. We leverage the longitudinal Normative Aging Study (NAS) cohort to investigate associations between plasma miRNAs and cognitive function among cognitively normal men.
This study includes data from up to 530 NAS participants (median age: 71.0 years) collected from 1996 to 2013, with a total of 1,331 person-visits (equal to 2,471 years of follow up). Global cognitive function was assessed using the Mini-Mental State Examination (MMSE). Plasma miRNAs were profiled using small RNA sequencing. Associations of expression of 381 miRNAs with current cognitive function and rate of change in cognitive function were assessed using linear regression ( = 457) and linear mixed models ( = 530), respectively.
In adjusted models, levels of 2 plasma miRNAs were associated with higher MMSE scores ( < 0.05). Expression of 33 plasma miRNAs was associated with rate of change in MMSE scores over time ( < 0.05). Enriched KEGG pathways for miRNAs associated with concurrent MMSE and MMSE trajectory included Hippo signaling and extracellular matrix-receptor interactions. Gene targets of miRNAs associated with MMSE trajectory were additionally associated with prion diseases and fatty acid biosynthesis.
Circulating miRNAs were associated with both cross-sectional cognitive function and rate of change in cognitive function among cognitively normal men. Further research is needed to elucidate the potential functions of these miRNAs in the CNS and investigate relationships with other neurological outcomes.
与衰老相关的认知能力下降是阿尔茨海默病和其他痴呆症的早期症状，其本身就会对个体执行重要日常功能的能力产生重大影响。尽管人们对细胞外 microRNAs（miRNAs）在中枢神经系统（CNS）疾病中的潜在作用越来越感兴趣，但对认知能力下降早期阶段的细胞外 miRNAs 的研究甚少。我们利用纵向规范衰老研究（NAS）队列来研究认知正常男性的血浆 miRNAs 与认知功能之间的关联。
本研究包括了从 1996 年到 2013 年期间，多达 530 名 NAS 参与者（中位年龄：71.0 岁）的数据，总共进行了 1331 人次的访问（相当于 2471 年的随访）。使用简易精神状态检查（MMSE）评估整体认知功能。使用小 RNA 测序对血浆 miRNAs 进行分析。使用线性回归（=457）和线性混合模型（=530）分别评估 381 种 miRNA 的表达与当前认知功能和认知功能变化率之间的关联。
在调整后的模型中，2 种血浆 miRNA 的水平与较高的 MMSE 评分相关（<0.05）。33 种血浆 miRNA 的表达与 MMSE 评分随时间的变化率相关（<0.05）。与同时 MMSE 和 MMSE 轨迹相关的 miRNA 的富集 KEGG 通路包括 Hippo 信号和细胞外基质-受体相互作用。与 MMSE 轨迹相关的 miRNA 的基因靶标还与朊病毒病和脂肪酸生物合成有关。
循环 miRNAs 与认知正常男性的横断面认知功能和认知功能变化率均相关。需要进一步的研究来阐明这些 miRNAs 在中枢神经系统中的潜在功能，并研究与其他神经学结果的关系。
