Lusardi Theresa A, Sandau Ursula S, Sakhanenko Nikita A, Baker Sarah Catherine B, Wiedrick Jack T, Lapidus Jodi A, Raskind Murray A, Li Ge, Peskind Elaine R, Galas David J, Quinn Joseph F, Saugstad Julie A
Knight Cancer Institute, Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, United States.
Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, United States.
Front Neurosci. 2021 Sep 9;15:720778. doi: 10.3389/fnins.2021.720778. eCollection 2021.
A history of traumatic brain injury (TBI) increases the odds of developing Alzheimer's disease (AD). The long latent period between injury and dementia makes it difficult to study molecular changes initiated by TBI that may increase the risk of developing AD. MicroRNA (miRNA) levels are altered in TBI at acute times post-injury (<4 weeks), and in AD. We hypothesized that miRNA levels in cerebrospinal fluid (CSF) following TBI in veterans may be indicative of increased risk for developing AD. Our population of interest is cognitively normal veterans with a history of one or more mild TBI (mTBI) at a chronic time following TBI. We measured miRNA levels in CSF from three groups of participants: (1) community controls with no lifetime history of TBI (ComC); (2) deployed Iraq/Afghanistan veterans with no lifetime history of TBI (DepC), and (3) deployed Iraq/Afghanistan veterans with a history of repetitive blast mTBI (DepTBI). CSF samples were collected at the baseline visit in a longitudinal, multimodal assessment of Gulf War veterans, and represent a heterogenous group of male veterans and community controls. The average time since the last blast mTBI experienced was 4.7 ± 2.2 years [1.5 - 11.5]. Statistical analysis of TaqMan miRNA array data revealed 18 miRNAs with significant differential expression in the group comparisons: 10 between DepTBI and ComC, 7 between DepC and ComC, and 8 between DepTBI and DepC. We also identified 8 miRNAs with significant differential detection in the group comparisons: 5 in DepTBI vs. ComC, 3 in DepC vs. ComC, and 2 in DepTBI vs. DepC. When we applied our previously developed multivariable dependence analysis, we found 13 miRNAs (6 of which are altered in levels or detection) that show dependencies with participant phenotypes, e.g., ApoE. Target prediction and pathway analysis with miRNAs differentially expressed in DepTBI vs. either DepC or ComC identified canonical pathways highly relevant to TBI including senescence and ephrin receptor signaling, respectively. This study shows that both TBI and deployment result in persistent changes in CSF miRNA levels that are relevant to known miRNA-mediated AD pathology, and which may reflect early events in AD.
创伤性脑损伤（TBI）病史会增加患阿尔茨海默病（AD）的几率。损伤与痴呆之间漫长的潜伏期使得研究由TBI引发的可能增加患AD风险的分子变化变得困难。在TBI后的急性期（伤后<4周）以及AD中，微小RNA（miRNA）水平都会发生改变。我们假设退伍军人TBI后脑脊液（CSF）中的miRNA水平可能表明患AD的风险增加。我们感兴趣的人群是在TBI后的慢性期有过一次或多次轻度TBI（mTBI）病史的认知正常退伍军人。我们测量了三组参与者脑脊液中的miRNA水平：（1）无TBI终生病史的社区对照（ComC）；（2）无TBI终生病史的曾部署到伊拉克/阿富汗的退伍军人（DepC），以及（3）有重复性爆炸mTBI病史的曾部署到伊拉克/阿富汗的退伍军人（DepTBI）。脑脊液样本是在对海湾战争退伍军人进行的纵向多模式评估的基线访视时采集的，代表了一组由男性退伍军人和社区对照组成的异质性群体。自最后一次经历爆炸mTBI以来的平均时间为4.7±2.2年[1.5 - 11.5]。对TaqMan miRNA阵列数据的统计分析显示，在组间比较中有18种miRNA存在显著差异表达：DepTBI与ComC之间有10种，DepC与ComC之间有7种，DepTBI与DepC之间有8种。我们还在组间比较中鉴定出8种miRNA存在显著差异检测：DepTBI与ComC之间有5种，DepC与ComC之间有3种，DepTBI与DepC之间有2种。当我们应用我们之前开发的多变量依赖性分析时，我们发现有13种miRNA（其中6种在水平或检测方面发生了改变）与参与者的表型（如载脂蛋白E）存在依赖性。对DepTBI与DepC或ComC中差异表达的miRNA进行靶标预测和通路分析，分别确定了与TBI高度相关的经典通路，包括衰老和 Ephrin 受体信号通路。这项研究表明，TBI和部署都会导致脑脊液miRNA水平的持续变化，这些变化与已知的miRNA介导的AD病理学相关，并且可能反映了AD的早期事件。
