Lu Jianglong, Wang Xianpeng, Xu Fanjie, Rao Changjun, Guo Yuhang, Su Zhipeng, Chen Siyan, Li Qun
Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Front Aging Neurosci. 2024 Jun 21;16:1412434. doi: 10.3389/fnagi.2024.1412434. eCollection 2024.
Neuroinflammatory processes have been identified as playing a crucial role in the pathophysiology of various neurodegenerative diseases, including idiopathic normal-pressure hydrocephalus (iNPH). iNPH, defined as a common disease of cognitive impairment in older adults, poses major challenges for therapeutic interventions owing to the stringent methodological requirements of relevant studies, clinical heterogeneity, unclear etiology, and uncertain diagnostic criteria. This study aims to assess the relationship between circulating inflammatory biomarkers and iNPH risk using bidirectional two-sample Mendelian randomization (MR) combined with meta-analysis.
In our bidirectional MR study, genetic data from a genome-wide association study (GWAS) involving 1,456 iNPH cases and 409,726 controls of European ancestry were employed. Single-nucleotide polymorphisms (SNPs) associated with exposures served as instrumental variables for estimating the causal relationships between iNPH and 132 types of circulating inflammatory biomarkers from corresponding GWAS data. Causal associations were primarily examined using the inverse variance-weighted method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode analyses. In the results, heterogeneity was assessed using the Cochran test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers test. Sensitivity analysis was conducted through leave-one-out analysis. Reverse MR analyses were performed to mitigate bias from reverse causality. Meta-analyses of identical inflammatory biomarkers from both data sources strengthened the findings.
Results indicated a genetically predicted association between Interleukin-16 (IL-16) [OR: 1.228, 95% CI: 1.049-1.439, = 0.011], TNF-related apoptosis ligand (TRAIL) [OR: 1.111, 95% CI: 1.019-1.210, = 0.017] and Urokinase-type plasminogen activator (uPA) [OR: 1.303, 95% CI: 1.025-1.658, = 0.031] and the risk of iNPH. Additionally, changes in human Glial cell line-derived neurotrophic factor (hGDNF) [OR: 1.044, 95% CI: 1.006-1.084, = 0.023], Matrix metalloproteinase-1 (MMP-1) [OR: 1.058, 95% CI: 1.020, 1.098, = 0.003] and Interleukin-12p70 (IL-12p70) [OR: 0.897, 95% CI: 0.946-0.997, = 0.037] levels were identified as possible consequences of iNPH.
Our MR study of inflammatory biomarkers and iNPH, indicated that IL-16, TRAIL, and uPA contribute to iNPH pathogenesis. Furthermore, iNPH may influence the expression of hGDNF, MMP-1, and IL-12p70. Therefore, targeting specific inflammatory biomarkers could be promising strategy for future iNPH treatment and prevention.
神经炎症过程在包括特发性正常压力脑积水（iNPH）在内的各种神经退行性疾病的病理生理学中起着关键作用。iNPH被定义为老年人认知障碍的常见疾病，由于相关研究的严格方法要求、临床异质性、病因不明和诊断标准不确定，给治疗干预带来了重大挑战。本研究旨在使用双向两样本孟德尔随机化（MR）结合荟萃分析来评估循环炎症生物标志物与iNPH风险之间的关系。
在我们的双向MR研究中，使用了来自一项全基因组关联研究（GWAS）的遗传数据，该研究涉及1456例iNPH病例和409726例欧洲血统的对照。与暴露相关的单核苷酸多态性（SNP）用作工具变量，以根据相应的GWAS数据估计iNPH与132种循环炎症生物标志物之间的因果关系。因果关联主要使用逆方差加权法进行检验，并辅以MR-Egger、加权中位数、简单模式和加权模式分析。在结果中，使用Cochran检验评估异质性。通过MR-Egger截距检验和MR多效性残差总和与异常值检验评估水平多效性。通过留一法分析进行敏感性分析。进行反向MR分析以减轻反向因果关系的偏差。对来自两个数据源的相同炎症生物标志物进行荟萃分析强化了研究结果。
结果表明，白细胞介素-16（IL-16）[比值比（OR）：1.228，95%置信区间（CI）：1.049 - 1.439，P = 0.011]、肿瘤坏死因子相关凋亡配体（TRAIL）[OR：1.111，95% CI：1.019 - 1.210，P = 0.017]和尿激酶型纤溶酶原激活剂（uPA）[OR：1.303，95% CI：1.025 - 1.658，P = 0.031]与iNPH风险之间存在遗传预测的关联。此外，人胶质细胞源性神经营养因子（hGDNF）水平的变化[OR：1.044，95% CI：1.006 - 1.084，P = 0.023]、基质金属蛋白酶-1（MMP-1）[OR：1.058，95% CI：1.020，1.098，P = 0.003]和白细胞介素-12p70（IL-12p70）[OR：0.897，95% CI：0.946 - 0.997，P = 0.037]被确定为iNPH的可能后果。
我们对炎症生物标志物与iNPH的MR研究表明，IL-16、TRAIL和uPA促成了iNPH的发病机制。此外，iNPH可能影响hGDNF、MMP-1和IL-12p70的表达。因此，针对特定炎症生物标志物可能是未来iNPH治疗和预防的有前景策略。
