Liu Qian, Meng Ling-Bing, Qi Tian-Qi, Ma Ya-Qing, Liang Guo-Wei
Department of Clinical Laboratory, Aerospace Center Hospital, Beijing, 100049, China.
Cardiometabolic Medicine Center, National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
Open Med (Wars). 2025 Aug 4;20(1):20251237. doi: 10.1515/med-2025-1237. eCollection 2025.
Disruption of cerebrospinal fluid (CSF) metabolites affects brain function and cognition, potentially altering the brain structure. To elucidate the causal relationships between CSF metabolites and the neurological outcomes, we conducted a two-sample Mendelian randomization analysis. Genome-wide association data from 689 individuals of European descent provided exposure levels for metabolites, analyzed alongside gene associations for cognitive performance ( = 257,841), brain atrophy measures (cortical surface area and thickness; = 51,665), and hippocampal volume ( = 33,536). Our analysis identified 30 metabolites exhibiting causal associations with brain atrophy and cognitive function: 20 linked to cognition and 10 to structural atrophy. Notably, butyrate correlated strongest with the cortical surface area, bilirubin with the cortical thickness, methionine sulfoxide with the hippocampal volume, threonate with cognitive performance, while oxidized Cys-gly, 6-succinyladenosine, and -acetylglucosamine were linked to fluid intelligence, prospective memory, and reaction time, respectively. Pathway analyses revealed that butanoate and niacinamide/niacin ester metabolism are significantly associated with brain atrophy and cognitive performance. These findings position CSF metabolites as promising therapeutic targets for neurodegenerative diseases, providing a causal framework to prioritize interventions. Experimental studies building on this genetic evidence hold potential to accelerate the development of mechanism-driven therapies targeting metabolic pathways in neurodegeneration.
脑脊液（CSF）代谢物的紊乱会影响脑功能和认知，可能改变脑结构。为了阐明脑脊液代谢物与神经学结果之间的因果关系，我们进行了两样本孟德尔随机化分析。来自689名欧洲血统个体的全基因组关联数据提供了代谢物的暴露水平，并与认知表现（n = 257,841）、脑萎缩测量指标（皮质表面积和厚度；n = 51,665）以及海马体积（n = 33,536）的基因关联一起进行分析。我们的分析确定了30种与脑萎缩和认知功能存在因果关联的代谢物：20种与认知相关，10种与结构萎缩相关。值得注意的是，丁酸盐与皮质表面积的相关性最强，胆红素与皮质厚度相关，甲硫氨酸亚砜与海马体积相关，苏糖酸与认知表现相关，而氧化型半胱氨酸 - 甘氨酸、6 - 琥珀酰腺苷和N - 乙酰葡糖胺分别与流体智力、前瞻性记忆和反应时间相关。通路分析表明，丁酸和烟酰胺/烟酸酯代谢与脑萎缩和认知表现显著相关。这些发现将脑脊液代谢物定位为神经退行性疾病有前景的治疗靶点，提供了一个因果框架来确定干预措施的优先级。基于这一遗传证据的实验研究有潜力加速针对神经退行性变中代谢途径的机制驱动疗法的开发。
