From the Stroke Research Group (E.L.H., H.S.M.), Department of Clinical Neurosciences, University of Cambridge; and Victor Phillip Dahdaleh Heart and Lung Research Institute (E.L.H., H.S.M.), University of Cambridge, United Kingdom.
Neurology. 2023 Aug 1;101(5):e489-e501. doi: 10.1212/WNL.0000000000207458. Epub 2023 Jun 8.
Cerebral small vessel disease is a major cause of stroke and dementia. Metabolomics can help identify novel risk factors to better understand pathogenesis and predict disease progression and severity.
We analyzed baseline metabolomic profiles from 118,021 UK Biobank participants. We examined cross-sectional associations of 325 metabolites with MRI markers of small vessel disease, evaluated longitudinal associations with incident stroke and dementia, and ascertained causal relationships using Mendelian randomization.
In cross-sectional analyses, lower levels of apolipoproteins, free cholesterol, cholesteryl esters, fatty acids, lipoprotein particle concentrations, phospholipids, and triglycerides were associated with increased white matter microstructural damage on diffusion tensor MRI. In longitudinal analyses, lipoprotein subclasses of very large high-density lipoprotein cholesterol (HDL) were associated with an increased risk of stroke, and acetate and 3-hydroxybutyrate were associated with an increased risk of dementia. Mendelian randomization analyses identified strong evidence supporting causal relationships for many findings. A few metabolites had consistent associations across multiple analysis types. Increased total lipids in very large HDL and increased HDL particle size were associated with increased white matter damage (lower fractional anisotropy: OR: 1.44, 95% CI 1.07-1.95, and OR: 1.19, 95% CI 1.06-1.34, respectively; mean diffusivity: OR: 1.49, 95% CI 1.11-2.01, and OR: 1.24, 95% CI 1.11-1.40, respectively) and an increased risk of incident all stroke (HR: 4.04, 95% CI 2.13-7.64, and HR: 1.54, 95% CI 1.20-1.98, respectively) and ischemic stroke (HR: 3.12, 95% CI 1.53-6.38; HR: 1.37, 95% CI 1.04-1.81). Valine was associated with decreased mean diffusivity (OR: 0.51, 95% CI 0.30-0.88) and had a protective association with all-cause dementia (HR: 0.008, 95% CI 0.002-0.035). Increased levels of cholesterol in small HDL were associated with a decreased risk of incident all stroke (HR: 0.17, 95% CI 0.08-0.39) and ischemic stroke (HR: 0.19, 95% CI 0.08-0.46) and were supported by evidence of a causal association with MRI-confirmed lacunar stroke (OR: 0.96, 95% CI 0.93-0.99).
In this large-scale metabolomics study, we found multiple metabolites associated with stroke, dementia, and MRI markers of small vessel disease. Further studies may help inform the development of personalized prediction models and provide insights into mechanistic pathways and future treatment approaches.
脑小血管病是中风和痴呆的主要病因。代谢组学可以帮助识别新的风险因素，从而更好地了解发病机制，并预测疾病进展和严重程度。
我们分析了来自 118021 名英国生物库参与者的基线代谢组学特征。我们考察了 325 种代谢物与小血管疾病 MRI 标志物的横断面关联，评估了与中风和痴呆发病的纵向关联，并使用孟德尔随机化确定了因果关系。
在横断面分析中，载脂蛋白、游离胆固醇、胆固醇酯、脂肪酸、脂蛋白颗粒浓度、磷脂和甘油三酯水平较低与弥散张量 MRI 上的白质微观结构损伤增加有关。在纵向分析中，大颗粒极高密度脂蛋白胆固醇（HDL）的脂蛋白亚类与中风风险增加相关，而乙酸盐和 3-羟基丁酸与痴呆风险增加相关。孟德尔随机化分析为许多发现提供了强有力的证据支持因果关系。一些代谢物在多种分析类型中具有一致的关联。大颗粒 HDL 中的总脂质增加和 HDL 颗粒大小增加与白质损伤（各向异性分数降低：OR：1.44，95%CI 1.07-1.95，OR：1.19，95%CI 1.06-1.34；平均弥散系数增加：OR：1.49，95%CI 1.11-2.01，OR：1.24，95%CI 1.11-1.40）和中风（HR：4.04，95%CI 2.13-7.64，HR：1.54，95%CI 1.20-1.98）和缺血性中风（HR：3.12，95%CI 1.53-6.38；HR：1.37，95%CI 1.04-1.81）的发病风险增加有关。缬氨酸与平均弥散系数降低有关（OR：0.51，95%CI 0.30-0.88），与全因痴呆呈保护性关联（HR：0.008，95%CI 0.002-0.035）。小颗粒 HDL 中的胆固醇水平增加与中风（HR：0.17，95%CI 0.08-0.39）和缺血性中风（HR：0.19，95%CI 0.08-0.46）发病风险降低有关，并且与 MRI 证实的腔隙性中风（OR：0.96，95%CI 0.93-0.99）的因果关联证据一致。
在这项大规模代谢组学研究中，我们发现了多种与中风、痴呆和小血管疾病 MRI 标志物相关的代谢物。进一步的研究可能有助于为个性化预测模型的开发提供信息，并为发病机制和未来的治疗方法提供新的见解。
