Association of Baseline Metabolomic Profiles With Incident Stroke and Dementia and With Imaging Markers of Cerebral Small Vessel Disease

Abstract

Background and objectives: 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.

Methods: 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.

Results: 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).

Discussion: 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.

Figure 1. Association of MRI Markers at First Imaging Visit Per 1-SD Higher Baseline Levels of Lipids and Other Metabolites With Adjustment for Possible Confounders and Vascular Risk Factors

Beta estimates and p values were obtained from linear or logistic regression models adjusted for age at recruitment, sex, UK Biobank recruitment center, Townsend deprivation index at recruitment, whether the person was taking blood pressure medication or statins, body mass index, smoking status, and type 2 diabetes mellitus status. Colors show magnitude and direction of p value for association of metabolite with each outcome (red indicates a positive association, and blue indicates an inverse association). Asterisks indicate significance: *p < 0.05; **FDR q < 0.05. FDR = false discovery rate.

Figure 2. Association of MRI Markers at First Imaging Visit Per 1-SD Higher Baseline Levels of Lipoprotein Subclasses With Adjustment for Possible Confounders and Vascular Risk Factors

Beta estimates and p values were obtained from linear or logistic regression models adjusted for age at recruitment, sex, UK Biobank recruitment center, Townsend deprivation index at recruitment, whether the person was taking blood pressure medication or statins, body mass index, smoking status, and type 2 diabetes mellitus status. Colors show magnitude and direction of p value for association of metabolite with each outcome (red indicates a positive association, and blue indicates an inverse association). Asterisks indicate significance: *p < 0.05; **FDR q < 0.05. FDR = false discovery rate; HDL = high-density lipoprotein cholesterol; IDL = intermediate-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; VLDL = very low-density lipoprotein cholesterol.

Figure 3. Association of MRI Markers at First Imaging Visit Per 1-SD Higher Baseline Levels of Relative Lipid, Lipoprotein, and Cholesterol Concentrations With Adjustment for Possible Confounders and Vascular Risk Factors

Beta estimates and p values were obtained from linear or logistic regression models adjusted for age at recruitment, sex, UK Biobank recruitment center, Townsend deprivation index at recruitment, whether the person was taking blood pressure medication or statins, body mass index, smoking status, and type 2 diabetes mellitus status. Colors show magnitude and direction of p value for association of metabolite with each outcome (red indicates a positive association, and blue indicates an inverse association). Asterisks indicate significance: *p < 0.05; **FDR q < 0.05. FDR = false discovery rate.

Figure 4. Adjusted Hazard Ratios for Incident All Stroke and All-Cause Dementia Per 1-SD Higher Baseline Metabolite Levels With Adjustment for Possible Confounders and Vascular Risk Factors

(A) All stroke. (B) All-cause dementia. Analyses were adjusted for age at recruitment, sex, UK Biobank recruitment center, Townsend deprivation index at recruitment, whether the person was taking blood pressure medication or statins, body mass index, smoking status, and type 2 diabetes mellitus status. Filled squares indicate associations significant at FDR q < 0.05. FDR = false discovery rate.

Figure 5. Mendelian Randomization Results Showing Causal Estimates for Association of Genetically Determined Metabolite Levels With Stroke, Dementia, and MRI Markers

Colors show the magnitude and direction of the p value of association for the estimate of the causal effect using Mendelian randomization (the method that yielded the most significant p value is shown, where red indicates a positive association and blue indicates an inverse association). Asterisks indicate significance: *p < 0.05; **FDR q < 0.05. A thick black border delineates associations that are also significant using the MR-Egger approach, indicating putative causal relationships that are more robust to pleiotropy. FDR = false discovery rate.