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.

Causal relationships involving brain imaging-derived phenotypes based on UKB imaging cohort: a review of Mendelian randomization studies

“…Previous metabolomics studies have identified metabolites associated with CSVD, cerebral microbleeds, and dementia. In a large-scale metabolomics study conducted by Harshfield and Markus (2023) , they analyzed the relationships of 325 metabolites with MRI markers of CSVD (WMH, FA, and MD), stroke, and dementia, and assessed the causality of these relationships using MR approach. They found 289 metabolic traits significantly associated with MRI markers of CSVD and future risk of stroke and dementia.…”

Current and Future Treatments of Vascular Cognitive Impairment

“…[224][225][226] These implicate a wide range of cSVD-associated biological processes, ranging from BBB and extracellular matrix organization, to lipid and lipoprotein metabolism and immune responses. 222,224,225 The wealth of knowledge gained is not just useful for mechanistic interrogations and discovery of blood-or plasma-based diagnostic markers; it may also help us devise individual or omics-based panels of biomarkers for monitoring treatment response. Because imaging marker progression takes a relatively long time to reveal, omics or biomarker readouts that permit complementary and potentially earlier assessment of the potential impacts of drug treatment on cerebrovascular health are highly desired.…”

“…Recent interesting works have uncovered blood epigenetic and metabolomic signatures that correlate with cSVD severity, 222,223 disease burden quantified by imaging markers, and cognitive function. [224][225][226] These implicate a wide range of cSVD-associated biological processes, ranging from BBB and extracellular matrix organization, to lipid and lipoprotein metabolism and immune responses. 222,224,225 The wealth of knowledge gained is not just useful for mechanistic interrogations and discovery of blood-or plasma-based diagnostic markers; it may also help us devise individual or omics-based panels of biomarkers for monitoring treatment response.…”

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study

“…Increasing research has revealed a link between metabolic alternations and CSVD. The large-scale metabolomics study and Mendelian analysis found multiple metabolites associated with imaging markers of CSVD, cognition, and conversion to dementia [ 26 – 28 ]. Accordingly, there may exist metabolic pathways that mediate the impact of SGLT1/2 inhibitors on CSVD progression.…”

“…Increasing research has revealed a link between metabolic alternations and CSVD. The largescale metabolomics study and Mendelian analysis found multiple metabolites associated with imaging markers of CSVD, cognition, and conversion to dementia [26][27][28].…”