Metabolic associations with stroke, dementia, and imaging markers of cerebral small vessel disease: a comprehensive metabolomics study

BackgroundCerebral small vessel disease is a major cause of ischemic stroke and vascular dementia, which are among the leading causes of death and disability worldwide. Metabolomics can help identify novel risk factors to better understand pathogenesis, predict disease progression and severity, and identify therapeutic targets. MethodsWe analyzed metabolomics profiles from 118,021 UK Biobank participants with baseline metabolomics measurements (baseline surveys, 2006-2010; latest follow-up, March 2022). We examined cross-sectional associations of 325 metabolites with clinical diagnoses of stroke and dementia and MRI markers of small vessel disease. We also evaluated relationships between metabolites and future risk of stroke and dementia and performed Mendelian randomization to ascertain causal relationships. ResultsAmong 118,021 participants (54% women; mean recruitment age, 56.5 years), 2,477 stroke and 1,785 dementia events were recorded (median follow-up, 13.1 years). 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. Lower levels of amino acids and fatty acids and higher levels of ketone bodies were associated with increased risk of dementia. In longitudinal analyses, lipoprotein subclasses of very large HDL were associated with increased risk of stroke, and acetate, 3-hydroxybutyrate, and relative lipoprotein lipid concentrations were associated with increased risk of dementia. Mendelian randomization analyses identified strong evidence supporting causal relationships for many associations. Conclusionsbiomarker profiling platform and experimentation 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 develop personalized prediction models for patients at increased risk of stroke and dementia and provide insights into mechanistic pathways and future treatment approaches. Key PointsO_ST_ABSQuestionC_ST_ABSAre metabolites associated with stroke, dementia, and MRI markers of cerebral small vessel disease? FindingsIn an analysis of individual-participant data from 118,021 participants, we identified 289 metabolites that were significantly associated with stroke, dementia, and MRI markers of small vessel disease. MeaningMetabolic markers were associated with risk of stroke, dementia, and MRI markers of small vessel disease, which could be used to develop personalized prediction models and novel treatment approaches for patients at increased risk of vascular-related conditions.