Using metabolomics to identify novel risk factors for lacunar stroke and vascular cognitive impairment

BackgroundLacunar stroke results from cerebral small vessel disease (SVD) and is a major cause of vascular dementia and cognitive decline. We evaluated the associations of metabolites with lacunar stroke, neuroimaging markers of SVD, and cognition to help elucidate SVD pathogenesis. MethodsIn a clinical cohort of 1,456 MRI-confirmed lacunar stroke cases and 952 controls, we assayed 250 metabolites using nuclear magnetic resonance spectroscopy. We investigated the association of metabolites with lacunar stroke, MRI markers of SVD, and cognitive impairment. We also conducted metabolite genome-wide association analyses and applied Mendelian randomization (MR) to investigate causality. ResultsWe identified 211 metabolites (84%) that were significantly associated with lacunar stroke. MR analyses identified significance evidence to support causal associations of two of these metabolites, glycine and %C/Total in M-LDL, with two lacunar stroke subtypes, ILI and MLI/LA, respectively. Five metabolites (Total S-HDL, S-HDL concentration, PL in S-HDL, %CE/Total in L-LDL, and lactate) were significantly associated with executive functioning/processing speed, but their causality could not be evaluated. MR analyses also identified evidence to support causal associations of {omega}-3/Total FA with two diffusion tensor imaging markers of SVD, which were not possible to evaluate in observational analyses. Glycine and %C/Total in M-LDL exhibited the most robust and consistent associations with lacunar stroke across subtypes both the observational and MR analyses. ConclusionsOur findings reveal novel risk factors and emphasize the importance of metabolomics in unravelling metabolic pathways involved in the pathogenesis of lacunar stroke and SVD and cognitive decline. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIIn a clinical cohort of MRI-confirmed lacunar stroke cases and controls, we found robust and consistent evidence across observational and causal inference analyses that glycine and the proportion of cholesterol within medium LDL were significantly associated with two lacunar stroke subtypes, emphasizing the importance of metabolomics in helping to elucidate SVD pathogenesis. C_LI What are the clinical implications?O_LIThese findings highlight the role of metabolites in affecting lacunar stroke and cognitive decline. C_LIO_LIMetabolomics can help guide the development of targeted interventions aimed at preventing stroke and mitigating the progression of cognitive decline. C_LI