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

Lacunar stroke results from cerebral small vessel disease (SVD) and is a major cause of vascular dementia and cognitive decline. We aimed to evaluate the associations of circulating serum metabolites with lacunar stroke, neuroimaging markers of SVD, and cognition to help elucidate the pathogenesis of SVD.

In a unique clinical cohort of 1,456 magnetic resonance imaging (MRI)-confirmed lacunar stroke cases and 952 controls, we examined 250 metabolites measured at baseline using nuclear magnetic resonance (NMR) spectroscopy. We investigated the association between metabolites with lacunar stroke and its subtypes, presence of white matter hyperintensities and cerebral microbleeds, and vascular cognitive impairment using the Brief Memory and Executive Test (BMET).

We identified 211 metabolites (84%) that were significantly associated with lacunar stroke after correction for multiple testing, out of which 203 were significantly associated with isolated lacunar infarcts (ILI) and 207 with multiple lacunar infarcts or leukoaraiosis (MLI/LA). There were no significant associations of metabolites with MRI markers of SVD or total BMET score; however, five metabolites pertaining to lipoprotein concentrations, lipoprotein ratios, and glycolysis (S_HDL_L, S_HDL_P, S_HDL_PL, L_LDL_CE_pct, and lactate) were significantly associated with the BMET executive functioning/processing speed (EF/PS) subdomain.

We found associations of a wide range of metabolites with lacunar stroke and its subtypes, several of which were also associated with executive functioning and processing speed. These results emphasise the importance of metabolomics in unravelling metabolic pathways involved in the pathogenesis of lacunar stroke and SVD and cognitive decline.