Background. Trimethylamine N-oxide (TMAO) is a gut-derived atherogenic metabolite. However, the role of TMAO and its precursors in the development of stroke remains unclear. We aimed to examine the associations between metabolites in TMAO biosynthesis and stroke risk. Methods.A nested case-control study was performed in a community-based cohort (2013-2018, n = 16,113). We included 412 identified stroke cases and 412 controls matched by age and sex. Plasma carnitine, choline, betaine, trimethyl lysine (TML), and TMAO were measured by ultrahigh performance liquid chromatographytandem mass spectrometry. Conditional logistic regression analyses were used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) between these biomarkers and stroke risk.Results. After adjustment for body mass index, smoking, hypertension, educational attainment, and estimated glomerular filtration rate, the corresponding OR for the highest versus lowest quartile was 1.74 (95% CI: 1.16-2.61, P trend = 0.006) for total stroke and 1.81 (95% CI: 1.14-2.86, P trend = 0.020) for ischemic stroke in an essentially linear dose-response fashion. A significant association between TMAO and nonischemic stroke was shown as a J-shape with OR for the highest versus second quartile of 5.75 (95% CI: 1.73-19.1). No meaningful significant risk association was found among plasma carnitine, choline, betaine, and TML with stroke risk.Conclusions. Increased TMAO was associated with higher stroke risk in the community-based population, whereas the TMAO precursors carnitine, choline, betaine, and TML were not associated. Further studies are warranted to confirm these findings and to further elucidate the role of TMAO in the development of stroke.

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Background Although previous studies have reported an association between multimorbidity and frailty, its direction and mechanism remain unclear. This study aimed to investigate the direction of this association, as well as the role of depression among older Europeans. Methods We used a cross-lagged panel design to evaluate the temporal relationship between multimorbidity and frailty and the role of depression. Multimorbidity status was assessed by the self-reporting of 14 chronic diseases. Frailty was assessed based on the frailty phenotype. The EURO-D 12-item scale was used to assess depression. Results There was a bidirectional relationship between frailty and multimorbidity. More severe multimorbidity predicted greater frailty (β = 0.159; P < 0.001) and vice versa (β = 0.107; P < 0.001). All paths from multimorbidity to frailty were stronger than the paths from frailty to multimorbidity (b1-a1: β = 0.051; P < 0.001). Likewise, early multimorbidity change was a significant predictive factor for late frailty change (β = 0.064; P < 0.001) and vice versa (β = 0.048; P < 0.001). Depression in wave 5 (T5) mediated the association between frailty in wave 4 (T4) and multimorbidity in wave 6 (T6) (indirect effect: β = 0.004; bootstrap 95% CI: 0.003, 0.006). Conclusions A positive, bidirectional association was observed between multimorbidity and frailty. Depression may be a potential cause of an increased risk of multimorbidity later in life in frail older adults. Early monitoring of frailty and depression may slow the progression of multimorbidity, thereby interrupting the vicious cycle.