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Association of Trimethylamine N-Oxide and Its Precursor With Cerebral Small Vessel Imaging Markers.

ABSTRACT: Background: High plasma levels of trimethylamine N-oxide (TMAO) and its precursor choline have been linked to stroke; however, their association with cerebral small vessel disease remains unclear. Here we evaluated the association of plasma levels of TMAO and choline with imaging markers of cerebral small vessel disease, including white matter hyperintensities, lacunes, and cerebral microbleeds. Methods: We performed a baseline cross-sectional analysis of a multicenter hospital-based cohort study from 2015 to 2018. The data were collected from 30 hospitals in China and included 1,098 patients with ischemic stroke/transient ischemic attack aged ≥18 years. White matter hyperintensities, lacunes, and cerebral microbleeds were evaluated with the patients' demographic, clinical, and laboratory information removed. White matter hyperintensities were rated using the Fazekas visual grading scale, while the degree of severity of the lacunes and cerebral microbleeds was defined by the number of lesions. Results: Increased TMAO levels were associated with severe white matter hyperintensities [adjusted odds ratio (aOR) for the highest vs. lowest quartile, 1.5; 95% confidence interval (CI), 1.0-2.1, p = 0.04]. High TMAO levels were more strongly associated with severe periventricular white matter hyperintensities (aOR for the highest vs. lowest quartile, 1.6; 95% CI, 1.1-2.3, p = 0.009) than deep white matter hyperintensities (aOR for the highest vs. lowest quartile, 1.3; 95% CI, 0.9-1.9, p = 0.16). No significant association was observed between TMAO and lacunes or cerebral microbleeds. Choline showed trends similar to that of TMAO in the association with cerebral small vessel disease. Conclusions: In patients with ischemic stroke or transient ischemic attack, TMAO and choline appear to be associated with white matter hyperintensities, but not with lacunes or cerebral microbleeds; TMAO and choline were associated with increased risk of a greater periventricular, rather than deep, white matter hyperintensities burden.

SUBMITTER: Chen Y

PROVIDER: S-EPMC8047127 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectivesCerebral 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.MethodsWe 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.ResultsIn 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).DiscussionIn 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.

Project description:BackgroundThis study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD).MethodsA total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed.ResultsAt baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05-1.70; cOR 1.28, 95% CI 1.02-1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00-1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25-3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14-2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16-2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08-1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20-2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04-1.39) and small vessel stroke (OR 1.21, 95% CI 1.06-1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p < 0.05).ConclusionsThis community-based population study found a suggestive association between NC and CSVD, especially for BG-EPVS and lacune, and provided evidence supporting the prognostic significance of NC.

Project description:IntroductionCerebral small vessel disease (CSVD) commonly exists in patients with symptomatic intracranial atherosclerotic disease (sICAD). We aimed to investigate the associations of hemodynamic features of sICAD lesions with imaging markers and overall burden of CSVD.Patients and methodsPatients with anterior-circulation sICAD (50%-99% stenosis) were analyzed in this cross-sectional study. Hemodynamic features of a sICAD lesion were quantified by translesional pressure ratio (PR = Pressurepost-stenotic/Pressurepre-stenotic) and wall shear stress ratio (WSSR = WSSstenotic-throat/WSSpre-stenotic) via CT angiography-based computational fluid dynamics modeling. PR ⩽median was defined as low ("abnormal") PR, and WSSR ⩾ fourth quartile as high ("abnormal") WSSR. For primary analyses, white matter hyperintensities (WMHs), lacunes, and cortical microinfarcts (CMIs) were assessed in MRI and summed up as overall CSVD burden, respectively in ipsilateral and contralateral hemispheres to sICAD. Enlarged perivascular spaces (EPVSs) and cerebral microbleeds (CMBs) were assessed for secondary analyses.ResultsAmong 112 sICAD patients, there were more severe WMHs, more lacunes and CMIs, and more severe overall CSVD burden ipsilaterally than contralaterally (all p < 0.05). Abnormal PR and WSSR (vs normal PR and WSSR) was significantly associated with moderate-to-severe WMHs (adjusted odds ratio = 10.12, p = 0.018), CMI presence (5.25, p = 0.003), and moderate-to-severe CSVD burden (12.55; p = 0.033), ipsilaterally, respectively independent of contralateral WMHs, CMI(s), and CSVD burden. EPVSs and CMBs were comparable between the two hemispheres, with no association found with the hemodynamic metrics.Discussion and conclusionThere are more severe WMHs and CMI(s) in the hemisphere ipsilateral than contralateral to sICAD. The hemodynamic significance of sICAD lesions was independently associated with severities of WMHs and CMI(s) ipsilaterally.

Project description:BackgroundTwenty-four-hour and nighttime blood pressure (BP) levels are more strongly associated with cardiovascular risk than office or daytime BP measurements. However, it remains undocumented which of the office and ambulatory BP measurements have the strongest association and predictive information in relation to the presence of type I, or arteriolosclerosis type, cerebral small vessel diseases (CSVD).MethodsA subset of 429 participants from the Maracaibo Aging Study [aged ≥40 years (women, 73.7%; mean age, 59.3 years)] underwent baseline brain magnetic resonance imaging (MRI) to visualize CSVD, which included log-transformed white matter hyperintensities (log-WMH) volume and the presence (yes/no) of lacunes, cerebral microbleeds (CMB), or enlarged perivascular spaces (EPVS). Linear and logistic regression models were applied to examine the association between CSVD and each +10-mmHg increment in the office and ambulatory systolic BP measurements. Improvement in the fit of nested logistic models was assessed by the log-likelihood ratio and the generalized R 2 statistic.ResultsOffice and ambulatory systolic BP measurements were related to log-WMH (β-correlation coefficients ≥0.08; P < 0.001). Lacunes and CMB were only associated with ambulatory systolic BP measurements (odds ratios [OR] ranged from 1.31 [95% confidence interval, 1.10-1.55] to 1.46 [1.17-1.84], P ≤ 0.003). Accounted for daytime systolic BP, both the 24-h (β-correlation, 0.170) and nighttime (β-correlation, 0.038) systolic BP measurements remained related to log-WMH. When accounted for 24-h or daytime systolic BP levels, the nighttime systolic BP retained the significant association with lacunes (ORs, 1.05-1.06; 95% CIs, ≥1.01 to ≤ 1.13), whereas the 24-h and daytime systolic BP levels were not associated with lacunes after adjustments for nighttime systolic BP (ORs, ≤ 0.88; 95% CI, ≥0.77 to ≤ 1.14). On top of covariables and office systolic BP, ambulatory systolic BP measurements significantly improved model performance (1.05% ≥ R 2 ≤ 3.82%). Compared to 24-h and daytime systolic BP, nighttime systolic BP had the strongest improvement in the model performance; for WMH (1.46 vs. 1.05%) and lacunes (3.06 vs. ≤ 2.05%).ConclusionsTwenty-four-hour and nighttime systolic BP were the more robust BP measurements associated with CSVD, but the nighttime systolic BP level had the strongest association. Controlling ambulatory BP levels might provide additional improvement in the prevention of CSVD.

Project description:ImportanceHematoma expansion is an important determinant of outcome in spontaneous intracerebral hemorrhage (ICH) due to small vessel disease (SVD), but the association between the severity of the underlying SVD and the extent of bleeding at the acute phase is unknown to date.ObjectiveTo investigate the association between key magnetic resonance imaging (MRI) markers of SVD (as per the Standards for Reporting Vascular Changes on Neuroimaging [STRIVE] guidelines) and hematoma volume and expansion in patients with lobar or deep ICH.Design, setting, and participantsAnalysis of data collected from 418 consecutive patients admitted with primary lobar or deep ICH to a single tertiary care medical center between January 1, 2000, and October 1, 2012. Data were analyzed on March 4, 2016. Participants were consecutive patients with computed tomographic images allowing ICH volume calculation and MRI allowing imaging markers of SVD assessment.Main outcomes and measuresThe ICH volumes at baseline and within 48 hours after symptom onset were measured in 418 patients with spontaneous ICH without anticoagulant therapy, and hematoma expansion was calculated. Cerebral microbleeds, cortical superficial siderosis, and white matter hyperintensity volume were assessed on MRI. The associations between these SVD markers and ICH volume, as well as hematoma expansion, were investigated using multivariable models.ResultsThis study analyzed 254 patients with lobar ICH (mean [SD] age, 75 [11] years and 140 [55.1%] female) and 164 patients with deep ICH (mean [SD] age 67 [14] years and 71 [43.3%] female). The presence of cortical superficial siderosis was an independent variable associated with larger ICH volume in the lobar ICH group (odds ratio per quintile increase in final ICH volume, 1.49; 95% CI, 1.14-1.94; P = .004). In multivariable models, the absence of cerebral microbleeds was associated with larger ICH volume for both the lobar and deep ICH groups (odds ratios per quintile increase in final ICH volume, 1.41; 95% CI, 1.11-1.81; P = .006 and 1.43; 95% CI, 1.04-1.99; P = .03; respectively) and with hematoma expansion in the lobar ICH group (odds ratio, 1.70; 95% CI, 1.07-2.92; P = .04). The white matter hyperintensity volumes were not associated with either hematoma volume or expansion.Conclusions and relevanceIn patients admitted with primary lobar or deep ICH to a single tertiary care medical center, the presence of cortical superficial siderosis was an independent variable associated with larger lobar ICH volume, and the absence of cerebral microbleeds was associated with larger lobar and deep ICHs. The absence of cerebral microbleeds was independently associated with more frequent hematoma expansion in patients with lobar ICH. We provide an analytical framework for future studies aimed at limiting hematoma expansion.

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Association of Trimethylamine N-Oxide and Its Precursor With Cerebral Small Vessel Imaging Markers.

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