Choline Pathway Nutrients and Metabolites and Cognitive Impairment After Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Choline metabolism was suggested to play pathophysiological roles in nervous system and atherosclerosis development. However, little is known about the impacts of choline pathway nutrients and metabolites on poststroke cognitive impairment. We aimed to prospectively investigate the relationships between circulating choline, betaine, and trimethylamine N-oxide with cognitive impairment among acute ischemic stroke patients. METHODS: We derived data from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). Plasma choline, betaine, and trimethylamine N-oxide concentrations at baseline were measured in 617 participants. Cognitive impairment was evaluated using the Mini-Mental State Examination and the Montreal Cognitive Assessment. Reclassification and calibration of models with choline-related biomarkers were evaluated. RESULTS: Plasma choline and betaine were inversely associated with cognitive impairment. Compared with the lowest tertile, adjusted odds ratios of Mini-Mental State Examination-defined cognitive impairment for participants in the highest tertiles of choline and betaine were 0.59 (95% CI, 0.39-0.90) and 0.60 (95% CI, 0.39-0.92), respectively. In addition, both choline and betaine offered incremental predictive ability over the basic model with established risk factors, shown by increase in net reclassification improvement and integrated discrimination improvement. There were similar significant relationships between choline and betaine with cognitive impairment as defined by the Montreal Cognitive Assessment. However, plasma trimethylamine N-oxide was only associated with cognitive impairment evaluated using the Mini-Mental State Examination; the adjusted odds ratio was 1.33 (95% CI, 1.04-1.72) for each 1-SD increment of trimethylamine N-oxide. CONCLUSIONS: Patients with higher choline and betaine levels had lower risk of cognitive impairment after ischemic stroke, supporting promising prognostic roles of choline pathway nutrients for poststroke cognitive impairment.

Plasma soluble suppression of tumorigenicity 2 and depression after acute ischemic stroke.

BACKGROUND AND PURPOSE: Soluble suppression of tumorigenicity 2 (sST2) might be related to stroke and depression, but the association of sST2 with poststroke depression (PSD) is unclear. The study aimed to prospectively assess the association between plasma sST2 levels and PSD. METHODS: A total of 635 acute ischemic stroke patients with sST2 measurements from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this analysis. We used the 24-item Hamilton Rating Scale for Depression to assess depression at 3 months, and PSD was defined as a score of ≥8. Logistic regression analysis was performed to estimate the risk of PSD associated with sST2, and net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to assess the predictive value of sST2. RESULTS: Two hundred fifty (39.4%) patients developed depression at 3 months after ischemic stroke. Patients with PSD had higher sST2 levels than patients without PSD (172.7 vs. 153.8 pg/ml; p = 0.003). After adjustment for age, sex, education, National Institutes of Health Stroke Scale score, and other covariates, the odds ratio for the highest quartile of sST2 compared with the lowest quartile was 1.84 (95% confidence interval, 1.10-3.08) for PSD. Adding sST2 to a conventional model notably improved risk prediction for PSD (category-free NRI = 19.34%, 95% confidence interval = 4.39%-34.28%, p = 0.017; IDI = 1.20%, 95% confidence interval = 0.25%-2.15%, p = 0.014). CONCLUSIONS: Increased plasma sST2 levels in the acute phase of ischemic stroke were significantly associated with the increased risk of PSD, independently of conventional risk factors.

Predictive Value of Cystatin C for Stroke Recurrence in Patients With Acute Ischemic Stroke.

BACKGROUND: This study explored the value of cystatin C (CysC) in predicting stroke recurrence in patients with acute ischemic stroke.Methods and Results:This was a post hoc analysis of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) on 3,474 acute ischemic stroke patients with documented serum CysC and high-sensitivity C-reactive protein (hsCRP) concentrations. Study outcomes included stroke recurrence and combined vascular events within 2 years after stroke. In stroke patients with higher (i.e., ≥4.8ng/mL), but not lower, hsCRP concentrations, a higher CysC concentration (i.e., ≥0.78 mg/L) was associated with a 2.48-fold increase in the risk of recurrent stroke (95% confidence interval [CI] 1.37-4.51; P=0.003) and a 2.04-fold increase in the risk of vascular events (95% CI 1.27-3.28; P=0.003). Serum hsCRP concentrations significantly modified the association of serum CysC with recurrent stroke (Pinteraction=0.001) and vascular events (Pinteraction=0.007). Moreover, CysC may improve reclassification of stroke recurrence (net reclassification improvement [NRI] 42.9%, P=0.001; integrated discrimination improvement [IDI] 1.2%, P=0.001) and vascular events (NRI 35.8%, P=0.001; IDI 1.1%, P=0.004). CONCLUSIONS: In ischemic stroke patients with high hsCRP concentrations, higher CysC concentrations increased the risk of stroke recurrence and vascular events. This indicates that the predictive value of CysC on stroke recurrence may depend on the inflammation status of patients.

White Matter Hyperintensity, Immediate Antihypertensive Treatment, and Functional Outcome After Acute Ischemic Stroke.

Background and Purpose- It remains unknown that whether white matter hyperintensity (WMH) severity influences the effect of antihypertensive treatment in acute ischemic stroke. We aimed to investigate the effects of early antihypertensive treatment on death and disability among patients with acute ischemic stroke according to WMH severities. Methods- This study was a secondary analysis of the data from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). Severity of WMH was evaluated using Fazekas rating scale score among 303 participants with available magnetic resonance imaging data and was categorized into none-mild WMH (Fazekas score 0-2) and moderate-severe WMH (Fazekas score 3-6). Functional outcome was death or major disability (modified Rankin Scale score of ≥3) at 14 days or hospital discharge and within 3 months. Results- WMH severity was significantly associated with an increased risk of death or major disability. Each 1 score increase in Fazekas score was associated with an adjusted odds ratio (95% CI) of 1.25 (1.03-1.51) for 14 days or hospital discharge and 1.39 (1.12-1.72) for 3-month functional outcome. There were no significant interactions between antihypertensive treatment and WMH severity (both P>0.1) on functional outcome at 14 days or hospital discharge and within 3 months. The neutral effects of immediate antihypertensive treatment were observed both in patients with moderate-severe WMH and none-mild WMH. Conclusions- Participants with higher WMH burden had increased risk of death or major disability after acute ischemic stroke. Early antihypertensive treatment had a neutral effect on clinical outcomes among acute ischemic stroke patients with a variety of WMH severities. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Dynapenic abdominal obesity and incident functional disability: Results from a nationwide longitudinal study of middle-aged and older adults in China.

BACKGROUND: There is little epidemiological evidence on the relationship of dynapenic abdominal obesity (DAO) and the development of functional disability, particularly in Asian populations. We aimed to investigate the association of DAO with new-onset functional disability in Chinese adults. METHODS: A total of 7881 participants aged ≥45 years from China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 2015 were included in the study. Dynapenia and abdominal obesity were respectively defined based on handgrip strength (<28 kg for male and <18 kg for female) and waist circumference (≥ 90 cm for male and ≥85 cm for female). The sample was divided into four groups: non-dynapenic/non-abdominal obesity (ND/NAO), non-dynapenic/abdominal obesity (ND/AO), dynapenic/non-abdominal obesity (D/NAO) and dynapenic/abdominal obesity (D/AO). Functional status was assessed by basic activities of daily living (BADL) or instrumental activities of daily living (IADL). Logistic regression model was used to explore the longitudinal association between dynapenic abdominal obesity and incident functional disability. RESULTS: After a 4-year follow-up, 1153 (14.6 %) developed BADL disability and 1335 (16.9 %) developed IADL disability. The multivariable-adjusted odds ratios (95 % CIs) for the D/AO versus ND/NAO were 2.21 (1.61-3.03) for BADL disability, and 1.68 (1.23-2.30) for IADL disability. In addition, DAO was associated with an increased risk for functional dependency severity (odds ratio, 2.08 [95 % CI, 1.57-2.75]). CONCLUSIONS: DAO was significantly associated with greater risk of functional disability among Chinese middle-aged and older adults. Our findings indicated that interventions targeted DAO might be effective in the primary prevention of functional disability.

Dynapenic abdominal obesity and the risk of depressive symptoms in middle-aged and older Chinese adults: Evidence from a national cohort study.

BACKGROUND: Population-based evidence on the relationship between dynapenic abdominal obesity and depressive symptoms is rare. We aimed to prospectively investigate the relationship between dynapenic abdominal obesity and depressive symptoms among middle-aged and older Chinese adults. METHODS: A total of 9322 participants free of depressive symptoms in the China Health and Retirement Longitudinal Study were included. The participants were divided into four groups: non-dynapenic/non-abdominal obesity (ND/NAO), non-dynapenic/abdominal obesity (ND/AO), dynapenic/non-abdominal obesity (D/NAO) and dynapenic/abdominal obesity (D/AO) according to the sex-specific grip strength (<28 kg for men and <18 kg for women) and waist circumference (≥85 cm for men and ≥80 cm for women) that in line with the Chinese criteria. Depressive symptoms was defined as a score of ≥12 for the 10-item Center for Epidemiological Studies Depression Scale. Logistic regression model was used to explore the association between dynapenic abdominal obesity and depressive symptoms. RESULTS: After an approximately 3-year of follow-up, 1810 participants (19.4 %) developed depressive symptoms. The multivariable-adjusted odds ratio for the D/AO versus ND/NAO was 1.61 (95 % CI: 1.31-1.98) for depressive symptoms. In addition, this relationship was more profound in participants aged<60 years (OR = 2.27, 95 % CI: 1.60-3.22) than participants aged ≥60 (OR = 1.36, 95 % CI: 1.05-1.77; P-interaction = 0.04). However, dynapenic obesity (defined by body mass index) was not linked to depressive symptoms. LIMITATIONS: Causal link and residual confounding were not addressed because of the observational study design. CONCLUSIONS: Dynapenic abdominal obesity was associated with an increased risk of depressive symptoms, especially among those aged<60 years.

Cell-penetrating heme oxygenase-1 in the therapy of atopic dermatitis in mice.

Atopic dermatitis (AD), also referred to as atopic eczema, is a long-term inflammatory condition that is characterized by itchy, red, swollen and cracked skin. Accumulating evidence suggests that AD is caused by genetic factors, environmental exposure and immune system dysfunction; however, its underlying molecular mechanism remains unclear. Current treatment strategies aim to decrease the severity and frequency of flares. Heme oxygenase-1 (HO-1) is a nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene that plays crucial roles against stress, inflammation and oxidation, and exerts cytoprotective effects. Previous studies have reported that treatment of AD induces high expression levels of HO-1 and Nrf2, indicating that HO-1 may play an important role in the treatment of AD. The present study constructed the recombinant protein, cell-penetrating peptide-HO-1 (CPP-HO-1), which was expressed in Escherichia coli and isolated with a 6xHis-tag using HiTrap His column (1 ml). AD was established using 4-dinitrochlorobenzene (DNCB) in mice. It was observed that the CPP-HO-1 fusion protein decreased the severity of AD, inhibited scratching in mice and decreased skin inflammation. Taken together, the results of the present study suggested that the CPP-HO-1 fusion protein may play a protective role against DNCB-induced AD in mice.

Remnant Cholesterol and Common Carotid Artery Intima-Media Thickness in Patients With Ischemic Stroke.

BACKGROUND: Remnant cholesterol makes great contribution to residual risk of cardiovascular disease, but population-based evidence on the relationship between remnant cholesterol and atherosclerosis is rare. Common carotid artery intima-media thickness (cIMT) is an imaging marker of subclinical atherosclerosis. We aimed to explore the association between remnant cholesterol levels and cIMT in patients with ischemic stroke. METHODS: One thousand four hundred ninety-six ischemic stroke patients with baseline serum lipids and carotid artery imaging data were included in this analysis. Fasting remnant cholesterol was calculated as total cholesterol minus HDL (high-density lipoprotein) cholesterol minus LDL (low-density lipoprotein) cholesterol. Abnormal cIMT was defined as mean cIMT and maximum cIMT value ≥1 mm. Logistic regression and restricted cubic spline models were used to assess the relationships between remnant cholesterol levels and abnormal cIMT. RESULTS: The multivariable-adjusted odds ratios (95% CIs) for the highest versus lowest quartile of remnant cholesterol were 2.06 (1.46-2.91) for abnormal mean cIMT and 1.70 (1.23-2.35) for abnormal maximum cIMT. There were linear associations between remnant cholesterol levels and both abnormal mean cIMT (P for linearity, <0.001) and abnormal maximum cIMT (P for linearity, 0.003). Moreover, the remnant cholesterol-cIMT association remained significant in the subsample of patients with optimal LDL cholesterol levels (n=179). CONCLUSIONS: Elevated fasting remnant cholesterol levels were positively associated with mean cIMT and maximum cIMT in patients with ischemic stroke, even in patients with optimal LDL cholesterol levels. Future prospective studies are needed to verify our findings and to assess the effect of remnant cholesterol-lowering interventions in patients with ischemic stroke.

Plasma Endostatin Levels at Acute Phase of Ischemic Stroke Are Associated with Post-Stroke Cognitive Impairment.

The effect of plasma endostatin on cognitive impairment after ischemic stroke remains unclear. We conducted this study to explore the association between plasma endostatin in the acute phase of ischemic stroke and post-stroke cognitive impairment (PSCI). Baseline plasma endostatin levels were measured, and cognitive function status was assessed by Montreal cognitive assessment at 3 months among 613 ischemic stroke patients. PSCI was defined as Montreal cognitive assessment score less than 26. The association of endostatin with PSCI was analyzed by logistic regression model. The receiver operating characteristic curve was applied to explore the optimal cutoff value of plasma endostatin levels in predicting PSCI. In a multivariable-adjusted model, the odds ratio for the highest vs lowest quartile of endostatin was 2.01 (95% CI, 1.15-3.53) for PSCI. Restricted cubic spline regression model showed a linear dose-response association between endostatin and PSCI (p for linearity = 0.01). The optimal cut point of endostatin was 84.22 ng/mL; higher endostatin levels (≥ 84.22 ng/mL) were associated with increased risk of 2.17-fold for PSCI (adjusted odds ratio, 2.17; 95% CI, 1.44-3.26; p = 0.0002). Furthermore, adding endostatin to a model containing conventional factors led to significant reclassification for PSCI (net reclassification improvement, 0.20; p = 0.025; integrated discrimination improvement, 0.016; p = 0.002). Our findings showed that elevated plasma endostatin levels were associated with cognitive impairment at 3 months after acute ischemic stroke, independently of established conventional risk factors, suggesting that endostatin may be an important biomarker of cognitive impairment after ischemic stroke.

Endostatin as a novel prognostic biomarker in acute ischemic stroke.

BACKGROUND AND AIMS: Endostatin is implicated in the atherosclerosis process and serves as a promising cardiovascular biomarker, while its clinical significance in ischemic stroke patients remains unclear. We aimed to examine the association between endostatin and mortality and disability after ischemic stroke. METHODS: A total of 3463 acute ischemic stroke patients with measured plasma endostatin from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this study. The primary outcome was death or severe disability (modified Rankin scale score of 4-6), and secondary outcomes included death and vascular events. RESULTS: After 3-month follow-up, 402 (11.61%) participants experienced severe disability or died. Compared with the lowest quartile of endostatin, odds ratios or hazard ratios (95% confidence intervals) for the highest quartile were 1.47 (1.04-2.09) for the primary outcome, and 2.36 (1.23-4.54) for death after adjustment for multiple covariates, including age, sex, admission NIH Stroke Scale score and systolic blood pressure. Each 1-SD higher log-transformed endostatin was associated with a 20% (6%-36%) increased risk for primary outcome. Adding plasma endostatin to the basic model constructed with conventional factors significantly improved risk stratification of primary outcome, as observed by the category-free net reclassification index of 20.5% (95% CI 10.1%-30.8%; p < 0.001) and integrated discrimination improvement of 0.3% (95% CI 0.01%-0.6%; p = 0.04). CONCLUSIONS: Increased baseline plasma endostatin levels in acute ischemic stroke were associated with increased risk of mortality and severe disability at 3 months. Plasma endostatin may serve as an important prognostic marker for risk stratification in patients with ischemic stroke.