Sex Differences in the Association Between LDL/HDL with Cognitive Decline in Older Adults: National Health and Nutrition Examination Survey.

Background: Lipids have a significant impact on the development and functioning of the nervous system, but the sex differences between the association of LDL/HDL, which reflects lipid metabolic status, and cognitive impairment remains unclear. Objective: We aimed to determine if there were sex differences between the association of LDL/HDL and cognitive function in US older adults. Methods: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 and 2013-2014 cycles. The main outcome was poor cognitive performance defined by the Digit Symbol Substitution Test (DSST) <  34 based on published literature. Results: A total of 1,225 participants were included in the study, with a cognitive impairment incidence of 25.6% (314/1,225). Multivariate regression models demonstrated a significant association between cognitive decline and each 1-unit increase in LDL/HDL, after adjusting for all covariates (adjusted odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.11-1.67). Furthermore, subgroup analysis revealed an interaction between LDL/HDL and cognitive impairment in sex subgroups. Conclusions: LDL/HDL was associated with cognitive impairment in the US older adult population in adjusted models, although the significance of this association was not observed in females.

Time-variant associations of ambulatory pulse rate with short-term neurologic functional outcomes following acute ischemic stroke.

This study aims to assess the associations of functional outcomes following acute ischemic stroke (IS) with ambulatory pulse rate (PR) and characterize the time-variant properties of the associations. The prospective cohort consisted of 1831 patients who had ambulatory blood pressure (BP) and PR monitoring following acute IS, and neurologic status evaluated at discharge and 3-month follow-up. The neurologic disability was defined as modified Rankin Scale ≥3. Logistic regression and generalized penalized functional regression models were used to examine the associations of ambulatory BP and PR with neurologic disability. Adjusting for covariates, the neurologic disability at discharge and 3-month was associated with high average 24-h, daytime, and nocturnal PR (odds ratio, OR = 1.20-1.34; p < 0.05 for all), high standard derivation of nocturnal PR (OR = 1.19 and 1.32; p < 0.05 for both), and low nocturnal PR decline (OR = 0.76 and 0.76; p < 0.05 for both). The OR functions of ambulatory PR on neurologic disability were "W-shaped" from 0 a.m. to 12 p.m., with ORs >1 in the wee hours and at noon, and ORs <1 before dawn and at night. The ambulatory BP profiles were not associated with neurologic disability at discharge or 3-month. The ambulatory PR is associated with the risk of short-term neurologic disability of stroke patients, with four different phases in a 24-h cycle. Ambulatory PR monitoring, especially nocturnal PR monitoring, has significant clinical implications for the prevention of short-term neurologic disability in stroke inpatients.

Corrigendum to "Long-term L-3-n-butylphthalide pretreatment attenuates ischemic brain injury in mice with permanent distal middle cerebral artery occlusion through the Nrf2 pathway" [Heliyon 8 (7), (July 2022), Article e09909].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e09909.].

Long-term L-3-n-butylphthalide pretreatment attenuates ischemic brain injury in mice with permanent distal middle cerebral artery occlusion through the Nrf2 pathway.

L-3-n-butylphthalide (NBP), which is used for treatment of mild and moderate acute ischemic stroke, exerts its effects by modulating the Nrf2 pathway. However, it has not been established whether NBP exerts its preventive effects in high-risk ischemic stroke patients through the Nrf2 pathway. We investigated whether NBP exerts its preventive effects through the Nrf2 pathway in long-term NBP pretreated dMCAO mice models. Nrf2+/+ wild-type and Nrf2-/- knockout mice were randomized into the vehicle group (equal volume vegetable oil), NBP-low-dose group (20 mg/kg) and NBP-high-dose group (60 mg/kg). The drug was administered once daily by gavage for a month. Then, a permanent distal middle cerebral artery occlusion model (dMCAO) was established after pretreatment with NBP. Neurological deficits, cerebral infarct volumes, brain water contents, activities of SOD, GSH-Px and MDA levels were determined. Further, axonal injury and demyelination, expression levels of Nrf2, HO-1 and NQO1 in ischemic brains were determined. Long-term NBP pretreatment significantly improved neurological functions, reduced cerebral infarction volumes, reduced brain water contents, increased SOD, GSH-Px activities, decreased MDA contents, reduced neurological injuries, axonal damage as well as demyelination, while increasing Nrf2, HO-1 and NQO1 mRNA as well as protein expressions in dMCAO mice models.

Effect of Lipoprotein(a) on Stroke Recurrence Attenuates at Low LDL-C (Low-Density Lipoprotein) and Inflammation Levels.

BACKGROUND: Lp(a) (lipoprotein(a)) contributes to cardiovascular disease mainly through proatherogenic and proinflammatory effects. Here, we aimed to evaluate whether a residual stroke risk of Lp(a) would remain when the LDL-C (low-density lipoprotein cholesterol) and inflammatory levels are maintained low. METHODS: This prospective cohort study included 9899 patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry who had measurements of plasma Lp(a) and were followed up for 1 year. Cutoffs were set at the 50 mg/dL for Lp(a). LDL-C was corrected for Lp(a)-derived cholesterol (LDL-Cc [LDL-C corrected]) and cutoffs were set at 55 and 70 mg/dL.The threshold values of IL-6 (interleukin 6) and hsCRP (high-sensitive C-reactive protein) were the median 2.65 ng/L and 2 mg/L. Multivariable-adjusted hazard ratio (HR) were calculated using Cox regression models for each category to investigate the associations of Lp(a) with stroke recurrence within 1 year. RESULTS: Among all patients, those with Lp(a) ≥50 mg/dL were at higher stroke recurrence risk than those with Lp(a) <50 mg/dL (11.5% versus 9.4%; adjusted HR, 1.20 [95% CI, 1.02-1.42]). However, the risk associated with elevated Lp(a) was attenuated in patients with LDL-Cc <55 mg/dL (high Lp(a) versus low Lp(a): 8.9% versus 9.0%; adjusted HR, 0.92 [95% CI, 0.65-1.30]) or IL-6 <2.65 ng/L (9.0% versus 7.8%; adjusted HR, 1.14 [95% CI, 0.87-1.49]). Notably, in the group with both low LDL-Cc and inflammation levels, the rate of patients with high Lp(a) did not significantly different from the rate of patients with low Lp(a; LDL-Cc <55 mg/dL and IL-6 <2.65 ng/L: 6.2% versus 7.1%; adjusted HR, 0.86 [95% CI, 0.46-1.62]; LDL-Cc <55 mg/dL and hsCRP <2 mg/L: 7.7% versus 7.6%; adjusted HR, 0.97 [95% CI, 0.57-1.66]). However, there was no interaction between the LDL-Cc, IL-6, hsCRP, and Lp(a) levels on stroke recurrence risk. CONCLUSIONS: Increased Lp(a) was significantly associated with stroke recurrence risk in patients with ischemic stroke/transient ischemic attack. However, at low LDL-Cc or IL-6 levels, the elevated Lp(a) -associated stroke recurrence risk was attenuated in a secondary prevention setting.

Time point of nocturnal trough systolic blood pressure as an independent predictor of cardiovascular events.

Nocturnal trough systolic blood pressure (NTSBP) and Time Point of Nocturnal Trough Systolic Blood Pressure (T-NTSBP) were important parameters of nocturnal blood pressure, the predictive values of which are unclear for stroke outcome. This study aimed to examine the relationship between NTSBP/T-NTSBP and stroke outcome. The authors used data from a nationwide ambulatory blood pressure monitoring cohort study conducted in China, which recruited 2348 ischemic stroke and transient ischemic attack (TIA) patients. NTSBP was defined as the lowest SBP during nighttime (22:00-6:00), and T-NTSBP was defined as the corresponding time point of NTSBP. The associations between NTSBP/T-NTSBP and stroke outcome (stroke recurrence and combined vascular event [CVE]) at 90 days or 1 year were analyzed using cox regression models. According to NTSBP classified by quartile, hazard ratio (HR) with 95% confidence interval (CI) for NTSBP quartile 4 (>129 mm Hg) was 2.727 (1.148-6.478) for CVE at 90-day, compared with quartile 1 (≤102 mm Hg). However, an attenuated association between NTSBP and CVE was observed at 1 year. In addition, we observed the group of T-NTSBP at 4:00-6:00 had a lowest CVE incidence at 90 days among four groups (22:00-23:59, 00:00-1:59 2:00-3:59, 4:00-6:00). After multivariable adjustment, T-NTSBP was significantly associated with CVE incidence at 90 days (T-NTSBP at the 4:00-6:00 versus the 22:00-23:59 group: HR, 0.433; 95%CI, 0.190-0.986), independent of NTSBP and average nocturnal SBP. Both of NTSBP and T-NTSBP were important predictors for short-term cardiovascular risk in ischemic stroke and TIA patients.

Elevated lipoprotein(a) and lipoprotein-associated phospholipase A2 are associated with unfavorable functional outcomes in patients with ischemic stroke.

BACKGROUND: The association of lipoprotein(a) [Lp(a)] and stroke functional outcomes was conflicting. The aim of the study was to clarify whether high Lp(a) is associated with unfavorable functional outcomes in patients with ischemic stroke. METHODS: A total of 9709 individuals from the third China National Stroke Registry cohort were recruited. Plasma level of Lp(a) at admission was measured with enzyme-linked immunosorbent assay. The cut-off was set at the median for Lp(a). Functional outcome was assessed using the modified Rankin scale (mRS) at 3 months and 1 year after ischemic stroke. The association between Lp(a) and functional outcomes was evaluated using a logistic regression model. RESULTS: The median age was 63.0 years, and 31.1% participants were women. Patients in higher Lp(a) group had higher incidences of unfavorable functional outcomes at 3 months. In logistic regression model, elevated Lp(a) levels were associated with unfavorable functional outcomes at 3 months (Q4 vs. Q1: odds ratio 1.33, 95% confidence interval 1.11-1.61). Subgroup analysis showed that in the lower Lp-PLA2 group, Lp(a) level was not associated with functional outcomes, but in the higher Lp-PLA2 group, Lp(a) level was significantly associated with functional outcomes. After grouped by different levels of Lp(a) and Lp-PLA2, the Lp(a) high/ Lp-PLA2 high group showed the highest incidence of unfavorable functional outcomes at 3 months and 1 year. CONCLUSIONS: Elevated Lp(a) level is associated with unfavorable functional outcomes in patients with ischemic stroke. The increment in both Lp(a) and Lp-PLA2 are associated with unfavorable functional outcomes at 3 months and 1 year after ischemic stroke.

The relation between plasma miR-126 levels and cerebral collateral circulation in patients with intracranial arterial stenosis.

OBJECTIVE: This study aimed to investigate the correlation between the circulating miR-126 regulation pathway and the cerebral collateral circulation (CCC), and to test whether miR-126 could serve as a potential biomarker for CCC formation in patients with intracranial arterial stenosis or occlusion. MATERIAL AND METHODS: This single-centre cross-sectional study enrolled patients who underwent cerebral angiography with severe stenosis (≥70%) or occlusion in at least one major intracranial artery. Collateral degree was graded according to the ASITN/SIR classification. The patients were divided into a good CCC group (grade 3-4) or a poor CCC group (grade 0-2). We investigated the plasma levels of miR-126, VEGF, Spred-1 and PIK3R2 by using qRT-PCR, ELISA and Western blot methods, respectively. In addition, we assessed the correlations of plasma miR-126 with VEGF, Spred-1, PIK3R2 and ASITN/SIR grade using the Spearman correlation test and investigated its predictive power for CCC status by using the receiver operating characteristic curve. RESULTS: A total of 68 patients were enrolled (44 with good CCC and 24 with poor CCC). Data showed that plasma miR-126 and VEGF were significantly higher in the good CCC group than in the poor CCC group. Plasma Spred-1 and PIK3R2 level were lower in the good CCC group than in the poor CCC group. In addition, miR-126 and VEGF were positively correlated with ASITN/SIR (miR-126: R = 0.595, P < 0.01; VEGF: R = 0.595, P < 0.01), whereas Spred-1 and PIK3R2 were negatively correlated with ASITN/SIR (Spred-1: R = -0.817, P < 0.01; PIK3R2: R = -0.513, P=0.01). However, the area under the curve of miR-126 level for CCC status was only 0.328 (95% CI: 0.158-0.498; p = 0.067). CONCLUSIONS: Plasma miR-126 level may be related to better CCC formation, one of the mechanisms that may be explained by upregulation of VEGF and reduction of Spred-1 and PIK3R2 protein expression. However, miR-126 might not be an independent predictor for CCC, given its low predictive value.

Different contribution of SBP and DBP variability to vascular events in patients with stroke.

BACKGROUND: High blood pressure variability (BPV) is a novel risk factor for cardiovascular disease. However, the heterogeneity of systolic blood pressure variability (SBPV) and diastolic blood pressure variability (DBPV) for different vascular events remains unclear. This study aims to investigate whether SBPV or DBPV has different contribution to vascular events in patients with acute ischaemic stroke (IS) or transient ischaemic attack (TIA). METHODS: Data from the BOSS (blood pressure and clinical outcome in TIA or IS) study were examined for vascular events at 3-month and 1-year follow-up. BPV was defined as the SD and coefficient of variation (CV) of day-to-day measurements within 3 months after IS/TIA. Vascular events include cardiovascular events (myocardial infarction, unstable angina, cardiac death and congestive heart failure) and cerebrovascular events (ischaemic or haemorrhagic stroke). Logistic regression model was used to test the associations between BPV and vascular events. RESULTS: Of 2325 patients with IS or TIA, 103 (4.43 %) experienced a recurrent stroke and 64 (2.75 %) had cardiovascular events within 3 months. Day-to-day SBPV was only associated with stroke recurrence (BPVSD: OR, 1.72, 95% CI 1.09 to 2.71; BPVCV: 1.86, 95% CI 1.19 to 2.92), but not cardiovascular events (BPVSD: 1.67, 95% CI 0.94 to 2.94; BPVCV: 1.51, 95% CI 0.86 to 2.64). However, DBPV seems to be related to both stroke (BPVSD: 1.60, 95% CI 1.02 to 2.49; BPVCV: 1.53, 95% CI 0.99 to 2.37) and cardiovascular events (BPVSD: 2.48, 95% CI 1.37 to 4.48; BPVCV: 1.92, 95% CI 1.09 to 3.36). Similar results were found at 1 year. CONCLUSIONS: For patients with IS/TIA, stroke recurrence was associated with both SBPV and DBPV; however, cardiovascular events seem to be only related to DBPV.

Exome sequencing study revealed novel susceptibility loci in subarachnoid hemorrhage (SAH).

AIM: To expand our current understanding of the genetic basis of subarachnoid hemorrhage (SAH), and reveal the susceptibility genes in SAH risk. METHODS: We conducted whole-exome sequencing (WES) in a cohort of 196 individuals, including 94 SAH patients and 94 controls, as well as 8 samples that belong to two pedigrees. Systematically examination for rare variations (through direct genotyping) and common variations (through genotyping and imputation) for SAHs were performed in this study. RESULTS: A total of 16,029 single-nucleotide polymorphisms (SNPs) and 108,999 short indels were detected in all samples, and among them, 30 SNPs distributed on 17 genes presented a strong association signal with SAH. Two novel pathogenic gene variants were identified as associated risk loci, including mutation in TPO and PALD1. The statistical analysis for rare, damaging variations in SAHs identified several susceptibility genes which were involved in degradation of the extracellular matrix and transcription factor signal pathways. And 25 putative pathogenic genes for SAH were also identified basic on functional interaction network analysis with the published SAH-associated genes. Additionally, pedigree analysis revealed autosomal dominant inheritance of pathogenic genes. CONCLUSION: Systematical analysis revealed a key role for rare variations in SAH risk and discovered SNPs in new complex loci. Our study expanded the list of candidate genes associated with SAH risk, and will facilitate the investigation of disease-related mechanisms and potential clinical therapies.

Lyophilizing thrombin powder-based treatment for hemostasis during coil embolization of ruptured cerebral aneurysm: Two case reports.

BACKGROUND: Rupture of cerebral aneurysm is an inevitable complication during embolization, followed by subsequent acute subarachnoid hemorrhage or intracranial hematoma, and results in the aggravation of a patient's condition. In particular, for patients who have had a ruptured aneurysm, urgent treatment strategies are required during operation. The most common hemostatic methods seen in clinical practices are as follows: after lowering the blood pressure, we continue to embolize the aneurysms with detachable coils as soon as possible or inject with Glubran/Onyx embolization liquids, as well as use a balloon catheter to temporarily block the blood supply. If the conditions are permissible, a balloon guiding catheter may even be used to restrict the proximal blood flow. At times, due to limitations of these methods, neurosurgeons are requested to perform craniotomy to treat the hemostasis. However, the delayed transition often leads to rapid deterioration of the patient's condition and even death due to cerebral hernia. CASE DESCRIPTION: We herein presented two cases of ruptured cerebral aneurysms to provide an alternative method for hemostasis and to save the lives of patients as much as possible. In an extremely urgent situation (conventional treatment is ineffective), we successfully saved the patient's life by injecting lyophilizing thrombin powder (LTP) solution into the aneurysmal sac and the parent artery through a microcatheter. CONCLUSIONS: To our knowledge, this is the first report of successful hemostasis during coil embolization of ruptured cerebral aneurysm with LTP. Further prospective studies are needed to confirm the safety and efficacy of LTP in cerebrovascular interventional therapy.