Gut Microbiome and Atherosclerosis: A Mendelian Randomization Study.

Background: According to recent studies, atherosclerosis and gut microbiota are related. Nevertheless, it has been discovered that the gut microbiota varies across studies, with its function still being debated, and such relationships not proven to be causal. Thus, our study aimed to identify the key gut microbiota taxa (GM taxa) at different taxonomic levels, namely, the phylum, class, order, family, and genus, to investigate any potential causal links to atherosclerosis. Methods: We employed summary data from the MiBioGen consortium on the gut microbiota to conduct a sophisticated two-sample Mendelian randomization (MR) analysis. Pertinent information regarding atherosclerosis statistics was acquired from the FinnGen Consortium R8 publication. To assess causality, the utilized principal analytical technique was the inverse variance-weighted (IVW) method. Supplementary to IVW, additional MR methodologies were employed, including weighted median, MR-Egger, weighted methods, and simple mode. Sensitivity analyses involved the application of Cochrane's Q-test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis. Results: Finally, after performing an MR study on the risk of 211 GM taxa on atherosclerosis, we discovered 20 nominal links and one strong causal link. Firmicutes (phylum ID: 1672) (odds ratio (OR) = 0.852 (0.763, 0.950), p = 0.004) continued to be connected with a lower incidence of coronary atherosclerosis, even after Bonferroni correction. Conclusions: Based on the discovered data, it was established that the phylum Firmicutes exhibits a causal relationship with a reduced occurrence of coronary atherosclerosis. This investigation could potentially provide novel insights into therapeutic objectives for atherosclerosis by focusing on the gut microbiota.

Personality predictors of dementia diagnosis and neuropathological burden: An individual participant data meta-analysis.

INTRODUCTION: The extent to which the Big Five personality traits and subjective well-being (SWB) are discriminatory predictors of clinical manifestation of dementia versus dementia-related neuropathology is unclear. METHODS: Using data from eight independent studies (Ntotal = 44,531; Ndementia = 1703; baseline Mage = 49 to 81 years, 26 to 61% female; Mfollow-up range = 3.53 to 21.00 years), Bayesian multilevel models tested whether personality traits and SWB differentially predicted neuropsychological and neuropathological characteristics of dementia. RESULTS: Synthesized and individual study results indicate that high neuroticism and negative affect and low conscientiousness, extraversion, and positive affect were associated with increased risk of long-term dementia diagnosis. There were no consistent associations with neuropathology. DISCUSSION: This multistudy project provides robust, conceptually replicated and extended evidence that psychosocial factors are strong predictors of dementia diagnosis but not consistently associated with neuropathology at autopsy. HIGHLIGHTS: N(+), C(-), E(-), PA(-), and NA(+) were associated with incident diagnosis. Results were consistent despite self-report versus clinical diagnosis of dementia. Psychological factors were not associated with neuropathology at autopsy. Individuals with higher conscientiousness and no diagnosis had less neuropathology. High C individuals may withstand neuropathology for longer before death.

MINE-BLAST TRAUMA AS A FACTOR IN THE EARLY DEVELOPMENT OF VASCULAR DISEASES OF THE BRAIN.

OBJECTIVE: The aim of this study is to investigate the state of bulbar conjunctival vessels, rheological properties of blood, catecholamines (adrenaline, norepinephrine), lipid metabolism, alkaline proteins of blood serum in patients with consequences of mild combat traumatic brain injury. PATIENTS AND METHODS: Materials and methods: 76 individuals aged 28 to 41 years were examined. The duration of the injury lasted from 2 to 4 years. The control group consisted of 28 individuals aged 45 to 49 years with primary cerebral atherosclerosis and manifestations of cerebral circulation disorders. The state of the bulbar conjunctiva vessels and blood circulation was studied using a slit lamp SHCHL-2B at 40-fold magnification. Rheological parameters, lipid metabolism, serum alkaline proteins, total catecholamines were studied according to generally accepted methods. RESULTS: Results: Changes in the vessels of the bulbar conjunctiva (stage II-III) were detected in 76% of the subjects, indicating the formation of cerebral vascular pathology, and in 87% of patients with initial cerebral atherosclerosis. The analysis of lipid metabolism showed significantly (p<0.05) increased data on all studied parameters (cholesterol, high-density lipoprotein, ß-lipoprotein, atherogenic index), both in patients with aftereffects of mild combat traumatic brain injury and in patients with initial cerebral atherosclerosis. An increase in alkaline proteins indices we detected in 62% of patients with aftereffects of mild combat cerebral trauma and in 55% of patients with initial cerebral atherosclerosis. At the same time, there was an increase in total catecholamines in the erythrocytes of patients with combat head injury. An increase in fibrinogen was noted in both groups, but in the group with initial cerebral atherosclerosis it was more pronounced. CONCLUSION: Conclusions: Combat traumatic brain injury contributes to the early formation of cerebral atherosclerosis and cerebral circulation disorders in this category of patients. The examination methods we have studied should be included in the survey plan for these patients. They are important not only for diagnosis, but also for improving treatment and preventing vascular disasters.

Efficacy and Safety of Divaza for the Correction of Oxidative Disturbances in Patients with Cerebral Atherosclerosis: A Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to determine if Divaza, a drug with nootropic and antioxidant effects, was safe and effective for the correction of oxidative disturbances and to stabilize cognitive impairment in patients with cerebral atherosclerosis. STUDY DESIGN: The study design consisted of a 12-week multicenter, randomized, double-blind, placebo-controlled, prospective trial in parallel groups. SETTING: The setting in which the study was conducted comprised 10 clinical centers across the Russian Federation. INTERVENTIONS: Patients were randomized into 2 groups and instructed to take either 2 tablets of the study drug or a placebo 3 times per day in conjunction with basic therapy. OUTCOMES: The primary outcome was a change in the average endogenous antioxidant potential after the completion of the study. The blood indicators of the oxidative stress (OS) were analyzed at the baseline and then after 12 weeks of therapy using iron-induced chemiluminescence analysis. The Montreal cognitive assessment test was used as a secondary outcome measure to evaluate cognitive impairment at the end of the study. RESULTS: 124 outpatients with a mean age of 60.7 ± 7.6 years were enrolled and randomly assigned to receive Divaza (n = 65) or a placebo (n = 59). An improvement of cognitive function was observed in all patients of the Divaza group at the end of the treatment; this was significantly better than the placebo group (100 [100] vs. 89.5 [89.1]%, respectively, p = 0.0272 [p = 0.0128]). The administration of Divaza restored the activity of the endogenous antioxidant system. The change in the average level of lipoprotein resistance to oxidation after 12 weeks of therapy, compared to the baseline, was significantly higher in the Divaza group (14.8 ± 14.7 [14.8 ± 14.7] seconds latent period vs. 6.4 ± 16.9 [6.9 ± 16.7] seconds in the placebo group (p = 0.007 [p = 0.0107]). CONCLUSIONS: Divaza is a safe and effective therapeutic option for attenuating OS and recovery of cognitive impairment in patients with cerebral atherosclerosis.

Pre-Admission CHADS2 and CHA2DS2-VASc Scores on Early Neurological Worsening.

BACKGROUND: Stroke risk scores (CHADS2 and CHA2DS2-VASc) not only predict the risk of stroke in atrial fibrillation (AF) patients, but have also been associated with prognosis after stroke. OBJECTIVE: The aim of this study was to evaluate the relationship between stroke risk scores and early neurological deterioration (END) in ischemic stroke patients with AF. METHODS: We included consecutive ischemic stroke patients with AF admitted between January 2013 and December 2015. CHADS2 and CHA2DS2-VASc scores were calculated using the established scoring system. END was defined as an increase ≥2 on the total National Institutes of Health Stroke Scale (NIHSS) score or ≥1 on the motor NIHSS score within the first 72 h of admission. RESULTS: A total of 2,099 ischemic stroke patients with AF were included. In multivariable analysis, CHA2DS2-VASc score (adjusted odds ratio [aOR] = 1.17, 95% confidence interval [CI] = 1.04-1.31) was significantly associated with END after adjusting for confounders. Initial NIHSS score, use of anticoagulants, and intracranial atherosclerosis (ICAS) were also found to be closely associated with END, independent of the CHA2DS2-VASc score. Multivariable analysis stratified by the presence of ICAS demonstrated that both CHA2DS2-VASc (aOR = 1.20, 95% CI = 1.04-1.38) and CHADS2 scores (aOR = 1.24, 95% CI = 1.01-1.52) were closely related to END in only patients with ICAS. In patients without ICAS, neither of the risk scores were associated with END. CONCLUSIONS: High CHA2DS2-VASc score was associated with END in ischemic stroke patients with AF. This close relationship is more pronounced in patients with ICAS.

The characterization of headache in patients with dyscirculatory encephalopathy of different genesis.

OBJECTIVE: The aim of the study was to study the headache features in patients with dyscirculatory encephalopathy of different genesis. PATIENTS AND METHODS: Materials and methods: Clinical-neurological and clinical-instrumental examination of 90 persons aged 40 to 68 was performed. The first group consisted of 60 patients with dyscirculatory encephalopathy and arterial hypertension (DE and AH), the second group - 30 patients with dyscirculatory encephalopathy and cerebral atherosclerosis (DE and CA). RESULTS: Results: In the study of headache in patients with DE + AH and DE + CA, the frequency of detection, the intensity on the VAS scale, and the nature of the headache, no significant difference was found between study groups. CONCLUSION: Conclusions: According to the results of the study, it was proved that patients with DE + CA had headache in the root area, with the circumstances of headache being significantly outweighed «for no apparent reason¼ (p = 0.007) and with changing weather conditions (р = 0.001). Arterial hypertension was a major factor in headache (p = 0.008) and in patients with DE + AH.

[Prospects of clinical application of cilostazol for peripheral artery disease]. / Perspektivy klinicheskogo primeneniia tsilostazola pri zabolevaniiakh perifericheskikh arterii.

This article presents a review of the literature on studying Cilostazol, a type 3 phosphodiesterase inhibitor, also providing the Russian and foreign statistics on the prevalence of peripheral artery disease. It is underlined that the majority of patients with peripheral artery disease have atherosclerotic lesions in the coronary and cerebral vascular basins. Cilostazol deservedly occupies the first lines in the sections of pharmacotherapy for intermittent claudication in international and Russian consensus documents on peripheral artery disease. The drug has an extensive evidence base for the following pharmacological effects: vasodilating, antiplatelet, endothelial protective, and vasculogenic. Clinical efficacy of Cilostazol was confirmed in 15 randomized clinical trials (3 718 patients with intermittent claudication) studying the use of Cilostazol taken twice daily at doses of 50 mg, 100 mg, and 150 mg as compared with placebo or versus pentoxifylline given in a dose of 400 mg three times daily, with a demonstrable increase in the pain-free walking distance and the maximal walking distance on the background of taking Cilostazol. The drug significantly improves the outcomes of endovascular interventions on arteries of lower extremities, decreasing the incidence of restenosis, prolonging limb survival, and reducing the frequency of major amputations. Many studies addressing the use of Cilostazol in patients with coronary and cerebral atherosclerosis have investigated the effect of the drug as a component of dual antiplatelet therapy (aspirin + Cilostazol) and triple antiplatelet therapy (aspirin + clopidogrel + Cilostazol) after endovascular interventions. The addition of Cilostazol to treatment resulted in a significant decrease in the occurrence of re-stenosis, with no increase in the incidence of haemorrhage. Cilostazol may be recommended for patients with multifocal atherosclerosis and resistance to aspirin and clopidogrel. Also presented in the article are the results of a Russian clinical trial studying comparative efficacy of Cilostazol and pentoxifylline in patients with intermittent claudication.

The Impact of Cerebral Atherosclerosis According to Location on Prognosis after Coronary Artery Bypass Grafting.

BACKGROUND: In the previous prospective observational study, we found that cerebral atherosclerosis is an independent predictor of acute stroke after coronary artery bypass grafting (CABG). However, it is unknown whether intracranial cerebral atherosclerosis (ICAS) is important as much as extracranial cerebral atherosclerosis (ECAS) in estimating the risk of post-CABG adverse events. Extending the previous study, we aimed to investigate the immediate and long-term prognostic value of the location of cerebral atherosclerosis in CABG patients. METHODS: This follow-up study of previously reported prospective cohort included 1,367 consecutive patients who received CABG between 2004 and 2007. All patients underwent preoperative magnetic resonance angiography (MRA) to assess intracranial and ECAS, both defined by significant steno-occlusion (≥50%). Participants were classified into 4 groups according to the location of cerebral atherosclerosis: no cerebral atherosclerosis, ECAS only, ICAS only, and ECAS + ICAS. Post-CABG stroke within 14 days (immediate outcome) and mortality (long-term outcome) following CABG were compared between the groups. Survival data for all participants through June 2016 were obtained from the Korean National Registry of Vital Statistics. The Cox proportional hazards model was used to estimate the hazard ratio (HR) of post-CABG stroke and mortality; patients lacking cerebral atherosclerosis were defined as the reference group. RESULTS: The median follow-up duration after CABG was 9.2 years (interquartile range 8.4-10.2 years). Of the participants, 278 (20.3%) patients had ICAS only, while 269 (19.7%) and 347 (25.4%) showed ECAS only and ECAS + ICAS, respectively, in their preoperative MRA. Having ICAS only (HR 5.07; 95% CI 1.37-18.75; p = 0.015) and having ECAS + ICAS (HR 8.43; 95% CI, 2.48-28.61; p = 0.001) independently predicted the immediate stroke, whereas being with ECAS only did not (HR 1.71; 95% CI 0.35-8.50; p = 0.509). Conversely, ICAS-only status was not independently associated with long-term mortality (HR 1.22; 95% CI 0.90-1.65; p = 0.207), whereas ECAS-only status (HR 1.42; 95% CI 1.05-1.90; p = 0.021) and ECAS + ICAS status (HR 1.58; 95% CI 1.20-2.07; p = 0.001) showed independent associations. CONCLUSIONS: Over 10 years of follow-up, cerebral atherosclerosis significantly associated with the development of adverse outcomes after CABG. The prognostic value of ICAS might be different from that of ECAS; immediate post-CABG stroke was more closely associated with ICAS, whereas there was a closer association between long-term post-CABG mortality and ECAS.

Activation of NLRP3 inflammasome by cholesterol crystals in alcohol consumption induces atherosclerotic lesions.

Epidemiological studies showed a strong association between alcoholism and incidence of stroke, for which the underlying causative mechanisms remain to be understood. Here we found that infiltration of immune cells and deposition of cholesterol at the site of brain artery/capillary injury induced atherosclerosis in chronic alcohol (ethanol) consumption in the presence or absence of high-fat diet. Conversion of cholesterol into sharp edges of cholesterol crystals (CCs) in alcohol intake was key to activation of NLRP3 inflammasome, induction of cerebral atherosclerosis, and development of neuropathy around the atherosclerotic lesions. The presence of alcohol was critical for the formation of CCs and development of the neuropathology. Thus, we observed that alcohol consumption elevated the level of plasma cholesterol, deposition and crystallization of cholesterol, as well as activation of NLRP3 inflammasome. This led to arteriole or capillary walls thickening and increase intracranial blood pressure. Distinct neuropathy around the atherosclerotic lesions indicated vascular inflammation as an initial cause of neuronal degeneration. We demonstrated the molecular mechanisms of NLRP3 activation and downstream signaling cascade event in primary culture of human brain arterial/capillary endothelial cells in the setting of dose-/time-dependent effects of alcohol/CCs using NLRP3 gene silencing technique. We also detected CCs in blood samples from alcohol users, which validated the clinical importance of the findings. Finally, combined therapy of acetyl-l-carnitine and Lipitor® prevented deposition of cholesterol, formation of CCs, activation of NLRP3, thickening of vessel walls, and elevation of intracranial blood pressure. We conclude that alcohol-induced accumulation and crystallization of cholesterol activates NLRP3/caspase-1 in the cerebral vessel that leads to early development of atherosclerosis.

Is obstructive sleep apnea associated with the presence of intracranial cerebral atherosclerosis?

PURPOSE: Intracranial cerebral atherosclerosis (ICAS) is one of critical atherosclerosis which closely related with stroke. Obstructive sleep apnea (OSA) is associated with systemic atherosclerosis, but it is unclear whether OSA is related with the presence of ICAS. We aimed to investigate the association between the presence of ICAS and severity of OSA in patients with suspected OSA. METHODS: This retrospective, cross-sectional study included 283 patients who suspected OSA (presence of one or more OSA-related symptom and high-risk category in Berlin questionnaire) and underwent polysomnography and brain magnetic resonance angiography (MRA). The ICAS was defined as ≥50% decrease of luminal diameter in MRA. The severity of OSA was defined by apnea-hypopnea index (AHI). RESULTS: The mean age was 60.7 ± 13.5 years, and 55.8% (158/283) were male in all included patients. The 53 (18.7%) patients had ICAS and 117 (41.3%) patients had moderate to severe OSA (AHI ≥ 15). Higher AHI was noted in patients with ICAS compared to those without ICAS (31.7 ± 25.8 versus 15.2 ± 17.4, p = 0.001). In multivariable logistic analyses, after adjusting for age, sex, and variables with p < 0.1 in univariable analyses (hypertension, diabetes mellitus, atrial fibrillation, previous stroke history, body mass index, lipid-lowing agents, arousal index, and minimum oxygen saturation), moderate to severe OSA were independently related with the presence of ICAS (odds ratio 4.17, 95% confidence interval 1.40-12.40, p = 0.010). CONCLUSIONS: Our findings suggest that moderate to severe OSA is associated with the presence of ICAS in patients with suspected OSA.

Value of higher-resolution MRI in assessing middle cerebral atherosclerosis and predicting capsular warning syndrome.

PURPOSE: To investigate the correlation between middle cerebral atherosclerosis and capsular warning syndrome (CWS) and assess the value of higher-resolution magnetic resonance imaging (MRI) in prognostication. MATERIALS AND METHODS: In all, 97 transient ischemic attack (TIA) patients who underwent an MRI from February 2010 to December 2013 were included in the retrospective study and divided into either a CWS or middle cerebral artery (MCA) TIA group according to their eventual clinical diagnosis. 3T MRI included fast-spin echo T2 -weighted imaging, double-inverse recovery T1 -weighted imaging, and T1 contrast-enhanced scan sequences. Baseline characteristics, MRI results in terms of MCA plaque formation, plaque characteristics such as enhancement, and development of infarction were compared between the two groups to study the distribution and characteristics of cerebral atherosclerotic plaques. Multivariate analysis identified factors associated with infarction 1 week after plaque identification. RESULTS: Based on the MR images, 76% of both groups of patients had middle cerebral atherosclerosis. Compared to TIA patients, the median age of CWS patients was younger (58 [range 42-73] vs. 67 [36-84] years, P = 0.003), and CWS patients had a lower rate of stroke history (10.9% vs. 41.2%, P = 0.001). Infarction was more common in CWS patients than in TIA patients (52.2% vs. 20.5%, P = 0.003) and a superior plaque was correlated with infarction occurrence (odds ratio 5.674, 95% confidence interval 1.112-28.958). CONCLUSION: Patients with CWS have large arterial plaques, including MCA plaques. There was a correlation between CWS and the MCA plaque location. J. Magn. Reson. Imaging 2016;44:1277-1283.

Analysis of Factors Affecting Good Neovascularization After Indirect Bypass Surgery: A Two-center Retrospective Study.

OBJECTIVE: The purpose of this study was to analyze factors affecting good neovascularization after indirect bypass surgery. METHODS: From August 2000 to July 2020, postoperative image results and medical records of 132 patients (159 hemispheres) who underwent EDAS of indirect bypass surgery at two institutions were reviewed retrospectively. Based on DSA results, angiogenesis after indirect bypass was divided into "good" or "poor" according to the Matsushima criteria. STA flap length affecting GPN were analyzed in the entire group (n = 159) and a MMD group (n = 134). RESULTS: In the entire group, GPN after EDAS was observed in 94 (59.1%) hemispheres. Age, MMD, hypertension, and bone flap size were identified as significant factors in univariate analysis. Also, in the MMD group, 86 (64.2%) hemispheres showed GPN. Hypertension and bone flap size were significant factors in both univariate and multivariate analyses. Cutoff values of bone flap size and GPN were 47.91 cm2 in the entire group and the MMD group. CONCLUSIONS: In all patients who received EDAS, good postoperative neovascularization was significant in those with a young age, MMD, without hypertension, and large bone flap size. No hypertension and large bone flap size were meaningful factors in the MMD group. AUROC showed that an appropriate bone flap size was 47.91 cm2. However, a further controlled prospective study is needed.

Two-sample Mendelian randomization to study the causal association between gut microbiota and atherosclerosis.

Background: According to some recent observational studies, the gut microbiota influences atherosclerosis via the gut microbiota-artery axis. However, the causal role of the gut microbiota in atherosclerosis remains unclear. Therefore, we used a Mendelian randomization (MR) strategy to try to dissect this causative link. Methods: The biggest known genome-wide association study (GWAS) (n = 13,266) from the MiBioGen collaboration was used to provide summary data on the gut microbiota for a two-sample MR research. Data on atherosclerosis were obtained from publicly available GWAS data from the FinnGen consortium, including cerebral atherosclerosis (104 cases and 218,688 controls), coronary atherosclerosis (23,363 cases and 187,840 controls), and peripheral atherosclerosis (6631 cases and 162,201 controls). The causal link between gut microbiota and atherosclerosis was investigated using inverse variance weighting, MR-Egger, weighted median, weighted mode, and simple mode approaches, among which inverse variance weighting was the main research method. Cochran's Q statistic was used to quantify the heterogeneity of instrumental variables (IVs), and the MR Egger intercept test was used to assess the pleiotropy of IVs. Results: Inverse-variance-weighted (IVW) estimation showed that genus Ruminiclostridium 9 had a protective influence on cerebral atherosclerosis (OR = 0.10, 95% CI: 0.01-0.67, P = 0.018), while family Rikenellaceae (OR = 5.39, 95% CI: 1.50-19.37, P = 0.010), family Streptococcaceae (OR = 6.87, 95% CI: 1.60-29.49, P = 0.010), genus Paraprevotella (OR = 2.88, 95% CI: 1.18-7.05, P = 0.021), and genus Streptococcus (OR = 5.26, 95% CI: 1.28-21.61, P = 0.021) had pathogenic effects on cerebral atherosclerosis. For family Acidaminococcaceae (OR = 0.87, 95% CI: 0.76-0.99, P = 0.039), the genus Desulfovibrio (OR = 0.89, 95% CI: 0.80-1.00, P = 0.048), the genus RuminococcaceaeUCG010 (OR = 0.80, 95% CI: 0.69-0.94, P = 0.006), and the Firmicutes phyla (OR = 0.87, 95% CI: 0.77-0.98, P = 0.023) were protective against coronary atherosclerosis. However, the genus Catenibacterium (OR = 1.12, 95% CI: 1.00-1.24, P = 0.049) had a pathogenic effect on coronary atherosclerosis. Finally, class Actinobacteria (OR = 0.83, 95% CI: 0.69-0.99, P = 0.036), family Acidaminococcaceae (OR = 0.76, 95% CI: 0.61-0.94, P = 0.013), genus Coprococcus2 (OR = 0.76, 95% CI: 0.60-0.96, P = 0.022), and genus RuminococcaceaeUCG010 (OR = 0.65, 95% CI: 0.46-0.92, P = 0.013), these four microbiota have a protective effect on peripheral atherosclerosis. However, for the genus Lachnoclostridium (OR = 1.25, 95% CI: 1.01-1.56, P = 0.040) and the genus LachnospiraceaeUCG001 (OR = 1.22, 95% CI: 1.04-1.42, P = 0.016), there is a pathogenic role for peripheral atherosclerosis. No heterogeneity was found for instrumental variables, and no considerable horizontal pleiotropy was observed. Conclusion: We discovered that the presence of probiotics and pathogens in the host is causally associated with atherosclerosis, and atherosclerosis at different sites is causally linked to specific gut microbiota. The specific gut microbiota associated with atherosclerosis identified by Mendelian randomization studies provides precise clinical targets for the treatment of atherosclerosis. In the future, we can further examine the gut microbiota's therapeutic potential for atherosclerosis if we have a better grasp of the causal relationship between it and atherosclerosis.

On the regional distribution of cerebral microvascular 'raspberries' and their association with cerebral atherosclerosis and acute circulatory failure.

Introduction: In this follow-up study, cerebral microvascular formations termed 'raspberries' were quantified according to cerebral atherosclerosis (C-ASCL) and acute circulatory failure (ACF). We also examined the regional distribution of raspberries throughout the brain. Materials and methods: The study population consisted of adult individuals who had undergone a diagnostic neuropathological autopsy. Groups were formed to examine the association between raspberries, C-ASCL and ACF (control group, C-ASCL group, C-ASCL+ACF group [n = 47 per group] and a combined C-ASCL-tot group [n = 94]). To examine the regional distribution, additional groups were formed based on previously known raspberry densities of the frontal cortex (high-, medium- and low-density group [n = 6 per group]). Raspberries were quantified on scanned haematoxylin-eosin-stained sections. Results: Cortical raspberry density did not differ at a statistically significant level between the control group, the C-ASCL group and the C-ASCL+ACF group (P = 0.10) but did so between the control group and the C-ASCL-tot group (P = 0.033). The total raspberry density of the high-, medium- and low-density groups differed at a statistically significant level (P = 0.005), which remained in group-to-group comparisons of the high- and medium-density groups (P = 0.015) and the high- and low-density groups (P = 0.002). Raspberries were rare in cerebral white matter and in the cerebellum. Conclusion: An association between raspberry density and C-ASCL is supported but is weaker than previously indicated. An association with ACF is not indicated. The raspberry density of the frontal cortex provides an approximation of the brain's total raspberry density.

Cerebral atherosclerosis and early ischemic stroke after left-sided valve replacement surgery.

OBJECTIVE: Studies have rarely investigated whether cerebral atherosclerosis increases the risk of stroke after valve replacement surgery. This study evaluated the influence of cerebral atherosclerosis on the risk of stroke after left-sided valve replacement surgery. METHODS: Between 2005 and 2015, preoperative magnetic resonance angiography was performed for 2085 patients who underwent left-sided valve replacement surgery in a tertiary single center to assess intracranial and extracranial cerebral atherosclerosis. The severity was retrospectively assessed on the basis of the atherosclerosis score, determined by the number of steno-occlusions of the cerebral arteries and the degree of atherosclerosis. Associations between cerebral atherosclerosis and postoperative stroke (within 30 days) were evaluated; the overall influence of total cerebral atherosclerosis, and the individual effects of intracranial and extracranial cerebral atherosclerosis on the risk of postoperative stroke were assessed using multivariable models. RESULTS: Preoperative cerebral atherosclerosis was identified in 626 (30.0%) patients, whereas intracranial cerebral atherosclerosis and extracranial cerebral atherosclerosis were identified in 367 (17.1%) and 412 (19.8%) patients, respectively. Stroke occurred in 54 (2.6%) patients, and the total cerebral atherosclerosis score was independently associated with an increased risk of stroke (odds ratio, 1.23; 95% confidence interval, 1.06-1.44). The intracranial cerebral atherosclerosis scores (odds ratio, 1.44; 95% confidence interval, 1.16-1.78), but not the extracranial cerebral atherosclerosis scores, independently predicted the incidence of stroke. CONCLUSIONS: Intracranial cerebral atherosclerosis was an important predictor of postoperative stroke, suggesting the necessity of further studies on the feasibility of preoperative screening for cerebral atherosclerosis in patients undergoing left-sided valve replacement surgery.

Fine-tuning of microglia polarization prevents diabetes-associated cerebral atherosclerosis.

Diabetes increases the occurrence and severity of atherosclerosis. When plaques form in brain vessels, cerebral atherosclerosis causes thickness, rigidity, and unstableness of cerebral artery walls, leading to severe complications like stroke and contributing to cognitive impairment. So far, the molecular mechanism underlying cerebral atherosclerosis is not determined. Moreover, effective intervention strategies are lacking. In this study, we showed that polarization of microglia, the resident macrophage in the central nervous system, appeared to play a critical role in the pathological progression of cerebral atherosclerosis. Microglia likely underwent an M2c-like polarization in an environment long exposed to high glucose. Experimental suppression of microglia M2c polarization was achieved through transduction of microglia with an adeno-associated virus (serotype AAV-PHP.B) carrying siRNA for interleukin-10 (IL-10) under the control of a microglia-specific TMEM119 promoter, which significantly attenuated diabetes-associated cerebral atherosclerosis in a mouse model. Thus, our study suggests a novel translational strategy to prevent diabetes-associated cerebral atherosclerosis through in vivo control of microglia polarization.

A Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with NTNG1 and CNOT3.

Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. Yet little is known about its genetic basis. To examine the association of common single nucleotide polymorphisms with cerebral atherosclerosis severity, we conducted a genomewide association study (GWAS) using data collected as part of two community-based cohort studies in the United States, the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Both studies enroll older individuals and exclude participants with signs of dementia at baseline. From our analysis of 1325 participants of European ancestry who had genotype and neuropathologically assessed cerebral atherosclerosis measures available, we found a novel locus for cerebral atherosclerosis in NTNG1. The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 (ß = -0.27, 95% CI = (-0.35, -0.19), p = 1.29 × 10-10) and rs10881463 (ß = -0.20, 95% CI = (-0.27, -0.13), p = 3.40 × 10-8). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4-NOT, which has been shown to be a master regulator of mRNA stability and translation and an important complex for cholesterol homeostasis. In summary, we identify a novel genetic locus for cerebral atherosclerosis and a potential mechanism linking this variation to cerebral atherosclerosis progression. These findings offer insights into the genetic effects on cerebral atherosclerosis.

Decreased 18F-Fluorodeoxyglucose Uptake in Lumbar Vertebrae of Stroke Patients.

BACKGROUND AND PURPOSE: We investigated 18F-fluorodeoxyglucose (FDG) uptake levels in the lumbar vertebrae, liver, and spleen of stroke patients with carotid atherosclerosis. METHODS: This study analyzed acute ischemic stroke patients with carotid atherosclerosis who underwent whole-body FDG positron-emission tomography between October 2015 and January 2017. FDG uptake in the lumbar vertebrae, liver, and spleen was measured and compared between stroke patients and control subjects without stroke history. Multivariate linear regression analysis was performed to identify independent factors related to FDG uptake in the proximal internal carotid artery (ICA). RESULTS: Twenty stroke patients aged 75.1±9.0 years (mean±standard deviation; 10 females) and 20 control subjects aged 62.9±10.7 years (6 females) were included. In comparison with the control group, the stroke group showed significantly higher FDG uptake in the proximal ICA (1.16±0.26 vs. 0.87±0.19, p<0.01), but significantly lower FDG uptake in the lumbar vertebrae (1.09±0.26 vs. 1.38±0.38, p=0.007) and liver (1.71±0.30 vs. 2.01±0.34, p=0.005). Multivariate linear regression analysis showed that the lumbar FDG uptake was negatively correlated with FDG uptake in the proximal ICA (standardized coefficient=-0.367, p=0.013) after adjusting for age and hypertension. CONCLUSIONS: Stroke patients showed decreased FDG uptake in the lumbar vertebrae. Further studies are warranted to evaluate the pathophysiological link between cerebral atherosclerosis and bone.

Hemodynamic Versus Anatomic Assessment of Symptomatic Atherosclerotic Middle Cerebral Artery Stenosis: the Relationship Between Pressure Wire Translesional Gradient and Angiographic Lesion Geometry.

Background: Intracranial cerebral atherosclerosis (ICAS) is a leading etiology of ischemic stroke. The diagnosis and assessment of intracranial stenosis are shifting from anatomic to hemodynamic for better risk stratification. However, the relationships between lesion geometry and translesional pressure gradient have not been clearly elucidated. Methods: Patients with symptomatic unifocal M1 middle cerebral artery (M1-MCA) stenosis were consecutively recruited. The translesional pressure gradient was measured with a pressure wire and was recorded as both mean distal/proximal pressure ratios (Pd/Pa) and translesional pressure difference (Pa-Pd). Lesion geometry measured on angiography was recorded as diameter stenosis, minimal lumen diameter, and lesion length. The correlations between pressure-derived and angiography-derived indices were then analyzed. Results: Forty-three patients were analyzed. A negative correlation was found between Pd/Pa and diameter stenosis (r = -0.371; p = 0.014) and between Pa - Pd and minimal lumen diameter (r = -0.507; p = 0.001). A positive correlation was found between Pd/Pa and minimal lumen diameter (r = 0.411; p = 0.006) and between Pa - Pd and diameter stenosis (r = 0.466; p = 0.002). Conclusions: In a highly selected ICAS subgroup, geometric indices derived from angiography correlate significantly with translesional pressure gradient indices. However, the correlation strength is weak-to-moderate, which implies that anatomic assessment could only partly reflect hemodynamic status. Translesional pressure gradient measured by pressure wire may serve as a more predictive marker of ICAS severity. More factors need to be identified in further studies.