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.

Intracranial arteriosclerosis is related to cerebral small vessel disease: a prospective cohort study.

Intracranial arteriosclerosis has been increasingly recognized as a risk factor for cognitive impairment and even dementia. A possible mechanism linking intracranial arteriosclerosis to cognitive impairment and dementia involves structural brain changes including cerebral small vessel disease (CSVD). To assess whether intracranial carotid artery calcification (ICAC) and vertebrobasilar artery calcification (VBAC), as proxies for intracranial arteriosclerosis, are related to CSVD. Within the population-based Rotterdam Study, between 2003 and 2006 a computed tomography (CT)-based measurement of ICAC and VBAC and at least one magnetic resonance imaging (MRI) measurement of structural brain changes were performed from 2005 onwards in 1,489 participants. To estimate the burden of calcification independent of age, we computed age-adjusted percentile curves for ICAC and VBAC separately, based on the calcification volumes. Using the longitudinal MRI data, we assessed whether a larger calcification burden accelerates structural brain changes using appropriate statistical models for repeated outcome measures. A larger burden of ICAC and VBAC was associated with an increase of CSVD markers accelerating over time. A larger burden of ICAC and VBAC was not significantly (p > 0.05) associated with accelerated brain atrophy. Arteriosclerosis is related to accelerating structural brain changes over time.

The aptamer BT200 blocks von Willebrand factor and platelet function in blood of stroke patients.

The effect of conventional anti-platelet agents is limited in secondary stroke prevention, and their effects are blunted under high shear stress in the presence of increased levels of circulating von Willebrand factor (VWF). VWF is critically involved in thrombus formation at sites of stenotic extracranial/intracranial arteries. A third generation anti-VWF aptamer (BT200) has been generated which could be useful for secondary stroke prevention. To characterize the effects of BT200 in blood of patients with large artery atherosclerosis stroke (LAA). Blood samples were obtained from 33 patients with acute stroke or transient ischemic attack to measure inhibition of VWF activity and VWF-dependent platelet function. Patients who received clopidogrel or dual antiplatelet therapy did not differ in VWF dependent platelet function tests from aspirin treated patients. Of 18 patients receiving clopidogrel with or without aspirin, only 3 had a prolonged collagen adenosine diphosphate closure time, and none of the patients had ristocetin induced aggregation in the target range. BT200 concentration-dependently reduced median VWF activity from 178 to < 3%, ristocetin induced platelet aggregation from 40U to < 10U and prolonged collagen adenosine diphosphate closure times from 93 s to > 300 s. Baseline VWF activity correlated (r = 0.86, p < 0.001) with concentrations needed to reduce VWF activity to < 20% of normal, indicating that BT200 acts in a target concentration-dependent manner. Together with a long half-life supporting once weekly administration, the safety and tolerability observed in an ongoing phase I trial, and the existence of a reversal agent, BT200 is an interesting drug candidate.

Label-free multiphoton microscopy as a tool to investigate alterations of cerebral aneurysms.

Cerebral aneurysms are abnormal focal dilatations of arterial vessel walls with pathological vessel structure alterations. Sudden rupture can lead to a subarachnoid hemorrhage, which is associated with a high mortality. Therefore, the origin of cerebral aneurysms as well as the progression to the point of rupture needs to be further investigated. Label-free multimodal multiphoton microscopy (MPM) was performed on resected human aneurysm domes and integrated three modalities: coherent anti-Stokes Raman scattering, endogenous two-photon fluorescence and second harmonic generation. We showed that MPM is a completely label-free and real-time powerful tool to detect pathognomonic histopathological changes in aneurysms, e.g. thickening and thinning of vessel walls, intimal hyperplasia, intra-wall haemorrhage, calcification as well as atherosclerotic changes. In particular, the loss or fragmentation of elastin as well as fibromatous wall remodelling appeared very distinct. Remarkably, cholesterol and lipid deposits were clearly visible in the multiphoton images. MPM provides morphological and biochemical information that are crucial for understanding the mechanisms of aneurysm formation and progression.

The parameters of carotid plaques' calcifications and clinical nature of the lesions in the context of revascularization treatment. The enlargement of calcifications is still the most important.

INTRODUCTION: It remains a challenge to determine criteria according to which patients with asymptomatic carotid stenosis could be properly qualified for revascularization treatment. Carotid calcification assessment seems to be here quite attractive. The aim of the study was the histological analysis of various parameters of calcifications in human carotid plaques in relation to the symptomatic/asymptomatic nature of the lesions. MATERIAL AND METHODS: The study involved carotid plaques taken from patients who have undergone endarterectomy of the internal carotid artery. RESULTS: Calcified plaques (with enlarged calcifications) were significantly more frequently asymptomatic than non-calcified plaques. The remaining calcification characteristics played no role. Calcified lesions disclosed the dominance of the fibrous component and the small lipid core significantly more frequently than non-calcified plaques. The percentage of females in the patients group with calcified lesions was significantly higher than in the group with non-calcified plaques. The percentage of males was lower. The former patients group used statins and angiotensin inhibitors significantly more frequently than patients with non-calcified plaques. Enlarged calcifications were independently associated with the asymptomatic nature of the carotid plaques. CONCLUSIONS: The enlargement of calcifications in carotid plaques is the only calcification parameter important for the clinical outcome of carotid atherosclerosis. Patients with calcified carotid plaques have a significantly lower risk of ischemic stroke than patients with non-calcified lesions.

Depression Predicts Delirium After Coronary Artery Bypass Graft Surgery Independent of Cognitive Impairment and Cerebrovascular Disease: An Analysis of the Neuropsychiatric Outcomes After Heart Surgery Study.

OBJECTIVE: Although depression is a known risk factor for delirium after coronary artery bypass graft (CABG) surgery, it is unclear whether this risk is independent of delirium risk attributable to cognitive impairment or cerebrovascular disease. This study examines depression, mild cognitive impairment (MCI), and cerebrovascular disease as post-CABG delirium risk factors. METHODS: This prospective observational cohort study was performed in a tertiary-care academic hospital. Subjects were without dementia and undergoing CABG surgery. Preoperative cognitive assessment included Clinical Dementia Rating and neuropsychological battery; depression was assessed using Depression Interview and Structured Hamilton. Baseline intracranial stenosis was evaluated by transcranial Doppler of bilateral middle cerebral arteries (MCAs). Study psychiatrists assessed delirium on postoperative days 2-5 using the Confusion Assessment Method. RESULTS: Our analytic sample comprised 131 subjects (average age: 65.8 ± 9.2years, 27% women). MCI prevalence was 24%, preoperative depression 10%, lifetime depression 35%, and MCA stenosis (≥50%) 28%. Sixteen percent developed delirium. Multivariate analysis revealed that age, MCI (odds ratio [OR]: 5.1; 95% confidence interval [CI]: 1.3-20.1), and preoperative depression (OR: 9.9; 95% CI: 1.3-77.9)-but not lifetime depression-predicted delirium. MCA stenosis and severity predicted delirium in univariate but not multivariate analysis. Right MCA stenosis severity predicted delirium severity, but left-sided stenosis severity did not. CONCLUSION: We established that the risk of delirium attributable to depression extends beyond the potential moderating influence of cognitive impairment and cerebrovascular disease alone. Even mild depression and cognitive impairment before CABG deserve recognition for their effect on post-CABG cognitive health.

PM2.5 exposure induces systemic inflammation and oxidative stress in an intracranial atherosclerosis rat model.

OBJECTIVES: Exposure to airborne particle (PM2.5 ) is a risk factor for intracranial atherosclerosis (ICA). Because of the established role of systemic inflammation and oxidative stress by PM2.5 , we determined whether these processes account for PM2.5 -mediated ICA, and also whether omega-3 fatty acid (O3FA) dietary supplementation could attenuate them. METHODS: Adult Sprague-Dawley rats were exposed to filtered air (FA) or PM2.5 and fed either a normal chow diet (NCD) or a high-cholesterol diet (HCD), administered with or without O3FA (5 mg/kg/day by gavage) for 12 weeks. The lumen and thickness of the middle cerebral artery (MCA) were assessed. Serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin-1ß (IL-1ß), and interferon gamma (IFN-γ) were detected by ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, mRNA levels of Nrf2, HO-1, NQO-1, and protein level of NOX subunit gp91 were quantified to determine the oxidative profile of brain vessels. RESULTS: PM2.5 increased (P < .05) ICA, especially in the HCD group; elevated serum TNF-α, IL-6, IL-1ß, and IFN-γ; increased cerebrovascular ROS, MDA, NOX activity, and gp91 protein levels; and decreased cerebrovascular SOD activity. Nrf2, HO-1, and NQO-1 mRNA levels were upregulated (P < .05) by PM2.5 exposure, especially in the HCD group. O3FA attenuated (P < .05) PM2.5 -induced systemic inflammation, vascular oxidative injury, and ICA. CONCLUSIONS: PM2.5 exposure induced systemic inflammation, cerebrovascular oxidative injury, and ICA in rats with HCD. O3FA prevented ICA development, and may therefore exert a protective effect against the atherogenic potential of PM2.5 .

Width of sulcus and thickness of gyrus in patients with cerebral atherosclerosis: a new tool for the prevention of vascular cognitive impairment

SUMMARY BACKGROUND AND PURPOSE Cerebral atherosclerosis is the main cause of lesions that contribute to vascular cognitive impairment and vascular dementia, followed by arteriosclerosis of small vessels and cerebral amyloid angiopathy. The purpose of this study was to compare the post-mortem radiological alterations of autopsied adults with the macroscopic alterations in the posterior region of these brains in order to establish a relationship between the two forms of analysis and to discuss the relevance of the prevention of vascular cognitive impairment in patients with encephalic atherosclerosis. MATERIALS AND METHODS Thirteen brains were analysed macroscopically to assess the degree of atherosclerosis of the basilar and the posterior cerebral arteries. The patients were autopsied in the Subject of General Pathology at General Hospital of Triângulo Mineiro Federal University in Uberaba, state of Minas Gerais, Brazil. The qualitative analysis of atherosclerosis was performed with classification into mild, moderate or severe. In the posterior region of the brains, width of sulcus and thickness of gyrus were measured by macroscopic analysis and by tomographic analysis. RESULTS AND CONCLUSIONS There was a decrease in calcarine sulcus width and an increase in medial temporal occipital gyrus thickness in patients with a higher degree of atherosclerosis, macroscopically and in tomography, respectively. Low oxygenation caused by atherosclerosis probably leads to an encephalic parenchyma inflammation that causes microglial cells hypertrophy provoking increase in the gyrus thickness and decrease in the sulcus width, as observed in the present study.

RESUMO INTRODUÇÃO E OBJETIVO A aterosclerose cerebral é a principal causa de lesões que contribuem para o comprometimento cognitivo vascular (CCV) e demência vascular, seguida da arteriosclerose de pequenos vasos e da angiopatia amiloide cerebral. Sendo assim, este estudo comparou as alterações radiológicas post mortem de adultos autopsiados com as alterações macroscópicas na região posterior desses encéfalos a fim de estabelecer uma relação entre as duas formas de análise e discutir sobre a relevância da prevenção do CCV em pacientes com aterosclerose encefálica. MATERIAL E MÉTODOS Treze encéfalos foram analisados macroscopicamente para avaliar o grau de aterosclerose das artérias basilar e cerebral posterior. Os pacientes foram autopsiados na disciplina de Patologia Geral no HC-UFTM em Uberaba, Minas Gerais, Brasil. A análise qualitativa da aterosclerose foi realizada com as classificações discreta, moderada ou acentuada. A espessura dos giros e a largura dos sulcos na região posterior dos encéfalos foram analisadas macroscopicamente e por tomografia computadorizada. RESULTADOS E CONCLUSÃO Houve diminuição na largura do sulco calcarino e aumento na espessura do giro occipital temporal medial de acordo com o aumento do grau de aterosclerose macroscopicamente e por tomografia, respectivamente. A baixa oxigenação causada pela aterosclerose provoca a inflamação do parênquima encefálico, provavelmente levando à hipertrofia das células da micróglia e ao consequente aumento dos giros e estreitamento dos sulcos, como observado no presente estudo.

Antiangiogenesis and medical therapy failure in intracranial atherosclerosis.

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and the one with the worst prognosis. In this study, we assessed the hypothesis that the balance of circulating pro- and antiangiogenic factors plays a role in the evolution of the disease and can be used as a potential marker for the disease course and a target for treatment. Seventy-four patients with severe ICAD were enrolled in this prospective observational study, medically optimized, and followed for 6 months. Thirteen pro- and eight antiangiogenic factors were measured in the participants' serum using a sandwich multiplex ELISA. Angiogenic profiles were calculated using principal component analysis. We tested the association between angiogenic profiles and recurring cerebrovascular events despite intensive medical therapy, disability at 6 months after enrollment, and angiographic neovascularization in patients who failed medical treatment and underwent indirect revascularization surgery. There is a strong association between a functionally antiangiogenic profile and recurrent stroke or TIA in patients with ICAD (OR = 7.2, CI 2.4-34.4). Multivariable regression analysis showed that this antiangiogenic profile was also associated with poor functional status after 6 months (p = 0.002), independent from other clinical features such as history of previous stroke, diabetes, and age. In patients who failed medical management and underwent indirect revascularization surgery, high endostatin and angiostatin levels were also associated with low angiographic neovascularization (p = 0.02). The results of this study point to the striking importance of antiangiogenesis as a determinant of ICAD patient prognosis and suggest a possible new target for therapy.

Morphometric measurements of extracranial and intracranial atherosclerotic disease: A population-based autopsy study.

BACKGROUND AND AIMS: Intracranial (IAD) and extracranial atherosclerotic diseases (EAD) have been mostly investigated using imaging methods. Autopsy studies allow for a direct and complete evaluation of the atherosclerotic disease. We aimed to investigate the frequency of IAD and EAD, their association, and related risk profiles in a large cross-sectional autopsy study. METHODS: We measured the intima-media thickness and stenosis of the common (CCA) and internal carotid arteries (ICA), using morphometric measurements. The main outcome was stenosis (≥50%) in the artery with the largest obstruction among the 12 cerebral arteries. We used multivariable logistic regression models to investigate the association between EAD and IAD. RESULTS: In 661 participants (mean age = 71.3 ± 11.7 y, 51% male), stenosis was more common in IAD than in EAD (59% vs. 51%). EAD was associated with Caucasian race, hypertension, and smoking, while IAD was associated with older age, less years of education, hypertension, diabetes, and a previous history of stroke. Stenosis in CCA and ICA was associated with more than two times the odds of having stenosis in the intracranial arteries (CCA: OR = 2.32, 95% CI = 1.64; 3.28; ICA: OR = 2.51, 95% CI = 1.76; 3.57). CONCLUSIONS: In this population-based autopsy study, IAD was common, even more common than EAD, but correlated with EAD.

Trajectories of physical function prior to death and brain neuropathology in a community-based cohort: the act study.

BACKGROUND: Mechanisms linking cognitive and physical functioning in older adults are unclear. We sought to determine whether brain pathological changes relate to the level or rate of physical performance decline. METHODS: This study analyzed data from 305 participants in the autopsy subcohort of the prospective Adult Changes in Thought (ACT) study. Participants were aged 65+ and free of dementia at enrollment. Physical performance was measured at baseline and every two years using the Short Physical Performance Battery (SPPB). Data from 3174 ACT participants with ≥2 SPPB measurements were used to estimate two physical function measures: 1) rate of SPPB decline defined by intercept and slope; and 2) estimated SPPB 5 years prior to death. Neuropathology findings at autopsy included neurofibrillary tangles (Braak stage), neuritic plaques (CERAD level), presence of amyloid angiopathy, microinfarcts, cystic infarcts, and Lewy bodies. Associations (adjusted for sex, age, body mass index and education) between dichotomized neuropathologic outcomes and SPPB measures were estimated using modified Poisson regression with inverse probability weights (IPW) estimated via Generalized Estimating Equations (GEE). Relative risks for the 20th, 40th, and 60th percentiles (lowest levels and highest rates of decline) relative to the 80th percentile (highest level and lowest rate of decline) were calculated. RESULTS: Decedents with the least vs. most SPPB decline (slope > 75th vs. < 25th percentiles) had higher SPPB scores, and were more likely to be male, older, have higher education, and exercise regularly at baseline. No significant associations were observed between neuropathology findings and rate of SPPB decline. Lower predicted SPPB scores 5 years prior to death were associated with higher risk of microinfarcts (RR = 3.08, 95% confidence interval (CI) 0.93-1.07 for the 20th vs. 80th percentiles of SPPB) and significantly higher risk of cystic infarcts (RR = 2.72, 95% CI 1.45-5.57 for 20th vs. 80th percentiles of SPPB). CONCLUSION: Cystic infarcts and microinfarcts, but not neuropathology findings of Alzheimer's disease, were related to physical performance levels five years before death. No pathology findings were associated with rates of physical performance decline. Physical function levels in the years prior to death may be affected by vascular brain pathologies.

Enlarged perivascular spaces in the basal ganglia are independently associated with intracranial atherosclerosis in the elderly.

BACKGROUND AND AIMS: Enlarged basal ganglia perivascular spaces (BG-PVS) are a marker of cerebral small vessel disease (SVD). The association between enlarged BG-PVS and atherosclerosis has been explored, but knowledge is limited to extracranial vessels. We aimed to assess whether enlarged BG-PVS correlate with carotid siphon calcifications (CSC), used as a surrogate of intracranial atherosclerosis. METHODS: Atahualpa residents aged ≥60 years underwent head computed tomography (CT) for assessment of CSC, and brain magnetic resonance imaging (MRI) for evaluation of BG-PVS and other imaging markers of SVD. We evaluated the association between BG-PVS and CSC severity (dependent variable) using regression models adjusted for demographics and cardiovascular risk factors. RESULTS: Of 437 candidates, 354 (81%) were included. Grade 1 CSC were observed in 131 (37%), Grade 2 in 99 (28%), Grade 3 in 92 (26%), and Grade 4 in 32 (9%) subjects. MRI showed >10 enlarged BG-PVS in 97 (27%) participants, moderate-to-severe white matter hyperintensities in 81 (23%), lacunar infarcts in 39 (11%), and deep microbleeds in 28 (8%). Fully-adjusted models showed a significant association between enlarged BG-PVS and CSC severity. Individuals with Grade 4 CSC have 3 times de odds of having enlarged BG-PVS than those with Grade 1 CSC. Enlarged BG-PVS were observed in 20% versus 41% of individuals with Grade 1 and Grade 4 CSC, respectively. CONCLUSIONS: Enlarged BG-PVS often coexist with CSC, suggesting that a common pathogenetic mechanism may explain the occurrence of both conditions.

Proteomic analysis and comparison of intra­ and extracranial cerebral atherosclerosis responses to hyperlipidemia in rabbits.

The present study aimed to investigate protein expression levels of intra­ and extracranial atherosclerosis in rabbits following administration of a high­fat diet. Rabbits were randomly divided into control (group A; n=9) and high­fat diet (group B; n=9) groups. At week 12, tissues were sectioned from the common carotid artery (CCA) and middle cerebral artery (MCA). Pathological analysis was performed. Differential protein expression levels were examined by 2­D gel electrophoresis (2­DE) and mass spectrometry (MS) analysis and validated by western blotting. Serum lipid levels, the intima­media thickness (IMT) and degree of atherosclerosis of the CCA and MCA were increased at week 12 in the high­fat diet group compared with rabbits that received a normal diet. 2­DE and MS analysis of the protein extracted from CCA and MCA detected >439 different proteins; the expression of 25 proteins was altered, and 8 proteins [albumin A chain, tropomyosin α­1 chain (TPM1), heat shock protein 70 (HSP70), α­smooth muscle actin, ß­galactose binding agglutinin, TPM4 isoform 2, cell keratin 9, single octylic acid glyceride ß­2) demonstrated significant alterations in expression levels. Due to limited antibody sources, only three differentially expressed proteins (TPM1, HSP70 and α­smooth muscle actin) were examined by western blotting. The results of our previous study demonstrated that hyperlipidemia affected the IMT of intracranial and extracranial cerebral arteries. In the present study, protein expression levels of TPM1 and α­smooth muscle actin from extracranial cerebral arteries were significantly increased compared with intracranial cerebral arteries; however, protein expression levels of HSP70 from intracranial cerebral arteries was increased compared with extracranial cerebral arteries. The differences may be closely associated with cell proliferation and metastasis, and oxidoreduction, in intra­ and extracranial cerebral atherosclerosis. HSP70 may have protective properties against atherosclerosis via underlying anti­inflammatory mechanisms, furthermore, differential protein expression levels (TPM1, HSP70 and α­smooth muscle actin) between intra­ and extracranial cerebral arteries may facilitate the identification of novel biological markers for the diagnosis and treatment of cerebral arteriosclerosis.

Relationship of thyroid function with intracranial arterial stenosis and carotid atheromatous plaques in ischemic stroke patients with euthyroidism.

This study aimed to help clarify the possible relationships of thyroid function with intracranial arterial stenosis or carotid atheromatous plaques in ischemic stroke patients with euthyroidism. We retrospectively reviewed the medical records of a consecutive series of ischemic stroke patients prospectively entered into the Chengdu Stroke Registry between February 2010 and March2012. We performed univariate and multivariate analysis to assess possible relationships of thyroid function with intracranial artery stenosis or carotid atheromatous plaques. Of the 172 patients analyzed (42 women; 61.7 ± 14.0 years old), 62 (32.0%) had carotid atheromatous plaques, and 81 (47.1%) had intracranial artery stenosis. Free thyroxine levels were lower in patients with carotid atheromatous plaques than in patients without plaques (15.80±2.09 vs. 16.92±2.69, P = 0.005).After adjusting for age, gender, hyperlipidemia, and previous smoking, free thyroxine levels were independently associated with carotid atheromatous plaques (OR 0.73, 95% CI 0.54-0.99, P = 0.04). In contrast, thyroid function indicators showed no associations with intracranial arterial stenosis. In conclusion, low free thyroxine levels were independently associated with carotid atheromatous plaques in ischemic stroke patients with euthyroidism, but thyroid function indicators were not associated with intracranial artery stenosis.

Risk factors, topographic patterns and mechanism analysis of intracranial atherosclerotic stenosis ischemic stroke.

BACKGROUND: The association between topographic patterns, risk factors and stroke mechanisms of ICAS in first-ever stroke remains unknown. METHODS: A large sample sized retrospective study was performed on first-ever ICAS ischemic stroke using DWI and MRA. RESULTS: Hypertension (60.92%), cigarette smoking (26.82%), MCA (76.65%) and multiple vessels (65.37%) stenosis, were the major factors favoring different mechanisms. Subcortical lesions were the most occurring topographic patterns (41.4%). The common mechanism was LBO (66.3%). Statistical analysis showed a significant relationship between lesion patterns and mechanisms (r = 0.384, P = 0.001). Single mechanism had the higher apoB/apoAI ratio (P = 0.005) and levels of plasma apoB (P = 0.007) compared with multiple mechanisms. The anterior circulation stroke were more multiple mechanisms as compared to the posterior circulation stroke (P = 0.001). LBO was more prevalent in posterior circulation stroke than in anterior circulation stroke (P = 0.001). CONCLUSIONS: The topographic patterns of ischemic lesions is helpful in early identification of different mechanisms of ICAS. Monitoring apoB and apoB/apoA1 may help to predict the mechanism of stroke with ICAS. The prevalence of mechanisms differ between anterior and posterior circulation stroke with ICAS.

Relation of serum homocysteine levels to cerebral artery calcification and atherosclerosis.

BACKGROUND AND AIMS: Elevated serum homocysteine level is known to be associated with increased risk of vascular event due to endothelial senescence. We investigated the association between serum homocysteine level and cerebral arteriosclerosis status including intracranial vascular calcification and atherosclerosis burden. METHODS: We identified 1193 consecutive patients (mean age = 68.6 ± 12.7, 537 female patients) who were admitted with acute cerebral infarction or transient ischemic attack from a single university medical center. The patients were categorized into three groups according to their serum homocysteine level. Cerebral artery calcification was assessed from the cavernous portion of both internal carotid arteries, and cerebral atherosclerosis burden was derived as the sum of stenosis degree of major intracranial arteries from brain computed tomography angiography. RESULTS: The mean homocysteine level was 14.1 ± 6.2 µmol/L, and intracranial cerebral artery calcification was present in 974 patients (81.6%), with 339 cases of advanced calcification (28.4%). The prevalence of cerebral artery calcification, advanced cerebral artery calcification and cerebral atherosclerosis burden showed increasing tendency throughout the homocysteine tertiles. Multivariable logistic regression analysis including age, sex, vascular risk factors, serum C-reactive protein, estimated glomerular filtration rate and homocysteine tertile disclosed that the highest serum homocysteine tertile was an independent predictor of advanced cerebral artery calcification (odds ratio = 1.45, confidence interval = 1.02-2.05) and advanced cerebral atherosclerosis (odds ratio = 1.42, confidence interval = 1.01-1.99) compared to the lowest group. CONCLUSIONS: An elevated serum homocysteine level was independently associated with intracranial arterial calcification and atherosclerosis burden. Future studies are warranted to test whether lowering serum homocysteine can delay cerebral arteriosclerotic changes.

Omega-3 fatty acid supplement prevents development of intracranial atherosclerosis.

OBJECTIVES: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and, in particular, has been implicated as a leading cause of recurrent ischemic stroke. We adapted a rat model of atherosclerosis to study brain intracranial atherosclerosis, and further investigated the effect of omega-3 fatty acids (O3FA) in attenuating development of ICAS. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into control normal-cholesterol or high-cholesterol diet groups with or without O3FA for up to 6weeks. During the first 2weeks, NG-nitro-l-arginine methyl ester (l-NAME, 3mg/mL) was added to the drinking water of the high-cholesterol groups. The rats received supplementation with O3FA (5mg/kg/day) by gavages. Blood lipids including low density lipoprotein (LDL), cholesterol (CHO), triglycerides (TG) and high density lipoprotein (HDL) were measured at 3 and 6weeks. The lumen of middle cerebral artery (MCA) and the thickness of the vessel wall were assessed. Inflammatory molecular markers were assessed by Western blot. RESULTS: A high-cholesterol diet exhibited a significant increase in the classic blood markers (LDL, CHO, and TG) for atherosclerosis, as well as a decrease in HDL. These markers were found to be progressively more severe with time. Lumen stenosis and intimal thickening were increased in MCA. O3FA showed attenuation of blood lipids with an absence of morphological changes. O3FA significantly reduced the inflammatory marker CD68 in MCA and prevented monocyte chemotactic protein (MCP-1) and interferon-γ (IFN-γ) expression in the brain. O3FA similarly decreased inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6), markers affiliated with monocyte activity in atherosclerosis. Furthermore, O3FA significantly inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1), a marker for endothelial activation. Lastly, O3FA increased ATP-binding cassette transporter A1 (ABCA1) protein expression via silent information regulator 1 (SIRT1) activation, thus increasing cholesterol efflux from macrophages to HDL. CONCLUSIONS: Long-term O3FA dietary supplementation prevents the development of intracranial atherosclerosis. This O3FA effect appears to be mediated by its prevention of macrophage infiltration into the vessel wall, therefore reducing inflammation and intimal thickening. While similar effects in humans need to be determined, O3FA dietary supplement shows promising results in the prevention of ICAS.

Pathogenic Heterogeneity of Distal Single Small Subcortical Lenticulostriate Infarctions Based on Lesion Size.

BACKGROUND: Single small subcortical infarctions (SSSIs) in the lenticulostriate artery territory can be classified as proximal single small subcortical infarction (pSSSI) or distal single small subcortical infarction (dSSSI) lesions depending on the involvement of the lowest part of the basal ganglia. It was reported that pSSSI lesions have more characteristics of large artery atherosclerosis, whereas dSSSI lesions are more characteristic of small vessel disease. Because infarction of small vessels is more likely to be distal and may result in small lesions, we hypothesized that the clinical features of dSSSI lesions might be heterogeneous and classified based on lesion size. METHODS: Lenticulostriate SSSI patients admitted within 72 hours of stroke onset were included from a prospectively registered hospital-based stroke database. We determined the location (lowest slice [LS] involved) and size (total number of slices [TNS] involved) of SSSIs on magnetic resonance imagings. Based on lesion location, SSSIs were divided into pSSSI (LS ≤ 2) and dSSSI (LS > 2); the latter were further subdivided into distal and small SSSI (ds-SSSI, TNS ≤ 2) or distal and large SSSI (dl-SSSI, TNS > 2). The clinical characteristics were compared between different groups. RESULTS: A total of 204 patients were included out of 1158 patients registered in the database. We found that ds-SSSI was most often associated with severe white matter hyperintensities. However, patients with dl-SSSI most often had a higher rate of additional concurrent atherosclerotic disease as coronary heart disease, compared to patients with ds-SSSI. CONCLUSIONS: The pathogenesis of dSSSI may be heterogeneous depending on lesion size.

Reduced endothelial progenitor cells in extracranial arterial stenosis but not intracranial arterial stenosis.

OBJECTIVE: Endothelial progenitor cells (EPCs) are novel markers of endothelial dysfunction and are related to cardiovascular disease. However, their relationship with cerebral atherosclerosis (CA) has not been investigated extensively. We aim to study the relationship between CA severity and EPC subpopulations levels. METHODS: We enrolled 197 patients in this study. EPCs were measured by flow cytometry. Digital subtraction angiography was used to assess CA. Arterial lesion severity was evaluated among cerebral arteries which showed steno-occlusion change and the extent of that condition. RESULTS: There was a significant inverse correlation between EPCs level and CA prevalence after adjusting for confounders (CD45(-/dim)CD34(+)CD309(+) cells: odds ratio [OR], 0.110; 95% confidence interval [CI], 0.026-0.475; P = .00; CD45(-/dim)CD133(+)CD309(+) cells: OR, 0.134; 95% CI, 0.030-0.599; P = .01; CD45(-/dim) CD34(+)CD133(+)CD309(+) cells: OR, 0.010; 95% CI, 0.001-0 .541, P = .02). Multivariate logistic regression analysis showed that only the EPCs level was significantly inversely associated with extracranial atherosclerosis rather than intracranial atherosclerosis (P > .05). CONCLUSIONS: Our data indicated that EPCs subpopulations were independent predictors for CA severity, even after controlling for traditional risk factors.

Brain arterial remodeling contribution to nonembolic brain infarcts in patients with HIV.

BACKGROUND: Cerebrovascular disease is a cause of morbidity in HIV-infected populations. The relationship among HIV infection, brain arterial remodeling, and stroke is unclear. METHODS: Large brain arteries (n = 1,878 segments) from 284 brain donors with and without HIV were analyzed to obtain media and wall thickness and lumen-to-wall ratio, and to determine the presence of atherosclerosis and dolichoectasia (arterial remodeling extremes). Neuropathologic assessment was used to characterize brain infarcts. Multilevel models were used to assess for associations between arterial characteristics and HIV. Associations between arterial characteristics and brain infarcts were examined in HIV+ individuals only. RESULTS: Adjusting for vascular risk factors, HIV infection was associated with thicker arterial walls and smaller lumen-to-wall ratios. Cerebral atherosclerosis accounted for one-quarter of the brain infarcts in HIV+ cases, and was more common with aging, diabetes, a lower CD4 nadir, and a higher antemortem CD4 count. In contrast, a higher lumen-to-wall ratio was the only arterial predictor of unexplained infarcts in HIV+ cases. Dolichoectasia was more common in HIV+ cases with smoking and media thinning, and with protracted HIV infection and a detectable antemortem viral load. CONCLUSIONS: HIV infection may predispose to inward remodeling compared to uninfected controls. However, among HIV+ cases with protracted immunosuppression, outward remodeling is the defining arterial phenotype. Half of all brain infarcts in this sample were attributed to the extremes of brain arterial remodeling: atherosclerosis and dolichoectasia. Understanding the mechanisms influencing arterial remodeling will be important in controlling cerebrovascular disease in the HIV-infected population.