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We determined the occurrence and association of cortical cerebral microinfarcts (CMIs) at 7 T MRI with risk factors, neuroimaging markers of small and large vessel disease, and cognitive functioning. Within the Medea-7T study, a diverse cohort of older persons with normal cognition, patients with vascular disease, and memory clinic patients, we included 386 participants (68 ± 9 years) with available 7 T and 1.5 T/3T brain MRI, and risk factor and neuropsychological data. CMIs were found in 10% of participants and were associated with older age (RR = 1.79 per +10 years, 95%CI 1.28-2.50), history of stroke or TIA (RR = 4.03, 95%CI 2.18-7.43), cortical infarcts (RR = 5.28, 95%CI 2.91-9.55), lacunes (RR = 5.66, 95%CI 2.85-11.27), cerebellar infarcts (RR = 2.73, 95%CI 1.27-5.84) and decreased cerebral blood flow (RR = 1.35 per -100 ml/min, 95%CI 1.00-1.83), after adjustment for age and sex. Furthermore, participants with >2 CMIs had 0.5 SD (95%CI 0.05-0.91) lower global cognitive performance, compared to participants without CMIs. Our results indicate that CMIs on 7 T MRI are observed in vascular and memory clinic patients with similar frequency, and are associated with older age, history of stroke or TIA, other brain infarcts, and poorer global cognitive functioning.

Aims: Stroke has risen to the fifth and third most common causes of death in the United States and the rest of the world, respectively. Vortioxetine (VTX) is a multimodal antidepressant agent that balances 5-HT receptors and represses the serotonin transporter. Our study aimed to examine the neuroprotective impacts of VTX against cerebral ischemia caused by occluding the middle cerebral artery (MCA)., Main Methods: Until the middle cerebral artery occlusion (MCAO) induction, VTX (10 mg/kg/day) was taken orally for 14 days. Behavioral assessments were carried out 24 h after the MCAO technique. The hippocampal and cortical tissues of the brain were isolated to assess the histological changes and the levels of the biochemical parameters., Key Findings: MCAO damage led to severe neurological deficits and histopathological damage. However, VTX improved MCAO-induced neurological deficits and ameliorated histopathological changes in both hippocampal and cortical tissues of MCAO rats. Western blot analysis showed increments of p-PERK, CHOP, ASK-1, NICD, HES-1, HES-5, and p-eIF2α expression levels in MCAO rats. Moreover, ELISA revealed an increase in the levels of ATF4, IRE1, Apaf-1, and HIF-1α, while VTX administration ameliorated most of these perturbations induced after MCAO injury., Significance: This research suggests that VTX could be a potent neuroprotective agent against ischemic stroke by inhibiting a variety of oxidative, apoptotic, inflammatory, and endoplasmic reticulum stress pathways., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chronic cerebral hypoperfusion (CCH), as a critical factor of chronic cerebrovascular diseases, has greatly influenced the health of patients with vascular dementia. Vitexin, a flavone C-glycoside (apigenin-8-C-β-D-glucopyranoside) that belongs to the flavone subclass of flavonoids, has been shown to possess antioxidant and anti-ischemic properties; however, the putative protective effects of vitexin on the CCH need further investigation. In the current study, the role of vitexin and its underlying mechanism were investigated with permanent bilateral common carotid artery occlusion (2VO) in rats as well as mouse hippocampal neuronal (HT22) cells with oxygen and glucose deprivation/reoxygenation (OGD/R) injury model. The results demonstrated that vitexin improved cognitive dysfunction as well as alleviated pathological neuronal damage in hematoxylin plus eosin (HE) and TUNEL results. The decreased levels of exchange protein directly activated by cAMP 1 (Epac1), Epac2, Ras-associated protein 1 (Rap1), and phospho-extracellular signal-regulated kinase (p-ERK) were reversed by vitexin in rats with CCH. Furthermore, this study indicated that vitexin alleviated CCH-induced inflammation injuries by reducing the expression of NOD-like receptor 3 (NLRP3), caspase-1, interleukin 1β (IL-1β), IL-6, and cleaved caspase-3. In vitro, vitexin increased the expression of Epac1 and Epac2, decreased the activation of the NLRP3-mediated inflammation, and improved cell viability. Taken together, our findings suggest that vitexin can reduce the degree of the progressing pathological damage in the cortex and hippocampus and inhibit further deterioration of cognitive function in rats with CCH. Epac and NLRP3 can be regulated by vitexin in vivo and in vitro, which provides enlightenment for the protection of CCH injury.

Background: The current study was conducted to explore the effects of chemerin and homocysteine (Hcy) levels and their associations with the occurrence and development of ischemic cerebrovascular disease (ICVD)., Methods: There involved a total of 187 patients with ICVD and 190 healthy people for physical examination in Cangzhou Central hospital from January 2020 to April 2021. The participants enrolled were divided into four groups based on the digital subtraction angiography: mild stenosis group (64 cases, stenosis rate 30-49 %), moderate stenosis group (72 cases, stenosis rate 50-69 %), severe stenosis group (51 cases, stenosis rate 70-99 %) and control group (190 cases, in healthy condition). The laboratory indexes of ICVD group and control group were observed and the four groups were further compared. Pearson linear correlation was applied to analyze the link between chemerin and Hcy levels and the degree of cerebral vascular stenosis in ICVD patients, and multivariate logistic regression was used to analyze the influencing factors of ICVD., Results: No significant difference was found in general information including age, gender, body mass index (BMI), heart rate, systolic blood pressure, diastolic blood pressure, smoking and drinking between the two groups (P > 0.05). Moreover, there was no significant difference in fasting blood glucose (FBG), total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels between the two groups (P > 0.05). However, the levels of triglyceride (TG), low density lipoprotein cholesterol (LDL-C), chemerin and Hcy in ICVD group were significantly higher than those in control group (P < 0.05). When comparing the four groups, there was no significant difference in FBG and TC levels (P > 0.05). The levels of TG, LDL-C, chemerin and Hcy in mild, moderate and severe stenosis groups were higher than those in control group, the above levels in moderate and severe stenosis group were higher than those in mild stenosis group, and severe stenosis group higher than moderate stenosis group (P < 0.05). Chemerin and Hcy levels were positively correlated with the degree of cerebral vascular stenosis in ICVD patients (r = 0.612, 0.519, P < 0.001). ICVD was regarded as the dependent variable, and the abovementioned general data as well as significant laboratory indicators, including TG, LDL-C, chemerin and Hcy, as independent variables. The results of multivariate logistic regression analysis revealed that TG, LDL-C, chemerin and Hcy were independent influencing factors of ICVD., Conclusions: Chemerin and Hcy levels exerted a close link to the occurrence and development of ICVD as independent influencing factors., (© 2021. The Author(s).)

Background and Objective: To investigate the association of silent vascular lesions, imaging negative ischemia, and symptomatic cerebrovascular disease with long-term progression of brain atrophy and cerebrovascular lesions in patients with arterial disease., Methods: Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, stroke status of participants at baseline was classified as no cerebrovascular disease (reference group, n = 829), symptomatic cerebrovascular disease (n = 206), silent vascular lesion (n = 157), and imaging-negative ischemia (n = 90) according to clinical and MRI findings. With the use of linear mixed models, changes in brain and white matter hyperintensity (WMH) volumes at baseline and during 12 years of follow-up were studied in stroke classifications. Relative risks were estimated for new infarcts during follow-up associated with stroke classifications. Analyses were adjusted for age, sex, cardiovascular risk factors, and medications., Results: Symptomatic cerebrovascular disease associated with 0.35 SD (95% confidence interval [CI] 0.24-0.47) smaller brain volume and 0.61 SD (95% CI 0.48-0.74) larger WMH volume at baseline and increased risk for new infarcts during follow-up (risk ratio [RR] 2.89, 95% CI 2.00-4.16). Silent vascular lesions were associated with 0.15 SD (95% CI 0.01-0.88) smaller brain volume, 0.02 SD (95% CI 0.01-0.03) steeper brain atrophy slope, and 0.48 SD (95% CI 0.32-0.64) larger WMH volume at baseline, in addition to increased risk for lacunes (RR 2.08, 95% CI 1.48-2.94). Individuals with imaging-negative ischemia had increased risk for cortical infarcts (RR 2.88, 95% CI 2.17-3.82)., Discussion: Patients with symptomatic cerebrovascular disease, silent vascular lesions, or imaging-negative ischemia have a different course of brain volume loss and cerebrovascular lesion development. These findings may have implications for future stroke risk and dementia and need further investigation., (© 2021 American Academy of Neurology.)

Rationale: In intracranial arterial dolichoectasia (IADE) development, the feedback loop between inflammatory cytokines and macrophages involves TNF-α and NF-κB signaling pathways and leads to subsequent MMP-9 activation and extracellular matrix (ECM) degeneration. In this proof-of-concept study, melittin-loaded L-arginine-coated iron oxide nanoparticle (MeLioN) was proposed as the protective measure of IADE formation for this macrophage-mediated inflammation and ECM degeneration. Methods: IADE was created in 8-week-old C57BL/6J male mice by inducing hypertension and elastase injection into a basal cistern. Melittin was loaded on the surface of ION as a core-shell structure (hydrodynamic size, 202.4 nm; polydispersity index, 0.158). Treatment of MeLioN (2.5 mg/kg, five doses) started after the IADE induction, and the brain was harvested in the third week. In the healthy control, disease control, and MeLioN-treated group, the morphologic changes of the cerebral arterial wall were measured by diameter, thickness, and ECM composition. The expression level of MMP-9, CD68, MCP-1, TNF-α, and NF-κB was assessed from immunohistochemistry, polymerase chain reaction, and Western blot assay. Results: MeLioN prevented morphologic changes of cerebral arterial wall related to IADE formation by restoring ECM alterations and suppressing MMP-9 expression. MeLioN inhibited MCP-1 expression and reduced CD68-positive macrophage recruitments into cerebral arterial walls. MeLioN blocked TNF-α activation and NF-κB signaling pathway. In the Sylvian cistern, co-localization was found between the CD68-positive macrophage infiltrations and the MeLioN distributions detected on Prussian Blue and T2* gradient-echo MRI, suggesting the role of macrophage harboring MeLioN. Conclusions: The macrophage infiltration into the arterial wall plays a critical role in the MMP-9 secretion. MeLioN, designed for ION-mediated melittin delivery, effectively prevents IADE formation by suppressing macrophage-mediated inflammations and MMP activity. MeLioN can be a promising strategy preventing IADE development in high-risk populations., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Alzheimer's disease (AD), as the most common neurodegenerative disease in elder population, is pathologically characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration. However, both Aβ and tau fails to cover the whole pathological process of AD, and most of the Aβ- or tau-based therapeutic strategies are all failed. Increasing lines of evidence from both clinical and preclinical studies have indicated that age-related cerebrovascular dysfunctions, including the changes in cerebrovascular microstructure, blood-brain barrier integrity, cerebrovascular reactivity and cerebral blood flow, accompany or even precede the development of AD-like pathologies. These findings may raise the possibility that cerebrovascular changes are likely pathogenic contributors to the onset and progression of AD. In this review, we provide an appraisal of the cerebrovascular alterations in AD and the relationship to cognitive impairment and AD pathologies. Moreover, the adrenergic mechanisms leading to cerebrovascular and AD pathologies were further discussed. The contributions of early cerebrovascular factors, especially through adrenergic mechanisms, should be considered and treasured in the diagnostic, preventative, and therapeutic approaches to address AD.

Background: Inflammation plays a pivotal role in acute ischemic stroke, and various inflammatory markers are known to predict prognosis of acute ischemic stroke. This study aimed to evaluate the prognostic value of systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII) after mechanical thrombectomy (MT) for acute ischemic stroke caused by large artery occlusion., Methods: The study enrolled 440 patients who underwent MT for large artery occlusion. SIRI and SII were calculated using laboratory data on admission. Prognosis was estimated with modified Rankin Scale at 3 months, and favorable clinical outcome was defined by a modified Rankin Scale score of 0-2. Receiver operating characteristic analysis was used to calculate the optimal cutoff values of SIRI and SII for predicting clinical outcome. Multivariate analysis was used to assess the relationship of SIRI and SII with clinical outcome., Results: In receiver operating characteristic analysis, the optimal cutoff values for SIRI and SII were 2.9 and 853, respectively (area under the curve 0.799, 95% confidence interval [CI] 0.756-0.843, P < 0.001 and area under the curve 0.679, 95% CI 0.643-0.745, P < 0.001, respectively). Multivariate analysis revealed that SIRI <2.9 (odds ratio 2.27, 95% CI 1.29-5.17, P = 0.019) and SII <853 (OR 1.82, 95% CI 1.16-3.10, P = 0.031) were independent predictors of favorable clinical outcome after MT., Conclusions: Decreased SIRI and SII were associated with favorable clinical outcome after MT. SIRI and SII represent potential prognostic factors in patients undergoing MT for large artery occlusion., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Obesity is frequently associated with cerebrovascular dysfunction; however, the underlying mechanism remains less well understood. In this study, by using pharmacological approaches, we show that neuroinflammation involving microglia plays an important role in obesity-related cerebrovascular dysfunction. PLX3397 treatment, which leads to depletion of microglia, reduced the wall thickness and collagen deposition in the basilar artery of diet-induced obesity (DIO) mice. Besides, the phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 was enhanced, suggesting improved endothelial function of the basilar artery. The wire myography data show that acetylcholine-elicited relaxation of basilar artery isolated from DIO mice was improved after the treatment with PLX3397. Moreover, our data demonstrate that brain administration of IL-18 impaired cerebrovascular function in mice with normal body weight. Together, these data suggest that neuroinflammation involving microglia is important in obesity-related vascular dysfunction in the brain. NEW & NOTEWORTHY We reported that microglia, the resident immune cells in the brain, contribute to obesity-related cerebrovascular dysfunction in mice. Moreover, we showed that excessive IL-18 can lead to vascular dysfunction in mouse brain.

Studying the neuropathologic autopsy findings in subjects with chronic kidney disease (CKD) or chronic renal failure (CRF) is difficult for several reasons: etiology of the CKD may be heterogeneous, affected patients may have one or more major co-morbidities that themselves can cause significant neurologic disease, and agonal events may result in significant findings that were of minimal significance earlier in a patient's life. We studied the constellation of neuropathologic abnormalities in 40 autopsy brains originating from subjects of ages 34-95 years (no children in the study). The most common pathologic change was that of ischemic infarcts (cystic, lacunar and/or microinfarcts), which were seen in over half of subjects. These were associated with both large artery atherosclerosis and arteriolosclerosis (A/S), the latter finding being present in 29/40 subjects. Charcot-Bouchard microaneurysms were present in the brains of three subjects, in one case associated with severe amyloid angiopathy. Microvascular calcinosis (medial sclerosis in the case of arterioles) was seen in the basal ganglia (n=8) and/or endplate region of the hippocampus (n=7) and occasional ischemic infarcts in one brain showed severe calcification. Sequelae of cerebrovascular disease (especially A/S or microvascular disease) are a common neuropathologic substrate for neurologic disability and brain lesions in this complex group of patients. Regulation of calcium metabolism within brain microvessel walls may be worthy of further research in both human brain specimens and animal models., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The evidence shows that individuals with type-1 diabetes mellitus (T1DM) are at greater risk of accelerated cognitive impairment and dementia. Although, to date the mechanisms are largely unknown. An emerging body of literature indicates that dysfunction of cerebral neurovascular network and plasma dyshomeostasis of soluble amyloid-β in association with impaired lipid metabolism are central to the onset and progression of cognitive deficits and dementia. However, the latter has not been extensively considered in T1DM. Therefore, in this review, we summarised the literature concerning altered lipid metabolism and cerebrovascular function in T1DM as an implication for potential pathways leading to cognitive decline and dementia., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Epigenetic clocks are calculated by combining DNA methylation states across select CpG sites to estimate biologic age, and have been noted as the most successful markers of biologic aging to date. Yet, limited research has considered epigenetic clocks calculated in brain tissue. We used DNA methylation states in dorsolateral prefrontal cortex specimens from 721 older participants of the Religious Orders Study and Rush Memory and Aging Project, to calculate DNA methylation age using four established epigenetic clocks: Hannum, Horvath, PhenoAge, GrimAge, and a new Cortical clock. The four established clocks were trained in blood samples (Hannum, PhenoAge, GrimAge) or using 51 human tissue and cell types (Horvath); the recent Cortical clock is the first trained in postmortem cortical tissue. Participants were recruited beginning in 1994 (Religious Orders Study) and 1997 (Memory and Aging Project), and followed annually with questionnaires and clinical evaluations; brain specimens were obtained for 80-90% of participants. Mean age at death was 88.0 (SD 6.7) years. We used linear regression, logistic regression, and linear mixed models, to examine relations of epigenetic clock ages to neuropathologic and clinical aging phenotypes, controlling for chronologic age, sex, education, and depressive symptomatology. Hannum, Horvath, PhenoAge and Cortical clock ages were related to pathologic diagnosis of Alzheimer's disease (AD), as well as to Aβ load (a hallmark pathology of Alzheimer's disease). However, associations were substantially stronger for the Cortical than other clocks; for example, each standard deviation (SD) increase in Hannum, Horvath, and PhenoAge clock age was related to approximately 30% greater likelihood of pathologic AD (all p < 0.05), while each SD increase in Cortical age was related to 90% greater likelihood of pathologic AD (odds ratio = 1.91, 95% confidence interval 1.38, 2.62). Moreover, Cortical age was significantly related to other AD pathology (eg, mean tau tangle density, p = 0.003), and to odds of neocortical Lewy body pathology (for each SD increase in Cortical age, odds ratio = 2.00, 95% confidence 1.27, 3.17), although no clocks were related to cerebrovascular neuropathology. Cortical age was the only epigenetic clock significantly associated with the clinical phenotypes examined, from dementia to cognitive decline (5 specific cognitive systems, and a global cognitive measure averaging 17 tasks) to Parkinsonian signs. Overall, our findings provide evidence of the critical necessity for bespoke clocks of brain aging for advancing research to understand, and eventually prevent, neurodegenerative diseases of aging., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Serum biomarkers are associated with hemorrhagic transformation and brain edema after cerebral infarction. However, whether serum biomarkers predict hemorrhagic transformation in large vessel occlusion stroke even after mechanical thrombectomy, which has become widely used, remains uncertain. In this prospective study, we enrolled patients with large vessel occlusion stroke in the anterior circulation. We analyzed 91 patients with serum samples obtained on admission. The levels of matrix metalloproteinase-9 (MMP-9), amyloid precursor protein (APP) 770, endothelin-1, S100B, and claudin-5 were measured. We examined the association between serum biomarkers and hemorrhagic transformation within one week. Fifty-four patients underwent mechanical thrombectomy, and 17 patients developed relevant hemorrhagic transformation (rHT, defined as hemorrhagic changes ≥ hemorrhagic infarction type 2). Neither MMP-9 (no rHT: 46 ± 48 vs. rHT: 15 ± 4 ng/mL, P = 0.30), APP770 (80 ± 31 vs. 85 ± 8 ng/mL, P = 0.53), endothelin-1 (7.0 ± 25.7 vs. 2.0 ± 2.1 pg/mL, P = 0.42), S100B (13 ± 42 vs. 12 ± 15 pg/mL, P = 0.97), nor claudin-5 (1.7 ± 2.3 vs. 1.9 ± 1.5 ng/mL, P = 0.68) levels on admission were associated with subsequent rHT. When limited to patients who underwent mechanical thrombectomy, the level of claudin-5 was higher in patients with rHT than in those without (1.2 ± 1.0 vs. 2.1 ± 1.7 ng/mL, P = 0.0181). APP770 levels were marginally higher in patients with a midline shift ≥ 5 mm than in those without (79 ± 29 vs. 97 ± 41 ng/mL, P = 0.084). The predictive role of serum biomarkers has to be reexamined in the mechanical thrombectomy era because some previously reported serum biomarkers may not predict hemorrhagic transformation, whereas the level of APP770 may be useful for predicting brain edema., Competing Interests: No authors have competing interests.

Ischemic episodes are a leading cause of death worldwide with limited therapeutic interventions. The current study explored mitochondrial phosphate-activated glutaminase (GLS1) activity modulation by PKCβII through GC-MS untargeted metabolomics approach. Mitochondria were used to elucidate the endogenous resistance of hippocampal CA2-4 and dentate gyrus (DG) to transient ischemia and reperfusion in a model of ischemic episode in gerbils. In the present investigation, male gerbils were subjected to bilateral carotids occlusion for 5 min followed by reperfusion (IR). Gerbils were randomly divided into three groups as vehicle-treated sham control, vehicle-treated IR and PKCβII specific inhibitor peptide βIIV5-3-treated IR. Vehicle or βIIV5-3 (3 mg/kg, i.v.) were administered at the moment of reperfusion. The gerbils hippocampal tissue were isolated at various time of reperfusion and cell lysates or mitochondria were isolated from CA1 and CA2-4,DG hippocampal regions. Recombinant proteins PKCβII and GLS1 were used in in vitro phosphorylation reaction and organotypic hippocampal cultures (OHC) transiently exposed to NMDA (25 μM) to evaluate the inhibition of GLS1 on neuronal viability. PKCβII co-precipitates with GAC (GLS1 isoform) in CA2-4,DG mitochondria and phosphorylates GLS1 in vitro. Cell death was dose dependently increased when GLS1 was inhibited by BPTA while inhibition of mitochondrial pyruvate carrier (MPC) attenuated cell death in NMDA-challenged OHC. Fumarate and malate were increased after IR 1h in CA2-4,DG and this was reversed by βIIV5-3 what correlated with GLS1 activity increases and earlier showed elevation of neuronal death (Krupska et al., 2017). The present study illustrates that CA2-4,DG resistance to ischemic episode at least partially rely on glutamine and glutamate utilization in mitochondria as a source of carbon to tricarboxylic acid cycle. This phenomenon depends on modulation of GLS1 activity by PKCβII and remodeling of MPC: all these do not occur in ischemia-vulnerable CA1.

NOD-like receptor protein 3 (NLRP3) inflammasome is tightly related to the pathogenesis of cerebral ischemia/reperfusion (I/R) injury, and oridonin (Ori) has shown the potential to alleviate ischemia/reperfusion injury with underlying mechanisms. Our study aims to figure out whether Ori protects against the cerebral ischemia/reperfusion injury by the NLRP3 inflammasome signaling. In this study, a temporary middle cerebral artery occlusion (MCAO) and reperfusion surgery was conducted on male C57BL/6 mice to mimic cerebral I/R injury in vivo. Cellular model of cerebral I/R in vitro was achieved by oxygen-glucose deprivation and reintroduction (OGD/R) in BV2 microglia cells. We found that Ori treatment significantly relieved the neurological deficits, neuronal injury and microglia activation in I/R mice according to morphological and histological analyses. Meanwhile, the inactivation of NLRP3 inflammasome was determined in Ori-treated mice with significantly down-regulated expressions of inflammasome-related genes. Western-blot analysis further demonstrated the negative effect of Ori on NF-κB signaling with diminished phosphorylation and degradation of IκBα as well as suppressed translocation of p65. Furthermore, we indicated that Ori suppressed the activation of NLRP3 inflammasome in OGD/R induced BV2 microglia cells by inhibiting NF-κB signaling. In summary, our findings make Ori a potential candidate for therapy of cerebral I/R injury in the future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To determine whether white matter network disruption mediates the association between MRI markers of cerebrovascular disease (CeVD) and cognitive impairment. Participants (n = 253, aged ≥60 years) from the Epidemiology of Dementia in Singapore study underwent neuropsychological assessments and MRI. CeVD markers were defined as lacunes, white matter hyperintensities (WMH), microbleeds, cortical microinfarcts, cortical infarcts and intracranial stenosis (ICS). White matter microstructure damage was measured as fractional anisotropy and mean diffusivity by tract based spatial statistics from diffusion tensor imaging. Cognitive function was summarized as domain-specific Z-scores.Lacunar counts, WMH volume and ICS were associated with worse performance in executive function, attention, language, verbal and visual memory. These three CeVD markers were also associated with white matter microstructural damage in the projection, commissural, association, and limbic fibers. Path analyses showed that lacunar counts, higher WMH volume and ICS were associated with executive and verbal memory impairment via white matter disruption in commissural fibers whereas impairment in the attention, visual memory and language were mediated through projection fibers.Our study shows that the abnormalities in white matter connectivity may underlie the relationship between CeVD and cognition. Further longitudinal studies are needed to understand the cause-effect relationship between CeVD, white matter damage and cognition.

At present, the prevention and control of cardiovascular diseases (CAVDs) has made initial advancements, although the prevention and control of cerebrovascular diseases (CEVDs) has not yet achieved the desired progress. In this paper, we review the prevention and control of CEVDs and CAVDs, and analyze the differences in prevention effects, and the pathological and physiological structures pertaining to CEVDs and CAVDs. Combined with the different effects of low-dose aspirin in the primary prevention of CEVDs and CAVDs by meta-analysis, aspirin plays a more important role in the primary prevention of CAVDs than CEVDs. We recognize the misunderstandings and blind spots concerning prevention and control of CEVDs, which can be summarized as follows: (1) CEVDs and CAVDs can be controlled by the same methods and drugs; (2) considering the same pathological factors for cardiovascular diseases; (3) a lack of understanding of the particularity of CEVDs; (4) a focus on platelets and neglect of cerebrovascular protection. In summary, our research clarifies the differences in the prevention measures and drugs used for CEVDs and CAVDs. Of particular concern is the serious lack of preventive drugs for CEVDs in clinical use. An ideal drug for the prevention of CEVDs should have protective effects on the blood, the vascular endothelium, the blood-brain barrier (BBB), and other related factors. Our review aims to highlight several issues in the current prevention of CEVDs and CAVDs, and to provide an optimized plan for preventive drug discovery., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Mild cognitive difficulties and progressive brain atrophy are observed in older people living with HIV (PLWH) despite persistent viral suppression. Whether cerebrovascular disease (CVD) risk factors and white matter hyperintensity (WMH) volume correspond to the observed progressive brain atrophy is not well understood., Methods: Longitudinal structural brain atrophy rates and WMH volume were examined among 57 HIV-infected participants and 40 demographically similar HIV-uninfected controls over an average (SD) of 3.4 (1.7) years. We investigated associations between CVD burden (presence of diabetes, hypertension, hyperlipidemia, obesity, smoking history, and atrial fibrillation) and WMH with atrophy over time., Results: The mean (SD) age was 64.8 (4.3) years for PLWH and 66.4 (3.2) years for controls. Participants and controls were similar in age and sex (P > 0.05). PLWH were persistently suppressed (VL <375 copies/mL with 93% <75 copies/mL). The total number of CVD risk factors did not associate with atrophy rates in any regions of interests examined; however, body mass index independently associated with progressive atrophy in the right precentral gyrus (β = -0.30; P = 0.023), parietal lobe (β = -0.28; P = 0.030), and frontal lobe atrophy (β = -0.27; P = 0.026) of the HIV-infected group. No associations were found in the HIV-uninfected group. In both groups, baseline WMH was associated with progressive atrophy rates bilaterally in the parietal gray in the HIV-infected group (β = -0.30; P = 0.034) and the HIV-uninfected participants (β = -0.37; P = 0.033)., Conclusions: Body mass index and WMH are associated with atrophy in selective brain regions. However, CVD burden seems to partially contribute to progressive brain atrophy in older individuals regardless of HIV status, with similar effect sizes. Thus, CVD alone is unlikely to explain accelerated atrophy rates observed in virally suppressed PLWH. In older individuals, addressing modifiable CVD risk factors remains important to optimize brain health., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Abdominal obesity and brachial-ankle pulse wave velocity (baPWV) are indicators of atherosclerosis. But few studies have shown the relationship between baPWV combined with waist-hip ratio (WHR) and cardiac-cerebrovascular events (CCVEs)., Methods: A total of 18944 subjects from Kailuan study were enrolled in this study. Follow-up was conducted three times over 4.82±1.92 years. All the participants were divided into 4 groups according to baPWV and WHR status on baseline: Q1 (normal baPWV, normal WHR), Q2 (normal baPWV, increased WHR), Q3 (increased baPWV, normal WHR) and Q4 (increased baPWV, increased WHR). The incidence and risk factors and further analysis of hypertension subgroups were analyzed., Results: During follow-up, 88 myocardial infarctions (MI), 278 cerebral ischemic strokes (CI), 285 strokes and 371 CCVEs occurred, with the cumulative incidence of 0.46%, 1.47%, 1.50%, and 1.96%, respectively. Multivariate Cox regression analysis revealed the risk of CI, stroke and CCVEs was higher in patients with increased baPWV and increased WHR than in the other three groups, followed by the Q3 group (increased baPWV, normal WHR) and Q2 group (normal baPWV, increased WHR) group (all adjusted P<0.01). Further hypertension subgroups analysis showed similar results, but differences were more significant among hypertensive patients. Accordingly, the combination of baPWV and WHR increased the risk of total CCVEs, especially in hypertensive patients., Conclusions: BaPWV and WHR were important risk factors for CCVEs and had synergistic effects. When baPWV increased, WHR may contribute more to the risk of CCVEs in hypertensive patients., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Cardiovascular diseases (CVDs) are the leading cause of death globally and the number of cardiovascular patients, which is estimated to be over 30 million in 2018, represent a challenging issue for the healthcare systems worldwide. Therefore, the identification of novel molecular targets to develop new treatments is an ongoing challenge for the scientific community. In this context, sphingolipids (SLs) have been progressively recognized as potent bioactive compounds that play crucial roles in the modulation of several key biological processes, such as proliferation, differentiation, and apoptosis. Furthermore, SLs involvement in cardiac physiology and pathophysiology attracted much attention, since these molecules could be crucial in the development of CVDs. Among SLs, ceramide and sphingosine-1-phosphate (S1P) represent the most studied bioactive lipid mediators, which are characterized by opposing activities in the regulation of the fate of cardiac cells. In particular, maintaining the balance of the so-called ceramide/S1P rheostat emerged as an important novel therapeutical target to counteract CVDs. Thus, this review aims at critically summarizing the current knowledge about the antithetic roles of ceramide and S1P in cardiomyocytes dysfunctions, highlighting how the modulation of their metabolism through specific molecules, such as myriocin and FTY720, could represent a novel and interesting therapeutic approach to improve the management of CVDs., (© 2021 Wiley Periodicals LLC.)

In vascular dementia (VaD) and Alzheimer's disease (AD), cerebral hypoperfusion and blood-brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin-associated glycoprotein to proteolipid protein-1 (MAG:PLP1), a post-mortem biochemical indicator of the adequacy of ante-mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood-brain barrier (BBB) leakiness; the level of vascular endothelial growth factor-A (VEGF), a marker of tissue hypoxia; and endothelin-1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age-matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aβ and phospho-tau parenchymal load, and Braak tangle stage. Aβ40 and Aβ42 were measured by ELISA in guanidine-HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aβ level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD-limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aβ-, tau- and endothelin-related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Objective: Three-dimensional (3D) printing techniques are rapidly advancing in the medical industry and in clinical practice. We aimed to evaluate the usefulness of 3D virtual and printed models of 6 representative cerebrovascular diseases using the software we developed., Methods: Six cases consisted of 4 intracranial aneurysms (IAs) including complex ones with intrasaccular thrombosis, large size and a skull base location; 1 cavernous malformation in the pons; and 1 arteriovenous malformation in the parietal lobe. The 3D modeling process was performed retrospectively in 3 cases and prospectively in 1 IA. Segmentation of raw data and rendering and modification for 3D virtual models were processed mostly automatically., Results: Most intracranial structures were satisfactorily made, including the skull, brain, vessels, thrombus, tentorium and major cranial nerves. Based on 3D modeling, surgical plan was changed in 1 prospective IA case. However, it was still difficult to discriminate small vessels and cranial nerves, to feel a realistic tactile sense and to directly perform presurgical simulations, such as dissection, removal, clipping and microanastomosis., Conclusions: The 3D modeling was thought to be very helpful in experiencing the operative views from various directions in advance, in selecting an appropriate surgical approach, and in educating physicians and patients. With advancements in radiological resolution, processing techniques and material properties, 3D modeling is expected to simulate real brain tissues more closely., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The aim of the study was the assessment of the neuroprotective potential of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline (DHQ) and its effect on inflammation, apoptosis, and transcriptional regulation of the antioxidant system in cerebral ischemia/reperfusion (CIR) in rats. The CIR rat model was constructed using the bilateral common carotid artery occlusion followed by reoxygenation. DHQ was administered at a dose of 50 mg/kg for three days. Histological staining was performed using hematoxylin and eosin. The level of S100B protein, 8-hydroxy-2-deoxyguanosine, and 8-isoprostane was assessed using an enzyme immunoassay. The intensity of apoptosis was assessed based on the activity of caspases and DNA fragmentation. The activity of enzymes was measured spectrophotometrically, the level of gene transcripts was assessed by real-time PCR. DHQ reduced the histopathological changes and normalized levels of S100B, lactate, pyruvate, and HIF-1 mRNA in the CIR rat model. In addition, DHQ decreased the oxidative stress markers in animals with a pathology. The tested compound also inhibited inflammation by decreasing the activity of myeloperoxidase, expression of interleukins and Nfkb2. DHQ-treated rats with CIR showed decreased caspase activity, DNA fragmentation, and AIF expression. DHQ changed activity of antioxidant enzymes to the control values, decreased the expression of Cat, Gsr, and Nfe2l2, which was overexpressed in CIR, and activated the expression of Sod1, Gpx1, Gsta2, and Foxo1. DHQ showed a neuroprotective effect on CIR in rats. The neuroprotective effect involve mechanisms such as the inhibition of oxidative stress, leading to a reduction in the inflammatory response and apoptosis and the modulation of the antioxidant defense components., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Eprosartan (EPRO), an angiotensin receptor type-1 (AT-1) blocker, exhibited neuroprotective activities in ischemic stroke resulting from focal cerebral ischemia in rats. The current study aimed to clarify the neuroprotective role of EPRO in middle carotid artery occlusion (MCAO)-induced ischemic stroke in rats. Fifty-six male Wistar rats were divided into four groups (n = 14 per group): sham-operated group, sham receiving EPRO (60 mg/kg/day, po) group, ischemia-reperfusion (IR) group, and IR receiving EPRO (60 mg/kg/day, po) group. MCAO led to a remarkable impairment in motor function together with stimulation of inflammatory and apoptotic pathways in the hippocampus of rats. After MCAO, the AT1 receptor in the brain was stimulated, resulting in activation of Janus kinase 2/signal transducers and activators of transcription 3 signaling generating more neuroinflammatory milieu and destructive actions on the hippocampus. Augmentation of caspase-3 level by MCAO enhanced neuronal apoptosis synchronized with neurodegenerative effects of oxidative stress biomarkers. Pretreatment with EPRO opposed motor impairment and decreased oxidative and apoptotic mediators in the hippocampus of rats. The anti-inflammatory activity of EPRO was revealed by downregulation of nuclear factor-kappa B and tumor necrosis factor-β levels and (C-X-C motif) ligand 1 messenger RNA (mRNA) expression. Moreover, the study confirmed the role of EPRO against a unique pathway of hypoxia-inducible factor-1α and its subsequent inflammatory mediators. Furthermore, upregulation of caveolin-1 mRNA level was also observed along with decreased oxidative stress marker levels and brain edema. Therefore, EPRO showed neuroprotective effects in MCAO-induced cerebral ischemia in rats via attenuation of oxidative, apoptotic, and inflammatory pathways., (© 2021 Wiley Periodicals LLC.)

Background: This study aimed to investigate the frequency and risk factors for cerebral artery stenosis and occlusion in patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome., Methods: We reviewed results of magnetic resonance angiography (MRA) or computed tomography angiography (CTA) in 61 patients with POEMS syndrome seen between 2010 and 2017. Stenosis or occlusion was assessed in the initial MRA/CTA. Multivariate analysis was used to identify risk factors for artery stenosis/occlusion. In an autopsy case, pathologic examination was conducted of the occluded middle cerebral arteries., Results: Stenosis (> 50 %) or occlusion of the major cerebral arteries was found in 29 (47.5 %) patients on the initial MRA/CTA. The internal carotid artery was involved most frequently (32.8 %), followed by the anterior (21.3 %) and middle (16.4 %) cerebral arteries. The basilar (1.3 %) and vertebral (3.6 %) arteries were rarely affected. Cerebral infarction developed in eight (13.1 %) patients. The serum vascular endothelial growth factor (VEGF) level was an independent predictor for stenosis/occlusion (odds ratio, 1.228; 95 % confidence interval, 1.042-1.447; P = 0.014). An autopsy study showed occluded middle cerebral arteries by fibrous and myxomatous thickening of intima with splitting of the internal elastic lamina. Follow-up MRA in 23 patients showed improved, worsened, and unchanged stenosis in 20.7 %, 8.7 %, and 69.6 %, respectively., Conclusions: Cerebral large-vessel stenosis or occlusion is frequently seen in approximately half of patients with POEMS syndrome. Vasculopathy was related to serum VEGF levels and thereby disease activity. Assessment of cerebral vessels is recommended in these patients to improve management.

Background: Cardiovascular deaths increased during the early phase of the COVID-19 pandemic in the United States. However, it is unclear whether diverse racial/ethnic populations have experienced a disproportionate rise in heart disease and cerebrovascular disease deaths., Methods: We used the National Center for Health Statistics to identify heart disease and cerebrovascular disease deaths for non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic individuals from March to August 2020 (pandemic period), as well as for the corresponding months in 2019 (historical control). We determined the age- and sex-standardized deaths per million by race/ethnicity for each year. We then fit a modified Poisson model with robust SEs to compare change in deaths by race/ethnicity for each condition in 2020 versus 2019., Results: There were a total of 339 076 heart disease and 76 767 cerebrovascular disease deaths from March through August 2020, compared with 321 218 and 72 190 deaths during the same months in 2019. Heart disease deaths increased during the pandemic in 2020, compared with the corresponding period in 2019, for non-Hispanic White (age-sex standardized deaths per million, 1234.2 versus 1208.7; risk ratio for death [RR], 1.02 [95% CI, 1.02-1.03]), non-Hispanic Black (1783.7 versus 1503.8; RR, 1.19 [95% CI, 1.17-1.20]), non-Hispanic Asian (685.7 versus 577.4; RR, 1.19 [95% CI, 1.15-1.22]), and Hispanic (968.5 versus 820.4; RR, 1.18 [95% CI, 1.16-1.20]) populations. Cerebrovascular disease deaths also increased for non-Hispanic White (268.7 versus 258.2; RR, 1.04 [95% CI, 1.03-1.05]), non-Hispanic Black (430.7 versus 379.7; RR, 1.13 [95% CI, 1.10-1.17]), non-Hispanic Asian (236.5 versus 207.4; RR, 1.15 [95% CI, 1.09-1.21]), and Hispanic (264.4 versus 235.9; RR, 1.12 [95% CI, 1.08-1.16]) populations. For both heart disease and cerebrovascular disease deaths, Black, Asian, and Hispanic populations experienced a larger relative increase in deaths than the non-Hispanic White population (interaction term, P <0.001)., Conclusions: During the COVID-19 pandemic in the United States, Black, Hispanic, and Asian populations experienced a disproportionate rise in deaths caused by heart disease and cerebrovascular disease, suggesting that these groups have been most impacted by the indirect effects of the pandemic. Public health and policy strategies are needed to mitigate the short- and long-term adverse effects of the pandemic on the cardiovascular health of diverse populations.

The intracranial segment of the vertebral artery (VA) is the unique part of the artery where the two VAs join to form a single vascular channel, viz. the basilar artery. In addition to this typical description, anatomical variations have been described; the presence of anatomical variation has been associated with some pathological processes, neurological complications, and the risk of vascular diseases in the posterior circulatory territory. We evaluated the typical anatomical features and variations of the VA4 component of the VA in a South African population to provide useful data on the prevalence of variation and morphometry of the distal VA. The study is an observational, retrospective chart review of 554 consecutive South African patients (Black, Indian, and Caucasian) who had been examined with multidetector computed tomography angiography (MDCTA) from January 2009 to September 2019. We observed various anatomical variations in the VA4 segment of the VA. We report the incidence of VA hypoplasia, hypoplastic terminal VA, and atresia. Fenestration and duplicate posterior inferior cerebellar artery (PICA) origin were also observed. The left intracranial VA was significantly larger than the right. Our study shows that anatomical variation of the intracranial VA is common in the population studied, with a total prevalence of 36.5%. Understanding the patterns of anatomical variations of the VAs will contribute significantly to the interpretation of ischemic areas and diagnosis of various diseases in the posterior circulatory territory.

Particulate matter (PM) has been proved to be a risk factor for the development of circulatory system diseases (CSDs) around the world. In this study, we collected daily air pollutants, emergency room (ER) visits for CSDs, and meteorological data from 2009 to 2012 in Beijing, China. After controlling for the long-term trend and eliminating the influence of confounding factors, the generalized additive model (GAM) was used to evaluate the short-term effects of PM 10 on CSDs and cause-specific diseases. The results showed that for every 10 μg/m 3 increase in PM 10 , the largest effect estimates in ER visits of total CSDs, arrhythmia, cerebrovascular diseases, high blood pressure, ischemic heart disease and other related diseases were 0.14% (95% CI: 0.06-0.23%), 0.37% (95% CI: - 0.23 to 0.97%), 0.20% (95% CI: 0.00-0.40%), 0.15% (95% CI: 0.02-0.27%), 0.18% (95% CI: 0.02-0.35%) and 0.35% (95% CI: - 0.04 to 0.79%), respectively. When NO 2 or SO 2 was added into the model, the effect estimates of PM 10 were mostly attenuated, while in those models with PM 2.5 added, the effect estimates of PM 10 were mostly increased. Stratified analysis indicated that PM 10 had a greater effect on males and the elderly.

Objective: Large systolic blood pressure (SBP) variability has been proposed as a novel risk factor for dementia above and beyond SBP levels, but the underlying neuropathology is largely unknown. We investigated the relationship among visit-to-visit SBP variability, cognitive deterioration, and underlying neuropathologic changes., Methods: We used longitudinal data (between 2005 and 2019) from the National Alzheimer's Coordinating Center. A total of 13,284 dementia-free participants ≥50 years of age were followed up over a median of 5.0 (interquartile range 3.1-7.6) years. Neuropathology data were available in 1,400 autopsied participants. Visit-to-visit SBP variability was quantified from repeated annual SBP measurements. Cognitive deterioration was defined as conversion from normal cognition to mild cognitive impairment (MCI) or dementia or from MCI to dementia., Results: Larger visit-to-visit SBP variability was associated with cognitive deterioration (adjusted odds ratio comparing extreme quintiles 2.64, 95% confidence interval 2.29-3.04, p < 0.001). It was also associated with a higher burden of vascular pathology (including microinfarcts, white matter lesions, atherosclerosis of the circle of Willis, and arteriolosclerosis) and with neurofibrillary tangle pathology assessed by Braak staging (all p < 0.05). The association with cognitive deterioration and vascular pathology appeared stronger among those with normal cognition vs those with MCI at baseline. These findings were observed after adjustment for age, sex, mean SBP, and other confounding variables. Similar results were observed for diastolic blood pressure variability., Conclusion: Larger visit-to-visit SBP variability was associated with cognitive deterioration. It was also associated with cerebrovascular pathology and neurofibrillary tangles. These results suggest the intertwined role of vascular and Alzheimer disease pathology in the etiology of dementia., (© 2021 American Academy of Neurology.)

In both humans and animal models, consumption of a high-saturated-fat diet has been linked to vascular dysfunction and cognitive impairments. Laboratory animals provide excellent models for more invasive high-fat-diet-related research. However, the physiological differences between humans and common animal models in terms of how they react metabolically to high-fat diets need to be considered. Here, we review the factors that may affect the translatability of mechanistic research in animal models, paying special attention to the effects of a high-fat diet on vascular outcomes. We draw attention to the dissociation between metabolic syndrome and dyslipidemia in rodents, unlike the state in humans, where the two commonly occur. We also discuss the differential vulnerability between species to the metabolic and vascular effects of macronutrients in the diet. Findings from animal studies are better interpreted as modeling specific aspects of dysfunction. We conclude that the differences between species provide an opportunity to explore why some species are protected from the detrimental aspects of high-fat-diet-induced dysfunction, and to translate these findings into benefits for human health.

Stroke is a common cause of death and disability. Allisartan isoproxil (ALL) is a new angiotensin II receptor blocker and a new antihypertensive drug discovered and developed in China. In the present study we investigated the therapeutic effects of ALL in stroke-prone renovascular hypertensive rats (RHR-SP) and the underlying mechanisms. The model rats were generated via two-kidney two-clip (2K2C) surgery, which led to 100% of hypertension, 100% of cerebrovascular damage as well as 100% of mortality 1 year after the surgery. Administration of ALL (30 mg · kg -1  · d -1 in diet, for 55 weeks) significantly decreased stroke-related death and prolonged lifespan in RHR-SP, but the survival ALL-treated RHR-SP remained of hypertension and cardiovascular hypertrophy compared with sham-operated normal controls. In addition to cardiac, and aortic protection, ALL treatment for 10 or 12 weeks significantly reduced cerebrovascular damage incidence and scoring, along with a steady reduction of blood pressure (BP) in RHR-SP. Meanwhile, it significantly decreased serum aldosterone and malondialdehyde levels and cerebral NAD(P)H oxidase expressions in RHR-SP. We conducted 24 h continuous BP recording in conscious freely moving RHR-SP, and found that a single intragastric administration of ALL produced a long hypotensive effect lasting for at least 12 h on systolic BP. Taken together, our results in RHR-SP demonstrate that ALL can be used for stroke prevention via BP reduction and organ protection, with the molecular mechanisms related to inhibition of angiotensin-aldosterone system and oxidative stress. This study also provides a valuable scoring for evaluation of cerebrovascular damage and drug efficacy.

Sestrin2 (SESN2) is a conserved stress-inducible protein (also known as hypoxia-inducible gene 95 (HI95)) that is induced under hypoxic conditions. SESN2 represses the production of reactive oxygen species (ROS) and provides cytoprotection against various noxious stimuli, including hypoxia, oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. In recent years, the determination of the regulation and signalling mechanisms of SESN2 has increased our understanding of its role in the hypoxic response. SESN2 has well-documented roles in hypoxia-related diseases, making it a potential target for diagnosis and treatment. This review discusses the regulatory mechanisms of SESN2 and highlights the significance of SESN2 as a biomarker and therapeutic target in hypoxia-related diseases, such as cancer, respiratory-related diseases, cardiovascular diseases and cerebrovascular diseases., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Previous studies have suggested that microRNA-186 (miR-186) can be induced under hypoxic conditions, and is associated with apoptosis. This study was undertaken to explore the exact role of this microRNA (miRNA) in the apoptotic death of neurons during cerebral ischemic/reperfusion (I/R) injury. To model cerebral ischemia/reperfusion (I/R) injuries, we utilized a transient middle cerebral artery occlusion approach in rats, as well as a model of oxygen-glucose deprivation/reoxygenation (OGD/R) in Neuro2a cells. We found that in both in vitro and in vivo models of cerebral I/R injuries, levels of miR-186 were markedly decreased. When we overexpressed miR-186, this was associated with a reduction in the apoptotic death of neuroblastoma cells in the OGD/R model system, whereas the opposite was true when this miRNA was instead inhibited. We further found miR-186 to directly target hypoxia-inducible factor 1α (HIF-1α) by interacting with the 3'-untranslated region of this mRNA. When we knocked down HIF-1α, this partially overcame the apoptotic death of cells in response to OGD/R injury and associated miR-186 downregulation. Our findings indicate that miR-186 is able to reduce ischemic injury to neurons at least in part through downregulating HIF-1α, suggesting that the miR-186/HIF-1α axis is a potential therapeutic target for the treatment of ischemic stroke., (© 2021 Wiley Periodicals LLC.)

Background and Purpose: Many neurological or psychiatric diseases affect the hippocampus during aging. The study of hippocampal regional vulnerability may provide important insights into the pathophysiological mechanisms underlying these processes; however, little is known about the specific impact of vascular brain damage on hippocampal subfields atrophy., Methods: To analyze the effect of vascular injuries independently of other pathological conditions, we studied a population-based cohort of nondemented older adults, after the exclusion of people who were diagnosed with neurodegenerative diseases during the 14-year clinical follow-up period. Using an automated segmentation pipeline, 1.5T-magnetic resonance imaging at inclusion and 4 years later were assessed to measure both white matter hyperintensities and hippocampal subfields volume. Annualized rates of white matter hyperintensity progression and annualized rates of hippocampal subfields atrophy were then estimated in each participant., Results: We included 249 participants in our analyses (58% women, mean age 71.8, median Mini-Mental State Evaluation 29). The volume of the subiculum at baseline was the only hippocampal subfield volume associated with total, deep/subcortical, and periventricular white matter hyperintensity volumes, independently of demographic variables and vascular risk factors (β=-0.17, P =0.011; β=-0.25, P =0.020 and β=-0.14, P =0.029, respectively). In longitudinal measures, the annualized rate of subiculum atrophy was significantly higher in people with the highest rate of deep/subcortical white matter hyperintensity progression, independently of confounding factors (β=-0.32, P =0.014)., Conclusions: These cross-sectional and longitudinal findings highlight the links between vascular brain injuries and a differential vulnerability of the subiculum within the hippocampal loop, unbiased of the effect of neurodegenerative diseases, and particularly when vascular injuries affect deep/subcortical structures.

To explore distribution and epidemic characteristics of CVD in followed-up HP patients. Using the Hypertension Follow-up Management System database in Jiading district in Shanghai. We designed a retrospective cohort study that included all followed-up hypertension patients between 2002 and 2020. The endpoint was the occurrence of CVD confirmed by the hospital; otherwise, the patients were tracked until September 30, 2020. Record information of every patient has been collected in the registration card and each followed-up record. Among 223,097 observational followed-up HP patients, the total number of person years of observation was 4,244,421.25 person-year, 11,143 patients had developed CVD from hypertension before the deadline, the total incidence density was 0.00263 per person-year (male 0.00292; female 0.00238) and the complication ratio of CVD in HP patients was 4.99% (male 5.25%; female 4.76%) during follow-up period. The proportion of ischemic cerebrovascular, hemorrhagic cerebrovascular and unclassified stroke was respectively 71.18%, 5.95% and 22.87% in hypertensive CVD. Complication ratio of CVD increased with age, the group under 30 was 0, and the group over 70 was the highest (6.90%). The complication ratio of grad I, grad II and grad III blood pressure were respectively 4.79%, 4.96% and 6.13%. The complication ratio was 4.92% in only high systolic blood pressure patients; 17.23% in only high diastolic blood pressure patients; 4.59% in high systolic and diastolic blood pressure patients. The peak of complication ratio of CVD was 9-10 years after the registered and followed-up. The proportion of CVD cases in HP patients from April to June was the largest in the four seasons; the proportion of patients from October to December was the minimum. HP patient was prone to falling cerebrovascular disease; the main type of disease was cerebral infarction. Complication ratio in male incidence was higher than that in female. The complication ratio of CVD increased with age, blood pressure and duration of HP patients. It had seasonal characteristics, which was relatively high from April to June within year.

Ethnopharmacological Relevance: Duoxuekang (DXK, ཁྲག་འཕེལ་བདེ་བྱེད།) is a clinical experience prescription of CuoRu-Cailang, a famous Tibetan medicine master, which has effective advantages in the treatment of hypobaric hypoxia (HH)-induced brain injury. However, its underlying mechanisms remain unclear., Aim of the Study: The present study was designed to investigate the effects of DXK on cerebrovascular function of HH-induced brain injury in mice., Materials and Methods: DSC-MR imaging was used to evaluate the effect of DXK on the brain blood perfusion of patients with hypoxic brain injury. HPLC analysis was used to detect the content of salidroside, gallic acid, tyrosol, corilagin, ellagic acid, isorhamnetin, quercetin and gingerol in DXK. The model of HH-induced brain injury in mice was established by an animal hypobaric and hypoxic chamber. The BABL/c mice were randomly divided into six groups: control group, model group, Hongjingtian oral liquid group (HOL, 3.3 ml/kg) and DXK groups (0.9, 1.8 and 3.6 g/kg). All mice (except the control group) were intragastrically administrated for a continuous 7 days and put into the animal hypobaric and hypoxic chamber after the last intragastric administration. Hematoxylin-eosin staining was employed to evaluate the pathological changes of brain tissue. Masson and Weigert stainings were used to detect the content of collagen fibers and elastic fibers of brain, respectively. Routine blood test and biochemical kits were used to analyze hematological parameters and oxidative stress indices. Immunofluorescence staining was applied to detect the protein levels of VEGF, CD31/vWF and α-SMA., Results: The results of DSC-MR imaging confirmed that DXK can increased CBV in the left temporal lobe while decreased MTT in the right frontal lobe, right temporal lobe and right occipital lobe of the brain. DXK contains salidroside, gallic acid, tyrosol, corilagin, ellagic acid, isorhamnetin, quercetin and gingerol. Compared with the model group, DXK can ameliorate the atrophy and deformation, and increase the number of pyramidal neurons in hippocampal CA3 area and cortical neurocytes. Masson and Weigert stainings results revealed that DXK can significantly increase the content of collagen fibers and elastic fibers in brain. Routine blood test results demonstrated that DXK can dramatically decrease the levels of WBC, MCH and MCHC, while increase RBC, HGB, HCT, MCV and PLT in the blood samples. Biochemical results revealed that DXK can markedly increase SOD, CAT and GSH activities, while decrease MDA activity. Immunofluorescence revealed that DXK can notably increase the protein levels of VEGF, CD31/vWF and α-SMA., Conclusions: In conclusion, this study proved that DXK can ameliorate HH-induced brain injury by improving brain blood perfusion, increasing the number of collagen and elastic fibers and inhibiting oxidative stress injury. The underlying mechanisms may be involved in maintaining the integrity of cerebrovascular endothelial cells and vascular function. However, further in vivo and in vitro investigations are still needed to elucidate the mechanisms of DXK on regulating cerebral blood vessels., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A carefully coordinated interplay between these cellular and non-cellular components is required to maintain normal neuronal function, and in line with these observations, a growing body of evidence has linked NVU dysfunction to neurodegeneration. Plasminogen activators catalyze the conversion of the zymogen plasminogen into the two-chain protease plasmin, which in turn triggers a plethora of physiological events including wound healing, angiogenesis, cell migration and inflammation. The last four decades of research have revealed that the two mammalian plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), are pivotal regulators of NVU function during physiological and pathological conditions. Here, we will review the most relevant data on their expression and function in the NVU and their role in neurovascular and neurodegenerative disorders.

Insulin is an important hormone for brain function, and alterations in insulin metabolism may be associated with neuropathology. We examined associations of molecular markers of brain insulin signaling with cerebrovascular disease. Participants were enrolled in the Religious Orders Study (ROS), an ongoing epidemiologic community-based, clinical-pathologic study of aging from across the United States. Using cross-sectional analyses, we studied a subset of ROS: 150 persons with or without diabetes, matched 1:1 by sex on age-at-death and education. We used ELISA, immunohistochemistry, and ex vivo stimulation with insulin, to document insulin signaling in postmortem midfrontal gyrus cortex tissue. Postmortem neuropathologic data identified cerebrovascular disease including brain infarcts, classified by number (as none for the reference; one; and more than one), size (gross and microscopic infarcts), and brain region/location (cortical and subcortical). Cerebral vessel pathologies were assessed, including severity of atherosclerosis, arteriolosclerosis, and amyloid angiopathy. In separate regression analyses, greater AKT1 phosphorylation at T 308 following ex vivo stimulation with insulin (OR = 1.916; estimate = 0.650; p = 0.007) and greater pS 616 IRS1 immunolabeling in neuronal cytoplasm (OR = 1.610; estimate = 0.476; p = 0.013), were each associated with a higher number of brain infarcts. Secondary analyses showed consistent results for gross infarcts and microinfarcts separately, but no other association including by infarct location (cortical or subcortical). AKT S 473 phosphorylation following insulin stimulation was associated with less amyloid angiopathy severity, but not with other vessel pathology including atherosclerosis and arteriolosclerosis. In summary, insulin resistance in the human brain, even among persons without diabetes, is associated with cerebrovascular disease and especially infarcts. The underlying pathophysiologic mechanisms need further elucidation. Because brain infarcts are known to be associated with lower cognitive function and dementia, these data are relevant to better understanding the link between brain metabolism and brain function.

Purpose: We investigated whether ADT use was associated with the risk of ischemic cardiovascular diseases (CVD) and cerebrovascular diseases (CrVD) in a nationwide population-based cohort., Methods: Claims data of the Health Insurance and Review Assessment system in South Korea were used. In total, 195,308 men with newly diagnosed prostate cancer between January 1, 2008 and December 31, 2017 were identified. After applying the exclusion criteria, 131,189 men were enrolled. The study cohort was divided into ADT and non-ADT groups. Study outcomes were newly developed CVD, cardiovascular intervention (CVI), and CrVD. To control for potential confounders, various cardiovascular risk factors were balanced between groups. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events., Results: Univariable analysis revealed that ADT was significantly associated with an increased risk of CVD and CrVD. Multivariable analysis did not reveal this association. In the propensity score matched cohort (n = 61,722), multivariable analysis demonstrated that ADT independently reduced the risk of CVD (HR 0.890; 95% CI 0.846-0.936; p < 0.0001), CVI (HR 0.873; 95% CI 0.770-0.991; p = 0.0352), and CrVD (HR 0.869; 95% CI 0.824-0.917; p < 0.0001). CVD risk was significantly decreased in patients using ADT for over 2 years. CVI and CrVD risks were significantly lower in men using ADT for over 3 years., Conclusion: This study demonstrated that ADT may reduce the risk of CVD, CVI, and CrVD, and ADT duration is associated with this risk reduction.

Vascular dementia is one of the most common forms of dementia in aging population. However, the molecular mechanisms involved in development of disease and the link between the cerebrovascular pathology and the cognitive impairments remain elusive. Currently, one common and/or converging neuropathological pathway leading to dementia is the mislocalization and altered functionality of the TDP-43. We recently demonstrated that brain ischemia triggers an age-dependent deregulation of TDP-43 that was associated with exacerbated neurodegeneration. Here, we report that chronic cerebral hypoperfusion in mice (CCH) produced by unilateral common carotid artery occlusion induces cytoplasmic mislocalization of TDP-43 and formation of insoluble phosho-TDP-43 aggregates reminiscent of pathological changes detected in cortical neurons of human brain samples from patients suffering from vascular dementia. Moreover, the CCH in mice caused chronic activation of microglia and innate immune response, development of cognitive deficits, and motor impairments. Oral administration of a novel analog (IMS-088) of withaferin A, an antagonist of nuclear factor-κB essential modulator (NEMO), led to mitigation of TDP-43 pathology, enhancement of autophagy, and amelioration of cognitive/motor deficits in CCH mice. Taken together, our results suggest that targeting TDP-43 pathogenic inclusions may have a disease-modifying effect in dementia caused by chronic brain hypoperfusion., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

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Background: Mixed-brain pathologies are the most common cause of progressive parkinsonism in older adults. We tested the hypothesis that the impact of individual pathologies associated with progressive parkinsonism differs among older adults., Methods: Data were from 1089 decedents who had undergone annual clinical testing and autopsy. Parkinsonism was based on a modified United Parkinson's Disease Rating Scale. Linear mixed-effects models were employed, to investigate the combinations of 9 pathologies related to progressive parkinsonism. Then we estimated the person-specific contributions of each pathology for progressive parkinsonism., Results: The average participant showed 3 pathologies. Parkinson's disease (PD) and 4 cerebrovascular pathologies (macroinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy [CAA]), but not Alzheimer's disease, TDP-43, hippocampal sclerosis, and microinfarcts, were independently associated with progressive parkinsonism. These pathologies accounted for 13% of additional variance of progressive parkinsonism. Thirty-one different combinations of these 5 pathologies were observed to be associated with progressive parkinsonism observed. On average, PD and CAA accounted, respectively, for 66% and 65% of person-specific progression of parkinsonism, while macroinfarcts, atherosclerosis, and arteriolosclerosis accounted for 41%-48%., Conclusion: There is much greater heterogeneity in the comorbidity and relative impact of individual brain pathologies affecting progressive parkinsonism than previously recognized and this may account in part for its phenotypic heterogeneity in older adults., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. We examined the relationship between HS, proteinopathies in frontotemporal cortices and hippocampus, Alzheimer disease, cerebrovascular changes, and age. We confirmed a strong association between HS and hippocampal TDP-43, whereas there was a weaker association between HS and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Nearly all of the FTLD-TDP cases had TDP-43 pathology in the hippocampus. HS was present in all FTLD-TDP type D cases, in 50% of the FTLD-TDP A cohort and in 6% of the FTLD-TDP B cohort. Our data also showed a significant association between HS and vascular changes. We reviewed the literature on HS and discuss possible pathophysiological mechanisms between TDP-43 pathology, cerebrovascular disease, and HS. Additionally, we introduced a quantitative neuronal cell count in CA1 to objectify the semiquantitative visual appreciation of HS., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Palmatine (PAL), a natural isoquinoline alkaloid, possesses extensive biological and pharmaceutical activities, including antioxidative stress, anti-inflammatory, antitumor, neuroprotective, and gastroprotective activities. However, it is unknown whether PAL has a protective effect against ischemic stroke and cerebral ischemia/reperfusion (I/R) injury. In the present study, a transient middle cerebral artery occlusion (MCAO) mouse model was used to mimic ischemic stroke and cerebral I/R injury in mice. Our study demonstrated that PAL treatment ameliorated cerebral I/R injury by decreasing infarct volume, neurological scores, and brain water content. PAL administration attenuated oxidative stress, the inflammatory response, and neuronal apoptosis in mice after cerebral I/R injury. In addition, PAL treatment also decreases hypoxia and reperfusion- (H/R-) induced neuronal injury by reducing oxidative stress, the inflammatory response, and neuronal apoptosis. Moreover, the neuroprotective effects of PAL were associated with the activation of the AMP-activated protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2) pathway, and Nrf2 knockdown offsets PAL-mediated antioxidative stress and anti-inflammatory effects. Therefore, our results suggest that PAL may be a novel treatment strategy for ischemic stroke and cerebral I/R injury., Competing Interests: No conflicts of interests are declared by the authors., (Copyright © 2021 Chaoliang Tang et al.)

Abstract: The persistent primitive olfactory artery is a very rare arterial variant with a little over a score of cases reported in literature so far. We present 3 cases illustrating this entity, which were incidentally diagnosed while imaging for other indications., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer's disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.

The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger a hyperinflammatory state characterized by elevated cytokine levels known as hypercytokinemia or cytokine storm, observed most often in severe patients. Though COVID-19 is known to be a primarily respiratory disease, neurological complications affecting both the central and peripheral nervous systems have also been reported. This review discusses potential routes of SARS-CoV-2 neuroinvasion and pathogenesis, summarizes reported neurological sequelae of COVID-19, and examines how aberrant cytokine levels may precipitate these complications. Clarification of the pathogenic mechanisms of SARS-CoV-2 is needed to encourage prompt diagnosis and optimized care. In particular, identifying the presence of cytokine storm in patients with neurological COVID-19 manifestations will facilitate avenues for treatment. Future investigations into aberrant cytokine levels in COVID-19 patients with neurological symptoms as well as the efficacy of cytokine storm-targeting treatments will be critical in elucidating the pathogenic mechanisms and effective treatments of COVID-19., (Copyright © 2020. Published by Elsevier Ltd.)