Inflammation and the Link to Vascular Brain Health: Timing Is Brain.

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the COVID-19 pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke. Here, we aim to highlight recent basic science and clinical evidence for many distinct inflammatory cascades active in these varying states of cerebrovascular injury. The role of cerebrovascular infections, spotlighted by the severe acute respiratory syndrome coronavirus 2 pandemic, and its association with increased stroke risk is also reviewed. Rather than converging on a shared mechanism, these emerging studies implicate varied and distinct inflammatory processes in vascular brain injury and repair. Recognition of the phasic nature of inflammatory cascades on varying states of cerebrovascular disease is likely essential to the development and implementation of an anti-inflammatory strategy in the prevention, treatment, and repair of vascular brain injury. Although advances in revascularization have taught us that time is brain, targeting inflammation for the treatment of cerebrovascular disease will undoubtedly show us that timing is brain.

Risk Factors, Lifestyle Behaviors, and Vascular Brain Health.

Although a relationship between traditional cardiovascular risk factors and stroke has long been recognized, these risk factors likely play a role in other aspects of brain health. Clinical stroke is only the tip of the iceberg of vascular brain injury that includes covert infarcts, white matter hyperintensities, and microbleeds. Furthermore, an individual's risk for not only stroke but poor brain health includes not only these traditional vascular risk factors but also lifestyle and genetic factors. The purpose of this narrative review is to summarize the state of the evidence on traditional and nontraditional vascular risk factors and their contributions to brain health. Additionally, we will review important modifiers that interact with these risk factors to increase, or, in some cases, reduce risk of adverse brain health outcomes, with an emphasis on genes and biomarkers associated with Alzheimer disease. Finally, we will consider the importance of social determinants of health in brain health outcomes.

Vascular Contributions to Brain Health: Cross-Cutting Themes.

As life expectancy grows, brain health is increasingly seen as central to what we mean by successful aging-and vascular brain health as central to overall brain health. Cerebrovascular pathologies are highly prevalent independent contributors to age-related cognitive impairment and at least partly modifiable with available treatments. The current Focused Update addresses vascular brain health from multiple angles, ranging from pathophysiologic mechanisms and neuroimaging features to epidemiologic risk factors, social determinants, and candidate treatments. Here we highlight some of the shared themes that cut across these distinct perspectives: (1) the lifetime course of vascular brain injury pathogenesis and progression; (2) the scientific and ethical imperative to extend vascular brain health research in non-White and non-affluent populations; (3) the need for improved tools to study the cerebral small vessels themselves; (4) the potential role for brain recovery mechanisms in determining vascular brain health and resilience; and (5) the cross-pathway mechanisms by which vascular and neurodegenerative processes may interact. The diverse perspectives featured in this Focused Update offer a sense of the multidisciplinary approaches and collaborations that will be required to launch our populations towards improved brain health and successful aging.

Polysaccharide from Ganoderma lucidum alleviates cognitive impairment in a mouse model of chronic cerebral hypoperfusion by regulating CD4+CD25+Foxp3+ regulatory T cells.

Ganoderma lucidum (G. lucidum) is a kind of edible and medicinal mushroom. G. lucidum polysaccharide-1 (GLP-1) is one of the polysaccharides purified from crude GLP. Chronic cerebral hypoperfusion (CCH) as the common pathological basis of various forms of dementia is an important cause of cognitive impairment. In this study, a step-down test was used to evaluate the cognitive ability of CCH mice. Flow cytometry was used to detect the proportion of CD4+CD25+Foxp3+ regulatory T (Foxp3+Treg) cells. ELISA analysis and western blot analysis were used to detect the transforming growth factor-ß1 (TGF-ß1) and Interleukin-10 (IL-10) levels that Foxp3+Treg cells secreted. Metabolomic analysis based on gas chromatography-mass spectrometry (GC-MS) was used to evaluate the effect of GLP-1 on dysfunctional metabolism caused by inflammation. Results indicate that GLP-1 exhibited an alleviating cognitive impairment effect on CCH mice. The mechanism was related to GLP-1 by increasing Foxp3+Treg cell levels to increase levels of IL-10 and TGF-ß1 and regulate abnormal energy metabolism. These findings could provide preliminary results to exploit G. lucidum as a health care product or functional food for the adjuvant therapy of cognitive impairment of CCH.

Acute cerebral venous outflow obstruction during convexity meningioma resection.

BACKGROUND: Cerebral venous outflow obstruction involves idiopathic intracranial hypertension, and the most common related condition is dural venous sinus stenosis or, in other words, an obstruction of the dural venous sinuses. In these cases, the pathological process is often chronic, displays only mild symptoms, and rarely requires urgent surgical intervention. In this study, we present a unique case involving an acute cerebral venous outflow obstruction that occurred during meningioma resection that ultimately had catastrophic consequences. MATERIALS AND METHODS: The patient's preoperative imaging only revealed an unremarkable frontal convexity meningioma with an average diameter exceeding 8 cm. She was admitted for a scheduled right frontoparietal craniotomy for lesion resection. RESULTS: The patient's unique congenital dural venous sinus structure along with a non-surgical epidural hematoma both contributed to a catastrophic outcome, causing a progressive hemispheric encephalocele, significant blood loss, and wound closure difficulties. CONCLUSION: Neurosurgeons should place an additional focus on cerebral venous outflow patency during tumor resection, even if the tumor does not involve the transverse or sigmoid sinuses. It is well known that the tacking sutures play an essential role in preventing an epidural hematoma, but the procedure to mitigate hematomas occurring outside the surgical field of view is not fully recognized by neurosurgeons. If dural tacking sutures are placed after complete tumor resection, the prophylactic effect for preventing EDH in the non-surgical areas may not be guaranteed. Therefore, we strongly advocate for the tacking sutures to be accurately placed before dural incisions are made.

Relationship of Four Blood Pressure Indexes to Subclinical Cerebrovascular Diseases Assessed by Brain MRI in General Japanese Men.

AIM: The relationship of blood pressure (BP) indexes (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], mean arterial pressure [MAP]) to subclinical cerebrovascular diseases (SCVDs) remains unclear. This study aimed to elucidate the relationship of four BP indexes measured at two visits on SCVDs assessed by magnetic resonance imaging (MRI) in general Japanese men. METHODS: In general Japanese men aged 40-79 years (N=616), office BP indexes were measured at two visits (Visits 1 [2006-2008] and 2 [2010-2014]). MRI images obtained on the third visit (2012-2015) were examined for prevalent SCVDs: lacunar infarction, periventricular hyperintensity (PVH), deep subcortical white matter hyperintensity (DSWMH), microbleeds, and intracranial artery stenosis (ICAS). Using a multivariable logistic regression analysis, we computed and estimated the odds ratio of each prevalent SCVD for one standard deviation higher BP indexes. The same analyses were performed using home BP. RESULTS: All four office BP indexes at both visits associated with lacunar infarction. Visit 1 and 2 DBP and Visit 1 MAP associated with PVH and DSWMH, and Visit 1 SBP associated with DSWMH. All Visit 2 BP indexes appear to show stronger association with microbleeds than Visit 1 indexes, and Visit 1 and 2 SBP, PP, and MAP showed similar associations with ICAS. Additional analyses using home BP indexes revealed similar relationships; however, the significance of some relationships decreased. CONCLUSION: In general Japanese men, BP indexes were associated with most of SCVDs, and BP indexes measured at different periods associated with different SCVDs assessed by MRI.

Modifications in Near Infrared Spectroscopy for Cerebral Monitoring During Carotid Endarterectomy in Asymptomatic and Symptomatic Patients.

BACKGROUND: To evaluate trends and differences in Near Infrared Spectroscopy (NIRS) monitoring during carotid endarterectomy (CEA) in patients affected by asymptomatic and symptomatic carotid artery stenosis, to predict postoperative neurological complications (PNCs). METHODS: NIRS data of CEAs performed in a University Hospital were retrospectively reviewed. All the interventions were performed under general anesthesia and patients with intraoperative complications were excluded. Mean regional Oxygen Saturation Index (rSO2), pre-clamp values (mean baseline value, MBv and Single Mark Baseline value, SMBv) were collected and compared to the lowest rSO2 values during carotid cross-clamp (LSO2v) calculated within 3 min (percentage drop, PD). ROC curve analysis with Youden's Test was performed to determine the best threshold value of PD, in order to identify PNCs in both asymptomatic and symptomatic groups. RESULTS: Between 2007 and 2015, a total of 399 CEAs were consecutively performed with NIRS monitoring. Three-hundred-seventy-two CEAs in 355 patients were reviewed. Asymptomatic stenoses were 291 (81.9%), eleven (2.9%) PNC were registered (5 in asymptomatic and 6 in symptomatic group). Asymptomatic and symptomatic diseases had different MBv (69.5 ± 7.5 vs. 71.8 ± 6.9, respectively; P = 0.011) and similar rSO2 value during carotid clamping (63.7 ± 8.0 vs. 63.7 ± 6.7, respectively: P = 0.958). Asymptomatic patients experiencing PNCs had a greater PD than non-PNCs group (20.5 ± 10.2% vs. 12.5 ± 7.6%, respectively using MBv as baseline value; P = 0.002), in contrast, in symptomatic patients, in which a low PD was associated with PNCs, it does not reach statistical significance (using MBv, 12.6 ± 5.4% vs. 14.8 ± 6.7%, respectively; P= 0.476). In order to detect PNCs, ROC analysis revealed an optimal PD cut-off value of -17% in asymptomatic CEAs. (Sensibility (Se) 0.80, Specificity (Sp) 0.76, PPV 0.05, NPV 0.99, Youden's index 0.56; P = 0.020) In symptomatic a threshold value of -9% was found, without reaching statistical significance. CONCLUSIONS: NIRS as cerebral monitoring during CEA can predict PNCs in asymptomatic stenosis. Asymptomatic and symptomatic groups differ in baseline and intraprocedural cut-off values to detect an augmented PNCs risk.

Cerebrovascular alterations in NAFLD: Is it increasing our risk of Alzheimer's disease?

Non-alcoholic fatty liver disease (NAFLD) is a multisystem disease, which has been classified as an emerging epidemic not only confined to liver-related morbidity and mortality. It is also becoming apparent that NAFLD is associated with moderate cerebral dysfunction and cognitive decline. A possible link between NAFLD and Alzheimer's disease (AD) has only recently been proposed due to the multiple shared genes and pathological mechanisms contributing to the development of these conditions. Although AD is a progressive neurodegenerative disease, the exact pathophysiological mechanism remains ambiguous and similarly to NAFLD, currently available pharmacological therapies have mostly failed in clinical trials. In addition to the usual suspects (inflammation, oxidative stress, blood-brain barrier alterations and ageing) that could contribute to the NAFLD-induced development and progression of AD, changes in the vasculature, cerebral perfusion and waste clearance could be the missing link between these two diseases. Here, we review the most recent literature linking NAFLD and AD, focusing on cerebrovascular alterations and the brain's clearance system as risk factors involved in the development and progression of AD, with the aim of promoting further research using neuroimaging techniques and new mechanism-based therapeutic interventions.

The impact of chronic mild hypoxia on cerebrovascular remodelling; uncoupling of angiogenesis and vascular breakdown.

BACKGROUND: Chronic mild hypoxia (CMH, 8% O2) stimulates robust vascular remodelling in the brain, but it also triggers transient vascular disruption. This raises the fundamental question: is the vascular leak an unwanted side-effect of angiogenic remodelling or is it a pathological response, unrelated to endothelial proliferation, in which declining oxygen levels trigger endothelial dysfunction? METHODS: To answer this question, mice were exposed to CMH (8% O2) for periods up to 14 days, after which, brain tissue was examined by immunofluorescence (IF) to determine which type of blood vessel (arteriole, capillary or venule) was most commonly associated with endothelial proliferation and vascular leak and how this correlated with tight junction protein expression. Vascular perfusion was examined using DiI. Data were analysed using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison post-hoc test. RESULTS: The following was observed: (1) most endothelial proliferation and extravascular fibrinogen leak occurred in capillaries and to a lesser degree in venules, (2) much to our surprise, endothelial proliferation and extravascular fibrinogen leak never colocalized, (3) interestingly however, endothelial proliferation was strongly associated with an intravascular fibrinogen staining pattern not seen in stable blood vessels, (4) DiI perfusion studies revealed that angiogenic vessels were adequately perfused, suggesting that fibrinogen retention in angiogenic vessels is not due to temporary closure of the vessel, but more likely because fibrinogen is retained within the vessel wall, (5) bromodeoxyuridine (BrdU) labelling as a means to more permanently label proliferating endothelial cells, confirmed lack of any connection between endothelial proliferation and extravascular fibrinogen leak, while (6) in contrast, proliferating microglia were detected within extravascular leaks. CONCLUSIONS: Taken together, our findings support the concept that in the short-term, hypoxia-induced endothelial proliferation triggers transient fibrinogen deposition within the walls of angiogenic blood vessels, but no overt vascular leak occurs in these vessels. Importantly, endothelial proliferation and extravascular fibrinogen leaks never co-localize, demonstrating that extravascular leak is not an unwanted side-effect of angiogenic endothelial proliferation, but rather a dysfunctional vascular response to hypoxia that occurs in a distinct group of non-angiogenic blood vessels.

Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer's disease: an adrenergic approach.

Alzheimer's disease (AD), as the most common neurodegenerative disease in elder population, is pathologically characterized by ß-amyloid (Aß) plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration. However, both Aß and tau fails to cover the whole pathological process of AD, and most of the Aß- 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.

Research on Association between Levels of Serum Adiponectin, Hs-CRP, and sICAM-1 and Hypertensive Cerebrovascular Complications.

The study is aimed at studying the association between the levels of serum adiponectin (ADPN), high-sensitivity C-reactive protein (hs-CRP), and soluble intercellular adhesion molecule-1 (sICAM-1) and hypertensive cerebrovascular complications. 50 patients with hypertensive cerebrovascular disease treated in Gansu Provincial Hospital from December 2016 to December 2018 were selected as the experimental group, and 50 normal people who underwent physical examination were selected as the control group. The blood pressure, heart rate, and the complications were recorded, and the serum blood lipid indexes were detected. Moreover, the content of serum ADPN, hs-CRP, and sICAM-1; the neurological indexes; brain-derived neurotrophic factor (BNDF); and neurone-specific enolase (NSE) were also determined using ELISA. The content of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and serum creatinine (SCR) in the experimental group was significantly higher than that in control group (p < 0.05); the incidence of cerebrovascular complications, systolic blood pressure, diastolic blood pressure, and heart rate increased (p < 0.05); the content of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), hs-CRP, and sICAM-1 obviously rose (p < 0.05); and the content of ADPN and HDL obviously declined (p < 0.05). Besides, the experimental group had evidently lower systolic blood flow velocity (Vs), diastolic blood flow velocity (Vd), and mean blood flow velocity (Vm) and evidently higher pulsatility index (PI) (p < 0.05). The levels of S100 and NSE in the experimental group increased significantly, and the level of BNDF decreased significantly (p < 0.05). In patients with hypertensive cerebrovascular disease, the level of ADPN declines; the levels of hs-CRP and sICAM-1 rise; the incidence rate of cerebrovascular complications is elevated; and there are changes in the blood lipid, cerebrovascular hemodynamic, and neurological indexes, thereby further promoting the occurrence and development of hypertensive cerebrovascular disease.

Large Vessel Occlusion Prediction in the Emergency Department with National Institutes of Health Stroke Scale Components: A Machine Learning Approach.

OBJECTIVE: To determine the feasibility of using a machine learning algorithm to screen for large vessel occlusions (LVO) in the Emergency Department (ED). MATERIALS AND METHODS: A retrospective cohort of consecutive ED stroke alerts at a large comprehensive stroke center was analyzed. The primary outcome was diagnosis of LVO at discharge. Components of the National Institutes of Health Stroke Scale (NIHSS) were used in various clinical methods and machine learning algorithms to predict LVO, and the results were compared with the baseline method (aggregate NIHSS score with threshold of 6). The Area-Under-Curve (AUC) was used to measure the overall performance of the models. Bootstrapping (n = 1000) was applied for the statistical analysis. RESULTS: Of 1133 total patients, 67 were diagnosed with LVO. A Gaussian Process (GP) algorithm significantly outperformed other methods including the baseline methods. AUC score for the GP algorithm was 0.874 ± 0.025, compared with the simple aggregate NIHSS score, which had an AUC score of 0.819 ± 0.024. A dual-stage GP algorithm is proposed, which offers flexible threshold settings for different patient populations, and achieved an overall sensitivity of 0.903 and specificity of 0.626, in which sensitivity of 0.99 was achieved for high-risk patients (defined as initial NIHSS score > 6). CONCLUSION: Machine learning using a Gaussian Process algorithm outperformed a clinical cutoff using the aggregate NIHSS score for LVO diagnosis. Future studies would be beneficial in exploring prospective interventions developed using machine learning in screening for LVOs in the emergent setting.

Elevated complement mediator levels in endothelial-derived plasma exosomes implicate endothelial innate inflammation in diminished brain function of aging humans.

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70-82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling. EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components. These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

The association between carotid blood flow and resting-state brain activity in patients with cerebrovascular diseases.

Cerebral hypoperfusion impairs brain activity and leads to cognitive impairment. Left and right common carotid arteries (CCA) are the major source of cerebral blood supply. It remains unclear whether blood flow in both CCA contributes equally to brain activity. Here, CCA blood flow was evaluated using ultrasonography in 23 patients with cerebrovascular diseases. Resting-state brain activity and cognitive status were also assessed using magnetoencephalography and a cognitive subscale of the Functional Independence Measure, respectively, to explore the relationships between blood flow, functional brain activity, and cognitive status. Our findings indicated that there was an association between blood flow and resting-state brain activity, and between resting-state brain activity and cognitive status. However, blood flow was not significantly associated with cognitive status directly. Furthermore, blood velocity in the right CCA correlated with resting-state brain activity, but not with the resistance index. In contrast, the resistance index in the left CCA correlated with resting-state brain activity, but not with blood velocity. Our findings suggest that hypoperfusion is important in the right CCA, whereas cerebral microcirculation is important in the left CCA for brain activity. Hence, this asymmetry should be considered when designing appropriate therapeutic strategies.

Cardiovascular and Cerebrovascular Implications of Growth Restriction: Mechanisms and Potential Treatments.

Fetal growth restriction (FGR) is a common complication of pregnancy, resulting in a fetus that fails to reach its genetically determined growth potential. Whilst the fetal cardiovascular response to acute hypoxia is well established, the fetal defence to chronic hypoxia is not well understood due to experiment constraints. Growth restriction results primarily from reduced oxygen and nutrient supply to the developing fetus, resulting in chronic hypoxia. The fetus adapts to chronic hypoxia by redistributing cardiac output via brain sparing in an attempt to preserve function in the developing brain. This review highlights the impact of brain sparing on the developing fetal cardiovascular and cerebrovascular systems, as well as emerging long-term effects in offspring that were growth restricted at birth. Here, we explore the pathogenesis associated with brain sparing within the cerebrovascular system. An increased understanding of the mechanistic pathways will be critical to preventing neuropathological outcomes, including motor dysfunction such as cerebral palsy, or behaviour dysfunctions including autism and attention-deficit/hyperactivity disorder (ADHD).

Optical Coherence Tomography Angiography as a Noninvasive Assessment of Cerebral Microcirculatory Disorders Caused by Carotid Artery Stenosis.

PURPOSE: Using retinal optical coherence tomography angiography (OCTA), we aimed to investigate the changes in important indicators of cerebral microcirculatory disorders, such as the properties of the radial peripapillary capillaries, vascular complexes, and the retinal nerve fiber layer, caused by carotid stenosis and postoperative reperfusion. METHODS: In this prospective longitudinal cohort study, we recruited 40 carotid stenosis patients and 89 healthy volunteers in the First Affiliated Hospital of Harbin Medical University (Harbin, China). Eyes with ipsilateral carotid stenosis constituted the experimental group, while the fellow eyes constituted the contralateral eye group. Digital subtraction angiography, CT perfusion imaging (CTP), and OCTA examinations were performed in all subjects. The vessel density of the radial peripapillary capillaries (RPC), superficial retinal vascular complexes (SVC), deep vascular complexes (DVC), choriocapillaris (CC), and the thickness of the retinal nerve fiber layer (RNFL) were assessed. Propensity-matched analysis was undertaken to adjust for covariate imbalances. Intergroup comparative analysis was conducted, and the paired sample t-test was used to evaluate the preoperative and postoperative changes in OCTA variables. RESULTS: The ocular vessel density in the experimental group was significantly lower than that in the control group (RPC: 55.95 vs. 57.24, P = 0.0161; SVC: 48.65 vs. 52.22, P = 0.0006; DVC: 49.65 vs. 57.50, P < 0.0001). Participants with severe carotid stenosis have reduced contralateral ocular vessel density (RPC 54.30; SVC 48.50; DVC 50.80). Unilateral stenosis removal resulted in an increase in vessel density on both sides, which was detected by OCTA on the 4th day (RPC, P < 0.0001; SVC, P = 0.0104; DVC, P = 0.0104). Moreover, the ocular perfusion was consistent with that established by CTP. CONCLUSION: OCTA can be used for sensitive detection and accurate evaluation of decreased ocular perfusion caused by carotid stenosis and may thus have the potential for application in noninvasive detection of cerebral microcirculation disorders. This trial is registered with NCT04326842.