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   2015| January-June  | Volume 1 | Issue 1  
    Online since September 30, 2015

 
 
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REVIEW ARTICLES
Sirt1 in cerebral ischemia
Kevin B Koronowski, Miguel A Perez-Pinzon
January-June 2015, 1(1):69-78
DOI:10.4103/2394-8108.162532  
Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD +)-dependent deacylases has been shown to govern several processes within the central nervous system as well as to possess neuroprotective properties in a variety of pathological conditions such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease, among others. Recently, Sirt1 in particular has been identified as a mediator of cerebral ischemia, with potential as a possible therapeutic target. To gather studies relevant to this topic, we used PubMed and previous reviews to locate, select, and resynthesize the lines of evidence presented here. In this review, we will first describe some functions of Sirt1 in the brain, mainly neurodevelopment, learning and memory, and metabolic regulation. Second, we will discuss the experimental evidence that has implicated Sirt1 as a key protein in the regulation of cerebral ischemia as well as a potential target for the induction of ischemic tolerance.
  15,038 1,853 47
Hypothermia for treatment of stroke
Jong Youl Kim, Midori A Yenari
January-June 2015, 1(1):14-25
DOI:10.4103/2394-8108.164997  
Stroke is a major cause of neurological disability and death in industrialized nations. Therapeutic hypothermia has been shown to protect the brain from ischemia, stroke, and other acute neurological insults at the laboratory level. It has been shown to improve neurological outcome in certain clinical settings including anoxic brain injury due to cardiac arrest and hypoxic-ischemic neonatal encephalopathy. Hypothermia seems to affect multiple aspects of brain physiology and it is likely that multiple mechanisms underlie its protective effect. Understanding the events that occur in the ischemic brain during hypothermia might help lead to an understanding of how to protect the brain against acute injuries.
  10,179 934 24
Recent advances in magnetic resonance imaging for stroke diagnosis
Radhika Rastogi, Yuchuan Ding, Shuang Xia, Meiyun Wang, Yu Luo, Hyun Seok Choi, Zhaoyang Fan, Meng Li, Timothy D Kwiecien, Ewart Mark Haacke
January-June 2015, 1(1):26-37
DOI:10.4103/2394-8108.164996  
In stroke, diagnosis and identification of the infarct core and the penumbra is integral to therapeutic determination. With advances in magnetic resonance imaging (MRI) technology, stroke visualization has been radically altered. MRI allows for better visualization of factors such as cerebral microbleeds (CMBs), lesion and penumbra size and location, and thrombus identification; these factors help determine which treatments, ranging from tissue plasminogen activator (tPA), anti-platelet therapy, or even surgery, are appropriate. Current stroke diagnosis standards use several MRI modalities in conjunction, with T2- or T2*- weighted MRI to rule out intracerebral hemorrhage (ICH), magnetic resonance angiography (MRA) for thrombus identification, and the diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) mismatch for penumbral identification and therapeutic determination. However, to better clarify the neurological environment, susceptibility-weighted imaging (SWI) for assessing oxygen saturation and the presence of CMBs as well as additional modalities, such as amide proton transfer (APT) imaging for pH mapping, have emerged to offer more insight into anatomical and biological conditions during stroke. Further research has unveiled potential for alternative contrasts to gadolinium for PWI as well, as the contrast has contraindications for patients with renal disease. Superparamagnetic iron oxide nanoparticles (SPIONs) as an exogenous contrast and arterial spin labeling (ASL) as an endogenous contrast offer innovative alternatives. Thus, emerging MRI modalities are enhancing the diagnostic capabilities of MRI in stroke and provide more guidance for patient outcome by offering increased accessibility, accuracy, and information.
  9,558 1,001 10
Alcohol abuse and docosahexaenoic acid: Effects on cerebral circulation and neurosurvival
Michael A Collins
January-June 2015, 1(1):63-68
DOI:10.4103/2394-8108.162533  
Alcohol abuse and alcoholism are major and yet surprisingly unacknowledged worldwide causes of brain damage, cognitive impairment, and dementia. Chronic abuse of alcohol is likely to elicit significant changes in essential polyenoic fatty acids and the membrane phospholipids (PLs) that covalently contain them in brain membranes. Among the fatty acids of the omega-3 polyenoic class, docosahexaenoic acid (DHA), which is relatively concentrated in mammalian brain, has proven particularly important for proper brain development as well as neurosurvival and protection. DHA losses in brains of chronic alcohol-treated animals may contribute to alcohol's neuroinflammatory and neuropathological sequelae; indeed, DHA supplementation has beneficial effects, including the possibility that its documented augmenting effects on cerebral circulation could be important. The neurochemical mechanisms by which DHA exerts its effects encompass several signaling routes involving both the membrane PLs in which DHA is esterified as well as unique neuroactive metabolites of the free fatty acid itself. In view of indications that brain DHA deficits are a deleterious outcome of human alcoholism, increasing brain DHA via supplementation during detoxification of alcoholics could potentially fortify against dependence-related neuroinjury.
  7,241 446 6
The role of shear stress and arteriogenesis in maintaining vascular homeostasis and preventing cerebral atherosclerosis
David Della-Morte, Tatjana Rundek
January-June 2015, 1(1):53-62
DOI:10.4103/2394-8108.164993  
Shear stress (SS) is a biomechanical force that is determined by blood flow, vessel geometry, and fluid viscosity. Although a wide range of known vascular risk factors promote development of atherosclerosis, atherosclerotic changes occur predominately at specific sites within the arterial tree, suggesting a critical role for local factors within the vasculature. Atherosclerotic lesions develop predominantly at branches, bends, and bifurcations in the arterial tree because these sites are exposed to low or disturbed blood flow and low SS. Low SS predisposes arteries to atherosclerosis by causing endothelial dysfunction. A natural system of preexisting cerebral collateral arteries protects against ischemia by bypassing sites of arterial occlusion through a mechanism of arteriogenesis. The main trigger for arteriogenesis is impaired vascular homeostasis (VH) in response to local changes in SS induced by ischemia. VH is a critical process for maintaining the physiological function of cerebral circulation. It is regulated through a complex biological system of blood flow hemodynamic and physiological responses to flow changes. Restoration of VH by increasing arteriogenesis and SS may provide a novel therapeutic target for stroke, especially in the elderly, who are more prone to VH impairment. In this review article, we discuss the mechanisms and structures necessary to maintain VH in brain circulation, the role of SS, and risk factors leading to atherosclerosis, including the effects of aging. We also discuss arteriogenesis as an adaptive and protective process in response to ischemic injury, the imaging techniques currently available to evaluate arterogenesis such as magnetic resonance imaging/positron emission tomography (MRI/PET), and the potential therapeutic approaches against ischemic injury that target arteriogenesis.
  6,950 639 9
ORIGINAL ARTICLE
Improved dynamic CT angiography visualization by flow territory masking
Søren Christensen, Bruce Campbell, Maarten G Lansberg, Jacqui Hislop-Jambrich, Stephen Davis, Patricia Desmond, Mark Parsons
January-June 2015, 1(1):114-118
DOI:10.4103/2394-8108.164991  
Backgound and Purpose: Computerized tomography (CT) perfusion (or CTP) source images from CT scanners with small detector widths can be used to create a dynamic CT angiogram (CTA) similar to digital subtraction angiography (DSA). Because CTP studies use a single intravenous injection, all arterial territories enhance simultaneously, and individual arterial territories [i.e., anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA)] cannot be delineated. This limits the ability to assess collateral flow patterns on dynamic CTAs. The aim of this study was to devise and test a postprocessing method to selectively color-label the major arterial territories on dynamic CTA. Materials and Methods: We identified 22 acute-stroke patients who underwent CTP on a 320-slice CT scanner within 6 h from symptom onset. For each case, two investigators independently generated an arterial territory map from CTP bolus arrival maps using a semiautomated method. The volumes of the arterial territories were calculated for each map and the average relative difference between these volumes was calculated for each case as a measure of interrater agreement. Arterial territory maps were superimposed on the dynamic CTA to create a vessel-selective dynamic CTA with color-coding of the main arterial territories. Two experts rated the arterial territory maps and the color-coded CTAs for consistency with expected arterial territories on a 3-point scale (excellent, moderate, poor). Results: Arterial territory maps were generated for all 22 patients. The median difference in arterial territory volumes between investigators was 2.2% [interquartile range (IQR) 0.6-8.5%]. Based on expert review, the arterial territory maps and the vessel-selective dynamic CTAs showed excellent consistency with the expected arterial territories in 18 of 22 patients, moderate consistency in 2 patients, and poor consistency in another 2 patients. Conclusion: Using a novel postprocessing technique, arterial territory maps and dynamic CTAs with vessel-selective color-coding can be derived from a standard CTP scan. These maps may be used to noninvasively assess collateral flow in patients with acute stroke.
  5,962 459 4
REVIEW ARTICLES
A molecular/genetic approach to cerebral small-vessel disease: Beyond aging and hypertension
Sharyl R Martini, Stephen R Williams, Paolo Moretti, Daniel Woo, Bradford B Worrall
January-June 2015, 1(1):79-87
DOI:10.4103/2394-8108.166376  
Lacunar infarction, white matter hyperintensities (WMH), deep cerebral microbleeds (dCMB), and deep intracerebral hemorrhage (ICH) are increasingly recognized as manifestations of a common underlying vasculopathy, encompassed by the term "cerebral small-vessel disease" (CSVD). Epidemiologic studies have found robust associations of the individual aspects of CSVD with aging and hypertension; however, heritability estimates and the disproportionate burden of CSVD in underrepresented minorities suggest that genetic factors contribute substantially to CSVD risk. Here we present the rationale for studying these phenotypes as part of a spectrum of CSVD, review aspects of genetic study design, summarize current knowledge of genetic contribution to CSVD, and discuss the next steps required to translate these genetic discoveries into therapies for this devastating disease. Genetic studies were identified using PubMed. Regions achieving genome-wide significance in association studies, meta-analyses of candidate gene studies, and studies of genes associated with Mendelian conditions exhibiting CSVD phenotypes have been summarized.
  5,505 633 4
Intracranial atherosclerosis and inflammation: Lessons from the East and the West
Juan F Arenillas
January-June 2015, 1(1):47-52
DOI:10.4103/2394-8108.162531  
Intracranial atherosclerosis (ICAS) is a major cause of ischemic stroke worldwide. Patients affected by this disease have a high risk of suffering further ischemic strokes and other major vascular events despite the best medical therapy available. However, identification of factors that characterize a high-risk ICAS patient is a clinical problem that is yet to be solved. Inflammation is known to play a crucial role in all the stages of atherosclerosis affecting extracranial arterial beds but its role in ICAS is not firmly established. Circulating inflammatory biomarkers may represent a valuable tool to assess the importance of systemic and local (intraplaque) inflammation in ICAS pathogenesis. In this article, we have reviewed studies with inflammatory biomarkers performed in symptomatic and asymptomatic ICAS patients published in the recent literature. Their findings strongly support the hypothesis that inflammation determines the risk of progression and complication of symptomatic ICAS.
  5,184 451 9
Cerebrovascular ischemic protection by pre- and post-conditioning
Jeffrey M Gidday
January-June 2015, 1(1):97-103
DOI:10.4103/2394-8108.166379  
Stroke and cardiac arrest involve injury to all the brain's resident cells and their respective progenitors, including neurons, all glial subtypes, vascular smooth muscle, vascular endothelium, and pericytes, resulting either in the death of the individual or in a lesion that likely manifests as long-term impairments across a number of cognitive and functional domains. Thousands of studies in experimental animals and results from a few clinical trials in humans have demonstrated that the mechanisms responsible for ischemic brain injury can be blocked or slowed by survival-enhancing epigenetic responses induced by "conditioning" the brain with a stress stimulus paradigm before or even after ictus. The resultant reduction in lesion size and functional deficits are often termed endogenous "neuroprotection," but this in fact involves cytoprotective responses on the part of all the aforementioned resident brain cells and the circulating immune cells as well. The present review will summarize findings demonstrating conditioning-induced protection of the cerebral vasculature, that in turn manifests as reductions in vascularly targeted inflammatory responses; less endothelial injury and improvements in structural integrity of the circulation across all levels of organization; enhanced perfusion with less thrombosis; reductions in vascular dysregulation and reactivity impairments; and, over the longer term, more robust angiogenesis and vascular remodeling. Advancing the mechanistic basis for these innately vasculoprotective phenotypes may provide therapeutic targets for limiting cerebral circulatory injury and dysfunction following stroke and cardiac arrest.
  4,984 520 20
The collaterome: A novel conceptual framework of systems biology in cerebrovascular disorders
David S Liebeskind
January-June 2015, 1(1):3-8
DOI:10.4103/2394-8108.162411  
The collaterome is the elaborate neurovascular architecture within the brain that regulates and determines the compensatory ability, response, and outcome of cerebrovascular pathophysiology. Based on the fundamental aspects of the cerebral collateral circulation, this model provides a conceptual framework or novel approach to cerebrovascular disorders that endorses systems biology rather than traditional reductionism. The nature of this holistic approach mirrors the innate or endogenous compensatory ability of collaterals, extending this concept to reconsider current approaches to cerebrovascular disorders. The distinction of asymptomatic and symptomatic physiology, and normal brain health versus cerebrovascular disease and the management of cerebrovascular disorders from diagnosis to therapeutic strategies may be reconsidered from this conceptual framework that builds upon established knowledge in the stroke literature.
  4,964 506 11
Imaging markers of stroke risk in asymptomatic carotid artery stenosis
Shyam Prabhakaran
January-June 2015, 1(1):38-46
DOI:10.4103/2394-8108.166373  
Carotid stenosis is a major cause of ischemic stroke. While symptomatic carotid stenosis requires prompt revascularization, there is significant debate about the management of asymptomatic carotid stenosis (ACS), especially in light of recent advances in medical therapy. As a result, there is an even greater need for reliable predictors of stroke risk in asymptomatic patients. Besides clinical factors and stenosis grade, plaque morphology and cerebral hemodynamics may be suitable prognostic tools. High-risk features, using Doppler and magnetic resonance imaging (MRI) suggest that subpopulations at sufficiently high risk (10% annually) can be identified and in whom revascularization would be most beneficial. In this review, imaging tools to aid in stroke risk stratification in patients with ACS are discussed.
  4,871 535 4
EDITORIAL
Forward thinking in stroke treatment: Advances in cerebrovascular reperfusion and neurorehabilitation
Xunming Ji
January-June 2015, 1(1):1-2
DOI:10.4103/2394-8108.166347  
  4,498 809 18
REVIEW ARTICLES
Pharmacologic pre- and postconditioning for stroke: Basic mechanisms and translational opportunity
Elga Esposito, Rakhi Desai, Xunming Ji, Eng H Lo
January-June 2015, 1(1):104-113
DOI:10.4103/2394-8108.166380  
Beyond reperfusion therapies, there are still no widely effective therapies for ischemic stroke. Although much progress has been made to define the molecular pathways involved, targeted neuroprotective strategies have often failed in clinical trials. An emerging hypothesis suggests that focusing on single targets and mechanisms may not work since ischemic stroke triggers multiple pathways in multiple cell types. In this review, we briefly survey and assess the opportunities that may be afforded by pre- and postconditioning therapies, with particular attention to pharmacologic pre- and postconditioning. Pharmacologic conditioning may be defined as the use of chemical agents either before or shortly after stroke onset to trigger mechanisms of endogenous tolerance that are thought to involve evolutionarily conserved signals that offer broad protection against ischemia. Importantly, many of the pharmacologic agents may also have been previously used in humans, thus providing hope for translating basic mechanisms into clinical applications.
  4,338 514 7
Review of past and present research on experimental models of moyamoya disease
Shuji Hamauchi, Hideo Shichinohe, Kiyohiro Houkin
January-June 2015, 1(1):88-96
DOI:10.4103/2394-8108.166377  
Moyamoya disease (MMD) is characterized by a progressive steno-occlusive disease affecting the terminal portions of the cerebral internal carotid artery (ICA) and by formation of an abnormal vascular network at the base of the brain. Several pathogeneses, including inflammation, immune complex, upregulation of angiogenic factors, and abnormality of endothelial progenitor cells (EPCs) have been hypothesized. However, the mechanisms of MMD are largely unknown, and in vivo and in vitro models of MMD have not yet been established. Previously, inflammation- and immune-complex-related animal models have been reported but failed to reproduce severe stenotic lesions in the terminal portion of ICA. Thereafter, several clinical studies revealed that angiogenic activity of circulating EPCs was defective in MMD patients. These results suggested that the function and quantity of EPCs could be useful as a cellular model of MMD. Very recently, RING finger protein 213 (RNF213) was identified as an MMD susceptibility gene, a discovery that led to the efforts to generate gene mutation-based animal models. Although RNF213 knockout animal models have not yet successfully represented the phenotype of MMD, they have provided new insights into the role of RNF213 in remodeling after vascular injury and postischemic angiogenesis. Furthermore, the use of induced pluripotent stem cells (iPSCs) and an appropriate differentiation protocol have made it possible to obtain abundant quantities of MMD-specific vascular cells. In summary, studies have shown that endothelial cells derived from MMD-iPSCs have impaired angiogenic activity, which is a finding consistent with the results of EPC studies. Further studies are needed to create true MMD-specific experimental models to promote understanding of MMC pathogenesis and aid drug development.
  4,375 420 7
A review of current clinical studies leading to improved outcomes in patients treated with newer-generation thrombectomy devices
Yaser Carcora, Mohammed Hussain, Xiaokun Geng, Yuchuan Ding
January-June 2015, 1(1):9-13
DOI:10.4103/2394-8108.166352  
Treatment with endovascular treatment in conjunction with intra-venous Tissue Plasminogen Activator (IV tPA) under specific clinical situations leads to improved functional outcomes in patients. This review addresses the efficacy of endovascular stroke treatment in patients selected under ideal inclusion criteria and treated with the most up to date embolectomy devices. Recent trials such as ESCAPE, MR CLEAN, EXTEND IA and SWIFT PRIME showed that demonstration of proximal vessel occlusion in CT scans, stratification of penumbral patterns, along with expedient recanalization with the most up to date embolectomy devices leads to a statistically significant improvement in function, NIHSS scores, and mortality in patients treated with endovascular tPA. SWIFT PRIME, in particular, demonstrated that patients demonstrated a 4.5 point improvement in NIHSS scores 27 hours after treatment and decreased mortality along with an increased number of patients with a Rankin score of 1-2 90 days after therapy. Evidence shows that endovascular stroke treatment leads to improved outcomes in patients who are selected based on refined CT guided inclusion criteria and rapid revascularization by newer generation embolectomy devices in conjunct with IA tPA.
  3,922 339 2