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   Table of Contents      
Year : 2018  |  Volume : 4  |  Issue : 4  |  Page : 145-152

Current progress in searching for clinically useful biomarkers of blood–brain barrier damage following cerebral ischemia

1 Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
2 Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
3 Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

Date of Submission20-Jul-2018
Date of Acceptance02-Oct-2018
Date of Web Publication31-Dec-2018

Correspondence Address:
Dr. Ke Jian Liu
Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, NM 87131, USA

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bc.bc_11_18

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Ischemic stroke is a leading cause of death and disability. Fear of intracranial hemorrhage (ICH) has been the primary reason for withholding tissue plasminogen activator (tPA) and thrombectomy, the only two widely accepted treatments for ischemic stroke. Thrombolysis treatment is only allowed in a very narrow time window (within 4.5–6 h). However, so far, other than the time window guideline, there is no reliable indicator available in the clinic to predict ICH before thrombolysis treatment. Recently, extensive research efforts have been devoted to the development of reliable indicators to predict ICH and safely guide the thrombolysis treatment. Accumulating evidence suggests that ischemic brain regions with a compromised blood–brain barrier (BBB) before tPA treatment develop ICH at the later time during thrombolytic reperfusion. Assessing BBB damage before thrombolysis could potentially help predict the risk of ICH after thrombolysis. This article reviews the literature reports on BBB damage biomarkers that have been developed in recent years, including biochemical markers such as BBB structural proteins, circulating brain microvascular endothelial cells, plasma albumin, and brain parenchyma proteins, as well as image markers such as magnetic resonance imaging assessment for BBB damage.

Keywords: Biomarkers, blood–brain barrier, cerebral ischemia, stroke

How to cite this article:
Li W, Pan R, Qi Z, Liu KJ. Current progress in searching for clinically useful biomarkers of blood–brain barrier damage following cerebral ischemia. Brain Circ 2018;4:145-52

How to cite this URL:
Li W, Pan R, Qi Z, Liu KJ. Current progress in searching for clinically useful biomarkers of blood–brain barrier damage following cerebral ischemia. Brain Circ [serial online] 2018 [cited 2023 Jun 4];4:145-52. Available from: http://www.braincirculation.org/text.asp?2018/4/4/145/249035

  Introduction Top

Stroke is one of the most common diseases causing death and disability. Ischemic stroke is the most common type of stroke, which approximately accounts for three-fourths of all strokes.[1] Fear of symptomatic intracranial hemorrhage (ICH) has been the primary reason for withholding tissue plasminogen activator and thrombectomy, the only two effective treatments for acute ischemic stroke. Currently, a fixed time window of within 4.5–6 h from stroke onset is used as the primary factor for ICH risk prediction in the thrombolytic therapy treatment guideline.[2],[3] Studies have demonstrated that ischemic brain regions with blood–brain barrier (BBB) breakdown during the early phase of stroke often develop ICH at later time points following thrombolytic reperfusion.[4],[5],[6] Therefore, an individualized measurable factor based on BBB damage is likely to be more accurate than using a fixed time window in predicting ICH risk. In this review, we focus on the potential clinically available indicators of BBB damage as biomarkers of ICH following thrombolytic reperfusion.

  Background Top

The function of blood–brain barrier

The central nervous system is formed by the neurons and glial cells in vertebrates. However, neurons are not renewable cells; therefore, it is essential to maintain homeostasis to protect neurons. BBB is a solute exchange barrier between the brain and blood to preserve this microenvironment, which was discovered and named by bacteriologist Ehrlich and Goldman in the late 19th century.[7] BBB is not only a mechanical barrier but also has essential physiological functions, including: (1) restricting free exchange of material between blood and the brain, (2) delivering the essential nutrients to the brain and excreting the metabolites from the brain into blood, (3) removing the toxic or unnecessary substances from brain to blood for protecting brain function, and (4) regulating hormonal functions. However, under the pathophysiological conditions, such as being affected by a tumor, inflammation, ischemia, or other factors, BBB is vulnerable to damage, causing increased permeability and losing “barrier” function.[8]

The structure of blood–brain barrier

The integrity of BBB is essential for maintaining its functions. Thus, a comprehensive understanding of the BBB structure is critical for studying the mechanism of BBB damage. Here, we briefly introduce the structure of BBB, which is composed of brain microvascular endothelium cells (BMECs), pericytes, and astrocyte foot processes around the capillaries and basement membrane.

Brain microvascular endothelium cells

BMECs are the first barrier that constitutes the BBB. The tight junctions between cells tightly bind the gap between endothelial cells like zippers, and there is no pore structure on the surface of the cell membrane on which some specific ions and transporters are expressed. Endothelial cells not only maintain the integrity of BBB but also act as a barrier to toxins and pathogens. Moreover, BMECs can regulate the microcirculation in the brain by producing and releasing a variety of vascular regulators such as endothelin, NO, and vascular endothelial growth factor (VEGF). Cerebral ischemia can cause BMECs swollen, apoptosis, further leading to BBB disruption. Besides, BMECs participate in the inflammatory cascades of cerebral ischemia to increase BBB damage.[9],[10],[11] The tight junctions connect the BMECs by binding one transmembrane protein, one cytoplasmic attachment protein, and one cytoskeletal protein. This structure is the foundation of the BBB. The transmembrane proteins include occludin, claudin, and junctional adhesive molecule. The cytoplasmic adhesion proteins include ZO-1, ZO-2, and ZO-3. Moreover, the cytoskeletal protein is actin.[12],[13] There are two pathways involved in the transtight junction flux. One is the pore pathway, which allows ions and small solutes pass through the tight junction. The other is the leak pathway, which is controlled by cytoskeletal dynamics or factors that affect cell homeostasis.[14],[15] Tight junction is an important factor in maintaining the integrity of the BBB. The structural changes in tight junctions lead to the BBB damage and increase vascular permeability, causing toxic substances flux into the brain and contributing to brain damage.[16] Numerous studies have shown that the expression of the structural components of the BBB, such as occludin, claudin-5, and ZO-1, decreases after cerebral ischemia.[17],[18],[19]


Pericytes, which are known as vascular smooth muscle cells, is an important cellular constituent of postcapillary venule and capillaries.[20] It is intimately connected to the endothelial cells by N-cadherin, gap junction, and tight junctions outside the blood vessels and shares the same basement membrane with endothelial cells.[21] The synthesis and release of albumin by pericytes have been considered as an important step in BBB differentiation.[22] Pericytes are involved in many crucial functions during a stroke, including the regulation of blood flow and BBB permeability as well as repair of the neurovascular unit.[23]


Astrocytes form the bridge that connects neuronal signaling and the vasculature in the central nervous system. Astrocytes are involved in the maintenance of BBB integrity mainly through the release of active substances, especially the growth factor, such as VEGF and glial cell line-derived neurotrophic factor. Moreover, the regulation of intracellular cAMP and other protein expressions by astrocytes also affects BBB integrity. In addition, there is a complicated relationship between astrocytes and brain capillaries, which plays a vital role in the maintenance of BBB function.[24],[25],[26]

Basement membrane

Basement membranes contain laminin, Type IV, collagen, and fibronectin. The extracellular matrix, as the main component of the basement membrane, is composed of macromolecules which are synthesized and secreted into extracellular space. Fibronectin binds the basement membrane to the surrounding tissues and the extracellular matrix, suggesting its role in maintaining BBB functions. The basement membrane can be degraded by matrix metalloproteinases (MMPs). Degradation of basement membrane components can increase the permeability of BBB, causing edema, hemorrhage, or even death.[8],[27]

The clinical significance of studying blood–brain barrier damages

The current research has shown that pathological BBB destruction is closely related to various diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, epilepsy, and dementia.[28] Here, we focus on the relationship between ischemic stroke and BBB injury. So far, thrombolysis and endovascular treatment are the only two FDA-approved effective therapies for the acute ischemic stroke. However, both of the procedures are associated with increased ICH.[29] Therefore, according to the American Heart Association/American Stroke Association guidelines, the patients can receive thrombolysis only within 4.5 h of stroke onset and/or receive endovascular treatment within 6 h of stroke onset.[30] The latest clinical research of DAWN (diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention) has shown that the patients, who have a 6–24 h stroke with a mismatch between clinical deficits and infarct, could benefit from the thrombectomy treatment.[31] Moreover, a DEFUSE3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke phase III) study has demonstrated that thrombectomy improves the outcome for the patient who has a 6–16 h ischemic stroke with a region of ischemic tissue but not yet infarcted.[32] Both of these latest studies have greatly extended the time window for treatment of recanalization for certain subgroups of stroke patients. It suggests that the “one-size-fits-all” time window may not be the best rule to select the candidates for recanalization treatment. Thus, it is urgent and critical to find reliable indicators to include currently “noneligible patients” for recanalization, allowing more stroke patients to benefit from the treatment.

The relationship between blood–brain barrier injury and cerebral ischemia-induced brain damage

Ischemic stroke causes endothelial cells damage, leading to the release of free radicals, cytokines, and other proteases. Then, the accumulation of free radicals and inflammatory reactions activates MMP, leading to tight junction proteins degradation and causing BBB disruption.[33],[34] Destruction of the BBB leads to the nonselective access of multiple inflammatory factors, proteases and various ions into the brain parenchyma, resulting in disruption of brain tissue environment and producing a series of secondary chemical reactions, such as energy failure, ion imbalance, acidosis, intracellular calcium overload, neuronal excitability, free radical-mediated lipid oxidation, inflammatory cell infiltration, and glial activation. These events eventually lead to brain edema, cerebral hemorrhage, and neuronal apoptosis and necrosis.[6],[33]

Biomarkers of blood–brain barrier damage

An ideal biomarker capable of responding to BBB injury should have the following characteristics: (1) high specificity, (2) high sensitivity, (3) high reliability, (4) easy and fast assessment, and (5) minimally invasive. So far, many biomarkers have been reported to indicate BBB damage; however, none of them meets all the characteristics for an ideal biomarker. Each of these reported biomarkers has its advantages and disadvantages. These biomarkers are summarized in [Table 1].
Table 1: Biomarkers of BBB damage following cerebral ischemia

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Blood–brain barrier structural proteins

BBB structural protein degradation is the first step of BBB destruction. Following BBB damage, the degraded proteins are released into blood circulation. Thus, measuring the BBB structural proteins in blood may reflect the extent of BBB damage.


Occludin is composed of 504 amino acids with a relative molecular weight of 64,000.[35] Occludin is an integral membrane protein localized at tight junction.[36] Clinical studies have shown that occludin levels in the serum of the patients with poststroke hemorrhage are significantly higher than those without hemorrhage, suggesting occludin has the potential to be used as a biomarker for predicting the risk of hemorrhage after cerebral ischemia.[36] Liu et al. have demonstrated that MMP-2 induces rapid degradation of occludin in the cerebral microvasculature during the early stage of ischemic stroke and causes the destruction of BBB in vitro and in vivo.[65] Our recent results, obtained in animal models and pilot clinical studies, show that cerebral ischemia/reperfusion-induced degradation of occludin in the microvascular endothelium causes increased BBB permeability. In blood samples of stroke animals, blood occludin level increases sharply at 4.5 h after ischemic stroke onset and remains at a highly elevation compared to their basal levels. These findings indicate that serum occludin may be a clinically feasible biomarker for assessing early BBB injury after ischemic stroke.[37],[38] Importantly, the blood occludin level reflects BBB damage with high specificity and sensitivity. Moreover, it is easy to access blood with low invasiveness. Although it is still in the experimental stage, it has significantly high potential to be used in clinical diagnosis in the future.

Cellular fibronectin

Cellular fibronectin (c-Fn) is a dimer composed of two 250-kDa subunits linked by two c-terminal disulfide bonds.[66] c-Fn is an essential component of the basement membrane, which is synthesized and secreted by endothelial cells. When the basement membrane is disrupted, c-Fn is released into the plasma, leading to the movement of polymorphonuclear leukocytes to the vascular injury site.[39] Since c-Fn is primarily localized in vascular endothelial cells, an elevation of this molecule in plasma may indicate endothelial damage. A clinical study has shown that plasma c-Fn level is elevated in patients with hemorrhagic transformation after acute ischemic stroke.[40] Additional evidence indicates that serum c-Fn level is highly associated with malignant middle cerebral artery infarction.[41] Therefore, high serum c-Fn may reflect the BBB injury and hemorrhagic transformation with high sensitivity. However, plasma levels of c-Fn are also increased in patients with secondary vascular lesions, such as vasculitis, sepsis, major acute trauma, diabetes, and ischemic stroke.[42],[43] Thus, c-Fn may not be a highly specific indicator of BBB damage.

Matrix metalloproteinases

MMPs are a family of endogenous proteolytic enzymes that degrade almost all extracellular matrixes. Currently, MMP-9 is considered to be closely related to BBB disruption. Using the specific inhibitor metallopeptidase inhibitor 1 to block MMP-9 in vivo, the researchers demonstrate that MMP-9 is responsible for the degradation of Type IV collagen, layer proteins, and fibrin, which are the major components of the basement membrane.[44],[45] Disruption of the basement membrane is the primary cause of cerebral edema and hemorrhagic transformation.[46] In addition, several studies have shown that MMP-9 causes degradation of tight junction proteins, such as occludin, claudin-1, and ZO-1.[67] Since the degradation of tight junction proteins leads to loss of BBB integrity,[19],[47] MMP-9 is closely related to the destruction of BBB. A recent clinical study has revealed that MMP-9 concentration is independently associated with BBB damage, indicating MMP-9 may be a potential biomarker for predicting the risk of ICH after thrombolysis.[48] However, the specificity is poor since MMP-9 is also increased in a variety of diseases, such as cancer, heart diseases, diabetes, epilepsy, and neurodegenerative diseases.[68],[69],[70],[71]

Circulating blood–brain microvascular endothelium cells

Brain microvascular endothelial cells (BMECs) are the major structural components of the BBB. BBB damage causes a dynamical exfoliation of BMEC. The exfoliated BMECs flux into the peripheral blood and become circulating blood BMECs (cBMECs).[49] Huang et al. have reported a correlation of BMECs and BBB disorders.[50] Therefore, measuring the amount of cBMECs in the blood may reflect the BBB damage level. However, the sensitivity of measuring cBMECs to assess BBB damage is relatively low, and the detection process is cumbersome. Thus, cBMECs is currently not a good candidate as a biomarker for BBB damage.

Other proteins in circulation

The highly selective semi-permeability of BBB separates proteins in the brain parenchyma from circulation. However, when BBB is disrupted, the brain parenchyma proteins can flux into blood circulation. Thus, the detection of specific brain parenchyma proteins in blood circulation should reflect BBB disruption.

S100 calcium-binding protein B (S100B)

S100 proteins are a family of acidic calcium-binding proteins. There are at least 21 different S100 proteins.[51] S100B is expressed primarily by mature astrocytes. In physiological conditions, S100B cannot across BBB. However, when BBB is extensively damaged, S100B can be released into the blood circulation through the compromised BBB. Clinical studies have found that S100B can be detected in the peripheral blood after BBB injury, and its concentration is related to the extent of BBB opening.[52],[53] Clinical and initial studies have demonstrated that blood S100B level is correlated with BBB damage level, suggesting that S100B may serve as a biomarker of BBB injury.[54] However, elevated S100B levels have been found not only when BBB permeability increases due to ischemic stroke but also when trauma occurs to the head.[55] Thus, S100B is not a specific biomarker for BBB damage after ischemic stroke.

Ubiquitin carboxyl-terminal hydrolase isozyme L1

Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1), also known as protein gene product 9.5 (PGP9.5) and PARK5, is discovered in 1987,[56] with a molecular weight proximately 24.8 kDa.[72] UCH-L1 is abundant in the brain parenchyma; approximately 2% of soluble proteins in the brain parenchyma are UCH-L1.[57] UCH-L1 is expressed in neurons and neuroendocrine cells in vertebrates and widely distributed in the nervous system.[58],[73],[74] UCH-L1 level increases in the cerebrospinal fluid (CSF) and blood circulation following traumatic brain injury and ischemic stroke. However, according to BJ Blyth's research,[75] serum UCH-L1 concentration is associated with abnormal BBB status 12 h after moderate-to-severe brain injury but not in mild brain injury. Based on these studies, both the specificity and sensitivity of UCH-L1 might be too low to be a reliable indicator of early BBB damage after ischemic stroke.

Plasma albumin

Albumins are commonly found in blood plasma, and the amount of albumin in CSF is negligible under the normal physiological conditions. However, after BBB disruption, albumin enters the CSF across the damaged BBB from blood plasma. Thus, the CSF/serum albumin ratio has been used as a reliable parameter for assessing the impairment of BBB,[59] including poststroke BBB injury.[60],[61] However, to acquire the CSF/serum albumin ratio, it requires obtaining both blood and CSF sample. The clinical acquisition of CSF through lumbar puncture is invasive. Thus, assessing CSF/serum albumin ratio to assess BBB damage hasn't been wildly used.

Brain imaging assessment

Besides molecular and cellular markers, imaging techniques are wildly used to assess BBB injury in the clinic. The most widely used brain imaging assessment is magnetic resonance imaging (MRI), especially T1-weighted dynamic contrast-enhanced MRI (DCE-MRI).[62] DCE-MRI is a sensitive and low invasive method to quantify the functional integrity of the BBB.[63] Hjort's study has shown that parenchymal enhancement (PE) is measurable by T1-weighted MRI as early as 2 h after thrombolytic therapy. All the patients, who have PE, showed ICH subsequently.[76] Warach et al. utilized DCE-MRI to observe a high-intensity acute reperfusion marker (HARM) and found that HARM was the most influential factors predicting early BBB injury.[64] However, MRI examination is expensive and time-consuming, and not all hospitals are equipped with MRI machines. In addition, contrast agent is required to obtain the BBB leakage signal by MRI. BBB leakage signal is only visible postthrombolysis treatment. Thus, using MRI to assess BBB damage before thrombolysis treatment to predict the risk of ICH after thrombolysis is not realistic within the limited time window before treatment.

  Conclusions Top

This systematic review has highlighted the biomarkers that have been developed to assess BBB damage following the acute ischemic stroke. The development of these biomarkers is based on the destruction of barrier functions of BBB [Figure 1]. With further understanding of the mechanism of BBB damage, it has been observed that the degradation of BBB structural proteins is directly related to compromised BBB integrity. These proteins have a high potential to become sensitive and specific biomarkers for BBB damage. However, because of the complexity and heterogeneity of the ischemic stroke, adequate clinical information and data are needed to verify the feasibility and reliability of these potential biomarkers.
Figure 1: Schematic diagram for the structure of blood–brain barrier and the generation of biomarkers for blood–brain barrier damage and development of symptomatic intracerebral hemorrhage following thrombolytic therapy for acute ischemic stroke

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Financial support and sponsorship

This work was partially supported by grants from the National Natural Science Foundation of China (81620108011, 81571175) and US National Institutes of Health (P30GM103400).

Conflicts of interest

There are no conflicts of interest.

  References Top

Writing Group Members, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation 2016;133:e38-360.  Back to cited text no. 1
Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 2002;33:831-6.  Back to cited text no. 2
Tilley BC, Lyden PD, Brott TG, Lu M, Levine SR, Welch KM, et al. Total quality improvement method for reduction of delays between emergency department admission and treatment of acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Arch Neurol 1997;54:1466-74.  Back to cited text no. 3
Khatri P, Wechsler LR, Broderick JP. Intracranial hemorrhage associated with revascularization therapies. Stroke 2007;38:431-40.  Back to cited text no. 4
Kassner A, Roberts TP, Moran B, Silver FL, Mikulis DJ. Recombinant tissue plasminogen activator increases blood-brain barrier disruption in acute ischemic stroke: An MR imaging permeability study. AJNR Am J Neuroradiol 2009;30:1864-9.  Back to cited text no. 5
Wang W, Li M, Chen Q, Wang J. Hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke: Mechanisms, models, and biomarkers. Mol Neurobiol 2015;52:1572-9.  Back to cited text no. 6
Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews, 2005; 57:173-85.  Back to cited text no. 7
Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis 2010;37:13-25.  Back to cited text no. 8
Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis 2013;36:437-49.  Back to cited text no. 9
Mokgokong R, Wang S, Taylor CJ, Barrand MA, Hladky SB. Ion transporters in brain endothelial cells that contribute to formation of brain interstitial fluid. Pflugers Arch 2014;466:887-901.  Back to cited text no. 10
Satoh K, Yoshida H, Imaizumi TA, Koyama M, Takamatsu S. Production of platelet-activating factor by porcine brain microvascular endothelial cells in culture. Thromb Haemost 1995;74:1335-9.  Back to cited text no. 11
Begley DJ, Brightman MW. Structural and functional aspects of the blood-brain barrier. Prog Drug Res 2003;61:39-78.  Back to cited text no. 12
Balda MS, Matter K. Tight junctions and the regulation of gene expression. Biochim Biophys Acta 2009;1788:761-7.  Back to cited text no. 13
Caron TJ, Scott KE, Fox JG, Hagen SJ. Tight junction disruption: Helicobacter pylori and dysregulation of the gastric mucosal barrier. World J Gastroenterol 2015;21:11411-27.  Back to cited text no. 14
Shen L, Weber CR, Raleigh DR, Yu D, Turner JR. Tight junction pore and leak pathways: A dynamic duo. Annu Rev Physiol 2011;73:283-309.  Back to cited text no. 15
Mitic LL, Anderson JM. Molecular architecture of tight junctions. Annu Rev Physiol 1998;60:121-42.  Back to cited text no. 16
Jiao H, Wang Z, Liu Y, Wang P, Xue Y. Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood-brain barrier in a focal cerebral ischemic insult. J Mol Neurosci 2011;44:130-9.  Back to cited text no. 17
Piontek J, Winkler L, Wolburg H, Müller SL, Zuleger N, Piehl C, et al. Formation of tight junction: Determinants of homophilic interaction between classic claudins. FASEB J 2008;22:146-58.  Back to cited text no. 18
Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 2007;27:697-709.  Back to cited text no. 19
Dore-Duffy P. Pericytes: Pluripotent cells of the blood brain barrier. Curr Pharm Des 2008;14:1581-93.  Back to cited text no. 20
Bagley RG, Weber W, Rouleau C, Teicher BA. Pericytes and endothelial precursor cells: Cellular interactions and contributions to malignancy. Cancer Res 2005;65:9741-50.  Back to cited text no. 21
Dore-Duffy P, Katychev A, Wang X, Van Buren E. CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab 2006;26:613-24.  Back to cited text no. 22
Liu S, Agalliu D, Yu C, Fisher M. The role of pericytes in blood-brain barrier function and stroke. Curr Pharm Des 2012;18:3653-62.  Back to cited text no. 23
Yamagata K, Tagami M, Nara Y, Mitani M, Kubota A, Fujino H, et al. Astrocyte-conditioned medium induces blood-brain barrier properties in endothelial cells. Clin Exp Pharmacol Physiol 1997;24:710-3.  Back to cited text no. 24
Bernoud N, Fenart L, Bénistant C, Pageaux JF, Dehouck MP, Molière P, et al. Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood-brain barrier endothelial cells in vitro. J Lipid Res 1998;39:1816-24.  Back to cited text no. 25
Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD. Blood-brain barrier: Structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 2006;1:223-36.  Back to cited text no. 26
Thomsen MS, Routhe LJ, Moos T. The vascular basement membrane in the healthy and pathological brain. J Cereb Blood Flow Metab 2017;37:3300-17.  Back to cited text no. 27
Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 2005;57:173-85.  Back to cited text no. 28
Hao Y, Zhang Z, Zhang H, Xu L, Ye Z, Dai Q, et al. Risk of intracranial hemorrhage after endovascular treatment for acute ischemic stroke: Systematic review and meta-analysis. Interv Neurol 2017;6:57-64.  Back to cited text no. 29
Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, et al. 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015;46:3020-35.  Back to cited text no. 30
Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018;378:11-21.  Back to cited text no. 31
Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018;378:708-18.  Back to cited text no. 32
Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 2011;42:3323-8.  Back to cited text no. 33
Förster C. Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol 2008;130:55-70.  Back to cited text no. 34
Ueno M. Molecular anatomy of the brain endothelial barrier: An overview of the distributional features. Curr Med Chem 2007;14:1199-206.  Back to cited text no. 35
Kazmierski R, Michalak S, Wencel-Warot A, Nowinski WL. Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients. Neurology 2012;79:1677-85.  Back to cited text no. 36
Pan R, Yu K, Weatherwax T, Zheng H, Liu W, Liu KJ, et al. Blood occludin level as a potential biomarker for early blood brain barrier damage following ischemic stroke. Sci Rep 2017;7:40331.  Back to cited text no. 37
Shi S, Qi Z, Ma Q, Pan R, Timmins GS, Zhao Y, et al. Normobaric hyperoxia reduces blood occludin fragments in rats and patients with acute ischemic stroke. Stroke 2017;48:2848-54.  Back to cited text no. 38
Miao Y, Liao JK. Potential serum biomarkers in the pathophysiological processes of stroke. Expert Rev Neurother 2014;14:173-85.  Back to cited text no. 39
Castellanos M, Leira R, Serena J, Blanco M, Pedraza S, Castillo J, et al. Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke. Stroke 2004;35:1671-6.  Back to cited text no. 40
Serena J, Blanco M, Castellanos M, Silva Y, Vivancos J, Moro MA, et al. The prediction of malignant cerebral infarction by molecular brain barrier disruption markers. Stroke 2005;36:1921-6.  Back to cited text no. 41
Peters JH, Maunder RJ, Woolf AD, Cochrane CG, Ginsberg MH. Elevated plasma levels of ED1+ (“cellular”) fibronectin in patients with vascular injury. J Lab Clin Med 1989;113:586-97.  Back to cited text no. 42
Kanters SD, Banga JD, Algra A, Frijns RC, Beutler JJ, Fijnheer R. Plasma levels of cellular fibronectin in diabetes. Diabetes Care 2001;24:323-7.  Back to cited text no. 43
Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: Inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 1998;29:1020-30.  Back to cited text no. 44
Ghaffarpour S, Ghazanfari T, Kabudanian Ardestani S, Pourfarzam S, Fallahi F, Shams J, et al. Correlation between MMP-9 and MMP-9/TIMPs complex with pulmonary function in sulfur mustard exposed civilians: Sardasht-Iran cohort study. Arch Iran Med 2017;20:74-82.  Back to cited text no. 45
Romi F, Helgeland G, Gilhus NE. Serum levels of matrix metalloproteinases: Implications in clinical neurology. Eur Neurol 2012;67:121-8.  Back to cited text no. 46
Liu W, Hendren J, Qin XJ, Shen J, Liu KJ. Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. J Neurochem 2009;108:811-20.  Back to cited text no. 47
Castellanos M, Sobrino T, Millán M, García M, Arenillas J, Nombela F, et al. Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: A multicenter confirmatory study. Stroke 2007;38:1855-9.  Back to cited text no. 48
Steiner J, Bernstein HG, Bielau H, Berndt A, Brisch R, Mawrin C, et al. Evidence for a wide extra-astrocytic distribution of S100B in human brain. BMC Neurosci 2007;8:2.  Back to cited text no. 49
Huang SH, Wang L, Chi F, Wu CH, Cao H, Zhang A, et al. Circulating brain microvascular endothelial cells (cBMECs) as potential biomarkers of the blood-brain barrier disorders caused by microbial and non-microbial factors. PLoS One 2013;8:e62164.  Back to cited text no. 50
Moore BW. A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun 1965;19:739-44.  Back to cited text no. 51
Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, et al. The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 2010;30:85-92.  Back to cited text no. 52
Nylén K, Ost M, Csajbok LZ, Nilsson I, Hall C, Blennow K, et al. Serum levels of S100B, S100A1B and S100BB are all related to outcome after severe traumatic brain injury. Acta Neurochir (Wien) 2008;150:221-7.  Back to cited text no. 53
Marchi N, Cavaglia M, Fazio V, Bhudia S, Hallene K, Janigro D. Peripheral markers of blood-brain barrier damage. Clin Chim Acta 2004;342:1-2.  Back to cited text no. 54
Koh SX, Lee JK. S100B as a marker for brain damage and blood-brain barrier disruption following exercise. Sports Med 2014;44:369-85.  Back to cited text no. 55
Day IN, Thompson RJ. Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel cytoplasmic marker for neurones and neuroendocrine cells. FEBS Lett 1987;210:157-60.  Back to cited text no. 56
Galter D, Westerlund M, Belin AC, Olson L. DJ-1 and UCH-L1 gene activity patterns in the brains of controls, Parkinson and schizophrenia patients and in rodents. Physiol Behav 2007;92:46-53.  Back to cited text no. 57
Larsen CN, Krantz BA, Wilkinson KD. Substrate specificity of deubiquitinating enzymes: Ubiquitin C-terminal hydrolases. Biochemistry 1998;37:3358-68.  Back to cited text no. 58
Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. Scand J Clin Lab Invest 1977;37:397-401.  Back to cited text no. 59
Olsson JE, Pettersson B. A comparison between agar gel electrophoresis and CSF serum quotients of IgG and albumin in neurological disease. Acta Neurol Scand 1976;53:308-22.  Back to cited text no. 60
Tibbling G, Link H, Ohman S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385-90.  Back to cited text no. 61
Cuenod CA, Balvay D. Perfusion and vascular permeability: Basic concepts and measurement in DCE-CT and DCE-MRI. Diagn Interv Imaging 2013;94:1187-204.  Back to cited text no. 62
Heye AK, Culling RD, Valdés Hernández Mdel C, Thrippleton MJ, Wardlaw JM. Assessment of blood-brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review. Neuroimage Clin 2014;6:262-74.  Back to cited text no. 63
Warach S, Latour LL. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke 2004;35:2659-61.  Back to cited text no. 64
Liu J, Jin X, Liu KJ, Liu W. Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage. J Neurosci 2012;32:3044-57.  Back to cited text no. 65
White ES, Muro AF. Fibronectin splice variants: Understanding their multiple roles in health and disease using engineered mouse models. IUBMB Life 2011;63:538-46.  Back to cited text no. 66
Vermeer PD, Denker J, Estin M, Moninger TO, Keshavjee S, Karp P, et al. MMP9 modulates tight junction integrity and cell viability in human airway epithelia. Am J Physiol Lung Cell Mol Physiol 2009;296:L751-62.  Back to cited text no. 67
Vafadari B, Salamian A, Kaczmarek L. MMP-9 in translation: From molecule to brain physiology, pathology, and therapy. J Neurochem 2016;139 Suppl 2:91-114.  Back to cited text no. 68
Chmielewska N, Szyndler J, Makowska K, Wojtyna D, Maciejak P, Płaźnik A, et al. Looking for novel, brain-derived, peripheral biomarkers of neurological disorders. Neurol Neurochir Pol 2018;52:318-25.  Back to cited text no. 69
Ramos-Fernandez M, Bellolio MF, Stead LG. Matrix metalloproteinase-9 as a marker for acute ischemic stroke: A systematic review. J Stroke Cerebrovasc Dis 2011;20:47-54.  Back to cited text no. 70
Bjerke M, Zetterberg H, Edman Å, Blennow K, Wallin A, Andreasson U. Cerebrospinal fluid matrix metalloproteinases and tissue inhibitor of metalloproteinases in combination with subcortical and cortical biomarkers in vascular dementia and Alzheimer's disease. J Alzheimers Dis 2011;27:665-76.  Back to cited text no. 71
Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem 2001;70:503-33.  Back to cited text no. 72
Wilkinson KD, Deshpande S, Larsen CN. Comparisons of neuronal (PGP 9.5) and non-neuronal ubiquitin C-terminal hydrolases. Biochem Soc Trans 1992;20:631-7.  Back to cited text no. 73
Larsen CN, Price JS, Wilkinson KD. Substrate binding and catalysis by ubiquitin C-terminal hydrolases: Identification of two active site residues. Biochemistry 1996;35:6735-44.  Back to cited text no. 74
Blyth BJ, Farahvar A, He H, Nayak A, Yang C, Shaw G, et al. Elevated serum ubiquitin carboxy-terminal hydrolase L1 is associated with abnormal blood-brain barrier function after traumatic brain injury. J Neurotrauma 2011;28:2453-62.  Back to cited text no. 75
Hjort N, Wu O, Ashkanian M, Sølling C, Mouridsen K, Christensen S, et al. MRI detection of early blood-brain barrier disruption: Parenchymal enhancement predicts focal hemorrhagic transformation after thrombolysis. Stroke 2008;39:1025-8.  Back to cited text no. 76


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