脑梗死与脑出血早期鉴别的血清标志物概述
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摘要
脑梗死是因局部脑组织血液供应障碍而导致脑组织坏死;脑出血则是因为各种原因导致脑实质内血管破裂出血。虽然二者发病时临床症状有一定相似性,但其发病机制及病理生理过程截然不同,这种差异可能会导致发病早期血清中一些蛋白及基因表达的差异。目前,文献中报道了几种可用于鉴别脑梗死及脑出血的血清标志物,并分析了这些标志物用于脑梗死及脑出血早期鉴别诊断的价值。本文将对这些血清标志物进行综述,希望能够为卒中早期鉴别诊断提供新思路。
Cerebral infarction is caused by cerebrovascular stenosis or occlusion, while intracerebral hemorrhage is caused by cerebrovascular rupture. Although the two kinds of stroke present similar symptoms, their pathogenesis are different, which could lead to different expressions of some proteins and genes at the acute phase of stroke. Recently, some literature reported several serum biomarkers which could differentiate cerebral infarction and cerebral hemorrhage and the early diagnostic value of these biomarkers. This article reviewed the progress of serum biomarkers which could differentiate cerebral infarction and cerebral hemorrhage at the early stage, to provide a reference for early differential diagnosis of stroke.
Cerebral infarction is caused by cerebrovascular stenosis or occlusion, while intracerebral hemorrhage is caused by cerebrovascular rupture. Although the two kinds of stroke present similar symptoms, their pathogenesis are different, which could lead to different expressions of some proteins and genes at the acute phase of stroke. Recently, some literature reported several serum biomarkers which could differentiate cerebral infarction and cerebral hemorrhage and the early diagnostic value of these biomarkers. This article reviewed the progress of serum biomarkers which could differentiate cerebral infarction and cerebral hemorrhage at the early stage, to provide a reference for early differential diagnosis of stroke.
引文
[1]LLOYD-JONES D,ADAMS R,CARNETHON M,et al.Heart disease and stroke statistics-2009 update:a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee[J].Circulation,2009,119(3):480-486.
[2]伞勇智,李峰,杨鸣,等.凝血机制新进展及脑梗死抗凝治疗的展望[J].中华脑血管病杂志(电子版),2012,6(2):35-40.
[3]官念,吴碧华,刘黎明,等.脑出血病因及相关机制的研究进展[J].中华老年心脑血管病杂志,2016,18(6):670-672.
[4]ENG L F,GHIRNIKAR R S,LEE Y L.Glial fibrillary acidic protein:GFAP-thirty-one years(1969-2000)[J].Neurochem Res,2000,25(9-10):1439-1451.
[5]DVORAK F,HABERER I,SITZER M,et al.Characterisation of the diagnostic window of serum glial fibrillary acidic protein for the differentiation of intracerebral haemorrhage and ischaemic stroke[J].Cerebrovasc Dis,2009,27(1):37-41.
[6]UNDéN J,STRANDBERG K,MALMJ,et al.Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation[J].J Neurol,2009,256(1):72-77.
[7]HERRMANN M,VOS P,WUNDERLICHMT,et al.Release of glial tissue-specific proteins after acute stroke:a comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein[J].Stroke,2000,31(11):2670-2677.
[8]BRUNKHORST R,PFEILSCHIFTER W,FOERCHC.Astroglial proteins as diagnostic markers of acute intracerebral hemorrhage-pathophysiological background and clinical findings[J].Transl Stroke Res,2010,1(4):246-251.
[9]PERSSON L,H?RDEMARK H G,BOLANDERH G,et al.Neurologic and neuropathologic outcome after middle cerebral artery occlusion in rats[J].Stroke,1989,20(5):641-645.
[10]WUNDERLICH M T,WALLESCH C W,GOERTLER M.Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke[J].Eur J Neurol,2006,13(10):1118-1123.
[11]FOERCH C,CURDT I,YAN B,et al.Serum glial fibrillary acidic protein as a biomarker for intracerebral haemorrhage in patients with acute stroke[J].J Neurol Neurosurg Psychiatry,2006,77(2):181-184.
[12]FOERCH C,NIESSNER M,BACK T,et al.Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke[J].Clin Chem,2012,58(1):237-245.
[13]REN C,KOBEISSY F,ALAWIEH A,et al.Assessment of serum UCH-L1 and GFAP in acute stroke patients[J/OL].Sci Rep,2016,6:24588.https://doi.org/10.1038/srep24588.
[14]BARGER S W,VAN ELDIK L J.S100 beta stimulates calcium fluxes in glial and neuronal cells[J].J Biol Chem,1992,267(14):9689-9694.
[15]KANNER A A,MARCHI N,FAZIO V,et al.Serum S100beta:a noninvasive marker of bloodbrain barrier function and brain lesions[J].Cancer,2003,97(11):2806-2813.
[16]BUTTNER T,WEYERS S,POSTERT T,et al.S-100 protein:serum marker of focal brain damage after ischemic territorial MCA infarction[J].Stroke,1997,28(10):1961-1965.
[17]DELGADO P,ALVAREZ SABIN J,SANTAMARINA E,et al.Plasma S100B level after acute spontaneous intracerebral hemorrhage[J].Stroke,2006,37(11):2837-2839.
[18]ZHOU S,BAO J,WANG Y,et al.S100βas a biomarker for differential diagnosis of intracerebral hemorrhage and ischemic stroke[J].Neurol Res,2016,38(4):327-332.
[19]GINGRICH M B,TRAYNELIS S F.Serine proteases and brain damage-is there a link?[J].Trends Neurosci,2000,23(9):399-407.
[20]DAMBINOVA S A,KHOUNTEEV G A,SKOROMETS A A.Multiple panel of biomarkers for TIA/stroke evaluation[J].Stroke,2002,33(5):1181-1182.
[21]DAMBINOVA S A,KHOUNTEEV G A,IZYKENOVA G A,et al.Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke[J].Clin Chem,2003,49(10):1752-1762.
[22]WILKINSON K D.Regulation of ubiquitindependent processes by deubiquitinating enzymes[J].FASEB J,1997,11(14):1245-1256.
[23]LIU M C,AKINYI L,SCHARF D,et al.Ubiquitin C-terminal hydrolase-L1 as a biomarker for ischemic and traumatic brain injury in rats[J].Eur J Neurosci,2010,31(4):722-732.
[24]REN C,ZOLTEWICZ S,GUINGAB-CAGMATJ,et al.Different expression of ubiquitin C-terminal hydrolase-L1 and alphaII-spectrin in ischemic and hemorrhagic stroke:Potential biomarkers in diagnosis[J/OL].Brain Res,2013,1540:84-91.https://doi.org/10.1016/j.brainres.2013.09.051.
[25]KORFIAS S,STRANJALIS G,PAPADIMITRIOUA,et al.Serum S-100B protein as a biochemical marker of brain injury:a review of current concepts[J].Curr Med Chem,2006,13(30):3719-3731.
[26]ROSSO C,ROSENBAUM D,PIRESC,et al.Lipoprotein-associated phospholipase A2 during the hyperacute stage of ischemic and hemorrhagic strokes[J/OL].J Stroke Cerebrovasc Dis,2014,23(4):e277-e282.https://doi.org/10.1016/j.jstrokecere brovasdis.2013.11.024.
[27]SHEARER K D,STONEY P N,MORGAN P J,et al.A vitamin for the brain[J].Trends Neurosci,2012,35(12):733-741.
[28]PLANE J M,WHITNEY J T,SCHALLERT T,et al.Retinoic acid and environmental enrichment alter subventricular zone and striatal neurogenesis after stroke[J].Exp Neurol.2008,214(1):125-134.
[29]CHOI B K,KIM J H,JUNG J S,et al.Reduction of ischemia-induced cerebral injury by all-transretinoic acid[J].Exp Brain Res,2009,193(4):581-589.
[30]HARVEY B K,SHEN H,CHEN G J,et al.Midkine and retinoic acid reduce cerebral infarction induced by middle cerebral artery ligation in rats[J].Neurosci Lett,2004,369(2):138-141.
[31]XIAO Y,XU A,HUI X,et al.Circulating lipocalin-2 and retinol-binding protein 4 are associated with intima-media thickness and subclinical atherosclerosis in patients with type 2diabetes[J/OL].PloS one,2013,8(6):e66607.https://doi.org/10.1371/journal.pone.0066607.
[32]KADOGLOU N P,LAMBADIARI V,GASTOUNIOTI A,et al.The relationship of novel adipokines,RBP4 and omentin-1,with carotid atherosclerosis severity and vulnerability[J].Atherosclerosis,2014,235(2):606-612.
[33]LLOMBART V,GARCIA-BERROCOSOT,BUSTAMANTE A,et al.Plasmatic retinolbinding protein 4 and glial fibrillary acidic protein as biomarkers to differentiate ischemic stroke and intracerebral hemorrhage[J].J Neurochem,2016,136(2):416-424.
[34]YAN S F,NAKA Y,HUDSON B I,et al.The ligand/RAGE axis:lighting the fuse and igniting vascular stress[J].Curr Atheroscler Rep,2006,8(3):232-239.
[35]CHANG J S,WENDT T,QU W,et al.Oxygen deprivation triggers upregulation of early growth response-1 by the receptor for advanced glycation end products[J].Circ Res,2008,102(8):905-913.
[36]DONATO R.RAGE:a single receptor for several ligands and different cellular responses:the case of certain S100 proteins[J].Curr Mol Med,2007,7(8):711-724.
[37]PARK I H,YEON S I,YOUN J H,et al.Expression of a novel secreted splice variant of the receptor for advanced glycation end products(RAGE)in human brain astrocytes and peripheral blood mononuclear cells[J].Mol Immunol,2004,40(16):1203-1211.
[38]MONTANER J,MENDIOROZ M,DELGADOP,et al.Differentiating ischemic from hemorrhagic stroke using plasma biomarkers:the S100B/RAGEpathway[J].J Proteomics,2012,75(15):4758-4765.
[39]WALLDIUS G,JUNGNER I.Apolipoprotein A-Iversus HDL cholesterol in the prediction of risk for myocardial infarction and stroke[J].Curr Opin Cardiol,2007,22(4):359-367.
[40]WALLDIUS G,AASTVEIT A H,JUNGNER I.Stroke mortality and the apoB/apoA-I ratio:results of the AMORIS prospective study[J].J Intern Med,2006,259(3):259-266.
[41]BARTER P J,NICHOLLS S,RYE K A,et al.Antiinflammatory properties of HDL[J].Circ Res,2004,95(8):764-772.
[42]MOVVA R,RADER D J.Laboratory assessment of HDL heterogeneity and function[J].Clin Chem,2008,54(5):788-800.
[43]WALSH K B,HART K,ROLL S,et al.Apolipoprotein A-I and Paraoxonase-1 Are Potential Blood Biomarkers for Ischemic Stroke Diagnosis[J].J Stroke Cerebrovasc Dis,2016,25(6):1360-1365.
[44]DYKSTRA-AIELLO C,JICKLING G C,ANDERB P,et al.Intracerebral hemorrhage and ischemic stroke of different etiologies have distinct alternatively spliced mRNA profiles in the blood:a pilot RNA-seq study[J].Transl Stroke Res,2015,6(4):284-289.--
[2]伞勇智,李峰,杨鸣,等.凝血机制新进展及脑梗死抗凝治疗的展望[J].中华脑血管病杂志(电子版),2012,6(2):35-40.
[3]官念,吴碧华,刘黎明,等.脑出血病因及相关机制的研究进展[J].中华老年心脑血管病杂志,2016,18(6):670-672.
[4]ENG L F,GHIRNIKAR R S,LEE Y L.Glial fibrillary acidic protein:GFAP-thirty-one years(1969-2000)[J].Neurochem Res,2000,25(9-10):1439-1451.
[5]DVORAK F,HABERER I,SITZER M,et al.Characterisation of the diagnostic window of serum glial fibrillary acidic protein for the differentiation of intracerebral haemorrhage and ischaemic stroke[J].Cerebrovasc Dis,2009,27(1):37-41.
[6]UNDéN J,STRANDBERG K,MALMJ,et al.Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation[J].J Neurol,2009,256(1):72-77.
[7]HERRMANN M,VOS P,WUNDERLICHMT,et al.Release of glial tissue-specific proteins after acute stroke:a comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein[J].Stroke,2000,31(11):2670-2677.
[8]BRUNKHORST R,PFEILSCHIFTER W,FOERCHC.Astroglial proteins as diagnostic markers of acute intracerebral hemorrhage-pathophysiological background and clinical findings[J].Transl Stroke Res,2010,1(4):246-251.
[9]PERSSON L,H?RDEMARK H G,BOLANDERH G,et al.Neurologic and neuropathologic outcome after middle cerebral artery occlusion in rats[J].Stroke,1989,20(5):641-645.
[10]WUNDERLICH M T,WALLESCH C W,GOERTLER M.Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke[J].Eur J Neurol,2006,13(10):1118-1123.
[11]FOERCH C,CURDT I,YAN B,et al.Serum glial fibrillary acidic protein as a biomarker for intracerebral haemorrhage in patients with acute stroke[J].J Neurol Neurosurg Psychiatry,2006,77(2):181-184.
[12]FOERCH C,NIESSNER M,BACK T,et al.Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke[J].Clin Chem,2012,58(1):237-245.
[13]REN C,KOBEISSY F,ALAWIEH A,et al.Assessment of serum UCH-L1 and GFAP in acute stroke patients[J/OL].Sci Rep,2016,6:24588.https://doi.org/10.1038/srep24588.
[14]BARGER S W,VAN ELDIK L J.S100 beta stimulates calcium fluxes in glial and neuronal cells[J].J Biol Chem,1992,267(14):9689-9694.
[15]KANNER A A,MARCHI N,FAZIO V,et al.Serum S100beta:a noninvasive marker of bloodbrain barrier function and brain lesions[J].Cancer,2003,97(11):2806-2813.
[16]BUTTNER T,WEYERS S,POSTERT T,et al.S-100 protein:serum marker of focal brain damage after ischemic territorial MCA infarction[J].Stroke,1997,28(10):1961-1965.
[17]DELGADO P,ALVAREZ SABIN J,SANTAMARINA E,et al.Plasma S100B level after acute spontaneous intracerebral hemorrhage[J].Stroke,2006,37(11):2837-2839.
[18]ZHOU S,BAO J,WANG Y,et al.S100βas a biomarker for differential diagnosis of intracerebral hemorrhage and ischemic stroke[J].Neurol Res,2016,38(4):327-332.
[19]GINGRICH M B,TRAYNELIS S F.Serine proteases and brain damage-is there a link?[J].Trends Neurosci,2000,23(9):399-407.
[20]DAMBINOVA S A,KHOUNTEEV G A,SKOROMETS A A.Multiple panel of biomarkers for TIA/stroke evaluation[J].Stroke,2002,33(5):1181-1182.
[21]DAMBINOVA S A,KHOUNTEEV G A,IZYKENOVA G A,et al.Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke[J].Clin Chem,2003,49(10):1752-1762.
[22]WILKINSON K D.Regulation of ubiquitindependent processes by deubiquitinating enzymes[J].FASEB J,1997,11(14):1245-1256.
[23]LIU M C,AKINYI L,SCHARF D,et al.Ubiquitin C-terminal hydrolase-L1 as a biomarker for ischemic and traumatic brain injury in rats[J].Eur J Neurosci,2010,31(4):722-732.
[24]REN C,ZOLTEWICZ S,GUINGAB-CAGMATJ,et al.Different expression of ubiquitin C-terminal hydrolase-L1 and alphaII-spectrin in ischemic and hemorrhagic stroke:Potential biomarkers in diagnosis[J/OL].Brain Res,2013,1540:84-91.https://doi.org/10.1016/j.brainres.2013.09.051.
[25]KORFIAS S,STRANJALIS G,PAPADIMITRIOUA,et al.Serum S-100B protein as a biochemical marker of brain injury:a review of current concepts[J].Curr Med Chem,2006,13(30):3719-3731.
[26]ROSSO C,ROSENBAUM D,PIRESC,et al.Lipoprotein-associated phospholipase A2 during the hyperacute stage of ischemic and hemorrhagic strokes[J/OL].J Stroke Cerebrovasc Dis,2014,23(4):e277-e282.https://doi.org/10.1016/j.jstrokecere brovasdis.2013.11.024.
[27]SHEARER K D,STONEY P N,MORGAN P J,et al.A vitamin for the brain[J].Trends Neurosci,2012,35(12):733-741.
[28]PLANE J M,WHITNEY J T,SCHALLERT T,et al.Retinoic acid and environmental enrichment alter subventricular zone and striatal neurogenesis after stroke[J].Exp Neurol.2008,214(1):125-134.
[29]CHOI B K,KIM J H,JUNG J S,et al.Reduction of ischemia-induced cerebral injury by all-transretinoic acid[J].Exp Brain Res,2009,193(4):581-589.
[30]HARVEY B K,SHEN H,CHEN G J,et al.Midkine and retinoic acid reduce cerebral infarction induced by middle cerebral artery ligation in rats[J].Neurosci Lett,2004,369(2):138-141.
[31]XIAO Y,XU A,HUI X,et al.Circulating lipocalin-2 and retinol-binding protein 4 are associated with intima-media thickness and subclinical atherosclerosis in patients with type 2diabetes[J/OL].PloS one,2013,8(6):e66607.https://doi.org/10.1371/journal.pone.0066607.
[32]KADOGLOU N P,LAMBADIARI V,GASTOUNIOTI A,et al.The relationship of novel adipokines,RBP4 and omentin-1,with carotid atherosclerosis severity and vulnerability[J].Atherosclerosis,2014,235(2):606-612.
[33]LLOMBART V,GARCIA-BERROCOSOT,BUSTAMANTE A,et al.Plasmatic retinolbinding protein 4 and glial fibrillary acidic protein as biomarkers to differentiate ischemic stroke and intracerebral hemorrhage[J].J Neurochem,2016,136(2):416-424.
[34]YAN S F,NAKA Y,HUDSON B I,et al.The ligand/RAGE axis:lighting the fuse and igniting vascular stress[J].Curr Atheroscler Rep,2006,8(3):232-239.
[35]CHANG J S,WENDT T,QU W,et al.Oxygen deprivation triggers upregulation of early growth response-1 by the receptor for advanced glycation end products[J].Circ Res,2008,102(8):905-913.
[36]DONATO R.RAGE:a single receptor for several ligands and different cellular responses:the case of certain S100 proteins[J].Curr Mol Med,2007,7(8):711-724.
[37]PARK I H,YEON S I,YOUN J H,et al.Expression of a novel secreted splice variant of the receptor for advanced glycation end products(RAGE)in human brain astrocytes and peripheral blood mononuclear cells[J].Mol Immunol,2004,40(16):1203-1211.
[38]MONTANER J,MENDIOROZ M,DELGADOP,et al.Differentiating ischemic from hemorrhagic stroke using plasma biomarkers:the S100B/RAGEpathway[J].J Proteomics,2012,75(15):4758-4765.
[39]WALLDIUS G,JUNGNER I.Apolipoprotein A-Iversus HDL cholesterol in the prediction of risk for myocardial infarction and stroke[J].Curr Opin Cardiol,2007,22(4):359-367.
[40]WALLDIUS G,AASTVEIT A H,JUNGNER I.Stroke mortality and the apoB/apoA-I ratio:results of the AMORIS prospective study[J].J Intern Med,2006,259(3):259-266.
[41]BARTER P J,NICHOLLS S,RYE K A,et al.Antiinflammatory properties of HDL[J].Circ Res,2004,95(8):764-772.
[42]MOVVA R,RADER D J.Laboratory assessment of HDL heterogeneity and function[J].Clin Chem,2008,54(5):788-800.
[43]WALSH K B,HART K,ROLL S,et al.Apolipoprotein A-I and Paraoxonase-1 Are Potential Blood Biomarkers for Ischemic Stroke Diagnosis[J].J Stroke Cerebrovasc Dis,2016,25(6):1360-1365.
[44]DYKSTRA-AIELLO C,JICKLING G C,ANDERB P,et al.Intracerebral hemorrhage and ischemic stroke of different etiologies have distinct alternatively spliced mRNA profiles in the blood:a pilot RNA-seq study[J].Transl Stroke Res,2015,6(4):284-289.--