ORIGINAL ARTICLE online ML Comm J Neurocrit Care 2009;2:50-55 ISSN 급성허혈성뇌졸중환자에서혈청 Glial Fibrillary Acidic Protein의임상적유용성 CHA 의과학대학교신경과학교실, 1

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1 ORIGINAL ARTICLE online ML Comm J Neurocrit Care 9;:- ISSN -8 급성허혈성뇌졸중환자에서혈청 Glial Fibrillary Acidic Protein의임상적유용성 CHA 의과학대학교신경과학교실, 임상의학연구소 김미화 오승헌 권영도 백민정 김유경 김현숙 김원찬 김옥준 Clinical Usefulness of Serum Glial Fibrillary Acidic Protein in Patients with Acute Ischemic Stroke Mi-Hwa Kim, MD, Seung-Hun Oh, MD, Young-Do Kwon, PhD, Min-Jung Baek, You-Kyung Kim, Hyun Sook Kim, MD, Won-Chan Kim, MD and Ok Joon Kim, MD, PhD Departments of Neurology, Institute for Clinical Research, Bundang CHA Medical Center, CHA University School of Medicine, Seongnam, Korea Background: Glial fibrillary acidic protein (GFAP) is known to be leaked into the peripheral blood through disrupted blood-brain barrier in brain injury. We investigate the usefulness of measurement of serum GFAP as a biomarker for prediction of diagnosis and prognosis in acute ischemic stroke. Methods: Serum GFAP levels were measured in 6 patients with acute ischemic stroke within hours of onset ( territorial and 9 lacunar infarctions) and 68 healthy controls. The patient s clinical status and functional outcome were evaluated by the National Institute of Health Stroke Scale (NIHSS) on admission and 7th day of onset, and modified Rankin Scale (mrs) at months of onset. The serum GFAP levels were compared according to the extent of infarct. Results: In stroke group, serum GFAP levels were highly elevated than control group (P=.). Serum GFAP test exhibited high specificity but low sensitivity (area under curve=.67, P=.7) for diagnosis of ischemic stroke. This low diagnostic sensitivity was attributed to low detection rate of lacunar infarction. The serum GFAP levels were correlated with the extent of infarct size (P<.). The serum GFAP levels were highly correlated with the short-term clinical severity in the acute phase (initial NIHSS: r=., P<., 7-day NIHSS: r=.68, P<.) and long-term functional outcome ( month mrs: r=.8, P<.). Conclusion: Measurement of serum GFAP level as a diagnostic biomarker for acute ischemic stroke is limited. However, serum GFAP measurement had predictive values of severities of neuronal damage and clinical outcome in patients with acute ischemic stroke. J Neurocrit Care 9;:- KEY WORDS: Glial fibrillary acidic protein Acute ischemic stroke Biomarker Diagnosis Prognosis. 서 최근허혈성뇌졸중에서뇌손상의정도를반영하는혈중생물학적표지자 (biomarker) 를이용하여뇌졸중의진단및임상적예후를예측할수있는지에대한연구들이진행되 Address for correspondence: Seung-Hun Oh, MD Department of Neurology, Bundang CHA Medical Center, CHA University School of Medicine, Yatap-dong, Bundang-gu, Seongnam 6-7, Korea Tel: , Fax: ohsh7@chamc.co.kr 본연구는보건복지가족부보건의료기술진흥사업의지원에의하여이루어진것임 (A97). 론 고있다. 생물학적표지자는뇌손상진단에가장널리사용되고있는뇌영상검사의기술적어려움과경제적문제를고려할때검사법이신속, 용이하고반복적으로측정할수있다는장점이있다. 현재까지임상적으로활용단계에있는생물학적표지자는없는상태이나, 이전급성허혈성뇌졸중에서연구된생물학적표지자들로는 S β, neuronspecific enolase(nse) 및 glial fibrillary acidic protein (GFAP) 등이있으며이중 GFAP는중추신경계의성상세포 (astrocyte) 에존재하는 8~9 nm의중간세사 (intermediate filament) 로구성된 kda 크기의단백질로알려져있다. GFAP는성상세포돌기 (process) 를안정적으로형성하 Copyright c 9 The Korean Neurocritical Care Society

2 Serum GFAP Level in Acute Ischemic Stroke MH Kim, et al. 여성상세포의움직임과형태를결정하는중요한역할을한다고생각되며기능적으로성상세포또는신경세포와신호전달에도관여한다고알려져있다. GFAP는뇌신경세포에고농도로존재하고분자량이적기때문에뇌손상이발생하여혈액뇌장벽 (blood-brain barrier: BBB) 이파괴되면혈액내로누출될수있어급성뇌손상의초기에혈청 GFAP 를측정하면뇌손상을진단하고손상의정도를민감하게예측할수있다는보고가있다. - 그러나현재까지 S β 단백질과 NSE에비하여급성허혈성뇌졸중에서혈청 GFAP 수치가진단이나예후를예측하는데관련된생물학적표지자로서의유용성은연구수가적어잘알려져있지않다. 이에저자들은급성허혈성뇌졸중환자에서혈청 GFAP 수치를측정하여 GFAP가뇌졸중진단이나임상적예후를예측하는데있어유용한지조사하였다. 대상및방법 대상 8년 월부터 9년 6월까지본원에내원한급성허혈성뇌졸중환자 6명과신경학적병력이없는 68명의정상대조군을대상으로하였다. 정상대조군 68명은본원신경과외래를통해일차성두통 (n=), 비특이적인어지럼증혹은말초성현훈증 (n=7), 그리고뇌졸중검진목적 (n=7) 으로방문한사람들로서모두 MRI 검사에서구조적이상이발견되지않았으며본연구의참여에동의한환자들로구성되었다. 병력청취상내원 개월이내에뇌경색, 뇌출혈, 뇌외상, 중추신경계감염및악성종양의과거력이있는환자는본연구에서배제하였고, 증상발생 시간이후내원하거나본연구참여를거부한환자는제외하였다. 대조군선정에서 MRI 이상이없더라도일과성뇌허혈발작에준하는신경학적증상을보인자, 또는합병증이동반된편두통환자는모집에서제외하였다. 모든환자와대조군에서뇌졸중위험인자로고혈압, 당뇨, 고지질혈증, 심장질환및흡연유무를조사하였다. 환자는내원시부터입원 7일째까지신경학적검사와 National Institute of Health Stroke Scale (NIHSS) 을기록하였고, 혈액검사등을시행받았으며내원 ~일사이에확산강조영상 (diffusion-weighted image: DWI) 을포함한뇌자기공명영상검사 (magnetic resonance image: MRI) 를시행하였다. Trial of ORG 7 in Acute Stroke Treatment(TOAST) 분류에 6 따라뇌경색의아형을각각분류하였고 DWI에서관찰된뇌경색의위치와크기는 Oxfordshire Community Stroke Project(OCSP) 의분류법에 7 따라전체앞뇌순환영역경색 (total anterior-circulation infarct: TACI), 일부앞뇌순환영역경색 (partial anteriorcirculation infarct: PACI), 열공성뇌경색 (lacunar infarct: LAI) 및뒷뇌순환영역경색 (posterior-circulation infarct: PCI) 으로분류하였다. 급성뇌경색 개월후측정한 modified Rankin Scale(mRS) 에서 ~점은양호한예후 (favorable outcome), ~6점은불량한예후 (poor outcome) 로판단하였다. 본연구에참여한모든환자와대조군에서검사동의서를받았으며본원임상연구심의위원회 (Institutional Review Board) 의승인을받았다. 혈청 GFAP 검사 6명의급성뇌경색환자들은증상발생 시간이내에정맥혈 cc를채취하였고, 68명의대조군은외래방문시에혈액을채취하였다. 채취된혈액을 EDTA tube에넣은후, rpm으로 분간원심분리하였다. 혈청을분리하여 GFAP 정량분석을실시할때까지 -8 에서냉동보관하였다. GFAP 정량분석은 Human GFAP ELISA kit(abnova corp., Taiwan) 를사용하였으며, 제조회사에서제시한프로토콜에따라실험을진행하였다. 실험방법을요약하면 GFAP 다클론항체 (polyclonal antibody) 로코팅된 96-well plate 에희석한 calibrators 와샘플들을각각 μl를넣고 rpm으로 시간동안 orbital shaker 에서반응시켰다. Wash solution 으로 회세척한후, Biotin-Labelled anti- GFAP antibody μl를넣고, rpm으로 시간동안 orbital shaker에서반응시켰다. Wash solution 으로 회세척한후, streptavidin-hrp conjugate μl를첨가하고, rpm으로 시간동안 orbital shaker 에서반응시켰다. Wash solution 으로 회세척한후, substrate Solution μl를넣고, 빛이차단된상온에서 ~ 분동안반응시켰다. 반응이진행된후 stop solution μl를넣고, precision microplate reader(emax, Molecular Devices, Sunnyvale, CA, USA) 로 nm에서흡광도를측정한후, 표준 curve에따라 GFAP 양을계산하였다. 통계분석통계분석으로 SPSS ver..(microsoft Corp., Chicago, IL, USA) 를사용하였다. 정상대조군과급성허혈성뇌졸중두군에서명목형변수는 χ 분석, 연속형변수는 student t-test를시행하여분석하였다. 내원 시간, 8시간, 7 시간이내 회연속혈청 GFAP를시행한 명의환자에서 Friedman 분석을시행하였다. 혈청 GFAP 수치의진단유용성을알아보기위하여정상군과환자군의 receiver operating characteristics(roc) 곡선과 area under curve

3 J Neurocrit Care 9;:- (AUC) 값을분석하였다. 허혈성뇌졸중을진단하는데있어 ROC 곡선상최적의민감도 (sensitivity) 와특이도 (specificity) 를나타내는혈청 GFAP의 cut-off 값을구하였다. 신경손상의정도에따른 TACI, PACI, LAI 세군에서혈청 GFAP 수치의차이를분석하기위하여 Kruskal-Wallis 분석을시행하였고각군의평균값을이용한사후분석 (posthoc analysis) 으로는 Tukey-b 분석을시행하였다. 혈청 GFAP 수치와내원당일과 7일째 NIHSS 점수와 개월째 mrs 점수와의관련성을비교하기위하여 Pearson s correlation co-efficiency 를측정하였다. 결과 총 6명의뇌경색환자와 68명의나이와성별을맞춘정상군에서혈청 GFAP 수치를검사하였다. 위험인자빈도를보면뇌경색환자에서흡연과허혈성심장질환의빈도가유의하게높았고고혈압, 당뇨병, 고지혈증의빈도는차이가없었다. 뇌경색환자군에서뇌경색아형에따른 TOAST 분류에서대혈관질환이.%, 심인성색전이 7.%, 소혈관질환이.% 로유사한분포로구성되었다. 뇌경색위치와크기에따른 OCSP 분류에서 TACI군이.%, PACI군이 9.7%, LAI군이.% 로총 8% 의환자가앞뇌순환부위뇌경색이었고 9% 의환자는 PCI군이었다. 환자군에서증상발생첫 시간이내에검사한혈청 GF- AP수치 (.9±.9 ng/ml) 는정상군의수치 (.7±.6 ng/ml) 에비해유의하게증가되었다 (Table ). TACI 와 PACI를보인환자들중 명에서증상발생시간에따른혈청 GFAP 농도의변화를보았다. 증상발생 시간이내, 시간에서 8시간, 8시간에서 7시간에따른혈청 GF- AP 농도변화의통계학적유의성은없었으나, 증상발생 시간에서 8시간에농도가증가하는경향을보였다 (P=.7)(Fig. ). 뇌경색환자군에서 시간이내검사한혈청 GFAP 수치를통한진단민감도 (sensitivity) 및특이도 (specificity) 의관계를구하였다. ROC 곡선에서산출된 AUC 값은.67 로 시간혈청 GFAP 수치의진단적유용성은우수하지는못했으나통계적유의성은관찰되었고 (P=.7), 혈청 GFAP 수치. ng/ml를절단값으로정하였을때진단특이도는 8%, 진단민감도는 9% 로나타났고. ng/ml를절단값으로정하였을때진단특이도는 % 였으나진단민감도는 % 로관찰되어허혈성뇌졸중을진단하기위한혈청 GFAP 검사는높은진단특이도를보였으나진단민감도는매우낮았다. 뇌경색환자군에서경색크기에따른혈청 GFAP 수치를분석하였을때 TACI군 (.9 ±.768 ng/ml) 과 PACI군 (.68±.76 ng/ml) 에서혈청 GFAP 농도가정상군에비해서유의하게증가되어있었다. 그러나 LAI군 (.8±. ng/ml) 에서는정상군과차이가관찰되지않았다 (P>.)(Fig. ). TABLE. Demographic data and serum GFAP level between control and patients with cerebral infarction Cerebral infarction (n=6) Control (n=68) P-value Age (yrs old) 66.±. 6.7±.. Male sex (.8) 8 (.).7 Current smoker 7 (.9) (.). Hypertension (6.) (.). Diabetes mellitus 6 (.) (7.6).8 Hyperlipidemia (.7) (.6). IHD (.7) (.9) <. TOAST LAD 6 (.) - - CE 7 (7.) - - SVD 6 (.) - - UD (.) - - Infarct extent & location TACI 7 (.) - - PACI (9.7) - - LAI 9 (.) - - PCI (9.) - - NIHSS-ini 6.7±. - - NIHSS-7d.9± mrs Favorable (-) - - Poor (-6) Serum.9±.9.7±.6. ( ): % of cases. IHD: ischemic heart disease, TOAST: trial of Org 7 in Acute Stroke Treatment, LAD: large-artery disease, CE: cardioembolism, SVD: small vessel disease, UD: undetermined, TACI: total anterior-circulation infarct, PACI: partial anterior-circulation infarct, LAI: lacunar infarct, PCI: posterior-circulation infarct, NIHSS-ini: initial NIHSS score, NIHSS-7d: NIHSS score at 7 days after stroke onset, mrs: modified Rankin scale.99 - hrs hrs 8-7 hrs FIGURE. Serial measurement of serum GFAP concentration in patients with acute hemispheric infarction (n=).

4 Serum GFAP Level in Acute Ischemic Stroke MH Kim, et al. 혈청 GFAP 수치와임상적인신경학적결손의정도및 장기예후를살펴보면혈청 GFAP 수치는내원시 (r=., P<.) 및증상발생 7 일 (r=.68, P<.) 에측정한 NIHSS 점수와유의한상관관계를보였으며 개월후 mrs 점수와도유의한상관관계를보였다 (r=.8, P<.) (Fig. ). 고 본연구에서혈청 GFAP 수치는대뇌반구영역의큰경색이있는환자들에서뚜렷이증가하였고단기간신경학적결손및장기간예후와상관관계를보였다. 이러한결과는이전의연구들과일치하는것으로허혈성뇌졸중에서혈청 GFAP 수치는신경손상의정도및임상적예후를예측하는데있어생물학적표지자로서활용될수있을것으로생각된다. 생물학적표지자로서의 GFAP 검사는처음에는뇌척수액내농도를측정하는연구로시작되었고급성뇌척수염 (acute encephalomyelitis), 뇌염, 뇌종양, 뇌졸중, 치매및정 *.9 TACI (n=7) **.68 FIGURE. Comparison of serum GFAP concentration according to infarct size. *significantly higher than PACI, LAI, normal groups (P<.), **significantly higher than LAI and normal groups (P<.). 찰.8.7 PACI (n=) LAI (n=9) Normal (n=68) 상압수두증환자를대상으로한연구들에서뇌척수액 (cerebrospinal fluid: CSF) 내 GFAP 농도가유의하게증가한다고보고되었다. 8-6 그러나뇌척수액내 GFAP의측정은요추천자 (lumbar puncture) 가침습적이고반복측정이어려우며중추신경계감염의위험성등으로임상적으로손쉽게시행하기에한계가있으며특히큰뇌경색의경우뇌탈출증 (herniation) 의위험성이있어시행자체가어렵다. 그러므로뇌척수액 GFAP 수치측정은허혈성뇌졸중에서임상적으로활용하기에는많은제한점이있다. 따라서말초혈액에서뇌손상을반영하는단백질을측정한연구들이증가하고있다. 뇌조직에특이하게고농도로존재하는뇌특이단백질들은뇌경색등과같이뇌조직에손상이생길경우손상된혈액뇌장벽 (blood brain barrier) 을통해누출되어직접체순환 (systemic circulation) 으로흘러가거나뇌실내맥락얼기 (choroid plexus) 나지주막섬모 (arachnoid villi) 를통해대뇌전맥동 (cerebral venous sinus) 안으로흡수될수있다. 7 따라서혈액내누출된뇌특이단백질을정량화하여뇌손상의정도를용이하게측정할수있게된다. 일반적으로허혈성뇌졸중발생수시간후부터혈청 GFAP 농도는증가하여 ~일내에최고농도에이른다고알려져있다. 8,9 그러므로 ~일내혈청 GFAP 농도가신경손상의정도를더잘반영할것이라고예상할수있다. 그러나임상적으로뇌졸중은빠른진단및신경손상의정도를신속히평가하는것이장기적예후에큰영향을미치기때문에본연구에서는 시간이내의혈청 GFAP를측정하여임상적유용성을알아보려고하였다. 또한본연구결과에서혈청 GFAP는증상발생 시간이내증가하여 ~8 시간에서높은농도로검출되는경향을보였으나통계적유의성은없었다. 이러한점은허혈성뇌졸중발생 시간이내에서도혈청 GFAP는충분한양이발견됨을시사하며임상적으로신경손상의정도를신속히파악하기위해서는 시간 r=. * r=.68 * r=.8 * NIHSS-ini NIHSS-7d 6 mrs FIGURE. Correlation analysis between serum GFAP concentration and clinical outcomes in patients with ischemic stroke. *P<.. NIHSS-ini: initial NIHSS score, NIHSS-7d: NIHSS after 7 days after onset, mrs: modified Rankin scale, r: Pearson s correlation co-efficiency.

5 J Neurocrit Care 9;:- 이내혈청 GFAP 측정이중요하다고생각된다. 이전여러연구에서혈중 GFAP가뇌손상의정도와예후를결정하는데유용한지표가될수있음을보고하고있다. -,8,, 이중 Herrmann 등 은급성뇌경색에서 GFAP 의혈청농도와뇌병변의크기, 신경학적상태와환자의단기예후와유의한관련이있고가장널리연구된 S β 단백질보다민감도에서더우수하였음을보고하여 GFAP 검사가허혈성뇌졸중에서유용한생물학적표지자가될수있음을제시하였다. 그러나본연구에서는허혈성뇌졸중을진단하는데있어혈청 GFAP 검사는높은특이도를보였으나민감도가낮아진단적목적의생물학적표지자로서의유용성은매우제한적이었다. 이러한낮은민감도는열공성뇌경색환자의혈청 GFAP 수치가정상군과차이가없었기때문으로열공성뇌경색과같은작은크기의뇌손상에서는혈청 GFAP 검사는진단적목적으로유용하지않다고생각된다. 이는이전대뇌반구영역뇌경색뿐만아니라열공성뇌경색에서도혈청 GFAP 수치가조기에증가한다고보고한이전의연구와상반된결과이다. 이러한결과의차이는검사방법의민감도의차이에기인한것일수도있으나본연구에참여한전체허혈성뇌졸중환자중열공성뇌경색환자의분포가 % 로이전연구의열공성뇌경색환자의분포 (%) 보다많고 NIHSS 점수가본연구에서는 6.7점으로이전의연구에포함된환자들의 NIHSS 점수인 9.6점보다낮아상대적으로증상이경미한환자의분포가많아혈청 GFAP의임상적유용성이낮았을가능성이있다. 그러나이전연구와본연구의결과에서경색이큰대뇌반구영역경색환자들을진단하는데있어혈청 GFAP 검사는높은민감도를보여대뇌반구영역경색과같은큰신경손상이의심되는환자에서는일부도움이될것으로생각된다. 급성허혈성뇌졸중에서 GFAP, S β, NSE와같은뇌특이단백질은매우높은특이도를보이나혈중농도가낮아민감도가낮고, 급성허혈성뇌졸중때증가하는 thrombomodulin, von Willebrand factor(vwf) 등과같은혈전관련단백질, vascular cell adhesion molecule-(vcam- ), tumor necrosis factor-α(tnf-α), matrix metalloproteinase-9(mmp-9), plasminogen activator inhibitor-(pai-) 등과같은염증매개물질들은뇌졸중급성기에민감도가높으나전신염증성질환등에서도증가할수있어특이도가낮다는단점이있다. - 최근이러한제한점을극복하기위해서특이도가높은뇌특이단백질과민감도가높은염증매개물질이나혈전관련단백질들을조합하여검사함으로써진단률을향상시키기위한연구들이진행되고있다. -6 Lynch 등 은 6명의허혈성뇌졸중 환자들에서 6종류의혈중단백질을검사하여 S β, MMP-9, VCAM-, vwf 등의조합검사 (panel study) 를통하여 9% 이상의진단특이도와민감도를나타냈다고보고하였고 Tuttolomondo 등 6 도 명의허혈성뇌졸중환자를대상으로 종류의단백질을검사하여이중 TNF-α, PAI-, 그리고 tissue plasminogen activator(tpa) 를조합검사시높은민감도와특이도를보인다고보고하였다. 최근전향적으로설계된연구로 the Biomarker Rapid Assessment in Ischemic Injury(BRAIN) 연구가보고되었는데, 임상적으로뇌졸중이의심되는,6명의환자를대상으로뇌영상검사로뇌경색을확진하기전단계에서 Triage Stroke Panel을이용한 S β, MMP-9, brain natriuretic factor(bnp), D-dimer 네종류의생물학적표지자를이용한진단정확도를조사하였다. 결과는허혈성뇌졸중진단에 8% 의민감도와 % 의특이도를보여주었고이러한결과는독립적인다른 cohort 에서도검증할수있었다. 7 또한생물학적표지자를통한진단예측결과는뇌 CT (computed tomography) 결과를단독으로분석한것에비해생물학적표지자를함께고려한분석이허혈성뇌졸중의예측에있어민감도를현저히증가시켰다고보고하고있어혈중생물학적표지자검사가임상적으로유용할가능성을제시하였다. BRAIN 연구에서도낮은특이도는추후해결해야할문제이나이제까지소규모의연구들에서제기되었던연구의설계나환자군선정에서의오류들과관련된문제점을극복한무작위전향적연구로생물학적표지자의진단적가치를검증한첫연구라는데의의가있다. 추후대규모환자를대상으로한혈청 GFAP 검사법에대한전향적연구가필요하며다른생물학적표지자와조합한검사법을개발하여진단정확도를향상시켜야할것으로생각된다. 결 본연구에서혈청 GFAP 검사는급성허혈성뇌졸중의진단을위한생물학적표지자로서의유용성은낮은진단민감도를보여제한적이었다. 그러므로혈청 GFAP 검사단독으로는임상적으로활용하기에는어렵다고생각된다. 그러나혈청 GFAP 검사는급성허혈성뇌졸중환자에서신경손상의정도및장기적인예후를예측하는데있어우수한생물학적표지자로임상에서활용될수있을것으로생각된다. REFERENCES. Eng LF, Ghirnikar RS, Lee YL. Glial fibrillary acidic protein: GFAPthirty-one years (969-). Neurochem Res ;:9-.. Foerch C, Curdt I, Yan B, Dvorak F, Hermans M, Berkefeld J, et al. 론

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전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II)

전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II) 전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II) - i - - ii - - iii - - iv - - v - - vi - - vii - - viii - - ix - -