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1 Korean J Fam Pract. 2014;4: 무증상건강검진수검자에서뇌의소혈관질환의위험요인 Original Article 나연자, 엄미라, 김주일, 공미희 1, 김현주 1, * 제주대학교병원가정의학과, 1 제주대학교의학전문대학원가정의학교실 Risk Factors of Cerebral Small-Vessel Disease in Asymptomatic Adults Yeon-Ja Na, Mi-Ra Eum, Joo-Il Kim, Mi-Hee Kong 1, Hyeon-Ju Kim 1, * Department of Family Medicine, Jeju National University Hospital; 1 Department of Family Medicine, Jeju National University School of Medicine, Jeju, Korea Background: As an indicator of cerebral small-vessel disease (CSVD), leukoaraiosis and lacunar infarct are known to possible to progress the chronic disease such as cerebral infarct or dementia. These lesions have observed incidentally on brain computed tomography or magnetic resonance imaging (MRI) for health check without neurologic symptom or sign. We investigated the risk factors of these lesions of asymptomatic adults. Methods: Two hundred and ninety-four individuals who underwent the brain MRI in one health promotion center from 1st April 2009 to 30th June 2013 were analyzed based on previous medical history, current medication, age, gender, body mass index, blood pressure, blood tests, and behavioral habits including alcohol drinking, smoking, and exercise. Results: CSVD group is 118 individuals (40.1%), 65 men and 53 women and there are no differences of prevalence between gender. Average age of CSVD group is 57.35±8.35 years, higher than 51.62±10.59 years of normal group (P<0.01). The prevalence of CSVD was increased by age increase when we classified into 3 age group of <40 years, years and 60 years (P for trend<0.01). Among risk factors of cardiovascular disease such as age and sex, hypertension, diabetes mellitus, and behavioral habits, only age and hypertension were shown statistically meaningful result. Furthermore, multivariate regression analysis adjusted by age, gender and other risk factors was shown the association of the age, hypertension with CSVD. Conclusion: This study suggests that hypertension were related with CSVD identified on MRI in asymptomatic adults, the prevalence of CSVD was increased as age increase. Keywords: Cerebral Small Vessel Disease; Leukoaraiosis; Stroke, Lacunar; Risk Factors 서론 중추신경계에대한전산화단층촬영 (computed tomography) Received: August 22, 2013, Accepted: November 5, 2014 *Corresponding Author: Hyeon-Ju Kim Tel: , Fax: fmhjukim@hanmail.net Korean Journal of Family Practice Copyright 2014 by The Korean Academy of Family Medicine 이나핵자기공명영상 (magnetic resonance imaging) 이용도가증가하면서검진을목적으로이들촬영을시행한수검자들에서특이신경학적증상없이뇌백질병변이나열공경색과같은뇌의소혈관질환 (cerebral small-vessel disease, microvascular disease or microangiopathic brain lesions) 이우연히발견되는경우를많이접할수있다. 뇌의소혈관질환은뇌의소동맥과세동맥뿐만아니라모세혈관및작은정맥의손상에의해발생하는병변으로주로뇌피질하부회백질이나심부백질에나타나며열공경색, 뇌백질병변, 주요출혈및미세출혈등을포함하는포괄적인개 가정의학 Vol. 4, No. 4 Dec

2 Yeon-Ja Na, et al: Risk Factors of Cerebral Small Vessel Disease 념이고 1) 뇌백질병변 ( 혹은백질변성 ) 과열공경색이소혈관질환의지표가되는것으로알려져있다. 2) 뇌백질병변은전산화단층촬영에서수두증이나다발성경화증과같은탈수초성질환없이뇌실주변부백질에비교적대칭적으로음영이감소하게나타나며, 3) 핵자기공명영상에서는액체감쇄역전회복영상 (fluid attenuated inversion recovery imaging, FLAIR) 에서뇌실주변백질의경계가불분명한고신호강도를보이고 T1 강조영상에서저신호강도를보이는병변으로나타나고열공경색은심부피질에 cm 미만의작은경색부위로나타나며뇌백질병변과구분하기힘든경우도있다. 4) 소혈관질환의발생기전에대해서는많은연구들이있었으나원인과기전을명확하게밝히지는못하였으며혈관내경의협착과뇌혈류의자동조절이상, 뇌혈류장벽의기능장애, 만성적인뇌허혈등이연관되어있다고알려져있다. 5-7) 위험인자들에대해서는고혈압, 당뇨병과같은기왕력이나고지혈증을비롯한심혈관질환의위험인자들이관련있게나타났다는보고들이있으나연구들마다서로상이한결과를보여주고있다. 8-10) 소혈관질환의경우무증상인경우가많으나점차뇌졸중이나인지기능감퇴, 치매등으로발전될수있는것으로보고되고있으므로, 11-14) 본연구에서는뇌졸중병력이없으며신경학적증상이없는건강검진수검자에서뇌백질병변과열공경색의위험인자들에대해알아보고자하였다. 방법 1. 연구대상 2009년 4월 1일부터 2013년 6월 30일까지제주대학교병원건강증진센터를방문하여검진목적으로뇌핵자기공명영상 (brain magnetic resonance imaging) 촬영을시행한신경학적증상이없는만 20세이상의성인중에서뇌졸중진단을받았거나약물치료중인자를제외한 294명 ( 남자 172명, 여자 122명 ) 의수검자를대상으로하였다. 2. 위험요인측정모든대상자에서자가기입설문지를통해의사의면담을통해과거와현재병력, 복용중인약물, 음주, 흡연과운동을포함한생활습관을조사하였다. 음주는주 3회이상평균음주여부를기준으로비음주군과음주군으로설정하였고, 현재흡연여부에따라비흡연군과흡연군으로, 하루에 30분이상주 3회이상의규칙적운동여부에따라운동군과비운동군으로구분하였다. 모든수검자는가벼운검진가운만착용한상태에서신장, 체중을측정한후체질량지수 (body mass index) 는체중 (kg) 을신장 (m) 의제곱으로나누어계산하였고, 허리둘레는숨을내쉰뒤장골능과 12번째늑골사이의둘레를측정하였고, 최소 5분이상안정을취한후자동혈압측정계 FT-700R ( JAWON MEDICAL Co., Ltd., Seoul, Korea) 를이용하여혈압을측정하였다. 검사실검사는 8시간이상공복상태로정맥혈을채혈하여공복혈당, 총콜레스테롤, 중성지방, 고밀도콜레스테롤, 저밀도콜레스테롤, 고감도C-반응단백, 당화혈색소를측정하였다. 3. 뇌의소혈관질환측정검진에사용된핵자기공명영상은 1.5T MRI (Magnetom Sonata, Siemens Medical Solutions, Erlangen, Germany) 였으며, axial T2-, T1-weighted spin echo, FLAIR, T2-weighted GRE 등으로검사하였다. 뇌백질병변은 T2-weighted영상에서고밀도음영이보이지만 T1-weighted영상에서는뚜렷한저밀도음영이관찰되지않는병변으로진단하였고, 열공경색은 T2-weighted 영상에서직경이 3 15 mm 정도의고밀도음영이면서 T1- weighted영상에서저밀도음영인병변을기준으로하였다. 9) 4. 통계분석통계분석된자료들은평균 ± 표준편차, 또는대상자의수와함께퍼센트 (%) 로표시하였다. 대상자들을정상군과소혈관질환군으로나누어일반적특성에대한비교하였으며, 연속형변수는독립표본 T검정 (independent t-test) 을, 범주형변수는카이제곱검정 (chi-square test) 을시행하였다. 연령별소혈관질환의유병률은선형대선형결합 (linear by linear association), 위험요인의비교위험도는다변량로지스틱회귀분석 (multivariate logistic regression analysis) 을이용하였다. 자료의분석에사용한프로그램은 PASW SPSS for windows ver (SPSS Inc., Chicago, IL, USA) 을이용하였고통계적유의수준은 0.05 미만으로하였다. 결과 1. 소혈관질환의유병률및연령과의상관성 294명의수검자중에서소혈관질환은 118명 (40.1%) 으로남자 65명, 여자 53명이었고성별에따른유병률의차이는없었다. 정상군의평균연령은 51.62±10.59세, 소혈관질환군은 57.35±8.36세로정상군보다높았으며통계적으로의미가있었다 (P<0.01) (Table 1). 40세미만, 40 59세, 60세이상의 3군으로나누어분석한결과유병률이각각 3.8%, 38.9%, 53.4% 로연령이증가할수록소혈관질환의유병률이높게나타났다 (P for trend <0.01) (Figure 1). 336 Vol. 4, No. 4 Dec 2014 Korean J Fam Pract

3 나연자외 : 뇌소혈관질환의위험요인 Table 1. General characteristics of study subjects with and without CSVD Characteristic CSVD (-) (n=176) CSVD (+) (n=118) P-value* Age (y) 51.62± ±8.36 <0.01 Male gender (%) 107 (60.8) 65 (55.1) 0.33 Height (cm) ± ± Body weight (kg) 67.12± ± Body mass index (kg/m 2 ) 25.02± ± Waist circumference (cm) 86.39± ± Systolic blood pressure (mm Hg) ± ± Diastolic blood pressure (mm Hg) 77.09± ± Total cholesterol (mg/dl) ± ± Triglyceride (mg/dl) ± ± High density lipoprotein (mg/dl) 51.34± ± Fasting blood sugar (mg/dl) 94.01± ± Hypertension 28 (15.9) 35 (29.7) 0.01 Diabetes mellitus 12 (6.8) 7 (5.9) 0.76 Smoking 44 (32.4) 20 (22.7) 0.12 Alcohol drinking 66 (44.6) 37 (39.4) 0.43 Exercise 42 (29.8) 41 (40.6) 0.08 Values are presented as mean±sd or number (%). CSVD: cerebral small-vessel disease including leukoaraiosis and lacunar infarct. *P-value of continuous variables by independent t-test and P-value of categorical variables by Pearson chi-square test. Current smoker. Over three times per week. Over 30 minutes in a day and over three times per week. Prevalence of CSVD (%) P for trend < < >60 Age group (y) Figure 1. The prevalence of CSVD according to age group. P for trend by linear by linear association. CSVD: cerebral small-vessel disease including leukoaraiosis and lacunar infarct. 2. 소혈관질환의위험요인분석잘알려진심혈관질환의위험인자들이뇌의소혈관질환에서도의미있게나타나는지알아보기위해고혈압, 당뇨병과같은기왕력과복약력및음주, 흡연, 신체활동과같은생활습관을포함하여혈압과신체계측치및혈중지질, 공복혈당등을정상군과소혈관질환군으로비교한결과혈압과체질량지수, 혈액검사등은유의한결과를보이지않았으나연령과고혈압이통계적으로의미있는결과를보였다 (Table 1). 뇌의소혈관질환과위험요인과의연관성을확인하고자 Table 1에서의미있는차이를보였던연령과고혈압뿐만아니라일반적인심뇌혈관질환의위험요인이될수있는당뇨병과흡연, 음주, 운동등의생활습관등을포함하여 8-10) 다변량로지스틱회귀분석을시행한결과연령과고혈압이의미있는결과를보였다 (Table 2). 이러한결과는현재고혈압약물복용군뿐만아니라신체계측시수축기혈압이 140 mm Hg 이상이거나이완기혈압이 90 mm Hg 이상으로나타난수검자들을포 가정의학 Vol. 4, No. 4 Dec

4 Yeon-Ja Na, et al: Risk Factors of Cerebral Small Vessel Disease Table 2. Relationship of cerebral small-vessel disease and risk factors by multivariate logistic regression analysis Variable Odds ratio (95% confidence interval) P-value Age (y) ( ) <0.01 Male gender ( ) 0.12 Hypertension ( ) 0.03 Diabetes mellitus ( ) 0.44 Smoking* ( ) 0.92 Alcohol drinking ( ) 0.97 Exercise ( ) 0.77 Multivariate logistic regression analysis was performed including age, sex, hypertension, diabetes mellitus, and life style (smoking, drinking, and exercise). *Current smoker. Over three times per week. Over 30 minutes in a day and over three times per week. 함한고혈압군으로분석을하였을때에도의미있게나타났다 (data not shown). 고찰 뇌백질병변과열공경색으로대표되는뇌의소혈관질환은인지기능장애및치매와연관성으로중요시되고있으나발병기전에대해서는명확히밝혀지지는않았다. 1) 그래서일반적으로알려진심뇌혈관질환의위험인자들과소혈관질환의발병과의연관성을밝히기위한많은연구들이시행되었다. 2007년 Khan 등 8) 의연구에의하면대혈관질환은고전적인동맥경화위험인자들과연관이있고특히연령, 당뇨, 고콜레스테롤혈증, 흡연및심근경색과관련이있으며, 소혈관질환은정상군과비교했을때는연령, 고혈압, 당뇨병, 흡연이관련있는것으로나타났으나대혈관질환과의비교분석에서는단지고혈압만이연관성이있다고하였고, 이러한결과는 2003년 Schulz 등 15) 의허혈성뇌경색의아형에따른위험인자메타분석연구에서뇌경색은남성, 흡연과콜레스테롤상승과연관되어있으며소혈관질환은고혈압만이연관되어있다고한것과유사한결과였다. 1990년대뇌전산화단층촬영을이용한뇌백질병변에대한국내연구에서뇌백질병변과연령, 고혈압, 열공경색이의미있게연관되어있으며특히노인의혈관성치매발생과깊게연관되어있다고보고하였고, 16) 고혈압과당뇨환자에서의연구는고혈압환자군만이통계적으로의미있게나타났으며 특히이완기혈압이높을수록뇌백질병변의정도가심하였으나고혈압이환기간이나수축기혈압, 연령은상관성을보이지않았다고하였다. 17) 뇌핵자기공명영상을이용한 2012년한국건강관리협회의연구는신경학적이상이없는검진수검자 4,255명을대상으로뇌백질병변과열공경색군을구분하여심혈관계위험인자와의상관성을분석하여대사증후군과의연관성을확인하였으며, 열공경색이뇌백질병변보다좀더진행된소혈관질환으로추정된다고하였으며, 12) 2006년 Kwon 등 18) 은무증상뇌경색의유병률및대사증후군과의연관성을최초로밝혔으며, 2008년 Bokura 등 19) 은무증상허혈성뇌병변을무증상뇌경색과뇌실주변고신호강도및피질하뇌백질병변으로구분하여이들병변과대사증후군과의상관성을보고하였다. 본연구에서는뇌백질병변과열공경색을포함하는소혈관질환군을정상군과비교분석하였으며연령과고혈압이뇌의소혈관질환과연관성이있는것으로나타났으나체질량지수및혈압, 공복혈당이나콜레스테롤과같은혈액학적검사결과와는상관성을보이지는않았으며이는앞서기술한 Khan 등 8) 의보고와유사한결과이나, 또한 Khan 등 8) 은뇌백질병변, 열공경색을소혈관질환의아형으로구분하여아형간위험인자들의차이가있음을기술하였다. 이러한결과는대혈관질환과는다르게소혈관질환의발생기전이동맥경화뿐만아니라혈관내피세포의기능장애를초래하게되는여러기전들이복합적으로작용할수있음을시사해주는바이다. 본연구는제주대학교병원에서자발적으로뇌핵자기공명영상촬영을시행한검진수검자들을대상으로한소규모단면연구로서연구결과가일반집단을대표할수없으며, 인과관계를입증할수없다는한계가있으며, 또한자가기입식설문지를이용하였기에정확한분석에어려움이있었다. 하지만무증상성인에서뇌백질병변이나열공경색과같은소혈관질환이상당히많이발견될수있음을확인하였고이들질환이인지기능장애나치매, 뇌경색으로진행할수있는만큼주의가요구된다고하겠다. 결론적으로본연구결과신경학적이상이없는성인에서뇌백질병변과열공경색등소혈관질환은고혈압과연관성이있었으며연령증가에따라이들병변이증가된것으로나타났다. 하지만기존심혈관질환의위험요인인비만, 혈중지질, 당뇨병, 생활습관등과는의미있는관련성은없는것으로나타났다. 앞으로대규모의데이터수집과인지기능검사의병행을통해뇌의소혈관질환및아형에따른위험인자들을분석한다면이들질환의기전을이해하고예방하는도움이될수있을것으로생각된다. 338 Vol. 4, No. 4 Dec 2014 Korean J Fam Pract

5 나연자외 : 뇌소혈관질환의위험요인 요약 연구배경 : 뇌백질병변과열공경색은뇌경색이나치매와같은만성질환으로진행될수있다고알려진뇌의소혈관질환의지표로서신경학적이상없이검진을목적으로뇌핵자기공명영상촬영시우연히관찰되는경우가많다. 본연구에서는이렇게우연히관찰된이들병변의유병률과위험요인에대해알아보고자하였다. 방법 : 2009년 4월 1일부터 2013년 6월 30일까지제주대학교병원건강증진센터를방문하여검진목적으로뇌핵자기공명영상촬영을시행한신경학적증상이없는만 20세이상의성인중에서뇌졸중진단을받았거나약물치료중인자를제외한 294명 ( 남자 172명, 여자 122명 ) 의수검자를대상으로뇌의소혈관질환 ( 뇌백질병변및열공경색 ) 에대한분석을시행하였다. 결과 : 294명의수검자중에서소혈관질환은 118명 (40.1%) 으로남자 65명, 여자 53명이었고, 성별에따른유병률의차이는없었다. 정상군의평균연령은 51.62±10.59세, 소혈관질환군은 57.35±8.35세로정상군보다높았으며통계적으로의미가있었다 (P<0.01). 40세미만, 40 59세, 60세이상의 3군으로나누어분석한결과연령이증가할수록소혈관질환의유병률이높게나타났다 (P for trend <0.01). 뇌의소혈관질환의위험인자로서고혈압, 당뇨병과같은기왕력과복약력및음주, 흡연, 신체활동과같은생활습관, 혈압과신체계측치및혈중지질, 공복혈당등을분석하였으며이들중에서고혈압이유일하게의미있는결과를보였고, 연령과성별, 당뇨병과생활습관등을다변량로지스틱회귀분석을통해분석한결과연령과고혈압이소혈관질환과통계학적으로의미있게관련된것으로나타났다. 결론 : 본연구에서는신경학적이상이없는건강검진수검자에서뇌핵자기공명영상에서확인된뇌의소혈관질환은연령이증가할수록유병률이높았으며, 고혈압과상관성이있는것으로나타났다. 중심단어 : 소혈관질환 ; 뇌백질병변 ; 열공경색 ; 위험요인 REFERENCES 1. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9: Schmidt R, Schmidt H, Fazekas F. Vascular risk factors in dementia. J Neurol 2000;247: Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987;44: Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993;43: O Sullivan M, Lythgoe DJ, Pereira AC, Summers PE, Jarosz JM, Williams SC, et al. Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis. Neurology 2002;59: Terborg C, Gora F, Weiller C, Rother J. Reduced vasomotor reactivity in cerebral microangiopathy: a study with near-infrared spectroscopy and transcranial Doppler sonography. Stroke 2000;31: Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke 1997;28: Khan U, Porteous L, Hassan A, Markus HS. Risk factor profile of cerebral small vessel disease and its subtypes. J Neurol Neurosurg Psychiatry 2007;78: Nah EH, Cho HI. Relationship of white-matter lesions and lacunar infarcts with cardiovascular risk factors. Lab Med Online 2012;2: Ben-Assayag E, Mijajlovic M, Shenhar-Tsarfaty S, Bova I, Shopin L, Bornstein NM. Leukoaraiosis is a chronic atherosclerotic disease. ScientificWorldJournal 2012;2012: Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348: Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM, et al. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003;34: Jokinen H, Gouw AA, Madureira S, Ylikoski R, van Straaten EC, van der Flier WM, et al. Incident lacunes influence cognitive decline: the LADIS study. Neurology 2011;76: Leistner S, Koennecke HC, Dreier JP, Strempel AK, Kathke M, Nikolova A, et al. Clinical characterization of symptomatic microangiopathic brain lesions. Front Neurol 2011;2: Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 2003;34: Cha JK, Lee KH, Kim DK, Chung KC, Kim MH. Relationship of leukoaraiosis with cerebrovascular disease. J Korean Neurol 가정의학 Vol. 4, No. 4 Dec

6 Yeon-Ja Na, et al: Risk Factors of Cerebral Small Vessel Disease Assoc 1991;9: Kim SE, Lee TY, Heo K, Cho HK. The frequency of leukoaraiosis in diabetes mellitus and hypertension; the quantitative correlation of leukoaraiosis and its risk factors. J Korean Neurol Assoc 1992;10: Kwon HM, Kim BJ, Lee SH, Choi SH, Oh BH, Yoon BW. Metabolic syndrome as an independent risk factor of silent brain infarction in healthy people. Stroke 2006;37: Bokura H, Yamaguchi S, Iijima K, Nagai A, Oguro H. Metabolic syndrome is associated with silent ischemic brain lesions. Stroke 2008;39: Vol. 4, No. 4 Dec 2014 Korean J Fam Pract

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 - -