Dementia and Neurocognitive Disorders 2005; 4: 63-7 혈관성인지장애의최신치료 이애영 충남대학교의과대학신경과학교실 New Treatment of Vascular Cognitive Impairment Ae Young Lee, M.D. Department of Neurology, College of Medicine, Chungnam National University, Daejeon, Korea Address for correspondence Ae Young Lee, M.D. Department of Neurology, Chungnam National University Hospital, 640 Daesa-dong, Jung-gu, Daejeon 301-721, Korea Tel: +82-42-220-7807 Fax: +82-42-252-8654 E-mail: aelee@cnu.ac.kr Patients with vascular cognitive impairment (VCI) have cognitive decline associated with underlying cerebrovascular disease (CVD). The concept of VCI has been broadened to refer all forms of mild to severe cognitive impairment caused by CVD. Characteristic neuropsychological profile of VCI, particularly subcortical ischemic vascular dementia, includes early and prominent disturbance of attention and executive function with less severe episodic memory impairment. Evidence from neuropsychological studies of VCI shows that cognitive profile in VCI is associated with disruption of frontosubcortical circuits by lacunes and white matter lesions which are frequently located in frontal subcortical areas. Early recognition of VCI before the progression to vascular dementia is the main goal of clinical interest. Primary and secondary prevention of stroke can decrease the incidence and prevalence of VCI. Treatment with cholinesterase inhibitors showed modest symptomatic improvement in cognitive and non-cognitive abilities in patients with vascular dementia. But patients with VCI are too heterogeneous to evaluate the clinical efficacy of therapeutic trials. Selectivity on specific type of VCI seems to be better for defining treatment effectiveness in the field of VCI. Key Words: Vascular dementia, Cerebrovascular disease, Treatment 혈관성인지장애 (Vascular cognitive impairment) 혈관성인지장애는뇌혈관질환에의한뇌손상때문에생긴인지기능저하를의미하며혈관성경도인지장애 (vascular mild cognitive impairment) 부터혈관성치매 (vascular dementia) 까지인지기능저하정도가다양하다 [1]. 현재사용하는혈관성치매 (vascular dementia) 의임상진단기준이알쯔하이머치매의전형적인증상인기억장애에초점을맞추어진단을내린다는점과치매진단에합당한정도로인지기능저하가진행되어야진단이가능하므로혈관성질환에의한인지장애환자의조기발견이쉽지않다는점때문에혈관성치매보다 혈관성인지장애 의사용을추천하고있다 [1, 2]. 혈관성인지장애는원인이되는혈관병리나또는인지기능저하를일으킨병변의위치에따라 Table 1과같이분류하기도하고 [3] 뇌졸중병변의종류에따라 1) 뇌경색성병변 ( 동맥폐색에따른완전경색과수질소동맥폐색과심장정지또는순환이상에의한불완전경색 ) 은대혈관질환 (large-vessel disease) 과소혈관질환 (small-vessel disease) 으로세분하며, 2) 출혈성병변 ( 고혈압성뇌출혈, 뇌아밀로이드혈관병증, 지주막하출혈, 뇌출혈후폐색성수두증, 경막하출혈 ), 3) 뇌정맥혈전증 (cortical vein & sinus thromboses) 과같이경색과출혈이동반된경우로나누기도한다 [4]. 다발성뇌경색치매 (multi-infarct dementia) 가대혈관질환에의한혈관성치매의가장흔한유형이며우측후뇌동맥 (posterior cerebral artery) 이나전뇌동맥 (anterior cerebral artery) 폐색에따른단일병변에의한치매 (strategic infarct dementia) 도대혈관질환에의한혈관성치매에속한다. 소혈관질환에의한혈관성치매는대뇌피질손상없이내포, 시상또는미상핵등에생긴열공성뇌경색에의한피질하허혈성혈관성치매 (subcortical ischemic vascular dementia) 가대표적이며다발성열공성뇌경색 (lacunar state) 이나빈스뱅거병 (Binswanger s disease) 이포함된다. 최근에는대혈관질환에의한혈관성인지장애보다백질변성의임상적의미나열공성뇌경색에의한인지기능저하와같은피질하허혈성혈관성치매에대한관심이높아지고있다. 소혈관질환에의한열공성뇌경색이나불완전경색으로분류되는백질변성은주로전전두엽-피질하회로 (prefrontal-subcortical circuit) 에손상을준다. 따라서혈관성인지장애는수행기능이상 (executive dysfunction) 과같은전두엽기능장애 (frontal lobe dysfunction) 와정신완서 (bradyphrenia) 와같은 63
64 이애영 Table 1. Classification and causes of sporadic vascular cognitive impairment Vascular risk factors, gentic factors, age, lifestyle Vascular dementia Multi-infarct dementia (cortical vascular dementia) Subcortical ischemic vascular dementia Strategic-infarct dementia Hypoperfusion dementia Hemorrhagic dementia Dementia caused by specific arteriopathies Mixed AD and vascular dementia Vascular mild cognitive impairment Large vessel Large cortical Infarcts Small vessel Small Infarcts (lacunae) Partial vessel White matter lesions Hypotensive eplsodes (Adopted from O Brien et al, 2003). MID Brain atrophy SIVD 피질하기능이상 (subcortical dysfunction) 이주로나타나며알쯔하이머치매의주증상인기억장애 (memory loss) 와뇌졸중으로인한국소적인피질기능이상으로실어증 (aphasia), 실행증 (apraxia), 또는실인증 (agnosia) 도나타날수있다 [2, 5-7]. 혈관성인지장애를시사하는임상적특징으로뇌졸중후갑자기발생한인지기능저하를들수있지만일부혈관성치매진단기준에서제시하는뇌졸중후 3개월이내발생하는인지장애는흔치않다 [8]. 혈관성치매의경과역시뇌졸중재발에따른단계적진행 (stepwise progression) 을보이는것으로알려져왔으나이런전형적인경과는전체혈관성치매환자의 30% 정도에서만관찰되는것으로보고되었다 [8]. 따라서혈관성인지장애가퇴행성치매처럼인지기능이점진적으로저하될수도있으며혹은인지기능이호전될수도있다. 혈관성치매나혈관성인지장애의진단을위해서뇌졸중의증거가필수적이지만뇌졸중병변이증상을일으키지않는경우도있으므로임상적으로뚜렷한뇌졸중의기왕력이반드시필요한것은아니다. 뇌졸중에의한국소적인결손징후 (focal signs) 가있으면혈관성치매또는혈관성인지장애진단을좀더확신할수는있으나신경학적국소증상이진단에필수적인것은아니다. 또한알쯔하이머병에비하여보행장애와요실금이혈관성치매에서더일찍나타나는경향을보여서진단에도움을주기는하지만임상적으로흔하지는않다. 따라서뇌졸중후갑작스런인지저하, 인지기능의단계적저하, 국소신경학적징후의동반, 뇌졸중과의시간적인과관계, 또는뇌졸중의기왕력이있다고반드시환자의인지기능저하가뇌졸중때문임을확신할수는없다. 뇌졸중에의하여발생하는치매는전체치매의약 20% 정도를차지하여알쯔하이머치매다음으로많은빈도를차지한다 [9]. 65세이상허혈성뇌경색환자의 25-33% 에서치매가발생하며 [10, 11] 허혈성뇌졸중이 60대에서치매위험도를 9배높이며 70대에서는뇌졸중에의한치매위험도가 30배가넘는다 [12]. 고령 (older age), 낮은교육수준, 흡연, 저혈압이나기립성저혈압, 뇌경색에동반된합병증 ( 예, 저산소증, 간질, 흡인성폐렴, 저혈압 ), 연하장애, 보행장애, 그리고뇌사진에서심한백질변성이나뇌위축이있는경우뇌졸중후치매가잘생긴다 [10, 13-15]. 따라서고령이나유전적소인, 또는혈관성위험인자에 Cognitive Impairment, dementia, non-cognitive features (eg, depression) Fig. 1. Pathophysiological mechanisms in vascular cognitive impairment. Vascular risk factors such as hypertension can cause of cerebral large- and small-vessel. Complete and incomplete cerebral infarction result in loss of neuron and cortical atrophy, which produce cognitive decline and non-cognitive symptoms such as depression and loss of volition in VCI. (Adopted from O Brien et al, 2003). 의하여뇌의대혈관또는소혈관폐색이생기고대뇌피질에손상을주는피질경색이나피질하열공성뇌경색과백질변성이발생하고뇌위축이동반되면혈관성인지장애가더잘나타난다 (Fig. 1)[3]. 임상적으로치매가뚜렷하지않은알쯔하이머치매에뇌경색이동반되면알쯔하이머치매의병리소견 ( 노인반또는신경섬유농축체 ) 과뇌졸중병변의상승작용을통하여임상적으로뚜렷한치매가생긴다 [16]. 그러므로혈관성인지장애나혼합형치매 (mixed dementia) 에서혈관성위험인자 (vascular risk factors) 를엄격하게조절함으로써혈관성인지장애가혈관성치매로진행하는것을막을뿐만아니라알쯔하이머치매의빈도도줄일수있다. 혈관성인지장애의치료 (Treatment of vascular cognitive impairment) 1. 뇌졸중예방에대한치료 혈관성인지장애의예방적인치료는뇌졸중의치료와예방으로서 (1) 급성뇌졸중의조기진단과적절한치료, (2) 뇌졸중재발방지, 그리고 (3) 뇌졸중위험인자를적극적으로치료함으로써혈관성치매와관련된뇌의변화를지연또는방지하는것이다 [17]. 뇌졸중급성기에부정맥, 심부전, 심근경색, 간질또는폐렴등이발생하면저산소성허혈변화가가중되어혈관성
혈관성인지장애의최신치료 65 치매발생을증가시키므로주의해야한다 [13]. 뇌졸중의예방및재발방지를위하여적극적인혈압조절이필요하다. 유럽에서시행된수축기고혈압연구 (SYST-EUR Study) 에서평균 3.9년동안관찰한결과장기적인고혈압치료가치매의위험도를 55% 감소시켰으며특히칼슘길항제 (nitrendipine) 가알쯔하이머치매와혈관성치매예방에효과가있었다 [18]. 65세이상지역거주민을대상으로한무작위임상연구에서도고혈압치료가뇌졸중재발위험을 28% 줄이고치매위험도를 38-55% 감소시켰다 [19]. 칼슘길항제인니모디핀 (nimodipine) 은소혈관과측부순환혈관을확장시켜병변쪽으로가는혈류를증가시키고손상받은신경원내로칼슘유입을차단하여신경을보호한다 [20, 21]. 니모디핀이다발성뇌경색치매 (multi-infarct dementia) 환자의인지기능과일상생활기능을향상시키지는못했지만 [22] 소혈관질환인피질하허혈성혈관성치매환자만을따로분석한결과주간생활기기활동 (instrumental activities of daily living) 과전두엽기능이뚜렷하게향상되는효과를보였다 [23]. 최근연구에의하면고지혈증치료제 (lipid-lowering agent) 인스타틴 (statins, 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitor) 이관상동맥질환이나고혈압또는당뇨같은혈관성위험인자를가진환자에게뇌졸중재발을막고 [24] 알쯔하이머치매에서 A 형성을차단하여치매위험률을감소시켰다 [25, 26]. 고지혈증이알쯔하이머치매를제외한다른유형의치매발병률을증가시켰으며스타틴을복용하는경우치매발병률이훨씬적었다 (OR=0.61, 95% CI=0.41-0.91)[26]. 특히 APOE 4를가진환자는다른유전자형을가진환자보다 5-7년후인지장애가더심하고 [27] 스타틴치료가 APOE 4 유전자형을가진환자의인지기능을호전시켰다 [28]. 심장질환은고령화와함께증가하며특히심방세동은뇌졸중의위험을 7배정도증가시키므로항응고제나항혈소판제를사용하여심장세동과관련된뇌졸중발생을줄여야한다. 뇌졸중의과거력이있거나일과성허혈발작 (transient ischemic attack) 의병력이있는사람은뇌졸중재발에대한위험도가 10배정도높아지므로적극적인치료로혈관성인지장애발생을막아야한다 [4]. 당뇨병이있으면뇌졸중위험도가 4배높아지고치매위험도는 2배정도높아지므로혈당관리를엄격하게하여뇌졸중과혈관성치매발생을예방해야한다 [4]. 혈중호모시스테인 (homocysteine) 이높으면혈관내피세포의기능을방해하여뇌혈관질환과치매의위험이높아진다 [29]. 최근연구에서혈중호모시스테인농도가 14 mol/l 이상이면알쯔하이머치매를비롯한치매위험도가두배로증가하였다 [30]. 혈중호모시스테인증가는혈관내피세포의기능이상에의하여특히대뇌소혈관질환을잘유발하므로열공성경색이나백질변성이심한환자에게엽산 (folate) 이나비타민 B12를투여하여호모시스테인을감소시킬수있다 [31]. Table 2. Drugs tested in patients with vascular cognitive impairment classified according to their possible mechanism of action. Antiplatelet Aspirin Triflusal Ergot derivatives Hydergine Nicergoline Vasodilators Hyclandelate Buflomedil Naftidrofuryl Denbufylline Nootropics Piracetam Oxiracetam CDP-choline (Adopted from Pantoni L, 2004). Xantine derivatives Pentoxifylline Propentofylline Hemorrheologic Sulodexide Neurotrophic Posatirelin Pyritinol Vincamine Ginkgo biloba Cerebrolysin Vinpocetine Calcium-antagonists Nicardipine Nimodipine 메만틴 (memantine) 은 N-methyl-D-aspartate 수용체차단제로서글루탐산염에의한흥분독성 (glutamate-induced excitotoxicity) 을막아서뇌세포손상을감소시킨다 [32]. 메만틴을투여하여중등도이상으로진행한혼합형치매환자의전반적인기능이향상되고간호의비중이감소하는효과를보였다 [33]. 메만틴은대혈관질환에의한혈관성치매보다는대뇌피질손상이없는소혈관질환에의한피질하허혈성혈관성치매에서우수한효과를보였다 [34]. 혈관성치매 (MMSE score 12-20) 환자를대상으로 28주동안메만틴 (20 mg/day) 과위약의효과를비교한연구에서메만틴으로치료한환자의인지기능이호전되었고심각한부작용도없었다 [35]. 메만틴이신경보호작용을보여서치매진행을지연시키는지는아직확실하지않지만환자의인지기능을호전시키는효과는기대할수있다. 그밖에도다양한기전의약제들이혈관성인지장애환자에게시도되었다 (Table 2)[36]. 2. 콜린에스테라제억제제 (Cholinesterase inhibitors) 알쯔하이머치매뿐아니라혈관성치매의인지기능저하도콜린결핍과관련이있다 [37]. 콜린형성을담당하는전뇌기저부 (basal forebrain) 는관통세동맥 (penetrating arterioles) 에의해혈액공급을받는데이혈관들은고혈압에쉽게영향을받는다 [38]. 콜린은전뇌기저부 (basal forebrain) 에있는브로카대각대 (diagonal band of Broca), 내측중격핵 (medial septal nuclei), 그리고마이너트기저핵 (nucleus basalis of Meynert) 에서생성되며 [39] 대뇌백질을경유하여대뇌피질로전달된다 [40]. 혈관성치매환자의전두엽에서흔히관찰되는열공성뇌경색이나백질변성에의하여대뇌피질로가는콜린경로가차단되어실행기능 (executive function) 과주의집중력 (atten-
66 이애영 tion) 에장애가초래될수있다 [41, 42]. 생화학적으로는혈관성치매환자의대뇌피질, 해마, 선조체, 그리고뇌척수액에서아세틸콜린활동도가저하되었다 [43]. 이런해부학적또는생화학적증거가혈관성인지장애환자에게콜린에스테라제억제제효용성을제시하였다. 현재알쯔하이머치매에서사용하고있는도네페질, 리바스티그민, 갈란타민을혈관성치매에서도사용할수있다. 혈관성치매환자를대상으로갈란타민 (24 mg/d) 과위약- 대조연구에서갈란타민을복용한환자가위약투여군에비하여인지기능이나일상활동, 행동증상에호전을보였다 [44]. 다기관이참여한도네페질-위약대조연구에서도도네페질치료군 (5 & 10 mg) 이위약군에비하여인지기능과전반적인모든기능이호전되었다 [45]. 따라서알쯔하이머치매의동반여부에관계없이혈관성인지장애환자에게콜린에스테라제억제제치료를고려해야한다. 결론치매의원인중에서뇌혈관질환이차지하는빈도는약 20-30% 정도이지만뇌혈관질환환자가기억장애클리닉이나치매클리닉에내원하는비율이낮은것을고려한다면실제로혈관성인지장애의빈도는훨씬더높을것이다. 혈관성인지장애환자의절반 (49%) 이 5년후치매로진행되며혈관성치매환자의 5년내사망률이 60% 로높은점을고려하면 [46] 혈관성인지장애의조기발견과뇌혈관질환위험인자에대한적극적인치료가매우중요하다. 위약-대조무작위임상연구를통하여다양한약제들이혈관성인지장애개선에도움이된다고보고하였지만공식적으로허가를받은치료제는없는실정이다. 현실적으로혈관성인지장애환자를대상으로한무작위임상연구가매우적고연구마다혈관성인지장애에대한진단기준이나약효평가기준이다르다는문제점도있다. 혈관성인지장애에는대뇌동맥폐색에의한피질손상부터소혈관질환에의한백질변성이동반되는피질하허혈성혈관성치매까지다양한병변을가진환자가포함되므로병변의종류나뇌졸중발생기전의다양성때문에치료제의효과평가가쉽지않다. 혈관성인지장애에대한통일된임상진단기준을마련하고뇌졸중발생기전이나병변의종류에따라환자를세분하여약제의효과를평가하는대규모무작위임상연구가필요한실정이다. 참고문헌 1. Hachinski VC, Bowler JV. Vascular dementia. Neurology 1993; 43: 2159-60. 2. Bowler JV, Hachinski V. The concept of vascular cognitive impairment. In: Erkinjuntti T, Gauthier S. Vascular cognitive impairment. London: Martin Dunitz. 2002; 9-25. 3. O Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, et al. Vascular cognitive impairment. Lancet Neurol 2003; 2: 89-98. 4. Roman GC. Vascular dementia: Distinguishing characteristics, treatment, and prevention. J Am Geriatr Soc 2003; 51: S296-S304. 5. Tatemichi TK, Desmond DW, Stern Y, Paik MC, Sano M, Bagiella E. Cognitive impairment after stroke: frequency, patterns, and relationship to functional disabilities. J Neurol Neurosurg Psychiatry 1994; 57: 202-7. 6. Breteler MM, van Swieten JC, Bots ML, Grobbee DE, Claus JJ, van den Hout JH, et al. Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: The Rotterdam Study. Neurology 1994; 44: 1246-52. 7. Cummings JL. Vascular subcortical dementias: clinical aspects. Dementia 1994; 5: 177-80. 8. Wetterling T, Kanitz RD, Borgis KJ. Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS- AIREN). Stroke 1996; 27: 30-6. 9. Geldmacher DS, Whitehouse PJ. Evaluation of dementia. N Eng J Med 1996; 335: 330-6. 10. Pohjasvaara T, Mantyla R, Salonen O. How complex interactions of ischemic brain infarcts, white matter lesions, and atrophy relate to poststroke dementia. Arch Neurol 2000; 57: 1295-300. 11. Desmond DW, Moroney JT, Paik MC, Sano M, Mohr JP, Aboumatar S, et al. Frequency and clinical determinants of dementia after ischemic stroke. Neurology 2000; 54: 1124-31. 12. Tatemich TK, Desmond DW, Mayeux R, Paik MC, Stern Y, Sano M, et al. Dementia after stroke: baseline frequency, risks, and clinical features in a hospitalized cohort. Neurology 1992; 42: 1185-93. 13. Moroney JT, Bagiella E, Desmond DW, Paik MC, Stern Y, Tatemichi TK. Risk factors for incident dementia after stroke. Role of hypoxic and ischemic disorders. Stroke 1996; 27: 1283-9. 14. Liu CK, Miller BL, Cummings JL, Mehringer CM, Goldberg MA, Howng SL, et al. A quantitative MRI study of vascular dementia. Neurology 1992; 42: 138-42. 15. Mungas D, Jagust WJ, Reed BR, Kramer JH, Weiner MW, Schuff N, et al. MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer s disease. Neurology 2001; 57: 2229-35. 16. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997; 277: 813-7. 17. Erkinjuntti T, Roman G, Gauthier S, Feldman H, Rockwood K. Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke 2004; 35: 1010-7. 18. Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu
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