임상병리검사과학회지 : 35 권제 1 호, 68-73, 2003 알츠하이머병환자에서콜린에스터라제억제제의투여에의한대뇌피질국소혈류의변화 영남대의료원신경과생리검사실 대구보건대학임상병리과 1 김천대학임상병리과 2 문성식 김영활 1 김병원 2 Change of Regional Cerebral Blood Flow in Alzheimer's Disease Patients treated with Cholinesterase Inhibitors Moon, Seung Sik., Kim, Young Hwal 1., Kim, Byung Weon 2 College of Medicine, Yeungnam University, Daegu, Korea Electrophysiolgy Laboratory Yeungnam University Hospital Department of Clinical Pathology, Daegu Health College Daegu, Korea 1 Department of Biomedical Laboratory Science, Gimcheon College, Gimcheon, Korea 2 Alzheimer`s Disease(AD) is a progressive, degenerative disease that attacks the brain resulting in impaired memory, thought processing, and behavior. This is associated with a loss in presynaptic cholinergic function. It has been suggested that cholinergic inhibitors could restore this function and improve some symptoms of AD. Previous studies have shown that cholinesterase inhibitors(chei) improve cognitive and global functions in patients with mild to moderate AD. This study aims to evaluate regional cerebral blood flow(rcbf) changes and contemporary clinical responses such as cognitive and psychiatric symptoms after ChEI treatment. The subjects were eight at risk AD patients(four males and four females, mean age 69.63 years) recruited from the department of Neurology at Yeungnam University Medical Center between August 2000 and April 2002. The clinical diagnosis of AD was based on DSM-Ⅳ and NINCDS-ADRDA criteria. Huchinski ischemic scores of all the patients were below 1. The mean treatment duration was 30.38 weeks, ranging between 24 to 44 weeks. Four patients received Rivastigmine(Exelon R ) 12mg after titration, three patients received Donepezil(Aricept R ) 10mg during the whole period, and one patient received Donepezil 10mg after the initial 5mg for three weeks. The base line and follow up Ethylene Cysteine Diethylester Single Photon Emission Computed Tomography( 99m TC-ECD SPECT) studies were done within one week prior to ChEI treatment and within one week following the study. Regions of interest(rois) were drawn over the left and right frontal lobe, temporal lobe, parietal lobe, and cerebellum. Region to cerebellar ratio(rcr)(each count in the ROIs divided by mean cerebellar ROI count) were calculated as a estimation 1) 교신저자 : 김병원,( 우 )740-704 경상북도김천시삼락동 754 번지김천대학임상병리과 Tel : 054-420-4048 E-mail : kimbw1@gimcheon.ac.kr 68
of rcbf, and base line RCRs were compared with those of the follow up. The results display an overall increase in global cerebral blood flow through K-MMSE(Korean-Mini Mental State Examination), CDR(Clinical Dementia Rating), CDR-SB(Clinical Dementia Rating-Sum of Box), GDS(Global Deterioration Scale), and NPI(Neuropsychiatric Inventory, Cummings). We found that the most significant increase in blood flow occurred in the bilateral parietal lobes(p<0.05). Reduction in the rcbf is more profound on the left hemisphere in the base line(p<0.05) where there is a significant increase of rcbf after ChEI treatment compared with to right hemisphere(p<0.05). Key Words: Alzheimer`s disease, Cholinesterase inhibitors, Regional cerebral blood flow I. 서론 알츠하이머병 (alzheimer`s disease : AD) 은광범위한대뇌피질의퇴행성변화에의해서초래되는질환으로서주증상이치매이며그외에정신이상및이상행동도함께수반된다. 이러한치매증상은대뇌의아세틸콜린 (acetylcholine, Ach) 의감소와관련이있다 (Davies와 Maloney, 1976). 아세틸콜린은 acethylcholin transferase(cat) 라는효소에의해생산되고 acethylcholine-esterase(acethy: AchE) 라는효소에의해분해되어그양이조절되는물질인데콜린에스테라제억제제 (cholinesterase inhibitor, ChEI) 를이용하여아세틸콜린의분해과정을억제해줄경우아세틸콜린의양이증가되어알츠하이머환자의치매증상이호전될수있다 (Giacobini와 Becker, 1989). 알츠하이머환자의경우뇌자기공명영상 (brain magnetic resonance imaging: brain MRI) 촬영을할경우대뇌피질의위축현상이나타난다. 또한뇌단일광전자단층촬영 (brain single photon emission computed tomography: brain SPECT) 을실시할경우역시전반적인대뇌피질의뇌혈류감소소견을보이며특히측두엽과두정엽의뇌혈류가초기부터감소되어있을뿐만아니라시간이지날수록감소가더심해져서나중에는전두엽까지뇌혈류가감소된다 (Brown 등, 1996). 이러한소견은뇌자기공명영상과함께알츠하이머를진단하는데있어서매우중요한진단방법중의한방법으로알려져있다 (Jagust 등, 2001). 콜린에스테라제억제제가알츠하이머환자의치매증상과정신증상에효과가있다는것은여러연구 (Birks 등, 2000(1); Birks 등, 2000(2); Cummings, 2000; Qizilbash 등, 2000) 를통해이미잘알려져있으나어떠한생리적변화 에의해서콜린성시스템에작용하여증상을호전시키고질환의경과를완화시키는지에대해서는명확하지않다. 그러나몇건의알츠하이머환자를대상으로한연구에서콜린에스테라제억제제투여를실시할경우저하된대뇌피질의전반적인뇌혈류를보존 (Nakano 등, 2001) 해주거나혹은개선 (Vennerica 등, 2002) 시켜줄뿐만아니라일부분의뇌혈류즉, 양측전두엽과측두엽의국소뇌혈류량 (rcbf: regional Cerebral Blood Flow) 을증가시켜주는것으로보고되어있다 (Staff 등, 2000). 또한특정정신증상과관련되어저하된뇌혈류량이정신증상의호전과더불어향상시켰다는보고 (Warren 등, 1998; Mega 등, 2000) 가있으며, Warren 등 (1998) 은환각증상을나타내는알츠하이머환자에서콜린에스테라제억제제인 Donepezil 투여후 99m TC-HMPAO( 99m TC-Hexamethylpropylene amine oxime) 를이용한뇌단일광전자단층촬영검사소견상전두엽과측두엽의뇌혈류가현저히증가한다고하였으며, Mega 등 (2000) 은안와 (orbital) 부와전두엽후방측면 (dorso-lateral frontal) 부의뇌혈류량이투여전부터심하게저하된알츠하이머환자의경우과민반응을보이고충동을억제할수없을뿐만아니라다행증이심한정신증상소견을보이는데이런환자에게콜린에스테라제억제제를투여할경우반응이좋다고보고한바있다. 따라서본연구는현재까지연구가이루어지지않은한국인알츠하이머환자를대상으로하여콜린에스테라제억제제투여전과투여후의뇌단일광전자단층촬영소견을비교하여콜린에스테라제억제제가한국인알츠하이머환자의대뇌피질의혈류량에미치는효과를조사하였다. 69
II. 재료및방법 F 1. 연구대상 2000년 8월부터 2002년 4월사이에영남대학병원신경과를내원한치매환자를대상으로신경학적검사를시행하여국소신경증상이없으면서 DSM Ⅳ 치매기준과 NINCDS/ADRDA(National Institute for Neurological and Communicative Disorders and Stroke/Alzheimer`s Disease and Related Disorders Association) criteria를만족하고 brain MRI 소견상다른치매의원인이없는 8명 (M:F=4:4) 을잠정알츠하이머 (probable AD) 로진단하고연구대상으로하였다. 모든환자에서 Huchinski 허혈계수는 1 이하였다. 연령은 61세에서 78세까지로하였으며평균연령은 69.63±5.60세였다. 콜린에스터라제억제제로이용되는 Rivastigmine(Exelon R ) 과 Donepezil(Aricept R ) 을각각 4명에게투여하였다. Rivastigmine은 3mg, 6mg, 9mg을각각 4주간씩투여한후증량하여 12주간투여하였으며나머지기간은 12mg을투여하였다. 그리고 Donepezil은 1명에게 3주간 5mg을투여한후 4주때부터 10mg을투여하였으며 3명은 10mg을연구시작부터종료시점까지투여하였다. 콜린에스테라제억제제의총투여기간은 24주에서 44주까지로평균기간은 30.38±7.82주였다. T C Fig. 1. Regions of interest. F: Frontal lobe, T: Temporal lobe, P: Parieta lobel, C: Cerebellum 대뇌반구의혈류량은대뇌피질전반에걸쳐뇌혈류량이감소하는알츠하이머에서도대체로혈류량의변화가적어일정하게유지되기때문에뇌혈류량의정량적지표로삼았다. 그리고국소뇌혈류량은다음과같은방법으로산출하였다. RCR = P Count of ROI Mean count of cerebellar hemispheres ROIs 각군에서콜린에스테라제억제제투여전 후관심영역의국소뇌혈류량변화의유의성을비교하기위하여표본의값이정규분포를따르는 P value test를이용하여통계학적분석을실시하였다. 2. 뇌단일광전자단층촬영검사 99m TC-ECD(ethylene cysteine diethylester) 를이용한뇌 III. 결 과 단일광전자단층촬영검사는콜린에스테라제억제제투여전과후각일주일이내시행하였으며뇌혈류량의변화를비교분석하였다. 뇌단일광전자단층촬영영상은 Fanbeam Collimator를장착한이중헤드감마카메라를이용하여얻었다. 환자를희미한불빛조명의조용한방에서앙와위자세로 10분간안정시킨후 740MBeq의 99m TC- ECD를정맥주사하였으며 1시간후에자료수집을시작하였다. 관심영역 (ROIs : regions of interests) 은양측대뇌의전두엽, 측두엽, 두정엽및소뇌의 8개부위로정하고각각의관심영역에서구한계수율 (count) 을대뇌의계수율로나누어상대적국소뇌혈류량 (RCR : region to cerebellar ratio) 을구하였다 (Fig. 1). 콜린에스테라제억제제투여후뇌혈류량은전반적으로호전되는경향을보였다. 특히양측두정엽에서는좌 우측대뇌반구의국소뇌혈류량이각각 0.06씩증가하여콜린에스테라제억제제투여전에비해뇌혈류량이의미있게증가하였다 (p<0.05). 양측전두엽과좌측측두엽의국소뇌혈류량도콜린에스테라제억제제투여후에모두동일하게 0.03씩증가하였으나통계적유의성은없었고, 우측측두엽에서는변화가없는것으로나타났다 (Table 1, Fig. 2). 좌 우측대뇌피질의뇌혈류량은투여전평균이좌측에서는 0.84±0.09, 우측에서는 0.87±0.09로나타나좌측에서유의하게감소되었고 (p<0.05), 투여후의평균은 70
Table 1. Change of RCR in the right and left hemisphere of each lobe after treated with ChEI(mean ± SD) ROIs AchEI RCR Frontal lobe Temporal lobe Parietal lobe Rt Lt Rt Lt Rt Lt Pre 0.86±0.10 0.85±0.11 0.87±0.11 0.82±0.10 0.87±0.08 0.85±0.06 Post 0.89±0.11 0.88±0.10 0.87±0.09 0.85±0.09 0.93±0.07 0.91±0.04 P value 0.52 0.35 1 0.50 0.02* 0.02* * : P < 0.05, ROIs : Regions of interest, RCR : Region to cerebellar ratio Rt : Right, Lt : Left ROIs P(Lt) P(Rt) T(Lt) T(Rt) F(Lt) F(Rt) 0.75 0.8 0.85 0.9 0.95 RCR * * Post-AchEI Pre-AchEI *p<0.05 Fig. 2. Change of the over time in the rcbf of AD patients(n=8). ROIs : regions of interest, RCR : region to cerebellar ratio Table 2. Change of RCR in the right and left hemisphere after treated with ChEI(mean ± SD) ROIs AchEI Rt hemisphere (F+T+P) RCR Lt hemisphere (F+T+P) P value Pre 0.87±0.09 0.84±0.09 0.02* Post 0.89±0.09 0.88±0.08 0.19 P value 0.13 0.04* * : P<0.05, F : Frontal lobe, T : Temporal lobe, P : Parietal lobe, ROIs : Regions of interest, RCR : Region to cerebellar ratio, Rt : Right, Lt : Left 좌 우측이 0.88±0.08과 0.89±0.09로역시좌측의뇌혈류량이콜린에스테라제억제제투여후유의하게증가되었다 (p<0.05)(table 2). IV. 고 찰 잠정알츠하이머환자를대상으로하여약 30 주 (7.5 개 월 ) 간콜린에스테라제억제제투여를한결과, 양측두정엽의뇌혈류량이의미있게증가되었다. 그리고통계적의미는없었지만나머지양측전두엽과좌측측두엽에서도동일한정도의혈류개선효과를보였다. 이러한결과는시간이경과할수록점점더진행되는알츠하이머의뇌혈류량의경우초기에는주로측두엽과두정엽의뇌혈류가감소되지만 (Johnson 등, 1987; Hunter 등, 1989; Burns 등, 1989) 시간이지날수록더심해져서나중에는전두엽까지뇌혈류가감소된다 (Brown 등, 1996; Neary 등, 1987) 는보고와같이약 30주간동안의콜린에스테라제억제제투여가두정엽의대사를증가시켰을뿐만아니라전두엽과측두엽에서병의진행을최소한으로완화시켰거나혹은뇌혈류량을일정수준으로유지하는데기여했을것으로생각된다. 한편두정엽의뇌혈류량만이유의하게증가한것은신경세포가완전히소실되지는않으면서콜린성자극의결핍으로인한세포기능감소증상이있는경증혹은중등증의알츠하이머환자의두정엽에콜린에스테라제억제제를투여하였기때문에뇌혈류량이의미있게증가될수있었던것으로보인다. 그리고측두엽의국소혈류는해마를포함한내측일부가초기부터이환되어있어서질병이진행됨에따라더넓게이환되는경향이있는데본연구에서사용한관심영역 (ROIs) 의일부분만이해마를포함한내측일부에해당되기때문에현저한뇌혈류량의변화를보기에는한계가있었다. 좌 우측대뇌피질의뇌혈류량을비교할경우콜린에스테라제억제제투여전에는우측에비해좌측이유의성있게감소해있는것을알수있는데 (p<0.05), 이는알츠하이머가주로우세반구인좌측에더이환됨을시사 71
한다. 또한콜린에스테라제억제제투여후에도뇌혈류량이감소된좌측에서투여전에비해현저하게뇌혈류가증가된것을알수있었다 (p<0.05). 본연구의결과는알츠하이머환자를대상으로약 35 주간 Donepezil을투여하였을때전반적인뇌혈류량의개선현상을볼수있었는데이는특히양측전두엽과측두엽의뇌혈류량이의미있게증가하였다는연구결과 (Staff 등, 2000) 와는다소차이가있었다. 위의연구는특히전두엽에서뇌혈류량이의미있게증가된소견을보이는것으로보고한바있으나본연구에서는콜린에스테라제억제제투여후두정엽의혈류가의미있게개선되었는데이는연구과정이너무길어서자연적으로진행하는병의경과로인해이미신경세포가심하게소실된두정엽이나측두엽보다좀더늦게이환된전두엽의신경세포에더효과적으로콜린에스테라제억제제가작용한것으로보인다. 이와같이콜린에스테라제억제제의투여효과가다양할뿐만아니라뇌혈류량의변화가일정하지않은이유는콜린에스테라제억제제가뇌혈관에직접작용하여뇌혈류량을증가시킬뿐만아니라 (Kasa 등, 2000) 시납스후신경활동을자극함으로써뇌혈류량을증가 (Furey 등, 2000) 시키기때문에각기다른대뇌부위가콜린에스테라제억제제에반응하는정도가다르거나, 앞서언급한바와같이투여시점즉, 질병의정도 ( 경증, 중증도 ) 에따라콜린에스테라제억제제에반응하는정도의차이가있거나, 근본적인알츠하이머병리가다르거나, 또한다른유전적다형성증등의몇가지이유로요약할수있다. 즉콜린성자극결핍으로인해비효율적으로세포기능이저하된신경세포는콜린에스테라제억제제가자극을하여도콜린성자극을전달할수없다. 본연구에서알츠하이머가심하게진행된경우에는콜린에스테라제억제제에의한뇌혈류량변화를기대하기어려운것으로판단되는데, 이러한결과는콜린에스테라제억제제가콜린성자극결핍이매우심한중증알츠하이머환자에서보다도경증및중등증알츠하이머에더효과적이며, 뇌허혈성실험모델쥐에서콜린에스테라제억제제가전반적인뇌혈류량을증가시켜주었지만허혈핵심부의혈류는개선시키지못하였다는연구 (Scremin 등, 1997) 와도일치하는소견이다. 즉, 알츠하이머환자가 초기콜린성자극에효과적으로반응하는시기가지나서시간이더욱경과되면더이상유효반응을하지않는시기가뒤따르는것으로생각되는데이러한결과는질환초기에콜린에스테라제억제제투여를받는것이질환의예후를어느정도결정짓는매우중요한인자가될수있음을시사하는것이다. V. 결론 알츠하이머환자를대상으로콜린에스테라제억제제를투여한결과, 전반적으로뇌혈류량이호전되는경향을보였으며특히양측두정엽의뇌혈류량이유의하게증가하였다 (p<0.05). 또한콜린에스테라제억제제투여전에는우측에비해좌측대뇌피질의뇌혈류량이유의하게감소해있었으나 (p<0.05) 콜린에스테라제억제제투여후에는뇌혈류량이감소되어있던좌측대뇌피질에서투여전에비해현저하게뇌혈류량이증가되었다 (p<0.05). 이상의결과를통하여콜린에스테라제억제제가알츠하이머환자의뇌혈류량을호전시킴을알수있었다 참고문헌 1. Birks JS, Meltzer D, Beppu H. Donepezil for mild and moderate Alzheimer's disease. Cochrane Database System Review 4, 2000 2. Birks J, Grimley EJ, Iakovidou V, Tsolaki M. Rivastigmine for Alzheimer's disease. Cochrane Database System Review 4, 2000 3. Brown DRP, Hunter R, Wyper DJ, Patterson J, Kelly RC, Montaldi D, McCulloch J. Longitudinal changes in cognitive function and regional cerebral function in Alzheimer`s disease : A SPECT blood flow study. Journal of Psychiatric Research 30:109-126, 1996 4. Burns A, Philpot MP, Costa DC, Ell PJ, Levy R. The investigation of Alzheimer`s disease with single photon emission tomography. Journal of Neurology, Neurosurgery and Psychiatry 52:248-253, 1989 72
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