online ML Comm Korean Journal of Biological Psychiatry Vol. 18, No. 1, February 2011 Original Article 일회 Donepezil 투약이알쯔하이머병환자에미치는영향및 반응군예측인자로서의가능성 곽용태 양영순 노용우 Whether Alzheimer s Disease is Responsive to a Single Oral Dose of Donepezil and this Response is Predictive Factor in Alzheimer s Disease Yong Tae Kwak, MD, Youngsoon Yang, MD, Yong Woo Noh, MD ABSTRACT O bjectives:though a proportion of Alzheimer s disease(ad) patients treated with donepezil have shown positive response on cognition, but the responders characteristics are still uncertain. This study attempts to identify whether a single oral dose of donepezil(5mg) can change cognition and the relationship between single dose responder items and long-term responder are examined. Methods:Twenty-three AD patients for single donepezil challenge study group and eleven AD patients for controls were participated in the study. Seven days after baseline study for neuropsychological test and EEG, same studies were rechecked after donepezil medication in study group. In donepezil study groups, 12 weeks after donepezil medication, neuropsychological test and EEG were rechecked. Results:After single donepezil challenge, forward digit span, Rey-Osterrieth Complex Figure Test copy, SVLT delayed recall were significantly improved, and beta spectra power in anterior, theta spectra power in posterior field were significantly decreased. According to linear regression analysis, forward digit span after single donepezil challenge was significantly positive correlated with long-term responders. Conclusions:This study suggests that single donepezil medication can significantly change cognitive functions and EEG in AD patients. Among these responsive items, forward digit span was significantly correlated with long-term responder. KEY WORDS:Alzheimer s disease Donepezil Single dose Responder Electroencephalography. Received:November 11, 2010 / Revised:November 25, 2010 / Accepted:January 10, 2011 Address for correspondence Yong Tae Kwak, MD, Department of Neurology, Yongin Hyoja Geriatric Hospital, 33 Sangha-ri, Guseong-myeon, Yongin 446-914, Korea Tel:031-288-0602, Fax:031-288-0539, E-mail:ytkwak@drkwak.com 효자병원신경과 Department of Neurology, Hyoja Geriatric Hospital, Yongin, Korea - 36 -
서론 알쯔하이머병은대뇌피질의위축을동반하는진행성퇴행성질환이다. 비록알쯔하이머병의병태생리는정확하게알려져있지않지만콜린신경계의장애가중요한역할을하고있으며, 1-4) 콜린분해효소억제제가알쯔하이머병의인지기능을호전시킨다. 4) 콜린분해효소억제제는아세틸콜린을분해하는 acetylcholinesterase 나 butyrylcholinesterase 효소를억제함으로써뇌신경의시냅스에서아세틸콜린양을증가시켜알쯔하이머병의결핍을부분적으로교정한다. 하지만콜린분해효소억제제는위장장애나간독성과같이임상적으로중요한부작용을보이며또한모든환자에서효과가있는것은아니다. 콜린분해효소억제제중하나인 donepezil은 acetylcholinesterase 를특이적으로억제하는약물로서비교적부작용이적으며, 5)6) 임상적으로는알쯔하이머병환자에서 15~58% 에서효과를보이는것으로알려져있고, 7) 장기적으로치료를할경우알쯔하이머병환자가요양원으로가는시간을지연시킨다. 8) 또한신경전기생리학적으로는 donepezil 사용시에뇌파에서 mean frequency가증가하고서파가감소하는것으로보고되었다. 9) 하지만 donepezil을포함한콜린분해효소억제제가모든알쯔하이머병환자에서효과를보이는것은아니며, 6)10) 어떤환자에서반응하고어떤환자에서는반응하지않는지잘알려져있지않다. 콜린분해효소억제제가임상적으로중요한부작용을일으킬수있으며가격이고가인것을고려하면알쯔하이머병환자중에어떤환자가약물치료에반응할지예측인자를찾아내는것이중요하며이에대한다양한연구가있어왔지만아직도정확하게알려져있지않다. 11-16) 또한콜린분해효소억제제들이인지기능에전반적인영향을주지만정확하게어떤기간안에어떤영역에어느정도영향을주는지는정확하지않은데초기에연구된 tacrine 의경우에도인지기능에대한긍정적인효과가기억력이나공감각과같은증상호전에기인하는것인지아니면다른인지기능영역의호전에기인하는지는논란이있다. 17)18) 약물반응군은일반적으로약물을몇달사용한후에임상적인기준에의하여정의한다. 그러나한번의투약 만으로도인지기능이나뇌파의변화가오는지는잘알려져있지않으며만약이런변화가있다면장기적인반응즉약물반응군과어떤연관성이있는지정확하게알려져있지않다. Tacrine 의경우일회의약물투약만으로도뇌파의변화와주의집중변화를관찰한연구가있고 19) donepezil 의경우특수한연구도구를이용하여일회투약에서인지기능의변화를보고한바가있으나 20) 본연구와같이 donepezil 일회투약후인지기능과뇌파변화그리고장기적호전군과연관성을고찰한연구는없었다. 본연구의목적은첫번째로다양한요소로구성되어있는인지기능구성요소중에는단한차례의 donepezil 투약만으로도반응하는인지기능요소와전기생리적변화가있는지확인하는것이며두번째는만약 donepezil 한번투약만으로도변화하는요소가있다면이들이장기적인변화와어떤연관성이있는지확인하는것이다. 방법 연구범위 2008 년 4월부터 2010 년 1월까지용인효자병원에내원한 donepezil 을복용한적이없는 23명과 donepezil 을복용하고있는 11명의 probable 알쯔하이머병환자를대상으로하였으며환자가입원할당시환자의연령과성별등의인구학적정보와병명, 유병기간, 발병연령등을기록하였다. 연구대상군과임상척도 1) 연구대상군은성별과연령을고려한 donepezil을복용하고있는 NINCDS-ADRDA 21) 진단기준의 probable 알쯔하이머병대조군 11명 ( 대조군 ) 과 donepezil 을복용한적이없는 probable 알쯔하이머병환자 23명을 ( 연구대상군 ) 대상으로하였다. 약물중독의경력, 과거나현재치매와관계없는신경과적, 정신과적, 신경외과적질환이나두부외상의경력이있는환자및최근 3개월사이에뇌파에영향을줄수있는약물을복용한환자는제외하였다. 2) 연구에참여한모든환자들은뇌자기공명영상 (M- RI) 이나뇌전산화단층촬영 (CT) 중적어도한가지이상의검사를하여뇌졸중, 뇌종양, 외상과같이다른기질적인병변이없음을확인하였다. - 37 -
3) 모든연구대상군에서보호자의서면동의를획득하였다. 연구방법신경심리검사도구모든환자에서일반적인인지기능척도로서 Korean Mini-Mental State Examination( 이하 K-MMSE) 22) 와 Clinical Dementia Rating Scale( 이하 CDR) 23) 을사용하였다. 인지기능검사로서좀더정확하고다양한인지기능평가를위하여 Seoul Neuropsychological Screening Battery( 이하 SNSB) 24) 를사용하였다 (Table 1). SNSB 는인지기능검사를전두엽, 언어기능, 공감각기능, 기억력, 구성실행능력등다양한인지기능검사를구조화한것이다. 대조군은이연구의인지기능검사의학습효과를배제하기위하여 7일간격으로검사를시행하였고이후대조군은더이상연구에참여하지않았다. 연구대상군에서이 SNSB 를포함한모든인지기능검사를처음내원당시와첫약물투약후검사에서사용하였다. Donepezil 12주약물투약후에는 K-MMSE와 CDR 검사만을사용하였다. 연구에사용한모든신경심리검사는환자의임상정보를모르고이연구에참여하지않은신경심리사에의하여시행되었다. 뇌파기록및스펙트럼분석뇌파검사는오전 9시에서 11시사이에정상적인수면을취한대상군에서 5분간눈을감고시행하였다. 전극은귀를기준으로하고 10~20 system 에의하여고정하였으며교류저항 (impedance) 을 10kΩ 이하로하였다. Band pass filter는 1~64Hz이고 60Hz의 notch filter를이용하였다. 뇌파신호는 Nyquist Theorem 에따라 128 sample/sec간격으로구하였으며이를 12-bit analogto-digital conversion 하였다. 인공파 (artifact) 를줄이고생리적인상태를가장잘반영할수있는상태에서뇌파를기록하고, 환자의진단명을모르는신경과전문의가 2초간격의적절한뇌파 20 epoch 를선택하여자료를분석하였다. Fast Fourier Transforms( 이하 FFT) 의 algorithm을이용하여선택된 epoch 에대하여 spectral density function 인 W(f) 25) 를구하여 1~4Hz(delta), 4~ 8Hz(theta), 8~13Hz(alpha), 13~30Hz(beta) 의 4가지주파수영역을분석하였다. 스펙트럼분석자료를정상분포화하기위하여절대값 (absolute value) 을로그변환한후다음과같이세영역으로분류하여이들의평균값을이용하여분석하였다. 전부 (Anterior field);f3, F4, F7, F8 중심측두부 (Centrotemporal field);c3, C4, T3, T4 Table 1. Demographic data of learning controls and patients of Alzheimer s disease Learning controls Alzheimer s disease(ad) p-value* Numbers 11 23 Sex Male 6 11 NS Female 5 12 Age(year) 70.1 ± 05.1 74.1 ± 04.1 NS Onset age(year) 67.3 ± 05.2 72.1 ± 06.4 NS Duration(month) 35.0 ± 12.8 24.0 ± 17.9 NS Education 08.1 ±0 3.0 06.7 ± 04.5 NS K-MMSE 15.5 ± 06.0 13.9 ± 05.2 NS CDR 1 9 13 2 2 08 3 0 02 NS GDS 18.7 ± 08.1 15.4 ± 07.6 NS Barthel index 20.5 ± 04.1 19.5 ± 02.3 NS Donepezil(mg) 5.0mg 5.0mg NS One person in AD study group was dropped out because of gastrointestinal trouble(cdr1, MMSE 14). *:p-value from Independent T-test, Chi-square test. NS:non-significant, K-MMSE:Korean Mini-Mental State Examination, CDR:Clinical dementia rating scale, GDS:Geriatric depression scale - 38 -
후부 (Posterior field);t5, T6, P3, P4, O1, O2 연구방법연구는 2가지단계로나누어시행한다. 첫번째로대조군을대상으로연구에사용된신경심리검사의학습효과를확인하였고두번째로연구대상군을대상으로 donepezil 일회투약의효과및 12주 donepezil 치료후반응군과의관계를확인하였다. 처음내원시 Donepezil을복용중인대조군과 donepezil 복용하지않은연구군을대상으로오전 9시경에뇌파검사를시행하며오전 10시에서 11시경에신경심리검사 (MMSE, CDR, SNSB) 를시행한다. 일주일후에 donepezil 을복용하지않은알쯔하이머병연구군에서 donepezil 5mg 을아침 8시에복용하고오전 9시경에뇌파검사를시행하며오전 10시에서 11시경에인지기능검사 (MMSE, CDR, SNSB) 를시행한다. 반면대조군은 donepezil 복용없이오전 9시뇌파검사후오전 10시에서 11시경에인지기능검사만시행한다. 이러한시간표는 donepezil 복용후약동학적으로최고의효과가 1~3 시간지난후에나타나는것을고려하였다. 26) 이후대조군은더이상검사를진행하지않고새로이 donepezil 을복용한군에서 12주후에 MMSE, CDR 과뇌파검사를시행하였다 (Fig. 1). 모든연구의통계적평가는연구계획에참여하지않은신경과의사에의하여시행하였다. 약 3개월후의미있는변화 ;K-MMSE 가 4점이상증가하였거나 CDR 점수가증가한경우를반응군으로정의한다. 27) Statistical analysis SPSS 13.0 통계프로그램을이용하여 Mann-Whitney test 및 chi-square test 를이용하여대조군과연구군의일반적인특징을비교하였으며, donepezil 치료후 K- MMSE, CDR, GDS와 Barthel 변화는 repeated-measures analysis of variance를사용하였다. 최종반응군에영향을주는요소를확인하기위하여서는 multiple regression analysis를사용하였다. 결과 연구대상군의인학적및임상적특징 Table 1에서보는바와같이대조군과연구대상군에서인구학적나이, 성별, 발병기간등에유의한차이는없었다. 이외에임상척도에서처음연구에참여할때대조군의 K-MMSE 점수는 15.5, CDR 은 1.18 로연구대상군의 K-MMSE 13.9 와 CDR 1.52 와통계적으로유의한차이는관찰되지않았다 (Table 1). 다만이중연구대상군중 1명이약물투약중위장장애로연구에탈락하였다 (CDR1, MMSE 14). Donepezil 투약에대한반응군정의 1) Donepezil 첫투약후의미있는변화의정의 ; 첫약물투약후인지기능영역중에한개이상호전을보이거나뇌파의변화를보이는경우 2) donepezil 약물투 Screening n = 34 Learning control n = 11 Donepezil study group n = 23 Week 0;NP test, EEG Week 1;NP test, EEG without intervention Week 0;NP test, EEG Week 1;NP test, EEG 2 hours after donepezil 5mg medication Week 13;NP test, EEG Fig. 1. Flow diagram of patient inclusion and timing of assessment according to donepezil medication. NP test: neuropsycological test. 대조군을통한신경심리검사의타당성연구에사용된 SNSB 검사의학습효과를배제하기위하여연구대상군과임상적으로유사한특징을가진대조군에서연구군과마찬가지로 7일간격으로반복검사를시행하였다. 그결과통계적으로유의한차이는관찰되지않았다 (Table 2). Donepezil 일회투약후신경심리검사와뇌파매개변수의반응항목확인연구대상군에서 donepezil 5mg 일회투약후반응을보이는항목을확인하기위하여투약후신경심리검사와뇌파검사를시행하였다. 신경심리검사항목중에서는 forward digit span, Rey-Osterrieth Complex Figure Test( 이하 RCFT) copy, SVLT delayed recall 이유의하게호전되었다 (Table 3). 또한정량적뇌파검사에서전부의베타파와, 후부의세타파에서유의한변화가관 - 39 -
Table 2. Baseline and repeated 7 days interval neurocognitive test in learning control group(mean ± standard deviation) Domain Baseline After 7 days p-value* Attention Forward digit span d4.9 ± d1.0 5.1 ± 1.6 NS Backward digit span 02.5 ± d0.6 2.7 ± 1.2 NS Language KBNT 11.1 ± 01.2 12.0 ± 2.3 NS and related Fluency 73.2 ± 03.3 74.5 ± 4.7 NS function Comprehension 67.7 ± 02.4 72.4 ± 5.5 NS Repetition 12.3 ± 03.1 12.3 ± 4.5 NS Calculation 05.3 ± 04.1 5.8 ± 3.2 NS Visuospatial RCFT copy 17.4 ± 10.3 16.2 ± 5.6 NS Pentagon drawing 01.7 ± 00.8 1.6 ± 0.4 NS Memory SVLT trial 1 03.2 ± 01.3 2.9 ± 2.4 NS SVLT trial 2 03.8 ± 01.7 3.6 ± 1.9 NS SVLT trial 3 04.7 ± 02.2 4.9 ± 2.9 NS SVLT delayed recall 01.5 ± 01.6 1.9 ± 2.2 NS RCFT immediate recall 03.8 ± 02.5 2.5 ± 3.9 NS RCFT delayed recall 02.7 ± 02.6 2.6 ± 3.0 NS Frontal/Executive COWAT animal 06.4 ± 02.7 6.9 ± 2.9 NS Supermarket 05.2 ± 03.0 5.0 ± 2.5 NS Letter 03.8 ±0 1.9 3.9 ± 0.8 NS K-MMSE 15.5 ± 06.0 16.0 ± 5.9 NS CDR 01.5 ± 00.7 1.4 ± 0.7 NS GDS 15.4 ± 07.6 13.9 ± 6.6 NS Barthel index 19.5 ± 02.3 19.4 ± 2.4 NS *:Independent T-test, Chi-square test was done. NS:non-significant, KBNT:Korean Boston Naming Test, RCFT: Rey-Osterrieth Complex Figure Test, SVLT:Seoul Verbal Learning Test, COWAT:Controlled Oral Word Association Task, K-MMSE:Korean Mini-Mental State Examination, CDR:Clinical dementia rating scale, GDS:Geriatric depression scale 찰되었다 (Table 4). Donepezil 복용 12주후 K-MMSE와 CDR의변화및반응군확인 23명의연구대상군중 1명이위장장애로약물을중단하였고 22명이 12주까지추적되어이들을대상으로통계처리하였다. 처음 donepezil 투약하기전과, 투약 2시간후, 투약 12 주후를비교하였다. 결과적으로 donepezil 투약전에비하여 donepezil 투약 12주후에 K-MMSE 와 CDR 점수가유의하게호전되었으며 (p < 0.05), 22명의환자중에 11명이 (50%) 반응군이었다 (Table 5, 6). 또한 12주 donepezil 투약후반응군의 K-MMSE 평균점수가 19.6 CDR 이 0.61 인데비하여비반응군은 14.6, 1.25였다 (Table 6). Donepezil 첫번째투약에서반응을보이는검사와 donepezil 투약 12주후반응군과의관계 Donepezil 첫투약후반응을보이는신경심리검사항목과뇌파의매개변수항목을확인한후 multiple liner regression analysis를이용하여이들항목이 donepezil 복용 12주후반응군과연관성이있는지를확인하였다. Donepezil 첫투약후시행한 forward digit span이 donepezil 복용 12주후반응군과유의하게연관이있으며정량적뇌파검사에서후부의세타파는영향을주는경향은있으나통계적으로유의하지는않았다 (Table 7). 고찰 이연구는한번의 donepezil 투약만으로도인지기능이나뇌파가변화하는지와이러한변화가 12주약물투 - 40 -
약후의약물반응군과연관성이있는지를확인하는것이다. 약물반응군은연구자에따라다양하게정의하는데경우에따라서는 ADAS-cog 점수가나빠지지않은 경우부터 10점이상좋아지는경우도있다. 하지만일반적으로 ADAS-cog 점수가 4점이상호전되거나 28) 본연구와같이 MMSE 4점이상호전되는경우로정의한다. Table 3. The changes of main neurocognitive profiles after single challenge of donepezil(mean ± standard deviation) Domain Baseline After single challenge p-value* Attention Forward digit span 4.3 ± 01.1 5.2 ± 01.5 0.01 Backward digit span 1.7 ± 01.4 1.8 ± 01.3 NS Language KBNT 11.3 ± 03.1 12.3 ± 02.5 NS and related Fluency 72.2 ± 03.1 74.1 ± 04.1 NS function Comprehension 65.7 ± 04.7 72.1 ± 06.4 0.15 Repetition 11.2 ± 03.4 12.3 ± 04.5 NS Calculation 4.8 ± 04.2 5.7 ± 03.9 NS Visuospatial RCFT copy 10.5 ± 10.6 14.3 ± 11.3 0.03 Pentagon drawing 1.6 ± 00.5 1.5 ± 00.5 NS Memory SVLT trial 1 2.2 ± 01.7 2.4 ± 01.7 NS SVLT trial 2 3.2 ± 01.6 3.7 ± 01.7 NS SVLT trial 3 3.5 ± 01.7 3.9 ± 02.0 NS SVLT delayed recall 0.4 ± 00.6 1.6 ± 00.8 0.03 RCFT immediate recall 1.3 ± 02.5 2.1 ± 03.9 NS RCFT delayed recall 0.5 ± 01.3 1.4 ± 03.9 NS Frontal/Executive COWAT animal 5.3 ± 02.5 5.2 ± 01.9 NS Supermarket 4.6 ± 02.1 4.1 ± 02.0 NS Letter 2.7 ± 00.9 2.8 ± 00.8 NS K-MMSE 13.9 ± 05.2 15.0 ± 04.6 NS CDR 1.5 ± 00.7 1.4 ± 00.7 NS GDS 15.4 ± 07.6 13.9 ± 06.6 NS Barthel index 19.5 ± 02.3 19.4 ± 02.4 NS *:Independent T-test, Chi-square test was done. NS:non-significant, KBNT:Korean Boston Naming Test, RCFT: Rey-Osterrieth Complex Figure Test, SVLT:Seoul Verbal Learning Test, COWAT:Controlled Oral Word Association Task, K-MMSE:Korean Mini-Mental State Examination, CDR:Clinical dementia rating scale, GDS:Geriatric depression scale Table 4. Difference of absolute value of qeeg between Alzheimer s disease(ad) and normal controls Baseline After single challenge p-value* Anterior field Delta 0.98 ± 0.13 0.99 ± 0.11 0.23 Theta 1.05 ± 0.17 1.03 ± 0.16 0.12 Alpha 1.01 ± 0.15 1.02 ± 0.15 0.28 Beta 1.33 ± 0.12 1.29 ± 0.10 0.02 Centrotemporal field Delta 0.97 ± 0.17 0.96 ± 0.14 0.21 Theta 1.15 ± 0.20 1.12 ± 0.18 0.12 Alpha 1.13 ± 0.15 1.18 ± 0.16 0.10 Beta 1.42 ± 0.14 1.39 ± 0.13 0.13 Posterior field Delta 1.05 ± 0.19 1.04 ± 0.17 0.20 Theta 1.26 ± 0.21 1.23 ± 0.19 0.04 Alpha 1.29 ± 0.19 1.30 ± 0.19 0.17 Beta 1.48 ± 0.11 1.46 ± 0.11 0.10 *:paired T test, :Statistical significance was found between baseline and after donepezil single challenge - 41 -
Table 5. Change of Korean Mini-Mental State Examination(K-MMSE) score after donepezil treatment Baseline Single challenge 12 week p-value* K-MMSE 13.9 ± 5.2 15.0 ± 4.6 17.1 ± 4.7 0.007 CDR 01.5 ± 0.7 01.4 ± 0.7 00.9 ± 0.4 0.040 GDS 15.4 ± 7.6 13.9 ± 6.6 13.9 ± 8.4 NS Barthel index 19.5 ± 2.3 19.4 ± 2.4 19.5 ± 1.2 NS *:repeated measure of ANOVA test, :statistical significance was found between baseline and 12 week. NS: non-significant, K-MMSE:Korean Mini-Mental State Examination, CDR:Clinical dementia rating scale, GDS: Geriatric depression scale Table 6. K-MMSE and CDR score in responsive and non-responsive group after 12 weeks donepezil medication Number(%) CDR K-MMSE Responsive group 11(50) 0.61 ± 0.31 19.6 ± 5.1 Non-responsive group 11(50) 1.25 ± 0.45 14.6 ± 2.9 K-MMSE:Korean Mini-Mental State Examination, CDR:Clinical dementia rating scale Table 7. Influence of single challenge responsive cognitive items and EEG spectral parameters on 12 week clinical response Parameters B SE B T R-square p-value* Forward digit span -0.542-0.585-3.653 0.849 0.035 RCFT COPY -0.135-0.151-0.959 0.408 SVLT delay recall -0.089-0.089-0.481 0.663 Anterior field beta -0.063-0.070-0.397 0.718 Posterior field theta -0.510-0.571-2.674 0.075 *:Multiple regression analysis was used. RCFT:Rey-Osterrieth Complex Figure Test, SVLT:Seoul Verbal Learning Test 대부분콜린분해효소억제제연구들이인지기능의전체적인점수가어느정도호전이되는지와반응군이몇 % 인지국한되어인지기능중어떤항목이어떤시간경과를가지고호전되는지에대해서는거의연구된바가없다. 과거 tacrine 연구에서는 tacrin 이회상 (recall), 이름대기 (naming), 언어 (language), 단어찾기 (word-finding) 등에는효과가있는데비하여재인 (recognition), 이해 (comprehension) 혹은기억 (remembering) 등에대해서는효과가없다고보고하였다. 29) 즉인지기능의호전이전체적이고전반적인것이아니라국소적인차이가있으며각국소적인인지기능이언제부터어떻게좋아지는지는정확하게알려져있지않다. 또한약물의효과를판정함에있어서언제까지경과관찰을하고판정을해야할지, 초기에호전가능한예측인자가있는지에대해서는잘알려져있지않다. 본연구의첫번째목적은다양한요소로구성되어있는인지기능구성요소중에는단한차례의 donepezil 투약만으로도반응하는인지기능요소와뇌파변화를확인하는것이고두번째목표는만약한번투약만으로도 변화하는요소가있다면이들이장기적인약물호전군과연관이있는지확인하는것이다. 첫번째목표를확인하기위하여시행한검사에서집중력을보는 forward digit span 과공감각능력을보는 RCFT copy, 언어기억력을평가하는 SVLT delayed recall 이유의하게호전되었다. 또한뇌파검사에서는전부에서베타파감소와후부에서세타파의감소가확인되었다. 다른여러연구에서알려진바와같이donepezil 복용 12주후에시행한인지기능검사에서유의한호전이관찰되었으며, 이를호전군과비호전군으로분류하였다. 호전군은전체연구군의 50% 이었으며, 호전군에영향을미치는요소를확인하기위하여 donepezil 첫투약후매개변수를포함하여분석한결과 forward digit span 검사가통계적으로유의하게연관되어있으며이외뇌파의변화가관련이있었으나통계적으로유의하지는않았다. Forward digit span에는주로주의집중과즉시기억 (immediate memory) 기능이관여하며 RCFT copy 에는전두엽기능및공감각기능이, SVLT delayed recall 에는지연기억 (delayed memory) 에관여하는것을고 - 42 -
려하면일회의 donepezil 투약만으로도미묘하지만여러인지기능이호전될수있는것을알수있으며특히 forward digit span 만이 12주약물투약후호전군에영향을주는것으로보아주의집중과즉시기억기능이 donepezil의일회복용에가장민감하게반응할뿐아니라이러한반응이 12주후다른반응의예측에도영향을줄수있음을보여준다. 30) 또한이러한변화가뇌파에서전부의베타파감소와후부의세타파감소를동반하는것으로보아서인지기능의변화가실지로뇌파변화와도연관되어있음을보여준다. 주의집중및즉시기억에는콜린신경계가중요한역할을한다. 31) Muscarinic antagonist 인 scopolamine 이나 nicotinic antagonist 인 mecamylamine이인지기능에손상을주며 32) 또한임상적으로 scopolamine에의하여형성된장애가한차례의 donepezil 투약만으로도호전될수있다. 33) 특히콜린분해효소억제제를투약받지않알쯔하이머병환자에서는장기간콜린결핍에의한콜린신경계의수용체가 up-regulation 되어있으며이런환자들이콜린분해효소억제제를투약하면콜린신경계와밀접하게연관된주의집중에민감하게반응을하며이렇게민감하게반응하는환자들이 12주후전체적인인지기능의호전에예측인자가될수있음을보여준다. 이결과는 donepezil이집중, 공감각, 기억력영역등다양한방면에서유의한변화가일어나지만실지로약물반응에영향을주는것은콜린신경계와밀접하게연관된주의집중이중요함을보여준다. 주의집중의중요성은같은콜린분해효소억제제인 tacrine study에서도관찰되며, 34) 이는콜린신경계와밀접한연관을가진 substantia innominata 의 MRI 나단일광자방출컴퓨터단층촬영 (single photon emission computed tomography, 이하 SPECT) 변화가약물반응에영향을준다는보고와도일치한다. 15) 결국이는콜린신경계의손상이있는환자에서 donepezil 의효과가있을것이며콜린신경계손상의가장중요한인지기능요소는주의집중이다. Donepezil 의치료에호전과관계된예측요인중에하나는 K-MMSE 점수가 18점이나 20점이하로대변되는중등도의치매환자이다. 27)35) 이는너무초기의환자는충분하게콜린신경계의손상이있지않기때문에콜린신경계를항진시키는약물이도움이되지않고너무진행된경우는콜린신경계자체의손상으로콜린신경계물질 을보강하는약물투약에영향이적을수있다는것을간접적으로보여준다. 하지만 K-MMSE 와같은인지기능검사가비록뇌신경계의변화를일부반영할수는있지만여러가지변수에의해서이를정확하게보여줄수없을수도있다. 그러므로좀더객관적인뇌혈류검사나 MRI 와같은검사로서콜린신경계의변화를관찰하지만아직이러한검사들이가격에비해서는효용성에서문제가있을수있다. 그러나 donepezil의일회투약은비교적저렴하며그반응이약물에대한직접적인반응을보는것이기때문에 donepezil 치료예측인자로서비용대비효과가크다. 다만본연구에서 forward digit span 만이 12주후에약물효과와연관성이있었고다른검사와는연관성이뚜렷하지않았는데이것이어떤의미인지는정확하지않다. 기억력이나공감각도주의집중의요소와관계가있기때문에이와연관되어호전이있었는지아니면기억력은특정시기에일시적으로만호전이있는지는정확하지않다. 하지만이전연구에서기억력이첫 4주에서만호전이있는것으로보아 donepezil 의효과가시간에따라인지기능영역별로다르게나타나며이는 donepezil 에의한뇌기능호전이국소적일수있음을시사한다. 이전에도콜린분해효소억제제의예측인자에대한연구가있었다. 초기에알쯔하이머병치료제로서사용된 tacrine 에서는자세에따른혈압감소나고령의환자가 tacrine 에반응하는경향을보인다고보고된반면, 14)36) 이와상반된주장도있었다. 37) 또한 SPECT 검사에서전두엽의혈류가유지된경우가 tacrine 이나 donepezil에반응을보이는것으로보아심한전두엽장애가있는환자에서는약제의효과가없거나진단에문제가있을가능성도있다. 16)17) 또한 MRI에서 substantia innominata에위축이있는경우에 donepezil 에반응이있다고보고하였다. 15) 이는콜린신경계가변화가있는경우에 donepezil 에효과가있음을시사한다. 하지만본연구는몇가지제한점이있다. 첫번째로대조군을이용하여양군을비교하는이중맹검연구를시행하여야하나알쯔하이머병환자에서약물을투약하지않고하는이중맹검연구가최근윤리적인문제때문에제한점이있어시행하지못하여최종결과해석에일부제한이있을수있다. 본연구에서는다만인지기능검사의학습효과를배제하기위하여기존에 donepezil 을복용하는환자를대조군으로연구하여약물효 - 43 -
과가아닌학습효과때문에호전될가능성을배제하려고하였지만이들역시약물을복용중인환자이기때문에정확하게약물을복용하지않은대조군은아니다. 두번째로는이연구가비교적연구대상이소수이며약물투약전, 직후에시행하였던 SNSB 를 12주후에는시행하지않고전반적인인지기능검사만을하여 12주후각영역별변화를확인하지못하여좀더세밀한변화를중장기적으로확인하지못한제한점이있다. 결론적으로 donepezil 일회의투약만으로도알쯔하이머병환자에서임상적, 전기생리학적인변화가올수있으며이는장기적인치료효과와도연관성이있다. 특히주의집중이초기부터비교적예민하게 donepezil에반응하며이는다방면적인인지기능에도영향을줄가능성이있으며이에대한연구가진행되어야할것으로생각된다. 중심단어 : 알쯔하이머병 Donepezil 일회투약 반응군 뇌파. Conflicts of interest The authors have no financial conflicts of interest. 참고문헌 1. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. Alzheimer s disease and senile dementia: loss of neurons in the basal forebrain. Science 1982;215: 1237-1239. 2. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 1981;10:122-126. 3. Giacobini E. Pharmacotherapy of Alzheimer disease: new drugs and novel strategies. Prog Brain Res 1993;98: 447-454. 4. Davis RE, Doyle PD, Carroll RT, Emmerling MR, Jaen J. Cholinergic therapies for Alzheimer s disease. Palliative or disease altering? Arzneimittelforschung 1995;45: 425-431. 5. Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med 1998;158:1021-1031. 6. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer s disease. Donepezil Study Group. Neurology 1998;50:136-145. 7. Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 2003;11:131-145. 8. Schneider LS, Qizilbash N. Delay in nursing home placement with donepezil. J Am Geriatr Soc 2004;52:1024-1026. 9. Kwak YT, Han IW, Bang OY. Changes of quantitative EEG after donepezil treatment in alzheimer s disease. J Korean Neurol Assoc 2001;19:245-250. 10. Giacobini E. Cholinesterase inhibitor therapy stabilizes symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S3-S10. 11. Wilcock GK. The treatment of Alzheimer s disease with anticholinesterase drugs. Alzheimer Rev 1993;4:73-77. 12. Byrne EJ, Arie T. Tetrahydroaminoacridine and Alzheimer s disease. BMJ 1994;308:868-869. 13. Winker MA. Tacrine for Alzheimer s disease. Which patient, what dose? JAMA 1994;271:1023-1024. 14. Schneider LS, Lyness SA, Pawluczyk S, Gleason RP, Sloane RB. Do blood pressure and age predict response to tacrine(tha) in Alzheimer s disease? A preliminary report. Psychopharmacol Bull 1991;27:309-314. 15. Kanetaka H, Hanyu H, Hirao K, Shimizu S, Sato T, Akai T, et al. Prediction of response to donepezil in Alzheimer s disease: combined MRI analysis of the substantia innominata and SPECT measurement of cerebral perfusion. Nucl Med Commun 2008;29:568-573. 16. Hanyu H, Shimizu T, Tanaka Y, Takasaki M, Koizumi K, Abe K. Regional cerebral blood flow patterns and response to donepezil treatment in patients with Alzheimer s disease. Dement Geriatr Cogn Disord 2003;15: 177-182. 17. Riekkinen P Jr, Riekkinen M, Soininen H, Kuikka J, Laakso M, Riekkinen P Sr. Frontal dysfunction blocks the therapeutic effect of THA on attention in Alzheimer s disease. Neuroreport 1997;8:1845-1849. 18. Sahakian BJ, Owen AM, Morant NJ, Eagger SA, Boddington S, Crayton L, et al. Further analysis of the cognitive effects of tetrahydroaminoacridine(tha) in Alzheimer s disease: assessment of attentional and mnemonic function using CANTAB. Psychopharmacology (Berl) 1993;110:395-401. 19. Alhainen K, Partanen J, Reinikainen K, Laulumaa V, Soininen H, Airaksinen M, et al. Discrimination of tetrahydroaminoacridine responders by a single dose pharmaco-eeg in patients with Alzheimer s disease. Neurosci Lett 1991;127:113-116. 20. Pietrzak RH, Maruff P, Snyder PJ. Methodological improvements in quantifying cognitive change in clinical trials: an example with single-dose administration of donepezil. J Nutr Health Aging 2009;13:268-273. 21. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Ser- - 44 -
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