Dementia and Neurocognitive Disorders 2014; 13: 89-93 ORIGINAL ARTICLE 치매진행정도에따른조기발현과지연발현알츠하이머병환자의행동심리증상비교 윤여주 * 김은주 홍창희 인제대학교해운대백병원정신건강의학과 *, 부산대학교의과대학신경과학교실, 부산대학교심리학과 Received: November 4, 2014 Revision received: December 14, 2014 Accepted: December 14, 2014 Address for correspondence Changhee Hong, Ph.D. Department of Psychology, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 609-735, Korea Tel : +82-51-510-2144 Fax:+82-51-581-1457 E-mail : hch2144@yahoo.co.kr Comparison of Behavioral and Psychological Symptoms between Early and Late Onset Alzheimer s Disease According to the Progression of Dementia Yeo-Ju Yoon, M.A.*, Eun-Joo Kim, M.D., Chang Hee Hong, Ph.D. Department of Psychiatry*, Inje university paik-hospital, Busan; Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan; Department of Psychology, Pusan National University, Busan, Korea The aim of this study was to investigate behavioral and psychological symptoms of dementia (BPSD) measured by caregiver-administered neuropsychiatric inventory (CGA-NPI) as a function of dementia severity in early onset () versus late onset Alzheimer s disease (). A total of 113 patients with AD consisting of 49 patients with and 64 patients with were enrolled consecutively. General cognitive function and severity of dementia were assessed by the Korean version of mini-mental status examination and clinical dementia rating (CDR), respectively. In the mild stage (CDR 0.5-1), patients had a significantly higher total CGA-NPI score than patients. Subgroup analysis demonstrated that disinhibition and night-time behavior were more common and severe in the group than the group. However, in the moderate to severe stage (CDR 2-3), patients had a significantly higher total CGA-NPI score with higher subscores in hallucination, agitation/aggression, irritability/lability, aberrant motor behavior, and appetite/eating change. This study suggested that the heterogeneity of BPSD in AD might be accounted for by dementia severity as well as age at symptoms onset. Key Words: Behavioral and psychological symptoms of dementia, Early onset Alzheimer s diseases, Agitation, Caregiver-administered neuropsychiatric inventory 서론국민건강보험공단건강보험정책연구원에따르면최근 6년간치매환자는 2006년 10만 5천명에서 2011년 31만 2천명으로무려 296.3% 가증가하였고, 특히 2007년을기점으로 65세미만치매환자의수는더욱급격하게증가하고있다고한다. 경제적, 사회적활동을하는 40대 ~60대초반치매환자의증가는환자본인뿐아니라주변가족들에게심리적, 경제적인부담감을더욱크게주기에이에대한평가와치료가더욱중요하다 [1, 2]. 전체치매중가장높은비율 (50-70%) 을차지하는알츠하이머병은발현시기에따라 65세미만에발현하는조기발현알츠하이머병 (early-onset alzheimer s disease, ) 집단과 65세이상에서발현하는지연발현알츠하이머병 (late-onset alzheimer s disease, ) 집단으로분류되기도한다 [3]. 이두하위유 형은임상적인경과나신경심리학적증상, 신경영상학적으로확인되는영역에서뚜렷한차이를보인다. 집단은 집단에비해인지적감퇴속도가빠르고경과도나쁘다 [4, 5]. 또한 집단보다유전적소인이커가족력을가진환자가더많고, 기억장애이외의시공간기능, 언어기능, 집행기능의저하및실행증을보이는비전형적인양상의환자가많다 [6, 7]. 대뇌시냅스의손실이나노인반 (senile plaque) 과신경섬유농축제 (neurofibrillary tangle) 의침착이심하고, 측두엽만이아니라전두엽과두정엽이위축되어있고대사도저하되어있다 [8-10]. 이처럼유전적, 신경심리학적, 신경영상학적연구에서보이는 집단과 집단의차이는행동심리증상 (behavioral & psychological symptoms of dementia, BPSD) 에도반영될것이다. 행동심리증상이란치매진행과정에서주로발생하는지각, 사고내용, 2014 Korean Dementia Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 89
90 윤여주 김은주 홍창희 정서또는행동증상으로치매환자의 60-95% 가경험하며, 치매의진단과경과에대한중요한정보를제공한다 [11]. 행동심리증상은인지장애보다보호자에게더큰스트레스를주는요인으로가족에게심리적, 신체적, 경제적부담감을안겨주지만인지기능과는달리조기에발견하여치료하면조절이가능하므로행동심리증상의양상과경과에대해보다깊은이해가요구된다 [12]. 이러한이론적, 실제적함의에도불구하고발현시기에따라 집단과 집단의행동심리증상을비교한연구가드물뿐아니라그나마실시된연구들사이에서도일관성이없는실정이다 [13, 14]. 그이유는치매의진행정도에따라나타나는행동심리증상의빈도나심각성이다름에도불구하고결과에영향을미칠수있는치매의진행정도를고려하지못했기때문인듯하다. 이연구에서는알츠하이머병의치매진행정도 ( 경도 / 중등도-중증 ) 를고려하여발현시기 (/) 에따른행동심리증상을비교하였다. 특히행동심리증상을요인수준과개별적인증상수준에서비교하여 집단과 집단의행동심리증상을보다체계적이고구체적으로이해하고자하였다. 대상과방법본연구는 2009년 3월부터 2011년 10월까지인지기능저하를주소로부산대학병원신경과외래에내원한환자들중신경과전문의의임상적소견, 신경심리학적평가, 신경학적검사, 임상병리검사, 뇌영상검사를통해알츠하이머병으로진단받은환자 113명을대상으로하였다. 상기환자들은정신장애의진단및통계편람제4판 (diagnostic and statical maual of mental disorder, 4th edition, DSM-Ⅳ) 의알츠하이머병진단기준 (1994) 과미국국립보건원신경, 의사소통질환및뇌졸중연구소 / 알츠하이머및연관질환협회 (National Institute of Neurological and Communicative Disease and Stroke/Alzheimer s Disease and Related Disorders Association, NINCDS-ADRDA) 의 Probable Alzheimer s disease 진단기준 (1984) 에부합하였다. 또한모든환자들에게뇌자기공명영상검사를시행하여뇌혈관질환을지닌환자들을배제하였고, Hachinski 허혈성척도점수가 4점이하인경우로정의하였다 [15]. 본연구는부산대학교병원의연구윤리위원회 (institutional review board, IRB) 의승인을거친후시행되었다. 행동심리증상을측정하기위해 caregiver-administered neuropsychiatric inventory (CGA-NPI) 를사용하였고, 전반적인인지기능과치매진행정도를측정하기위해한국판간이정신상태검사 (Korean version of mini-mental status examination, K-MMSE) 와한국판임상치매평가척도 (clinical dementia rating, CDR) 를사용하였다 [16-18]. 발현시기에따라서알츠하이머병환자를 65세미만의 집단과 65세이상의 집단으로나누었고, CGA-NPI를사용하여두 집단의차이가있는지알아보았다. 또한경도 (mild) 집단은 CDR 0.5-1, 중등도 - 중증 (moderate to severe) 집단은 CDR 2-3 으로구성하고, 치매의진행정도별발현시기가다른두집단의행동심리증상에대 해비교하였다. 수집된자료는 SPSS 18.0 for Windows 를사용하여분석하였다. 두 집단간인구통계학적변인은 chi-square 분석과독립 t-test 를실시하 였고, 두집단의치매진행정도와발현시기에따른행동심리증상 은변량분석 (ANOVA) 를실시하였다. 또한치매진행정도와발현시 기에따른행동심리증상의요인과각하위항목에대해 1 차적으로 다변량분석 (MANOVA) 을실시하였고, 2 차적으로치매진행정도 를두집단으로나눈후, Mann-Whitney 검정을실시하여 집 단과 집단간의행동심리증상의요인별항목과각하위항목 들을비교하였다. 결과 Table 1 은집단별연령및발현연령, 유병기간, 교육수준, 치매진 행정도를나타내는검사들의평균과표준편차이다. 집단에 서는성별의차이가없었으나, 집단에서는여성이의미있게 더많은양상이었고, 가 8.85 년으로 에비해더높은교 육수준을보였다. 그외유병기간에는차이가없었고, 치매진행정 도를나타내는 K-MMSE, CDR 점수에서도차이를보이지않았다. 발현시기 (/) 와치매진행정도 ( 경도 / 중등도 - 중증 ) 에 따른행동심리증상의전체점수를이원변량분석하였다. Table 2 는 발현시기와치매진행정도에따른행동심리증상의평균과표준편 차를나타낸것이다. 전체환자의 CGA-NPI 의평균점수는 20.88 점 이었고, 가장높은점수를보인증상은무감동 / 무관심 (3.33 점 ) 이었 고, 그뒤로과민 / 불안정 (2.39 점 ), 야간의행동 (2.30 점 ), 비정상적인 반복행동 (2.27 점 ), 망상 (2.09 점 ) 순으로나타났다. 가장낮은점수를 Table 1. Demographic and clinical features between and group (n = 49) (n = 64) t or χ 2 Sex (M/F) 25/24 20/44 4.53* Age 62.96 ± 6.01 77.13 ± 5.12 Onset age 58.18±5.78 72.73±4.87 Duration 4.78 ± 2.76 4.39 ± 3.38 0.65 Education 8.85 ± 4.89 5.46 ± 4.94 3.63 K-MMSE 14.80 ± 6.92 15.48 ± 4.66-0.60 CDR 1.35 ± 0.67 1.18 ± 0.57 1.41 CDR 0.5 (n=15) 6 9 CDR 1 (n=67) 26 41 CDR 2 (n=26) 14 12 CDR 3 (n=5) 3 2 *p< 0.05; p< 0.01. K-MMSE, Korean-mini mental state examination; CDR, clinical dementia rating.
치매진행정도에따른조기발현과지연발현알츠하이머병환자의행동심리증상비교 91 보인증상은다행감 / 기분이들뜸 (0.25점) 이었다. 전체 CGA-NPI 점수에서중등도-중증알츠하이머병환자집단의점수는경도환자집단보다유의하게높았으나 [F(1,109) = 31.76, p< 0.001], 환자와 환자의전체점수간의차이는나타나지않았다 [F(1,109) = 2.49, p > 0.1]. 그러나 Fig. 1과같이치매진행정도와발현시기의상호작용효과는유의하게나타났다 [F(1,109) =13.08, p < 0.001]. 즉, 경도에서전체증상의점수는 집단이 집단보다유의하게높았고 [F(1,80) = 5.23, p < 0.05], 중등도-중증에서는 집단이 집단보다유의하게높은점수를보였다 [F(1,29) = 5.17, p < 0.05]. 발현시기 (/) 와치매진행정도 ( 경도 / 중등도 -중증) 에따른행동심리증상의하위항목을분석하기위해이전연구에서 개발된요인을사용하였다. Lange RT, Hopp GA, Kang N (2004) 은 neuropsychiatric inventory-nursing home version (NPI-NH) 를요인분석하여다섯가지요인을보고하였는데, 첫번째요인은초조 (Agitation) 로구성항목은초조 / 공격성, 과민 / 불안정으로구성되었고, 두번째요인인기분 (Mood) 은우울 / 낙담, 무감동 / 무관심, 불안, 세번째요인인정신증적증상 (Psychosis) 은망상, 환각, 네번째요인인수면 / 운동활동 (Sleep/Motor Activity) 은비정상적인반복행동, 야간의행동, 다섯번째요인인고양된행동 (Elevated Behavior) 은다행감 / 기분이들뜸, 탈억제로구성되었다 [19]. 먼저치매진행정도와발현시기에따른행동심리증상의요인과각하위항목에대해다변량분석 (MANOVA) 을실시하였으나, 행동심리증상점수의표준편차가매 Table 2. Subscale score of CGA-NPI between and according to the progression of dementia Domains Total Mild (n=82) Moderate-severe (n=31) (n=32) (n=50) (n=17) (n=14) Delusions 2.09 ± 3.79 0.31 ± 1.09 1.46 ± 2.95 6.06 ± 5.69 3.57 ± 4.03 Hallucinations 0.54 ± 1.73 0.31 ± 0.18 0.18 ± 0.66 2.76 ± 3.63 0.29 ± 0.47 Agitation/Aggression 1.72 ± 2.48 0.75 ± 1.32 1.24 ± 1.88 4.41 ± 3.16 2.36 ± 3.15 Depression/ Dysphoria 1.32 ± 2.04 0.97 ± 1.45 1.40 ± 2.13 2.24 ± 2.95 0.71 ± 1.14 Anxiety 1.78 ± 2.96 1.16 ± 2.19 1.36 ± 2.27 3.65 ± 4.09 2.43 ± 4.20 Elation/Euphoria 0.25 ± 1.27 0.00 ± 0.00 0.06 ± 0.24 0.65 ± 1.32 1.00 ± 3.21 Apathy/Indifference 3.33 ± 3.50 2.66 ± 2.43 2.76 ± 3.58 4.47 ± 3.87 5.50 ± 3.92 Disinhibition 1.09 ± 2.19 0.31 ± 1.12 1.12 ± 2.40 2.47 ± 2.43 1.07 ± 2.30 Irritability/Lability 2.39 ± 3.18 1.78 ± 2.25 2.08 ± 3.29 5.18 ± 3.84 1.50 ± 1.91 Aberrant motor behavior 2.27±3.82 1.06±2.56 1.76±3.46 5.94±4.62 2.36±4.09 Sleep/Night-time behavior 1.81±2.96 0.34±1.18 2.04±3.18 2.71±3.48 3.29±3.22 Appetite/Eating disorder 2.30±3.55 1.25±2.58 2.64±4.09 4.00±3.00 1.43±3.25 Total CGA-NPI score 20.88±20.23 10.63±9.98 18.10±16.65 44.53±27.11 25.50±17.16 CGA-NPI, caregiver-administered neuropsychiatric inventory. 50 40 30 20 10 0 Mild Moderate-severe Fig. 1. Comparison of total score of CGA-NPI between and according to the progression of dementia. Table 3. Comparison of subscale score of CGA-NPI between and according to the progression of dementia Domains (n = 32) Mild (n=82) (n = 50) Moderate-severe (n=31) (n = 17) Delusions 664.50 93.00 Hallucinations 744.00 60.00* Agitation/Aggression 702.00 65.00* Depression/Dysphoria 718.00 74.50 Anxiety 777.00 89.50 Elation/Euphoria 752.00 104.00 Apathy/Indifference 717.00 98.00 Disinhibition 638.00* 74.00 Irritability/Lability 749.50 47.00 Aberrant motor behavior 726.00 67.00* Sleep/ Night-time behavior 532.00 104.00 Appetite/Eating disorder 656.00 52.50 Total CGA-NPI score 582.50* 72.00 (n = 14) *p< 0.05; p< 0.01. Mann-Whitney test; CGA-NPI, caregiver-administered neuropsychiatric inventory.
92 윤여주 김은주 홍창희 우크며, 변량동질성검증결과, 각집단의변량이동질하지않다는문제가있었다. 그래서증상의요인별항목과각하위항목에대해서는 Mann-Whitney 검정을실시하였다. 치매의진행정도가경도일때는수면 / 운동활동에서 집단이 집단보다유의하게더높은점수를보였고 [U=559.50, p< 0.05], 중등도- 중증에서는초조에서 집단이 집단보다유의하게더높은점수를보였다 [U = 51.00, p < 0.01]. 행동심리증상의각하위항목에대한 Mann- Whitney 검정결과를 Table 3에제시하였다. 치매의진행정도가경도일때는특히탈억제 [U = 638.00, p < 0.05] 와야간의행동 [U = 532.00, p< 0.01] 에서 집단이 집단보다유의하게더높은점수를보였고, 중등도-중증에서는환각 [U = 60.00, p<0.05], 초조 / 공격성 [U= 65.00, p< 0.05], 과민 / 불안정 [U= 47.00, p< 0.01], 비정상적인반복행동 [U = 67.00, p < 0.05], 식욕 / 식습관의변화 [U = 52.50, p < 0.01] 항목에서 집단이 집단보다유의하게더높은점수를보였다. 고찰이연구에서는발현시기 (/) 와치매진행정도 ( 경도 / 중등도-중증 ) 에따라알츠하이머병을구분함으로써행동심리증상의차이를발견하고자하였다. 경도의치매상태에서는 집단이더높은행동심리증상점수를나타내었고, 중등도-중증에서는 집단이더높은행동심리증상점수를나타내었다. 즉, 경도상태에서는 집단의행동심리증상이 집단보다심하지않으나, 중등도-중증으로진행하면심해지는양상으로서치매진행경과에따라 집단에서행동심리증상은더욱가파른증가를보였다. 두집단간행동심리증상에대한세부항목에서도차이를보였는데, 경도의치매상태에서는 환자가수면 / 운동활동관련요인, 세부적으로보면, 탈억제와야간의행동에서더심각한양상을보였다. 중등도- 중증에서는 환자가초조관련요인, 세부적으로보면환각, 초조 / 공격성, 과민 / 불안정, 비정상적인반복행동, 식욕 / 식습관의변화에서더심각한양상을보였다. 이러한행동심리증상의세부적인차이는신경영상학적연구와도관련이될듯한데, 집단이 집단보다전두엽의심한대사저하를나타내었고, 또한초조증상이전두엽변성과관련성이높음을알수있다. 초조는직접적인필요성이나혼돈상태에의해발생하지않는부적절한언어적, 음성적, 행동적이상으로정의되며 [20], 세로토닌, 노르에피네프린, 도파민등의신경전달물질의변화와함께뇌섬엽 (insula) 과전측대상피질 (anterior cingulate cortex), 안와전두엽 (orbitofrontal lobe) 기능부전과의관련성이보고된다 [21-24]. 이러한증거는이연구에서나타나는결과와같이, 치매가진행함에따라 집단에서초조 / 공격성과과민 / 불안정, 비정상적인반복행동과같은전두엽과관련성이높은행동심리증상이더심각하게나타남을시사할수있다. 본연구에서는치매진행정도와발현시기에따라알츠하이머병을구분함으로써두집단에서행동심리증상의차이를발견하고자하였다. 집단은 집단과유전적, 신경심리학적증상, 신경영상학적대뇌영역, 임상경과, 그리고행동심리증상에서도많은차이를보이므로두집단을질병학적으로구분하고차별적인치료계획을수립할필요성이있다. 후속연구에서는 집단에서더많이나타나는초조행동에대해주목하면서신경영상학을접목한연구를통해유사한결과가나타나는지살펴보아야하겠다. 또한치매진행정도에대해서는횡적연구를통해비교한한계가있어개인간변산성을통제하지못했으므로추후로는종적연구를통해치매가진행함에따라행동심리증상이어떤양상으로변화하고, 발현시기에따른두집단의행동심리증상의세부항목이어떤차이를보이는지알아보아야할것같다. 참고문헌 1. Luscombe G, Brodaty H, Freeth S. Younger people with dementia: diagnostic issues, effects on carers and use of services. International Journal of Geriatric Psychiatry 1998; 13: 323-30. 2. Sampson EL, Warren JD, Rossor MN. Young onset dementia. Postgraduate Medical Journal 2004; 80: 125-39. 3. Amaducci LA, Rocca WA, Schoenberg BS. Origin of the distinction between Alzheimer s disease and senile dementia: how history can clarify nosology. Neurology 1986; 36: 1497-9. 4. Heyman A, Wilkinson WE, Hurwitz BJ, Helms MJ, Haynes CS, Utley CM, et al. Early-onset Alzheimer s disease: clinical predictors of institutionalization and death. Neurology 1987; 37: 980-4. 5. Jacobs D, Sano M, Marder K, Bell K, Bylsma F, Lafleche G, et al. Age at onset of Alzheimer s disease: relation to pattern of cognitive dysfunction and rate of decline. Neurology 1994; 44: 1215-20. 6. Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer s disease: more than age alone. Journal of Alzheimer s Disease 2010; 19: 1401-8. 7. Koss E, Edland S, Fillenbaum G, Mohs R, Clark C, Galasko D, et al. Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer s disease: A CERAD analysis, Part XII. Neurology 1996; 46: 136-41. 8. Bigio EH, Hynan LS, Sontag E, Satumtira S, White CL. Synapse loss is
치매진행정도에따른조기발현과지연발현알츠하이머병환자의행동심리증상비교 93 greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis. Neuropathology and Applied Neurobiology 2002; 28: 218-27. 9. Kim EJ, Cho SS, Jeong Y, Park KC, Kang SJ, Kang E, et al. Glucose metabolism in early onset versus late onset Alzheimer s disease: an SPM analysis of 120 patients. Brain 2005; 128(Pt 8): 1790-801. 10. Mielke R, Herholz K, Grond M, Kessler J, Heiss WD. Differences of regional cerebral glucose metabolism between presenile and senile dementia of Alzheimer type. Neurobiology of Aging 1992; 13: 93-8. 11. Finkel S. Introduction to behavioural and psychological symptoms of dementia (BPSD). International Journal of Geriatric Psychiatry 2000; 15 Suppl 1: S2-4. 12. Matsumoto T, Adachi H, Hirono N, Tanabe H. Caregiver burden associated with behavioral and psychological symptoms of dementia in elderly people in the local community. Dementia and Geriatric Cognitive Disorders 2007; 23: 219-24. 13. Hori K, Oda T, Asaoka T, Yoshida M, Watanabe S, Oyamada R, et al. First episodes of behavioral symptoms in Alzheimer s disease patients at age 90 and over, and early-onset Alzheimer s disease: comparison with senile dementia of Alzheimer s type. Psychiatry Clinical Neurosciences 2005; 59: 730-5. 14. Toyota Y, Ikeda M, Shinagawa S, Matsumoto T, Matsumoto N, Hokoishi K, et al. Comparison of behavioral and psychological symptoms in early-onset and late-onset Alzheimer s disease. International Journal of Geriatric Psychiatry 2007; 22: 896-901. 15. Hachinski VC, Iliff LD, Zilhka E, Du Boulay GH, McAllister VL, Marshall J, et al. Symon L.Cerebral blood flow in dementia. Arch Neurol. 1975; 32: 632-7. 16. Kang SJ, Choi SH, Lee BH, Jeong Y, Hahm DS, Han IW, et al. Caregiver- Administered Neuropsychiatric Inventory (CGA-NPI). Journal of Geriatric Psychiatry and Neurology 2004; 17: 32-5. 17. Kang Y, Na DL, Hahn S. A validitiy study on the Korean Mini-Mental State Examination (K-MMSE) in dementia patients. J Korean Neurol Assoc 1997; 15: 300-8. 18. Choi SH, Lee BH, Hahm DS, Jeong JH, Yoon SJ. Estimating the validity of the Korean version of Expanded Clinical Dementia Rating (CDR) scale. J Korean Neurol Assoc 2001; 19: 585-91. 19. Lange RT, Hopp GA, Kang N. Psychometric properties and factor structure of the Neuropsychiatric Inventory Nursing Home version in an elderly neuropsychiatric population. International Journal of Geriatric Psychiatry 2004; 19: 440-8. 20. Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in a nursing home. Journal of Gerontology 1989; 44(3): M77-84. 21. Bruen PD, McGeown WJ, Shanks MF, Venneri A. Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer s disease. Brain 2008; 131(Pt 9): 2455-63. 22. Tekin S, Mega MS, Masterman DM, Chow T, Garakian J, Vinters HV, et al. Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Annals of Neurology 2001; 49: 355-61. 23. Trzepacz PT, Yu P, Bhamidipati PK, Willis B, Forrester T, Tabas L, et al. Frontolimbic atrophy is associated with agitation and aggression in mild cognitive impairment and Alzheimer s disease. Alzheimers Dement 2013; 9: S95-S104. 24. Cho H, Seo SW, Kim JH, Kim C, Ye BS, Kim GH, et al. Changes in subcortical structures in early- versus late-onset Alzheimer s disease. Neurobiol Aging 2013; 34: 1740-7.