정신신체의학 22(1) : 23-30(2014) 원저 알쯔하이머형치매환자에서행동심리증상과 호모시스테인과의연관 인제대학교의과대학일산백병원정신건강의학교실, 1 건양대학교의과대학정신건강의학교실 2 이지민 1 임우영 2 김현 1 이강준 1 Correlation of Behavioral and Psychological Symptoms and Homocysteine in Patients with Dementia of Alzheimer s Type Ji Min Lee, M.D., 1 Woo-young Im, M.D., 2 Hyun Kim, M.D., 1 Kang Joon Lee, M.D. 1 1 Department of Psychiatry, Ilsan Paik Hospital, Inje Unversity School of Medicine, Goyang, Korea 2 Department of Psychiatry, Konyang Unversity Hospital, Daejon, Korea ABSTRACT Objectives:Homocysteine has been associated with cognitive impairment and various psychiatric symptoms. This study was designed to examine the relationship exists between plasma homocysteine concentration and behavioral and psychological symptoms of dementia(bpsd). Methods:41 subjects with dementia of Alzheimer s type were included in this study. We carried out history taking, physical examination, and cognitive assessment for the diagnosis of dementia of Alzheimer s type based on DSM-IV. We scored the Mini Mental State Examination(MMSE), Global Deterioration Scale(GDS), Clinical Dementia Rating(CDR), and the Korean Neuropsychiatric Inventory(K-NPI). We also measured levels of homocysteine, folate, and vitamin B 12 in the plasma. Results:We found statistically significant positive correlations between homocysteine concentration with NPI total score, and with scores of several sub-domains such as delusion, agitation/aggression, depression/dysphoria, and elation/euphoria. No significant correlation existed between homocysteine levels and scores of MMSE, GDS, and CDR. Conclusions:This study shows that plasma homocysteine levels are associated with BPSD. Further research is necessary to identify pathophysiologic mechanisms underlying these relationships. 23 KEY WORDS : Dementia of Alzheimer s type ㆍ Homocysteine ㆍ BPSD. 서론 우리나라의급속한고령화로인해노인성질환이크게늘어나고있다. 특히치매에대한사회적관심이증가하고있으 나, 치료가쉽지않아치매의발병이전에조기발견과예방, 조기치료에대한중요성이강조되고있다. 여러종류의치매중에서도알쯔하이머병 (Alzheimer s disease, 이하 AD) 이가장큰부분을차지하고있는데이질환은점진적으로인지기능의퇴행을일으키고, 지적기능의전반적인손상, 기억 Received: May 7, 2014 / Revised: June 19, 2014 / Accepted: June 25, 2014 Corresponding author: Kang Joon Lee, Department of Psychiatry, College of Medicine, Inje University Ilsan Paik Hospital, 170 Juhwa-ro, Ilsanseo-gu, Goyang 411-706, Korea Tel:031) 910-7260 Fax:031) 910-7268 E-mail:lkj@paik.ac.kr
24 력및사고력, 기분, 행동, 지각, 판단력등에도장애를나타내기때문에이환된노인들에게독립적인생활능력의저하를일으켜결국가정적, 사회적부담을크게증가시킨다. 치매의진단에도움을줄수있는검사중의하나가혈액검사인데호모시스테인 (homocysteine), 엽산 (folate), 비타민 B 12 (vitamine B 12) 가많이사용되며특히호모시스테인농도상승이치매와깊은연관이있음이점차입증되고있어, 이것의측정이필수적인진단과정에포함되고있다. 1) 더욱이비타민 B 12 와엽산이질병의현재상태를반영하지않을수있다는연구결과가보고되고있어호모시스테인이치매환자에서비타민 B 12 와엽산보다더나은검사수치로생각되고있다. 2) 필수아미노산인메티오닌의대사과정에서발생하는호모시스테인이시스테인이나메티오닌으로전환되지않고일정량이상축적되면심혈관질환을일으킨다. 이는혈관을수축상태로만들고혈압과혈전을조절해주는인자인프로시타시클린생성을억제하며, 저밀도지단백등을축적하여혈관벽에손상을일으킨다. 결국우리몸의혈관을파괴하고노화시킴으로써혈전이나혈액응고를불러오게되어, 동맥경화, 치매, 뇌졸중등심혈관계질환을일으키는가장강력한원인이되는독성물질이되는것이다. 3,4) 이러한호모시스테인을분해해서시스테인으로전환하거나메티오닌으로되돌리는데필요한효소들은엽산, 비타민 B 12 을요구하기때문에이들이부족하면혈중호모시스테인수치는증가하기시작한다. 1) 최근연구에의하면호모시스테인농도는엽산과비타민 B 12 의민감한표지자이고, 혈장호모시스테인농도증가는심혈관계질환뿐만아니라인지손상및치매의심각도와도깊은연관이있음이발표되고있다. 또한고호모시스테인혈증은정신증, 우울증그리고기타정신과적문제와도관련되어있다는흥미로운연구결과도보고되고있다. 5,6) 이런관점에서접근해보면치매의행동심리증상 (Behavioral and Psychological Symptoms of Dementia, 이하 BPSD) 이위의혈액검사인자들과관련이있음을추측해볼수있겠다. 또한 AD 가아닌전두측두엽치매와같은행동이상을나타내는다른형태의치매와도연관되지는않을지기대해볼수있겠다. 이전에호모시스테인과치매의행동심리증상과의연관관계를연구한논문이몇편있었으나, 임상적으로뚜렷한연관성을찾지는못하였다. 본논문은한국인에서혈중호모시스테인이 AD와연관된다는여러연구결과를기초로 AD의혈액검사결과를비교분석하고행동심리증상과의연관성에대하여살펴보고자하였다. 한국인에서의행동심리증상과혈중호모시스테인농도에대한연구는이제까지시행된바가없었다. 본연구결과는향후임상실제에서치매의진단과치료적인측면에서도움을줄수있을것이다. 방법 1. 대상및방법 2011년 9월부터 2014년 1월까지의기간동안기억력저하를주소로일산백병원정신건강의학과치매클리닉을방문한환자들중 AD로진단된환자를대상으로하여병력청취, 정신상태검사및신체검사, 신경인지기능검사, 혈액검사가수행되었다. DSM-IV 진단기준에의해 AD로진단된환자들중 MMSE-KC(Korean version of Mini Mental State Examination in the CERAD-K) 23점이하, 7,8) 65세이상인환자를대상으로하였다. AD 이외에다른원인에의한치매로진단받았거나, 두부외상또는뇌손상의과거력, 신경퇴행성질환 ( 파킨슨병, 헌팅톤병등 ), 약물남용의과거력이있거나갑상선기능이상이나기타인지기능에장애를줄수있는내과적문제가있는환자및동반된정신병적혹은기분장애가있는환자는연구에서제외하였다. 또한비타민 B 12 혹은엽산경구제제를복용한사람들도제외하였다. 환자들의전반적인인지기능및심각도의단계평가는한국판간이정신상태검사 (MMSE-KC) 9) 와전반적퇴화척도 (Global Deterioration Scale, GDS), 10) 임상치매평가척도 (Clinical Dementia Rating) 11) 를이용하여측정하였다. 그리고환자들의행동장애와정신증상의유무및행태를평가하기위해한국형신경행동검사 (Korean neuropsychiatric inventory, 이하 K-NPI) 를이용하였다. 평가이전 4주동안환자에게서나타난 12가지의행동변화에대해서측정하였으며각각의항목에서특정이상행동이나타날경우그빈도 (0~4 점 ) 와심한정도 (0~3점 ) 를다시선택하도록하였고, 해당하는이상행동이없는경우는다음항목으로넘어가도록하였다. 이후각항목의빈도와심한정도를곱한값인 composite score (0~12점) 을구하였고, 12개항목의 composite score를모두합하여총 K-NPI(0~144점 ) 점수를구하였다. 본연구는인제의대일산백병원임상연구윤리위원회의심사및승인을받았다. 2. 평가도구 1) 한국판간이정신상태검사 (MMSE in the Korean version of the CERAD assessment packet, MMSE-KC) 영어판 CERAD평가집에포함된 MMSE( 이하 CERAD- MMSE) 는 Folstein 등이개발한 MMSE 8) 중일부검사의질문내용및채점기준을구체적으로기술하는등약간의수정을가했으나전체적인검사구성에있어서는 Folstein MMSE 와거의같다. MMSE-KC 의경우 CERAD-MMSE 의질문내용및방법, 채점기준등을따라충실히번안하되, 일부문항
의경우기존에한국에서널리사용되어온 MMSE-K 12) 를참고하였다. 2) 전반적퇴화척도 (Global deterioration scale, GDS) 전반적퇴화척도 (Global deterioration scale, 이하 GDS) 는인지기능뿐아니라, 일상생활활동, 이상행동등을포함하는평가도구로환자의교육수준에크게영향을받지않는다. 치매임상단계를 7단계로평가하도록구성되었고, 1~3단계까지는전치매단계이며 4~7단계는치매단계이다. GDS는국내에서도신뢰도가검증되었고, 기존의치매평가검사들과우수한상관관계를보여타당도가입증된바있다. 13) 이를통해서시간에따른환자의변화를파악할수있어서치료의경과나예후를평가하는데유용하게사용할수있다. 3) 임상치매평가척도 (Clinical Dementia Rating, CDR) 임상치매평가척도 (Clinical Dementia Rating, 이하 CDR) 는환자및보호자와의면담을통하여환자의인지및사회기능을평가하는도구이다. 기억력, 지남력, 판단력과문제해결능력, 사회활동, 집안생활과취미, 그리고위생및몸치장의 6가지세부항목으로구성되어있으며각항목마다 0에서 5점까지의척도를사용한다. 이 6가지영역의점수를고려하여최종 CDR 점수를계산한다. 4) 한국형신경정신행동검사 (Korean neuropsychiatric inventory, K-NPI) 신경정신행동검사 (Neuropsychiatric Inventory, 이하 NPI) 는치매환자의행동장애를평가하기위하여개발되었고그타당도와신뢰도가검증되어여러나라의언어로번역되어사용되고있는평가도구이다. 14-16) 국내에서도표준화된한국어판 NPI(K-NPI) 가개발되어여러치매질환에적용하여타당성과신뢰성을인정받았다. NPI는치매환자들에게서나타나는이상행동을 12가지의영역 -망상(delusion), 환각 (hallucination), 초조 / 공격 (agitation/aggression), 우울 / 불쾌감 (depression/dysphoria), 불안 (anxiety), 다행감 / 들뜬기분 (euphoria/elation), 무감동 / 무관심 (apathy/indifference), 탈억제 (disinhibition), 과민 / 불안정 (irritability/lability), 이상운동증상 (aberrant motor behavior), 수면 / 야간행동 (sleep/nighttime behavior), 식욕 / 식습관의변화 (appetite/eating change)- 으로평가하며, 동시에그에따른보호자의고통정도를평가하게된다. 각항목은빈도 (0~4점) 와심한정도 (0~3점) 로평가된다. 각항목에서빈도와심한정도를곱한값인 composite score(0~12점 ) 를구하였고, 12개항목의 composite score를모두합하여총 NPI(0~144점 ) 점수를구하였다. 5) 혈액채취모든대상군에서혈중호모시스테인, 비타민 B 12, 엽산농도 를측정하였는데, 12시간이상공복후아침에환자의상박에서정맥채혈하였다. 전혈은시트르산염이포함된진공채혈관에담아얼음으로냉각후즉시 3,000rpm 으로 10분동안원심분리하여혈장을 -70 로냉동보관하였다. 혈중호모시스테인농도는혈장에서 IMx kit를사용하여형광편광면역검사법으로측정하였다. 3. 통계자료는 Statistical Package for Social Science(SPSS) 15.0 for windows를사용하여분석하였고 p값이 0.05 이하인경우통계적으로의미있는것으로판정하였다. 전체환자군을 MMSE 점수에따라두그룹으로나눠서통계학적정보를분석하기위해서독립 t검정을사용했고, 범주형변수의분석을위해서카이제곱검정을사용했다. 대상자의호모시스테인, 비타민 B 12, 엽산과 MMSE-KC, GDS, CDR, NPI 점수사이의상관관계는 Pearson s correlation을사용하여분석하였다. 결과 1. 인구통계학적정보및임상적자료 본연구에포함된환자들은총 41명이었고남성이 13명, 여성이 28명이었다. 모두 AD로진단받았으며, 평균연령은 77.83±9.29 세이었다. 평균 MMSE-KC, GDS, CDR 점수는각각 17.56±4.95, 4.2±0.84, 0.95±0.31 이었다. MMSE 점수가 21~23점인경도치매환자는 14명, 11~20점인중등도치매환자는 27명이었다 (Table 1). NPI 각항목에따른점수는 Table 2와같이나타났으며, 평균점수는 20.59±22.31 점이었다. 2. 연구대상에서의호모시스테인, 엽산, 비타민 B 12 환자군에서혈중호모시스테인농도는 13.78±6.63μmol/ L로나타났으며, 엽산농도는 9.83±6.72ng/mL, 비타민 B 12 농도는 578.98±235.93pg/mL로나타났다. 부가적으로인지기능저하수준에따른호모시스테인농도를알아보기위하여경도치매군과중등도치매군에서의호모시스테인농도도비교해보았다. MMSE 점수가 21점이상인경도치매환자군에서호모시스테인, 엽산, 비타민 B 12 의농도가각각 11.61±5.22μmol/L, 12.3±9.09ng/mL, 644.29±259.73pg/ ml으로나타났고, MMSE 점수가 21점미만인중등도치매환자군에서호모시스테인, 엽산, 비타민 B 12 의농도가각각 14.91±7.08μmol/L, 8.55±4.82ng/mL, 545.11±220pg/mL 으로나타났다. 두군사이에서엽산, 호모시스테인, 비타민 B 12 에서의유의한차이는없었다 (Table 1). 25
Table 1. Demographic and clinical data of patients with Alzheimer s disease Total(N=41) Mild(N=14) Moderate(N=27) Mild vs. moderate Statistics value Sex(female) 013(28) 005(9) 008(19) 0.158 a 0.691 Age 077.83(9.29) 078.79(9.48) 077.33(9.34) 0.004 b 0.951 Folate 009.83(6.72) 012.3(9.09) 008.55(4.82) 3.49 b 0.069 Homocysteine 013.78(6.63) 011.61(5.22) 014.91(7.08) 0.873 b 0.356 Vit. B12 578.98(235.93) 644.29(259.73) 545.11(220) 0.883 b 0.353 MMSE 017.56(4.95) 023.07(2.02) 014.7(3.29) 6.127 b 0.018* GDS 004.2(0.84) 003.5(0.76) 004.56(0.64) 0.468 b 0.498 CDR 000.95(0.31) 000.71(0.26) 001.07(0.27) 3.065 b 0.088 NPI total 020.59(22.31) 015.43(17.13) 023.26(24.44) 1.195 b 0.281 Values are presents with mean(sd). * : significant p<0.05. a statistical methods used χ 2 test, df=1, b statistical methods used student s t test, df=39. MMSE : Mini Mental State Examination, GDS : Global Deterioration Scale, CDR : Clinical Dementia Rating Scale, NPI : Neuropsychiatric Inventory p 26 Table 2. Mean NPI scores of 41 AD patients Mean NPI score Delusion 2.39(3.54) Hallucination 1.15(3.2)0 Agitation/aggression 1.9(2.66) Depression/dysphoria 2.12(3.08) Anxiety 1.85(2.73) Euphoria/elation 0.24(0.99) Apathy/indifference 2.68(3.64) Disinhibition 0.59(1.6)0 Irritability/lability 1.73(2.94) Aberrant motor behavior 2.46(4.2)0 Sleep/night time behavior 2.0(3.63) Appetite/eating change 1.46(2.47) AD : Alzheimer s disease, NPI : Neuropsychiatric Inventory 3. 호모시스테인, 엽산, 비타민 B 12 농도와 NPI, MMSE-KC, GDS, CDR과의연관성 Pearson 상관분석을시행하였고혈중호모시스테인농도와 NPI 총점사이에서유의한상관관계가있었다. NPI 세부항목별로살펴보면망상 (delusion), 초조 / 공격성 (agitation/aggression), 우울 / 불쾌감 (depression/dysphoria), 들뜸 / 다행감 (elation/euphoria) 등의영역에서유의한상관관계가있었다 (Table 3). 그러나 NPI의나머지여덟가지항목에서는유의한상관관계가나타나지않았다. 한편호모시스테인과 MMSE-KC, GDS, CDR 점수사이의상관관계는유의하지않았다. 비타민 B 12 와 NPI, MMSE-KC, GDS, CDR 그리고엽산과 NPI, MMSE-KC, GDS, CDR 점수사이의상관관계도유의하지않았다 (Table 4). 고찰 본논문은 AD에서혈중호모시스테인, 엽산, 비타민 B 12 의농도와치매의행동심리증상과의상관관계를밝히고자시행하였다. 이제까지호모시스테인, 엽산, 비타민 B 12 와인지기능 Table 3. Correlation of plasma Homocysteine levels and scores of NPI Homocysteine level(μmol/l) Total -0.318* 0.043* Delusion -0.423** 0.006** Hallucination -0.102 0.526 Agitation/aggression -0.359* 0.021* Depression/dysphoria -0.372* 0.017* Anxiety -0.005 0.974 Euphoria/elation -0.341* 0.029* Apathy/indifference -0.225 0.158 disinhibition -0.205 0.199 Irritability/lability -0.244 0.124 Aberrant motor behavior -0.182 0.255 Sleep/night time behavior -0.096 0.551 Appetite/eating change -0.208 0.193 * : p<0.05, ** : p<0.01 Table 4. Correlation of plasma Homocysteine levels and scores of MMSE, GDS, CDR 과의연관관계를연구한논문은많았으나, 행동심리증상과 의연관관계를연구한논문은거의없었다. 본논문의결과 AD 환자에서혈중호모시스테인과 NPI 총점사이에유의한상관 관계가있었으며특히망상 (delusion), 초조 / 공격성 (agitation/ aggression), 우울 / 불쾌감 (depression/dysphoria), 들뜸 / 다 행감 (elation/euphoria) 등의세부항목에서유의한상관관계 가있었다. 이는이전에 Tabet 등이수행한호모시스테인과행 동심리증상사이에유의한연관이없다는연구결과 17) 와는상 반되었으나, 호모시스테인이정신과적증상과연관이있다는 r Homocysteine level(μmol/l) MMSE -0.119 0.460 GDS -0.233 0.143 CDR -0.069 0.670 r MMSE : Mini Mental State Examination, GDS : Global Deterioration Scale, CDR : Clinical Dementia Rating Scale p p
또다른연구들과는유사한결과이었다. 5,6,18-20) 이전의연구결과와다르게본논문에서호모시스테인이행동심리증상과연관이있다고나온사실은한국인의인종적특성일수도있겠으며, 추후관련된연구를통해확인이필요할것으로보인다. 또한본연구에서비타민 B 12 와엽산은행동심리증상과연관이없는것으로나타났으며, 이는이전의 Engelborghs, Whyte 등이보고한연구와유사한결과이었다. 21,22) 혈중호모시스테인농도증가가 AD에미치는영향으로는여러가지가설이있는데 23) 이중주요한것들로는호모시스테인으로인한산화적손상 (oxidative stress), 24) 탈메틸화 (demethylation), 25) 아밀로이드베타의상승, 26) 타우단백의인산화 27) 등이대표적이지만아직까지명확히밝혀져있지는않다. 과거연구에서호모시스테인의상승이인지기능의저하와연관된다는사실이보고되었다. Schafer 등이수행한연구에서는고령의인구에서호모시스테인의농도가높으면인지기능의저하가나타난다고밝혔다. 28) 또한 Oxford project to Investigate Memory and Ageing(OPTIMA) 에서혈장호모시스테인은고령인구군에서인지기능점수와음의관계로상응한다고밝혔다. 29) 또한 Rotterdam Scan Study에서는치매가없는고령인구에서혈장호모시스테인이증가할수록인지기능이저하되는것을밝혔다. 30) 그러나 Irizzary 가수행한연구에서는호모시스테인수치가나이의증가에따라서상승하지만, AD군과대조군사이에서호모시스테인수치의유의한차이는없는것으로보고하였다. 31) 논문별로차이는있지만전반적으로호모시스테인의농도상승이인지기능의저하와연관이있는것으로나타나고있다. 그러나우리의연구에서는호모시스테인의농도와인지기능이통계적으로유의한연관관계를보이지않았는데, 이는우울증, 불안장애등의공존질환이충분히배제되지못해서다른변인들과교란이되어나타난결과일수있겠다. 그리고통계표본의수가적은것도영향을미쳤을것으로보인다. 치매에서의우울증과호모시스테인과의연관에대해서는거의실행된연구가없었다. Chen 등은중등도의 AD환자에서주요우울장애의공존과고호모시스테인혈증이상관관계가있음을보고하였다. 32) 또한고령의환자군을대상으로우울증과호모시스테인과의관계를연구한몇몇논문이있었으나결과가일관되게나타나지는않았다. 33-36) 우리의연구에서는호모시스테인의증가와 NPI상에서의우울 / 불쾌감 (depression/dysphoria) 항목수치와유의한연관관계가있었으며, 이는 Chen이이전에수행하였던연구결과 32) 와유사한것이었다. 아직까지호모시스테인과치매환자에서의우울증과의연관성에대하여정립된기전은없고, 다만호모시스테인과고령환자의우울증에대한몇가지가설은대두되고있다. 대표적인가설로는혈관성병리가우울증의주요원인이라는 것이다. 37) 고호모시스테인혈증이혈관내피세포의기능부전및만성염증반응을일으켜 38) 알쯔하이머형치매를악화시키고이러한혈관성인자로인하여 혈관성우울증 이생기는것으로추정된다. 알쯔하이머형치매에서염증반응이중요한기전이라는것은이미알려져있는사실이다. 39) 치매에서호모시스테인과사고장애에대한영역은거의연구된바가없고, 단지호모시스테인과조현병과의관계에대한소수의연구결과만이보고된바있다. Spiro 등은호모시스틴뇨증을보이는조현병환자를보고하면서조현병일부에서메티오닌대사이상가능성을제시하였고, 40) 다른연구에서는조현병환자들에게호모시스테인의전구물질인메티오닌을투여하였을때증상이악화되었을밝혔다. 5,41) 이후에좀더체계적인연구가이루어져서 Regland 등은조현병환자들을대상으로한연구에서고농도호모시스테인의빈도가조현병환자군의 45% 에서관찰되었다고하였으며이는엽산, 코발라민결핍과같은영양상태나항정신병약물과는관계없는유전적메틸화결함이라고기술하였다. 42) Levine 등은 193명의조현병환자군과 762명의정상대조군을성별, 연령별로나누어혈중호모시스테인농도가조현병이있는젊은남성에서더욱높았다는결과를얻어내었으나 43) Virgos 등은조현병환자군과정상군사이에차이가없다는상반된보고를발표하기도하였다. 44) 비록일관되지않은결과이지만, 이상의연구를통해서고호모시스테인혈증과조현병사이에연관성이있음을추정해볼수있겠다. 이에대해연관된기전을살펴보면호모시스테인이 DNA에손상을일으켜세포자멸사 (apoptosis) 와흥분독성 (excitotoxicity) 을유발한다는주장과호모시스테인이 NMDA(N-methyl-D-aspartate) 수용체의글라이신 coagonist 부위와글루타메이트부위에흥분독소 (excitotoxin) 로작용한다는주장이있다. 45,46) 본연구에서는 AD환자들에서호모시스테인농도의증가에따라서망상 (delusion), 초조 / 공격성 (agitation/aggression) 등의정신증을시사하는항목이올라갔는데, 이를통해 AD에서도조현병에서와비슷한기전에의해서상기결과가나타난다고추정해볼수있겠다. 또본연구에서호모시스테인과들뜸 / 다행감 (elation/euphoria) 사이에유의한상관관계가나타났는데, 치매환자에서호모시스테인과조증증상에대한연관연구는이제까지거의이루어지지않고있는실정이다. 양극성장애에국한하여살펴보면, 최근연구에서양극성장애에서의호모시스테인대사장애가관찰되고있다. Ozbek 등은정상대조군보다양극성장애환자에서호모시스테인농도가더높고엽산농도는낮음을발표하였다. 47) 이와같이고호모시스테인혈증이양극성장애에서신경인지결손의병태생리에일정역할을하는것같지만, 48,49) 아직이에대한정보는많이부족한상태이 27
28 므로조증증상에서의호모시스테인의역할을분석하기위한 계속적인연구가요구되고있다. 본연구를임상실제에서치매환자의진단및치료에적용 시켜생각해본다면, 호모시스테인측정을치매진단의보조 적인도구로이용해볼수가있겠으며, 호모시스테인을분해 하는데도움을주는비타민 B 12 혹은엽산투여를고호모시 스테인혈증예방의보조적인치료방법으로또한고려해볼 수있겠다. 이연구의제한점은행동심리증상의각영역이서로영향 을줄수있다는점을보완하지못한것이다. 그리고각영역 의연관성을고려하지못하고단순히상관관계로분석한것 은결과해석에제한을줄수있겠다. 또한연령과성별조정 을하지못한점, 환자의표본수가많지않은점도결과의신 뢰도에영향을줄수있겠다. 그리고후향적연구이다보니 인지기능평가날짜와혈액검사날짜가완전히일치하지는 않았다. 그럼에도불구하고두검사날짜의간격을 3 개월이 내로제한을두어시간적개연성을높이려노력하였다. 환자 의식사내용에대한자료수집도미흡한부분이있었다. 향후 이러한제한점을보완한대규모연구를통하여호모시스테 인과치매의행동심리증상과의관계를좀더명확하게밝혀 내어야할것이다. REFERENCES (1) Vogel T, Dali-Youcef N, Kaltenbach G, Andres E. Homocysteine, vitamin B12, folate and cognitive functions: a systematic and critical review of the literature. Int J Clin Pract 2009;63:1061-1067. (2) Nilsson K, Gustafson L, Hultberg B. Plasma homocysteine is a sensitive marker for tissue deficiency of both cobalamines and folates in a psychogeriatric population. Dement Geriatr Cogn Disord 1999;10:476-482. (3) Facila L, Nunez JE, G VB, Sanchis J, Bodi V, Chorro FJ, Llacer A. Early determination of homocysteine levels in acute coronary syndromes, is it an independent prognostic factor? Int J Cardiol 2005;100:275-279. (4) Virtanen JK, Voutilainen S, Happonen P, Alfthan G, Kaikkonen J, Mursu J, Rissanen TH, Kaplan GA, Korhonen MJ, Sivenius J, Salonen JT. Serum homocysteine, folate and risk of stroke: Kuopio Ischaemic Heart Disease Risk Factor(KIHD) Study. Eur J Cardiovasc Prev Rehabil 2005;12:369-375. (5) Reif A, Pfuhlmann B, Lesch KP. Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1162-1168. (6) Monji A, Yanagimoto K, Maekawa T, Sumida Y, Yamazaki K, Kojima K. Plasma folate and homocysteine levels may be related to interictal schizophrenia-like psychosis in patients with epilepsy. J Clin Psychopharmacol 2005;25:3-5. (7) Mitchell AJ. A meta-analysis of the accuracy of the mini-mental state examination in the detection of dementia and mild cognitive impairment. J Psychiatr Res 2009;43:411-431. (8) Folstein MF, Robins LN, Helzer JE. The Mini-Mental State Examination. Arch Gen Psychiatry 1983;40:812. (9) Lee D, Lee K, Lee J, Kim K, Jhoo J, Youn J, Kim S, Woo S, Woo J. A Normative study of the Mini-Mental State Examination in the Korean Elderly. J Korean Neuropsychiatric Association 2002;41:508-525. (10) Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 1982;139:1136-1139. (11) Choi S, Na D, Lee B, Hahm D, Jeong J, Yoon S, Yoo K, Ha C, Han I. Estimating the validity of the Korean version of expanded Clinical Dementia Rating(CDR) Scale. J Korean Neurol Assoc 2001;19:585-591. (12) Park J, Kwon Y. Standardization of Korean Version of the Mini- Mental State Examination(MMSE-K) for Use in the Elderly. J Korean Neuropsychiatr Assoc 1989;28:612-617. (13) Choi S, Na D, Lee B, Hahm D, Jeong J, Jeong Y. The validity of the Korean Version of Global Deterioration Scale. J Korean Neurol Assoc 2002;20:612-617. (14) Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308-2314. (15) Hirono N, Mori E, Ikejiri Y, Imamura T, Shimomura T, Hashimoto M, Yamashita H, Ikeda M. [Japanese version of the Neuropsychiatric Inventory--a scoring system for neuropsychiatric disturbance in dementia patients]. No To Shinkei 1997;49: 266-271. (16) Fuh JL, Liu CK, Mega MS, Wang SJ, Cummings JL. Behavioral disorders and caregiversʼ reaction in Taiwanese patients with Alzheimerʼs disease. Int Psychogeriatr 2001;13:121-128. (17) Tabet N, Rafi H, Weaving G, Lyons B, Iversen SA. Behavioural and psychological symptoms of Alzheimer type dementia are not correlated with plasma homocysteine concentration. Dement Geriatr Cogn Disord 2006;22:432-438. (18) Chen CS, Tsai JC, Tsang HY, Kuo YT, Lin HF, Chiang IC, Devanand DP. Homocysteine levels, MTHFR C677T genotype, and MRI Hyperintensities in late-onset major depressive disorder. Am J Geriatr Psychiatry 2005;13:869-875. (19) Atmaca M, Tezcan E, Kuloglu M, Kirtas O, Ustundag B. Serum folate and homocysteine levels in patients with obsessivecompulsive disorder. Psychiatry Clin Neurosci 2005;59616-620. (20) Regland B, Abrahamsson L, Blennow K, Grenfeldt B, Gottfries CG. CSF-methionine is elevated in psychotic patients. J Neural Transm 2004;111:631-640. (21) Engelborghs S, Vloeberghs E, Maertens K, Marien P, Somers N, Symons A, Clement F, Ketels V, Saerens J, Goeman J, Pickut BA, Vandevivere J, De Deyn PP. Correlations between cognitive, behavioural and psychological findings and levels of vitamin B12 and folate in patients with dementia. Int J Geriatr Psychiatry 2004;19:365-370. (22) Whyte EM, Mulsant BH, Butters MA, Qayyum M, Towers
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fer R, Zach J, Born C, Bernhard B, Fast K, Grunze H, Engel RR, Severus E. Association of cognitive deficits with elevated homocysteine levels in euthymic bipolar patients and its impact on psychosocial functioning: preliminary results. Bipolar Disord 2007;9:63-70. 국문초록 연구목적 호모시스테인은인지기능의손상과다양한정신과증상들과연관되어있다. 본연구는혈중호모시스테인농 도와치매의행동심리증상사이에연관성을검증하기위해서시행되었다. 방법 DSM-IV 에의해알쯔하이머형치매로진단된환자 41 명의혈중호모시스테인, 엽산, 비타민 B 12 농도를측 정하였다. 그리고병력청취, 신체검사와간이정신상태기능검사 (MMSE), 전반적퇴화척도 (GDS), 임상치매평가 척도 (CDR), 한국형신경정신행동검사 (K-NPI) 를수행하였다. 결과 호모시스테인농도와 NPI 총점수사이에통계적으로유의한양의상관관계가관찰되었고망상, 초조 / 공격성, 우울 / 불쾌, 들뜸 / 흥분과같은여러하위항목과도양의상관관계가관찰되었다. 호모시스테인농도와 MMSE, GDS, CDR 점수사이에는유의한상관관계가관찰되지않았다. 결론본연구는혈중호모시스테인농도가치매의행동심리증상과연관되어있음을보여준다. 추가적인연구를 통하여이와연관된병태생리학적기전을밝히는것이필요하다. 중심단어 : 알쯔하이머형치매 호모시스테인 행동심리증상 (BPSD). 30