Original Article Journal of Korean Geriatric Psychiatry 2017;21(2):67-74 ISSN Copyright 2017 Korean Association for Geriatric Psychiatry 알츠하

Original Article Journal of Korean Geriatric Psychiatry 2017;21(2):67-74 ISSN 1226-6329 Copyright 2017 Korean Association for Geriatric Psychiatry 알츠하이머병환자에서정신증적증상과연관된좌측판개부및좌측외측후두회의피질두께변화 인제대학교의과대학해운대백병원정신건강의학교실, 1 인제대학교융합의학과, 2 인제대학교의용공학부 / 항노화헬스케어연구소, 3 국립공주병원정신건강의학과 4 이두형 1 김경미 1 박선철 1 김태형 2 최승은 1 정태영 1 이봉주 1 문치웅 3 이정구 1 김영훈 4 Altered Cortical Thicknesses of Left Pars Opercularis and Left Lateral Occipital Gyrus Can Be Associated with Psychotic Symptoms in Patients with Alzheimer s Disease Doo Hyoung Lee, MD, 1 Gyung Mee Kim, MD, 1 Seon-Cheol Park, MD, 1 Tae Hyung Kim, MS, 2 Seung Eun Choi, MA, 1 Tae-Yeong Jeong, MD, 1 Bong Ju Lee, MD, 1 Chi Woong Mun, PhD, 3 Jung Goo Lee, MD, 1 and Young Hoon Kim, MD 4 Department of Psychiatry, 1 Inje University College of Medicine, Haeundae Paik Hospital, Busan, Department of Health Science & Technology, 2 Inje University, Gimhae, School of Biomedical Engineering/uHARC, 3 Inje University, Gimhae, Department of Psychiatry, 4 Gongju National Hospital, Gongju, Korea Objective:The aims of this study was to present an association between the presence of psychotic symptoms and cortical thicknesses/subcortical volumes in patients with Alzheimer s disease (AD). Methods:Fourteen AD patients with psychotic symptoms and 41 without psychotic symptoms underwent 3T MRI scanning. After adjusting the effects of confounding variables, the cortical thicknesses were compared between the AD patients with and without psychotic symptoms in multiple regions, across the continuous cortical surface. In addition, the subcortical volumes were compared with a structure-by-structure manner. Results:AD patients with psychotic symptoms were characterized by significant smaller cortical thickness of left pars opercularis (F=4.67, p=0.02) and left lateral occipital gyrus (F=6.05, p=0.04) rather than those without psychotic symptoms, after adjusting the effects of age and scores on the Stroop test, non-psychotic items of Neuropsychiatry Inventory and Clinical Dementia Rating, triglyceride level and total intracranial volume. However, there were no significant differences in the subcortical volume between the two groups. Conclusion:These results suggest that AD psychosis may reflect more severe deterioration of neuropathologic change in specific brain region. KEY WORDS:Alzheimer s diseaseㆍleft lateral occipital gyrusㆍleft pars opercularisㆍpsychotic symptoms. 서론 알츠하이머병은점진적진행경과를보이는신경퇴행성질환으로, 치매의가장흔한원인으로알려져있다. 1) 국내의경 우, 65세이상인구를대상으로한 2012년보건복지부조사결과에따르면대상군중 9.18% 가치매진단을받았으며, 치매환자군중 71.3% 가알츠하이머병에해당하는것으로추산되었다. 2) 절반혹은그이하의알츠하이머병환자에서망상 접수일자 : 2017 년 5 월 22 일 / 심사완료 : 2017 년 7 월 11 일 / 게재확정일 : 2017 년 7 월 17 일 Address for correspondence Young Hoon Kim, M.D., Department of Psychiatry, Gongju National Hospital, 623-21 Gobunti-ro, Gongju 32601, Korea Tel : +82.41-850-5700, Fax : +82.41-855-6969, E-mail : npkyh@chol.com Address for correspondence Jung Goo Lee, M.D., Department of Psychiatry, Inje University Haeundae Paik Hospital, 875 Haeun-daero, Haeundae-gu, Busan 48108, Korea Tel : +82.51-797-1236, Fax : +82.51-797-0298, E-mail : iybihwc@naver.com 67

68 Journal of Korean Geriatric Psychiatry 2017;21(2):67-74 및환청을포함하는정신증적증상이동반되어있는것으로알려져있는데, 3) 알츠하이머병에서의정신증적증상의존재는입원가능성의예측인자가되며, 나아가더욱높은사망률의예측인자가되기도한다. 4) 또한, 알츠하이머병에서의정신증적증상은환자의행동문제와연관이되며이는보호자의부담및보호자우울증의원인요소로작용하기도한다. 5) 질환의급격한진행경과와의연관성, 증상과연관되는환자의기능손실및삶의질저하, 사망률의증가및보호자의손실등을미루어알츠하이머병에서의정신증적증상의기질적원인에대한연구의필요성이대두되고있다. 선행연구들을통해, 알츠하이머병환자에서정신증적증상이이환되었을경우, 그렇지않은군에비해더욱심각한인지기능의손상및더욱급격한병경과의진행과연관이있다는것이보고되었다. 6) 신경원섬유매듭과베타아밀로이드판의축적은알츠하이머병의특징적인병리소견이며, 해당병리소견의증가는알츠하이머병의증상악화와밀접한연관이있다. 7)8) 한선행연구에서정신증적증상을동반한알츠하이머병환자군의경우정신증적증상을동반하지않은환자군에비해, 수용성베타1-40 아밀로이드가감소하여수용성베타 1-42/ 수용성베타1-40 아밀로이드비율이증가하였는데, 이는정신증적증상을동반한알츠하이머병환자군에서이를동반하지않은알츠하이머병환자군에비해베타아밀로이드단백질로인한신경독성이증가되어있을수있음을시사한다. 9) 또다른알츠하이머병의특징적인병리소견인타우단백질의경우, 한선행연구에서정신증적증상을동반한알츠하이머병환자군에서정신증적증상을동반하지않은알츠하이머병환자군에비해뇌척수액의타우단백질정도가증가해있었으며, 10) 또다른선행연구에서는정신증을동반한알츠하이머병환자군에서의세포내고인화타우단백질축적이정신증을동반하지않은알츠하이머병환자군에비해증가해있었다. 11) 종합하면, 뇌실질의신경원섬유매듭, 베타아밀로이드판의축적, 타우단백질축적의증가등알츠하이머병의병리적소견의악화는알츠하이머병환자군에서의정신증적증상발생과연관이있을수있다. 알츠하이머병에서신경원섬유매듭과베타아밀로이드판의축적은회색질의점진적소실을야기하며, 이는알츠하이머병의특징적인임상소견인대뇌실질의위축으로이어진다. 12) 따라서정신증적증상이동반되지않은환자군과비교하여, 정신증적증상이동반된알츠하이머병환자군에서의베타아밀로이드단백질및타우단백질로인한신경독성의증가는대뇌실질의위축을비롯한뇌구조적변화와연관되어있을수있다. 한편, 알츠하이머병환자군에서의정신증적증상유무와특정영역의대뇌실질감소와의연관성에대한몇몇연구결과들이보고된바있다. 한후향적연구는알츠하이머병에서정 신증적증상의존재와전두전엽, 전방대상회, 섬엽및측두엽의용적감소가연관이있다고보고하였다. 13) 또다른한연구에서는알츠하이머병환자에서정신증적증상이존재하는환자군의경우정신증적증상이존재하지않는군에비해측전두엽, 측두정엽및전방대상회의피질위축이관찰되었다. 14) 반면에, 또다른선행연구에서는알츠하이머환자군에서의정신증적증상유무와대뇌실질의감소간의명확한연관성이관찰되지않았다. 15) 기존의연구결과들이일관되거나명확한양상을나타내지않으므로, 알츠하이머병에서정신증적증상의존재와대뇌실질의감소간의연관성에대해연구하고그의의를논의하는것이요구될것이다. 대뇌실질위축연구에있어피질두께및피질하구조물의부피에대한방법론을적용하였다. 그이유는, 피질두께에대한분석은대뇌피질두께와피질의표면, 피질주름등을함께측정하는복셀기반형태계측법, 종단변형분석법등에비해직접적인특정뇌영역의피질두께차이를분석하는데유용하기때문이다. 16) 또한, 피질두께는회색질의밀도를나타내는특징적인표지자중하나이다. 16) 알츠하이머병에서의정신증적증상유무와특정대뇌영역의실질감소와의연관성을명확하게하기위하여, 본연구에서저자들은정신증을동반한알츠하이머병환자군과정신증을동반하지않은알츠하이머병환자군두군간임상적특징의차이를비교하였고, 알츠하이머병환자의정신증적증상유무와뇌특정영역피질두께및피질하구조물의부피와의연관성을분석하였다. 대상및방법 대상군선행연구에서언급하였듯이, 2) 본연구에서저자들은 2010 년 3월 1일부터 2014 년 6월 30일까지인지기능의저하를주소로인제대학교해운대백병원정신건강의학과치매클리닉에내원한 518 명을대상으로후향적의무기록검토를통해연구자료를수집하였으며, 뇌자기공명영상자료및임상적특성을고려하여대상군을선정하였다. 본연구의대상군포함기준은 1) 연령 60 세, 2) National Institute of Neurologic and Communicative Disorders and Stroke and Alzheimer s Disease and Related Disorder Association 진단체계에따라알츠하이머치매를진단받은경우, 2) 3) 한국형확장판임상치매평가척도 (Korean version of expanded Clinical Dementia Rating, CDR) 점수 0.5점이상, 2점이하, 17) 그리고 4) 3D T1 강조뇌자기공명영상검사, 신경인지검사, 혈중지질농도, 혈중호모시스테인농도, 혈중엽산농도를포함하는혈액학적검사및 Apolipoprotein E(APOE) 유전자형검사를모두시행한경우이다. 본연구의대상군배제기준은 1) 연령<60 세,

Doo Hyoung Lee, et al:altered Cortical Thicknesses Can Be Associated with Psychotic Symptoms Alzheimer s Disease 69 2) 정신장애의진단및통계편람제4판 (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, DSM- IV) 에따라알츠하이머치매이외다른정신건강의학과적제 1축질환이있는경우, 2) 3) 두부외상의과거력이있는경우, 4) 뇌혈관질환이동반된경우, 5) 섬망이있는경우, 그리고 6) 심각한내과질환이동반된경우이다. 해당기준에따라 55명의알츠하이머병환자가본연구의대상군으로선정되었다. 본연구는인제대학교해운대백병원기관생명윤리위원회의승인을받았다 (2016-06-001-002). 인지기능및타정신건강의학과적증상평가를위한평가도구본연구에서는대상군의진단과, 정신건강의학과적증상및인지기능의평가를위한포괄적인평가를시행하였다. 치매환자의중증도평가를위해 CDR을시행하였다. 17)18) 해당검사는기억력, 지남력, 판단력 & 문제해결능력, 사회적활동, 가정생활 & 취미, 개인위생항목들을포함하며, 영문판 CDR 과유사한타당도를보였다. 17) 대상군의인지기능및신경심리학적증상평가를위해한국판 Consortium to Establish a Registry for AD(CERAD-K) 와서울신경심리검사 (Seoul Neuropsychological Screening Battery, SNSB) 를시행하였다. CE- RAD-K는 Mini-Mental Status Examination in the Korean version of the CERAD Assessment Packet(MMSE-KC), 단어유창성검사, 보스턴이름대기검사, 구성행동검사, 단어목록기억검사, 단어목록회상검사, 단어목록재인검사, 길만들기검사A, 길만들기검사 B의 8가지항목을포함하며알츠하이머병환자군의인지기능평가에대한신뢰도및타당도가입증되었다. 19) SNSB 는숫자바로외우기검사, 숫자거꾸로외우기검사, 스트룹검사, constrating program, go-no-go 검사를포함하며, 이를통해대상군의인지, 주의집중, 기억력, 언어, 시각공간기능, 실행기능의다섯가지영역을평가하였다. 20) 대상군의우울삽화증상을평가하기위하여 15문항의한국형노인우울간이척도 (Geriatric Depression Scale 15-item version, GDS-15) 를시행하였다. 21) 보호자의정보를기반으로하는평가척도인한국판 Neuropsychiatric Inventory(K-NPI) 를통하여환청, 망상, 초조, 불쾌감, 불안, 고양감, 무감동, 탈억제, 짜증, 비정상운동증상, 수면행동, 섭식변화등의정신건강의학과적증상을평가하였다. 대상군의정신증적증상유무및중증도의정량화를위해본연구에서는선행연구를인용하였다. 22) NPI- 정신증점수는 K-NPI 의환청, 망상항목의구성점수 ( 빈도와중증도의곱 ) 의총합으로정의하였다. NPI- 비정신증점수는 K-NPI 의환청, 망상을제외한기타항목, 즉초조, 불쾌감, 불안, 고양감, 무감동, 탈억제, 짜증, 비정상운동증상, 수면행동, 섭식변화항목의구성점수 ( 빈도와중증도의곱 ) 의총합으로정의하였다. 22) 혈액학적검사및 APOE 유전자형검사평가혈중지질농도, 혈중호모시스테인농도, 혈중엽산농도를포함하는혈액학적검사및 APOE 유전자형검사를모든대상군에게시행하였다. 혈액은 12시간이상공복을유지한대상군의상완정맥에서숙련된간호사에의해채혈하였다. 채취한혈액을통해혈청학적검사및유전자형검사를시행하였다. 혈중지질농도의경우 Hitachi 7600(Hitachi, Tokyo, Japan) 장비를통해분석을시행하였다. 혈중호모시스테인농도는 Roche Modular System(Roche, Mannheim, Germany) 장비를통해분석하였으며, 혈중엽산농도는 Abbott Architect J2000(abbott Laboratories, Chicago, IL, USA) 장비를통해분석하였다. 2) APOE 유전자형검사를위해정맥혈로부터 DNA 추출을시행하였으며, 대립유전자특이중합효소연쇄반응 (allele specific primer-polymerase chain reaction) 및전기영동 (electrophoresis) 의과정을통해유전자형분석을시행하였다. 해당검사의경우검사의진행을서울의과학연구소에의뢰하였다. 2) 영상의학자료분석본연구에참여한모든대상군은 Philips AchievaTx 3.0T (Philips Healthcare, Best, Netherlands) 장비를사용하여뇌자기공명영상검사를시행하였으며, 3D T1 강조영상펄스열을통해뇌자기공명영상을획득하였다 (repetition time=1,800 ms, echo time=2.07 ms, inversion time=900 ms, flip angle= 12, acquisition matrix=256 256, field of view=250 250 mm 2, slice thickness=1 mm, total number of slices=256, isotropic voxel resolution of 1 1 1 mm 3 ). 대상군의뇌자기공명영상은디지털영상으로전환되어 Digital Imaging and Communication in Medicine에저장된후, Neuroimaging Informatics Technology Initiative 파일로변환되었다. 이후영상자료는뇌영역의부피및피질두께의분석을위해 FreeSurfer ver. 5.3(MGH, Harvard, Boston, MA, USA, http:// surfer.nmr.mgh.harvard.edu) 프로그램을통해분석되었다. 뇌자기공명영상의피질두께방법으로표면기반분석방법과복셀기반분석방법이있는데, 23) FreeSurfer 자동적뇌영상영역분할을통해뇌영역의부피및피질두께의분석을시행하는대표적인표면기반분석방법으로, 뇌의해부학적변화를분석하는데가장많이활용되는프로그램중하나이다. 해당프로그램을통한분석의타당도는조직학적방법과의비교연구및복셀기반분석방법과의비교연구등을통해입증되었다. 24)25) FreeSurfer 프로그램을통한 T1 강조뇌자기공명영상자료의분석은다음의단계를거친다. 영상신호강도표준화후, 뇌영상자료에서두개골및뇌를제외한기타조직이제거된다. 이후뇌영상자료는 Talairach 좌표공간으로자동적으로등록되며, 백질과회백질영역이분할

70 Journal of Korean Geriatric Psychiatry 2017;21(2):67-74 된다. 이후뇌피질및피질하구조들이연질막공간 (pial spaces) 로재구성되며, 각구조물들은뇌특정영역의해부학적분류에따라분류된다. 해당과정을통해특정뇌피질두께및피질하회백질부피가추출된다. 26) 해당뇌해부학적영역중, 본연구의특정관심영역을설정하여분석하였다. 통계분석본연구의통계적분석은 IBM SPSS ver. 22.0(IBM Corp., Armonk, NY, USA) 을통해시행하였다. 우선, 연속형변인들에대해서는 Kolmogorov-Smirnov test를시행하여정규성분포를확인하였다. 정신증을동반한알츠하이머병환자군과정신증을동반하지않은알츠하이머병환자군두군간임상적특징의차이를비교하기위해, 이산형변인에대해서는 chi-square 를시행하였으며연속형변인에대해서는독립 t-검정 (independent t-test) 을시행하였다. 알츠하이머병환자의정신증적증상유무와뇌특정영역피질두께및피질하부피와의연관성분석에있어혼란변인의영향을보정하기위해공분산분석 (analysis of covariance, ANCOVA) 을시행하 였다. 모든변수들의통계학적유의수준은 p<0.05, 양방향으로설정하였다. 결과 대상자들의임상적특성정신증적증상을동반한알츠하이머병환자군 (n=14) 과정신증적증상을동반하지않은알츠하이머병환자군의임상적특성을비교하였다 (Table 1). 대상자들의전체평균연령은 77.6 세 [standard deviation(sd)=6.4] 였으며, 평균교육연수는 6.4년 (SD=5.1) 이었다. 전체환자군의평균 MMSE-KC 점수는 18.6 점 (SD=5.7) 이었다. 정신증적증상을동반한환자군의경우정신증적증상을동반하지않은환자군에비해높은연령을보였다 (t=-2.28, p=0.03). 두환자군간성별, 교육연수, APOE4 유전형, GDS 에서유의한수준의차이는보이지않았다. 정신증적증상을동반한알츠하이머병환자군에서, 그렇지않은환자군에비해 CDR 점수가유의하게높았으며 (t=-4.00, p<0.01), SNSB 중스트룹검사에서유의하게낮은 Table 1. Baseline characteristics of Alzheimer s disease patients with and without psychotic symptoms Total sample (n=55) Psychotic symptoms Present (n=14) Absent (n=41) Statistical coefficient Age, mean (SD), years 77.6 (6.4) 80.8 (4.8) 76.5 (6.5) t=-2.28 0.03 Female, n (%) 38 (69.1) 9 (64.3) 29 (70.7) Χ 2 =0.20 0.65 Education, mean (SD), years 6.4 (5.1) 6.9 (4.9) 6.2 (5.1) t=0.48 0.63 APOE4 allele, n (%) 26 (47.3) 21 (51.2) 5 (35.7) Χ 2 =1.01 0.32 MMSE, mean (SD) 18.6 (5.7) 17.0 (6.1) 19.1 (5.6) t=1.17 0.25 CERAD, mean (SD) Construction apraxia 8.2 (2.3) 8.4 (1.7) 8.2 (2.5) t=-0.29 0.77 Word list delayed recall 0.8 (1.3) 0.8 (1.3) 0.8 (1.3) t=-0.08 0.94 SNSB, mean (SD) Digit span forward 4.4 (1.1) 4.3 (1.0) 4.5 (1.1) t=0.40 0.69 Digit span backward 2.9 (0.9) 3.0 (0.4) 2.9 (0.9) t=-0.62 0.54 Stroop test 41.9 (23.9) 27.7 (17.0) 46.9 (24.2) t=2.42 0.02 Contrasting program 17.8 (2.8) 17.6 (2.8) 17.9 (2.8) t=0.25 0.80 Go-no-go test 15.9 (4.5) 14.6 (5.1) 16.3 (4.3) t=1.00 0.32 Barthel index, mean (SD) 19.0 (3.0) 18.1 (2.8) 19.2 (3.1) t=1.19 0.24 NPI psychotic score, mean (SD) 1.42 (3.35) 5.57 (4.67) 0 (0.0) t=-4.47 <0.01 NPI non-psychotic score, mean (SD) 12.9 (14.6) 24.9 (21.7) 8.7 (7.9) t=-2.72 0.02 CDR, mean (SD) 0.9 (0.5) 1.4 (0.6) 0.8 (0.4) t=-4.00 <0.01 GDS, mean (SD) 3.3 (4.0) 3.3 (3.5) 3.3 (4.1) t=0.01 0.99 Blood chemistries Triglyceride, mean (SD), mg/dl 112.4 (60.7) 139.6 (80.8) 103.1 (50.1) t=-2.00 0.05 HDL cholesterol, mean (SD), mg/dl 50.9 (13.9) 51.0 (14.1) 50.6 (13.8) t=0.09 0.92 LDL cholesterol, mean (SD), mg/dl 120.7 (30.6) 122.2 (32.2) 120.2 (30.4) t=-0.21 0.83 Homocysteine, mean (SD), mg/dl 9.9 (3.9) 10.7 (4.8) 9.6 (3.6) t=-0.92 0.36 Folic acid, mean (SD), nmol/l 7.6 (4.4) 6.6 (3.9) 7.9 (4.5) t=1.01 0.32 Total intracranial volume, mean (SD), mm 3 361360.3 (42380.5) 329510.6 (37635.6) 372235.7 (38576.3) t=3.60 <0.01 p-value APOE4 : apolipoprotein E4, CDR : Clinical Dementia Rating, CERAD : Consortium to Establish a Registry for Alzheimer s Disease, GDS : Geriatric Depression Scale, HDL : high-density lipoprotein, LDL : low-density lipoprotein, MMSE : Mini-Mental Status Examination, NPI : Neuropsychiatric Inventory, SD : standard deviation, SNSB : Seoul National Screening Battery

Doo Hyoung Lee, et al:altered Cortical Thicknesses Can Be Associated with Psychotic Symptoms Alzheimer s Disease 71 점수를보였다 (t=2.42, p=0.02). MMSE-KC, CERAD-K 및 SNSB 내다른검사항목에서는두군간유의한차이는없었다. 정신증적증상을동반한알츠하이머병환자군에서정신증적증상을동반하지않은환자군에비해, 평균 NPI- 비정신증점수가유의하게높았다 (t=-2.72, p=0.02). 정신증적증상을동반한군에서정신증적증상을동반하지않은군에비해전체뇌용적이유의하게감소되어있었다. 혈액학적검사의경우정신증적증상을동반한환자군에서정신증적증상을동반하지않은환자군에비해중성지질수치가유의하게증가해있었으며 (t=-2.00, p=0.05) 다른검사항목에서는두군간유의한차이를보이지않았다. 대상자들의피질두께및피질하회백질부피대상자들의뇌자기공명영상 T1 강조이미지를 FreeSurfer 프로그램으로처리하여추출한대뇌피질두께및피질하회백질부피를 ANCOVA 를통해분석하였으며, 나이, 전체뇌용적, MMSE-KC 점수, 스트룹검사점수, NPI- 비정신증점수, CDR 점수, 중성지질수치등 chi-square 및독립 t-검정에서양군간유의한차이를보였던변인들을공변량으로정의하고그잠재적인영향을보정하였다. 피질두께의경우 (Table 2) 정신증적증상을동반한알츠하이머병환자군에서정신증적증상을동반하지않은군에비해좌측판개부 (pars opercularis, F=4.67, p=0.04) 및좌측외측후두회 (lateral occipital gyrus, F=6.05, p=0.02) 에서유의한감소를보였다. 피질하구조물부피의경우 (Table 3) 양환자군간유의한수준의차이는관찰되지않았다. 고찰 본연구는알츠하이머병환자중정신증적증상을보이는환자들과정신증적증상을보이지않는환자들간, 뇌자기공명영상으로얻어진대뇌피질두께와피질하부피의차이및인지기능을비롯한임상적특징의차이를알아보고자하였다. 그결과, 첫째, 정신증적증상을동반한알츠하이머병환자군의경우정신증적증상을동반하지않은환자군에비해유의하게연령이높았으며, 더높은 CDR 점수, 더낮은스트룹검사점수, 더높은 NPI-비정신증점수를보였다. 둘째, 전체뇌용적의경우정신증적증상을동반한알츠하이머병환자군에서그렇지않은군에비해유의하게감소되어있었으며, 피질하구조물부피의경우양군에서유의한차이를보 Table 2. Regions of more significantly decreased cortical thickness in Alzheimer s disease patients with psychotic symptoms relative to those without psychotic symptoms Left, mean (SD), mm Total sample (n=55) Psychotic symptoms Present (n=14) Absent (n=41) Effect size (Cohen s d) Statistical coefficient p-value* Lateral occipital 1.82 (0.17) 1.70 (0.20) 1.86 (0.13) -1.09 F=6.05 0.02 Pars opercularis 2.28 (0.27) 2.01 (0.32) 2.37 (0.17) -1.69 F=4.67 0.04 * : Adjusting the effects of age and scores on the Stroop test, Neuropsychiatric Inventory (non-psychotic) and Clinical Dementia Rating, triglyceride level and total intracranial volume using the analysis of covariance. SD : standard deviation Table 3. Subcortical volumes of Alzheimer s disease patients with and without psychotic symptoms Total sample Psychotic symptoms Effect size Statistical (n=55) Present (n=14) Absent (n=41) (Cohen s d) coefficient p-value* Left, mean (SD), mm 3 Caudate 3,567.1 (629.1) 3,581.1 (402.9) 3,562.3 (693.8) 0.03 F=0.22 0.64 Thalamus 6,574.9 (870.9) 6,362.9 (981.3) 6,647.3 (830.5) -0.33 F=1.15 0.29 Pallidum 1,406.0 (186.0) 1,396.3 (257.2) 1,409.3 (158.6) -0.07 F=0.00 0.99 Putamen 4,306.0 (553.8) 4,197.5 (363.4) 4,343.0 (604.7) -0.27 F=0.06 0.81 Hippocampus 2,959.5 (542.5) 2,881.1 (539.2) 2,986.2 (547.7) -0.20 F=0.08 0.77 Amygdala 1,065.4 (219.4) 1,041.2 (236.7) 1,073.6 (215.7) -0.15 F=0.65 0.43 Right, mean (SD), mm 3 Caudate 3,217.8 (559.2) 3,143.8 (468.4) 3,243.0 (590.2) -0.18 F=0.04 0.84 Thalamus 5,905.5 (662.0) 5,811.8 (720.2) 5,937.5 (647.2) -0.19 F=0.05 0.81 Pallidum 1,301.0 (181.4) 1,310.9 (181.8) 1,297.6 (183.4) 0.07 F=0.88 0.36 Putamen 4,045.7 (536.3) 3,840.0 (487.4) 4,115.9 (539.7) -0.53 F=0.00 0.97 Hippocampus 3,078.5 (565.2) 2,908.7 (564.6) 3,136.5 (560.5) -0.41 F=0.73 0.40 Amygdala 1,158.4 (205.9) 1,156.0 (254.7) 1,159.2 (190.1) -0.02 F=2.06 0.16 * : Adjusting the effects of age and scores on the stroop test, Neuropsychiatric Inventory (non-psychotic) and Clinical Dementia Rating, triglyceride level and total intracranial volume using the analysis of covariance. SD : standard deviation

72 Journal of Korean Geriatric Psychiatry 2017;21(2):67-74 이지않았다. 마지막으로, 정신증적증상을동반한알츠하이머병환자군에서정신증적증상을동반하지않은군에비해좌측판개부및좌측외측후두회의피질두께가유의하게감소되어있었다. 알츠하이머병에서의정신증적증상의존재가연령의증가, 높은 CDR 점수및다른행동증상과유의하게연관이있음을보고한선행연구결과가있었다. 27) 한선행연구에서는알츠하이머병에서망상과환청이동반된환자군의경우해당증상들이동반되지않은군에비해인지기능및일상수행기능의저하가두드러짐을보고하였다. 5) 총 55개의연구들을검토한한선행연구에서도알츠하이머병에서정신증적증상이동반되었을경우, 증가한연령과관계가되며더욱손상된인지기능을보임을보고하였다. 28) 본연구에서, 정신증적증상을동반한알츠하이머병환자군은정신증적증상을동반하지않은알츠하이머병환자군에비해유의하게높은연령과, 유의하게높은 NPI-비정신증점수및 CDR 점수를보였다. 높은 NPI- 비정신증점수는정신증적증상을제외한, 동반된행동증상의증가를시사하며높은 CDR 점수는인지기능및일상수행기능의더욱악화된손상을의미할수있으므로본연구의결과는앞서언급한선행연구의결과들과부합한다고볼수있다. 또한본연구에서정신증적증상을동반한알츠하이머병환자군의경우전체뇌용적이정신증적증상을동반하지않은환자군보다유의하게감소하여있었다. 알츠하이머병에서뇌실질의감소가진행되는병태생리학적기전을고려하였을때, 7)8) 해당소견은정신증적증상을동반한알츠하이머병환자군에서알츠하이머병의기저병태생리가더욱진행된상태로추정할수있는가능성을제시한다. 이는, 정신증적증상이동반된알츠하이머병환자군의경우정신증적증상이동반되지않은알츠하이머병환자군에비해더욱진행된인지기능의손상및일상생활수행능력의저하, 동반행동증상의증가를보고한선행연구들및본연구의결과와도같은맥락에서해석될수있을것으로추정된다. 선행연구들에서정신증적증상을동반한알츠하이머병환자군의경우정신증적증상을동반하지않은환자군에비해더욱진행된특정대뇌영역의위축이관찰되었다. 29-31) 한선행연구에서는망상을동반한알츠하이머병환자군에서이를동반하지않은알츠하이머병환자군에비해컴퓨터단층촬영영상상우측전두엽의더욱진행된위축소견이관찰되었다. 30) 다른선행복셀기반형태계측연구결과에따르면, 망상을동반한알츠하이머병환자군에서이를동반하지않은알츠하이머병환자군에비해우측하전두회, 하두정소엽, 좌측하전두회, 내전두회및전장의회백질의감소가더욱진행된소견을보였다. 31) 또다른복셀기반형태계측연구에서는알츠하이머병에서망상이동반된경우, 그렇지않은환자군에비해우측해마꼬리의회백질용적이감소하여있었 다. 32) 알츠하이머병환자군중망상적증상이동반된여성환자군에서망상적증상이동반되지않은환자군에비해뇌자기공명영상상좌측내전두엽및좌측상전두엽영역의피질두께의감소가보고되었다. 33) 전술한바와같이, 대뇌실질의위축은알츠하이머병환자들의특징적인소견이며이는신경원섬유매듭과베타아밀로이드판의축적으로인한회색질의소실에기인한다. 7)8) 알츠하이머병에서정신증적증상이동반되어있을경우베타아밀로이드단백질및타우단백질로인한신경독성이증가할수있다는선행연구결과와연관하여추정컨대, 9-11) 정신증적증상이동반된알츠하이머병환자군에서정신증적증상을동반하지않은환자군에비해특정대뇌영역의회백질이감소한선행연구결과들은해당환자군에서의신경원섬유매듭및베타아밀로이드판의더욱진행된축적등악화된질환의기저신경학적병인에기인하였을수있음을시사한다. 본연구에서정신증이동반된알츠하이머병환자군의경우정신증이동반되지않은환자군에비해좌측판개부및좌측외측후두회의피질두께가감소되어있었는데, 이는알츠하이머병환자군에서의정신증적증상의존재와특정대뇌영역실질의위축이연관이있다는선행연구들의결과와일치하며, 알츠하이머병에서정신증적증상이동반되었을경우에해당영역에서알츠하이머병의질환경과악화를추정케한다. 본연구에서, 알츠하이머병에서정신증이동반된환자군의경우그렇지않은환자군에비해좌측판개부의피질두께가감소되어있었다. 판개부는브로드만구역 44번에위치하며전두엽의하전두회의일부이다. 알츠하이머병환자군을대상으로한선행연구에서정신증적증상이동반된경우정신증적증상이동반되지않은환자군에비해좌측하전두회의회백질밀도가감소되어있었으며, 31) 이는본연구의결과와일치한다. 하전두회는전두엽의일부로판개부, 삼각부, 안와부로구성된다. 좌측하전두회는반응과행동의억제, 작업변경, 원치않는기억억제, 과거시도로부터의작업기억의억제등을포함하는억제인지기능과연관된다. 34)35) 선행연구에따르면, 좌측하전두회의구조적손상은해당억제인지기능의기능적손상을야기할수있다. 34) 본연구에서, 인지기능중자동반응의억제와관련된선택적집중력을측정하는신경인지검사인스트룹검사의점수가정신증적증상을동반한알츠하이머병환자군에서, 정신증적증상을동반하지않은군에비해유의하게낮았다. 정신증적증상을동반한환자군에서그렇지않은환자군에비해좌측판개부의피질두께가감소되어있었던본연구의결과를미루어, 정신증이동반된알츠하이머병환자군은정신증이동반되지않은알츠하이머병환자군에비해선택적집중능력에손상이있을수있으며, 이는좌측판개부의피질감소와연관한억제인지기능의손상과연관이있을수있을것으로추정된다. 양전자방출단층촬영

Doo Hyoung Lee, et al:altered Cortical Thicknesses Can Be Associated with Psychotic Symptoms Alzheimer s Disease 73 과기능적뇌자기공명영상촬영을통한선행연구들에서, 스트룹검사를시행할시판개부가포함된좌측하전두회영역의활성이증가하였다는보고는이러한추론과부합한다고볼수있다. 36)37) 본연구에서, 정신증적증상이동반된알츠하이머병환자군에서정신증적증상이동반되지않은환자군에비해좌측외측후두회의피질두께역시감소하여있었다. 외측후두회는브로드만구역 18, 19번에위치하며, 후두엽의일부이다. 시각자극의처리는후두엽의시각계에서수행된다. 브로드만구역 18, 19번은선조외시각피질로, 후두엽내에서일차시각피질을둘러싸며위치한다. 38) 선조외시각피질은시각연합피질로, 시각신호의고위복합처리및다른대뇌영역으로의시각정보전달에관여한다. 39) 환시는알츠하이머병환자군에서정신증적증상중하나인환각의가장흔한형태로, 40) 알츠하이머병환자군에서후두엽의구조적변화와환시사이의연관성을몇몇선행연구들에서보고하고있다. 41)42) 선행연구에서환시가동반된알츠하이머병환자군의, 전체뇌용적대비후두엽용적의비율이환시가동반되지않은환자군에비해감소하여있었다. 41) 또다른한선행연구에서는환시가동반된알츠하이머병환자군에서, 환시가동반되지않은환자군에비해뇌자기공명영상상후두엽뇌실주위영역의고신호강도가증가되어있었다. 42) 비록본연구에서정신증적증상을환각과망상으로세분화하지는않았지만, 정신증적증상이동반된알츠하이머병환자군에서정신증적증상이동반되지않은환자군에비해시각연합피질기능을수행하는좌측외측후두회의피질두께가감소한결과는선행연구의결과들과유사한맥락에서해석될수있을것이다. 본연구의한계점은다음과같다. 첫째, 연구의대상군이일지역대학병원을내원한환자로국한되며표본수가많지않아알츠하이머병환자군전체를대표하기힘들수있다는점이다. 더욱정확한결과를도출하기위하여본연구에서는대상환자군의선정기준을제한하였으며, 뇌영상의학적검사이외에도혈액학적검사, 임상심리검사등임상적특징을관찰하기위하여다수의검사를시행한환자를대상군으로하였다. 하지만이로인하여제한된환자군을대상으로하였다는한계점이있으며, 알츠하이머병환자군전체를대표하기위해서는많은표본수를대상으로한후속연구의필요성이대두된다. 둘째, 알츠하이머병환자군으로연구대상군을한정하여질환이이환되지않은정상대조군과비교한결과를얻지못했다는한계점이있다. 셋째, 본연구는후향적단면연구로서대상군의시간에따른임상경과변화및뇌실질의변화에대한연구가이루어지지못했다는제한점이있다. 향후질환경과에따른, 알츠하이머병에서의정신증적증상의유무와뇌실질의변화간연관성에대해연구가이루어진다면유의미한결과를도출할수있을것으로추정된다. 마 지막으로, 본연구에서는알츠하이머병환자군중망상또는 환청을겪는환자군을정신증적증상이동반된알츠하이머 병환자군으로분류하였다. 이는몇몇선행연구의방법을따 른것이나, 43)44) 망상과환청각각의증상과뇌실질변화와의 연관성에대한연구를시행하지못했다는제한점이있다. 본연구는, 알츠하이머병환자군에서정신증적증상이동 반되었을경우에그렇지않는경우에비해좌측판개부및 좌측외측후두회의피질두께가저하된결과를보고하였다. 이는알츠하이머병내에서의정신증적증상과해당부위들사 이의잠재적인연관성을제시하는것으로볼수있다. 아울러 알츠하이머병환자군에서정신증적증상이동반이되었을경 우인지기능의저하, 기능적손상, 전체뇌용적의저하등알 츠하이머병의악화경과와연관이있을수있다는결과도함 께보고되었다. 본연구의결과는알츠하이머병환자군의정 신증적증상이, 특정대뇌부위에서의더욱악화된신경병리 적손상을의미할수있음을시사한다. 중심단어 : 알츠하이머병 좌측외측후두회 좌측판개부 정신증적증상. REFERENCES 1) Kim KW, Park JH, Kim MH, Kim MD, Kim BJ, Kim SK, et al. A nationwide survey on the prevalence of dementia and mild cognitive impairment in South Korea. J Alzheimers Dis 2011;23:281-91. 2) Lee SJ, Kim TH, Huh L, Choi SE, Lee BJ, Kim GM, et al. The correlation of levels of serum lipid, homocysteine, and folate with volumes of hippocampus, amygdala, corpus callosum, and thickness of entorhinal cortex in patients with amnestic mild cognitive impairment or dementia of Alzheimer s type. Korean J Biol Psychiatry 2015;22:223-32. 3) Wragg RE, Jeste DV. Overview of depression and psychosis in Alzheimer s disease. Am J Psychiatry 1989;146:577-87. 4) Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B, et al. Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch Neurol 2005;62:1601-8. 5) Cheng ST, Lam LC, Kwok T. Neuropsychiatric symptom clusters of Alzheimer disease in Hong Kong Chinese: correlates with caregiver burden and depression. Am J Geriatr Psychiatry 2013;21:1029-37. 6) Murray PS, Kumar S, Demichele-Sweet MA, Sweet RA. Psychosis in Alzheimer s disease. Biol Psychiatry 2014;75:542-52. 7) Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer s disease. Cereb Cortex 1991;1:103-16. 8) Zubenko GS, Moossy J, Martinez AJ, Rao G, Claassen D, Rosen J, et al. Neuropathologic and neurochemical correlates of psychosis in primary dementia. Arch Neurol 1991;48:619-24. 9) Murray PS, Kirkwood CM, Gray MC, Ikonomovic MD, Paljug WR, Abrahamson EE, et al. β-amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis. Neurobiol Aging 2012;33: 2807-16. 10) de Souza LC, Chupin M, Lamari F, Jardel C, Leclercq D, Colliot O, et al. CSF tau markers are correlated with hippocampal volume in Alzheimer s disease. Neurobiol Aging 2012;33:1253-7. 11) Murray PS, Kirkwood CM, Gray MC, Fish KN, Ikonomovic MD, Hamilton RL, et al. Hyperphosphorylated tau is elevated in Alzheimer s disease with psychosis. J Alzheimers Dis 2014;39:759-73. 12) Schuff N, Woerner N, Boreta L, Kornfield T, Shaw LM, Trojanowski JQ, et al. MRI of hippocampal volume loss in early Alzheimer s disease in relation to ApoE genotype and biomarkers. Brain 2009; 132(Pt 4):1067-77.

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