Dementia and Neurocognitive Disorders 2010; 9: 107-14 ORIGINAL ARTICLE 알츠하이머병진행에따른해마의기능적연결변화 : FDG-PET 을이용한뇌영역간상관분석 조상수 김은주 * 강수진 이병화 김상은 나덕렬 서울대학교의과대학분당서울대학교병원핵의학과, 부산대학교의과대학신경과학교실 * 성균관대학교의과대학삼성서울병원신경과 Received : May 18, 2010 Revision received : December 24, 2010 Accepted : December 28, 2010 Address for correspondence Duk L. Na, M.D. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-3591 Fax: +82-2-3410-0052 E-mail: dukna@skku.edu *S.S.C. was supported by the Eisai Korea young investigator grant funded by the Korean Dementia Association. This study was partly supported by grants from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea (A050079) and grant from the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology of Republic of Korea (No. 20100002035/ No. 20090093889). Changes in Functional Connectivity of Hippocampus during the Progress of Alzheimer Disease: Interregional Correlation Analysis Using FDG-PET Sang Soo Cho, Ph.D., Eun-Joo Kim, M.D, Ph.D.*, Sue J. Kang, M.S., Byung Hwa Lee, M.A., Sang Eun Kim, M.D., Ph.D., Duk L. Na, M.D., Ph.D. Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Department of Neurology*, Pusan National University School of Medicine and Medical Research Institute, Busan; Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Background: Deficit of memory function is a main symptom found in Alzheimer disease (AD) even in the early stage of disease. Since the hippocampus is a critical area for memory function, hippocampal atrophy can serve as a biomarker of AD. To identify whether the hippocampus connectivity may change as the disease progress in patients with AD, interregional-connectivity analysis were conducted using [ 18 F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) and statistical parametric mapping (SPM). Methods: We examined metabolic correlation of the hippocampus using a sample of 72 AD patients who had undergone FDG-PET. Count normalized regional FDG activities were extracted from left and right hippocampi using the pre-identified region of interest (ROI) by automated anatomical labeling (AAL) and MarsBar toolbox implanted in SPM2. Inter-regional analyses using the left or right hippocampus as seeds were conducted in each CDR group (0.5, 1, and 2/3). Normalized mean radioactive counts from left or right hippocampus were used as independent variables in a general linear model to search for voxels correlated with seed area across the whole brain. Results: In CDR 0.5 group, both left and right hippocampal seeds yielded correlations that were limited to themselves; there was no correlation in contralateral homologous regions or any other cortical/subcortical regions. In CDR 1 group, however, the left and right hippocampal seeds yielded positive correlation in ipsilateral temporal cortex, visual cortex and frontal motor areas. In CDR 2/3 group, distinctive hippocampal metabolic connectivity patterns in each hemisphere were found. Left hippocampal seed yielded correlations that were limited to itself, while right hippocampus showed enlarged correlations in temporal cortex and occipital visual cortex as well as frontal cortex including orbitofrontal cortex and basal ganglia. Conclusions: The changes in the hippocampal communication loop we observed in this study may reflect changes in local neuroplasticity according to the progression of AD. Our results may have implication for understanding the decline and compensation mechanism of memory function in AD patients. Key Words: Alzheimer disease (AD), Hippocampus, Regional Cerebral Glucose Metabolism, Positron-Emission Tomography (PET), Statistical Parametric Mapping (SPM) 서론알츠하이머병 (Alzheimer disease, AD) 은광범위한진행적인지기능손상으로정의되는퇴행성뇌질환중하나이다. 연령 증가에따라높은유병률을보이는데, 세계적으로 85세이후의유병률은 24-33% 에달하는것으로알려져있다 [1]. 인지적으로는주의및집행기능, 의미기억, 시지각기능의저하가수반되며특히질환의초기부터발현되는증상으로는선행성일화 107
108 조상수 김은주 강수진외 3 인 기억장애가대표적이다 [2-6]. 전통적으로기억의저장기능을담당하는해마 (hippocampus) 를포함한내측측두엽영역 (medial temporal lobe) 이치매관련연구에서주목받아온것이바로이때문이다. 기억력의저하가해마를포함한주변영역의병리를반영한다는증거는다양하다. AD에의한인지적기능저하와해마와의연관성은뇌형태학 (morphology) 연구와베타아밀로이드 (b amyloid) 및타우 (tau) 병리연구들을통해제시되어왔다. 예를들면, 해마의위축은정상피험자와초기 AD로진단된환자군모두에서인지기능의저하와연관되어있는것으로보고되고있고 [7, 8], 최근연구에서는내후각뇌피질 (entorhinal cortex) 및해마영역의위축이 AD는물론경도인지기능장애 (mild cognitive impairment) 에서도확인되었다 [9]. 사후부검조사를사용한 Reitz 등 [10] 의연구에서는 AD 환자의해마에서관찰된아밀로이드변성과타우 (tau) 의병리가각각질환초기와후기의기억기능저하의원인임을보여주었는데, 이연구에의하면기억수행도는내후각뇌피질과해마의아밀로이드반 (plaque), 신경원섬유덩굴 (neurofibrillary tangles), 신경그물실 (neuropil threads) 과관련되어있었다. 흥미롭게도최근개발된아밀로이드판영상기술을통한연구도역시유사한결과를보여주고있는데, AD 환자의해마에서정상노인에비하여높아진 [ 11 C]PIB 섭취 [11] 가확인되었고정상노인에서도해마부의아밀로이드변성이일화기억의손실과관련되어있다고보고된바있다 [12]. 안정상태에서뇌포도당대사정보를보여주는 [ 18 F]fluorodeoxyglucose (FDG) 양전자단층촬영 (Positron-Emission Tomography, PET) 영상은치매환자에서뇌신경원의대사저하를구별해내는신뢰성있는방법이다. 이영상법을이용해뇌구조들간의상호작용을계산해내는것이가능한데, 비교적많은피험자를대상으로안정상태뇌포도당대사영상을얻고뇌특정영역을중심영역으로하여다른영역과의상관을보는연구방법이그것이다 [13]. AD 환자의해마위축을포함한병리적변화들을고려할때해마와다른뇌영역간의연결성의측정은이질환에서관찰되는인지적기능저하의진행을이해하는데의미있는자료를제공할것으로보인다. 지금까지해마연결성의연구는주로초기 AD 환자를대상으로하였고, AD의진행에따른해마와다른뇌영역간의기능적연결성변화를살펴본연구는없었다. 본연구에서는 AD의중증도를임상적치매척도 (Clinical Dementia Rating, CDR) [14] 에따라서구분하여 AD 진행에따른해마와뇌영역간의연결성을살펴보고자한다. 뇌퇴행성질환이나뇌손상환자에서흔히발견되는인지적보상시스템 의작동예를고려하면, 실제적기능수행과밀접히관련된 CDR 에따라단순히해마손상이나타나는것과는구별되는기능적연결성의변화가일어날가능성이있다. 따라서, 이연구는안정상태의 FDG PET 영상과뇌영역간상관분석방법을이용하여좌측과우측해마를각각중심영역 (seed area) 으로해마와다른피질및피질하영역의기능적연결성을 CDR 그룹별로측정함으로써 AD의중증도에따라해마의기능적연결성이어떠한변화를보이는지를알아보고자하였다. 1. 연구대상 대상과방법 서울소재의대학병원의기억장애클리닉을방문하여 AD로진단된환자 72명 ( 여자 51명 ; 평균연령 74.1±4.9세 ; 연령범위 66-86세 ) 을대상으로하였다. 모든환자는 NINCDS-ADRDA (National Institute for Neurological and Communicative Disorders and Stroke/Alzheimer s Disease and Related Disorders) [15] 진단기준에의하여 AD로임상진단되었으며 Petersen의규준 [16] 에근거하여 CDR 0.5 중경도인지장애는는분석에서제외되었다. 조발성 (early onset) 과후발성 (late onset) AD 의차이를제시한기존연구결과를근거 [17] 로하여 65세이상발병한후발성 AD 환자만을본연구분석에포함하였다. 모든환자에서한국판간이신경정신상태검사 (Korean version of Mini-Mental State Exam, K-MMSE) 를실시하였다 [18]. 상세한환자정보와각 CDR그룹의 K-MMSE 점수는 Table 1에제시하였다. 2. PET 영상및분석 각피험자의 [ 18 F]FDG PET 영상은 GE Advance TM (Milwau- Table 1. Demographics and MMSE scores of Alzheimer s disease patients Total CDR 0.5* CDR 1* CDR 2/3* p value Age (yr) 74.1±4.9 73.9±4.6 73.8±4.8 75.1±5.5 0.37 Gender (F:M) 51:21 18:5 22:10 11:6 0.61 K-MMSE 19.7±5.1 22.9±3.9 20.5±3.1 14.6±5.1 <0.0001 *Data are given as mean±sd unless otherwise indicated; Values refer to the result of one-way ANOVA; Subject number. F, female; M, male; K-MMSE, Korean version of Mini-Mental State Examination; CDR, Clinical Dementia Rating.
알츠하이머병진행에따른해마의기능적연결변화 : FDG-PET 을이용한뇌영역간상관분석 109 kee, WI, USA) PET 스캐너를이용하여 3D 영상획득방법으로획득하였다. 내인성해상도는 7 mm FWHM (full width at half maximum) 이었고 4.25 mm 두께의 35장의영상으로촬영하였다. 최소 6시간의금식후에 4.8 MBq/kg [ 18 F]FDG를 1 분에걸쳐주입하고소음과시각자극이최소화된안정실에서안정하도록하였다. 피험자는방사성동위원소주입 30분후스캐너실로옮겨져 10 여분간방출영상촬영을실시하였다. 이렇게얻어진방출영상은헤닝필터 (Hanning filter, cut-off frequency of 0.06 cycles/pixel as 128 128 35 matrices with a size of 1.95 1.95 4.25 mm) 를적용한역투과방식 (back-projection algorithm) 을사용해재구성하였다. 모든재구성영상은감쇠 (attenuation) 함수 (m=0.096 cm -1 ) 에따라감쇠보정한후최종영상을획득하였다. 영상분석을위한영상전처리와통계분석에 Statistical Parametric Mapping 2 (SPM2, Wellcome Department of Cognitive Neurology, London) 를사용하였다. Analyze 파일형식으로변환된개별영상을 SPM에서제공하는표준지도 (Montreal Neurological Institute [MNI] template) 위에공간정규화 (spatial normalization) 하여동일공간적위치에정렬하였다. 마지막으로신호대잡음비를높이고보정되지않은뇌피질의개인차를최소화하기위하여공간정규화된영상을대상으로가우시안커널 (12 mm FWHM) 을이용한편평화 (smoothing) 를실시하였다. 치매진행에따른전반적뇌포도당대사저하의영향으로인한국소뇌포도당대사의과대평가요소를제거하기위하여비교적 AD의발병과진행에영향을적게받는것으로알려진소뇌의계수를기준으로계수정규화 (count normalization) 를실시하였다. 임상적심각도에따라 AD 환자군을 3집단으로나누어상관 분석을실시하였는데 CDR 0.5는최경도치매, CDR 1은경도치매, CDR 2와 3은중등도이상치매로분류하였다. 해마를중심영역 (seed area) 으로한뇌영역간상관분석을위하여, automated anatomical labeling (AAL) 에포함된좌측및우측해마 volume of interest (VOI) 를이용해공간정규화된각영상들에서표준화된해마의평균방사선활성화계수 (radioactive counts) 를구하였다. 이때각계수의추출을위하여 SPM2와연계하여사용가능한 MarsBar를사용하였다. 추출된모든영상의좌우해마계수를공변량으로하여각단위소수준의상관분석을전체뇌를대상으로실시하였다 (FDR corrected a=0.05, extent threshold k=20) (Fig. 1). 이때연령은오염변인으로통제되었다. 통계분석결과각각좌우해마와유의미한상관을보인뇌영역의정위좌표 (stereotaxic coordinate) 들은 MNI 좌표에서 Talairach 좌표 [19] 로전환하여보고하였다. 정적상관분석만을실시하였고중심영역으로의자기상관 (auto correlation) 은결과보고에서제외하였다. 결과 SPM을이용한뇌영역간상관분석결과에서 CDR에따라해마에서다른대뇌영역으로의상관맵 (map) 패턴의변화를확인할수있었다. 피질영역에서확인된좌우해마를중심영역으로한기능적상관맵을 Fig. 2에제시하였다. CDR 0.5 환자에서는좌우해마모두해마자신과해마옆이랑으로의자기상관만을보였고대측해마나다른대뇌영역과의유의미한상관을보이지않았다 (Figs. 3, 4). CDR 1 환자는좌측해마를중심영역으로한영역간상관분석에서는자기상 Fig. 1. Image analysis procedure. All images were spatially transformed to the standard space and hippocampus seeds were determined on smoothed images. Normalized [ 18 F]fluorodeoxyglucose counts of hippocampus seed area were calculated. Fig. 2. Pattern of hippocampal interregional correlation map in cortical area. Images were rendered on high resolution MRI.
110 조상수 김은주 강수진외 3 인 Fig. 3. Multi-sliced images of left hippocampus interregional correlation map (FDR corrected a=0.05, k=20). Fig. 4. Multi-sliced images of right hippocampus interregional correlation map (FDR corrected a=0.05, k=20). Table 2. Regions showed metabolic correlation with left hippocampus average count in each CDR stage (FDR corrected a=0.05, extent threshold k=20) Coordinate* Region BA T-value X Y Z CDR 0.5 L Parahippocampal gyrus -25-14 -13 6.37 CDR 1 L Parahippocampal gyrus BA 28-24 -20-12 7.45 L Thalamus -12-29 0 6.15 L Middle temporal gyrus BA 21-59 -6-3 5.61 L Superior temporal gyrus BA 22/41/42-61 -8 0 5.52 L Amygdala -20-5 -15 5.49 L Insula BA 13-44 -15 10 5.03 L Postcentral gyrus BA 40-55 -24 16 5.01 L Transverse temporal gyrus BA 41-46 -23 14 4.8 L Precentral gyrus BA 4-46 -17 41 4.76 L Claustrum -28 18 1 3.90 L Posterior cingulate BA 24/31-4 -13 41 3.51 L Paracentral lobule BA 31-4 -31 44 3.50 L Anterior cingulate BA 25-2 3-10 3.31 R Posterior cingulate BA 24 16-17 40 3.24 R Precuneus BA 7 14-46 56 3.08 R Paracentral lobule BA 5 14-34 51 2.85 L Middle frontal gyrus BA 46-44 42 16 2.90 L Superior frontal gyrus BA 9-40 40 27 2.89 R Lingual gyrus BA 19 26-64 3 2.84 CDR 2/3 L Parahippocampal gyrus BA 36-28 -33-13 5.50 L Mammillary body -4-8 -8 5.25 L Medial globus pallidus -8-2 -3 4.53 L Anterior cingulate BA 25-2 7-9 4.11 L Superior temporal gyrus BA 12-55 7-10 4.62 L Middle temporal gyrus BA 21-63 -12-4 4.09 L Fusiform gyrus BA 36-48 -30-19 4.22 L Superior temporal gyrus BA 42-57 -21 8 3.51 *Talairach coordinate (mm). L, left; R, right; BA, Brodmann s area. 관이외에동측의측두-두정영역과전두엽운동영역, 2차시각영역, 대상회, 시상을아우르는확장된상관패턴을보였다. CDR 2/3 환자에서는 CDR 1에서보이던광범위한확장된영역간상관패턴대신중심영역으로의자기상관과측두영역과방추상회, 전측대상회만의제한적영역간연결확장을보이고있었다 (Fig. 3, Table 2). 우측해마상관의경우좌측해마와달리 CDR이높아짐에따라점진적으로확산된해마상관패턴을보이고있었다. 이확장된상관영역은 CDR 1 그룹의경우측두엽과 2차시각영역, 소뇌, 편도체를포함한변연계는물론광범위한전두부, 기저핵을포함하고있었다. CDR 2/3에서는 CDR 1에서관찰된연결성확장영역에더해, 두정-후두영역까지우측해마의연결성확
알츠하이머병진행에따른해마의기능적연결변화 : FDG-PET 을이용한뇌영역간상관분석 111 Table 3. Regions showed metabolic correlation with right hippocampus average count in each CDR stage (FDR corrected a=0.05, extent threshold k=20) Coordinate* Region BA T-value X Y Z CDR 0.5 R Parahippocampal gyrus BA 20 38-18 -18 6.72 R Caudate 36-18 -11 6.48 L Medial frontal gyrus BA 9-10 35 30 4.49 R Middle temporal gyrus BA22 71-41 0 4.28 R Superior temporal gyrus BA 22 69-38 7 3.77 R Orbitofrontal gyrus BA 11 26 48-19 3.95 R Inferior frontal gyrus BA 45/47 40 24 4 4.16 R Precentral gyrus BA 6 67 1 13 4.14 CDR 1 R Parahippocampal gyrus BA 20 38-18 -18 7.69 R Superior temporal gyrus BA 22 46-22 -9 6.2 R Amygdala 24-4 -10 5.82 R Medial globus pallidus 10-2 -3 5.62 R Inferior temporal gyrus BA 20 53-24 -17 5.47 R Uncus BA 20 36-11 -28 5.43 R Middle temporal gyrus BA 20/21 59 9-19 5.35 R Fusiform gyrus BA 20 63-5 -27 5.23 R Insula 36 16 1 5.02 R Putamen 20 2-3 4.98 R Thalamus 6-13 6 4.98 R Middle frontal gyrus BA 10 40 39 9 4.88 R Inferior frontal gyrus BA11/47 51 32-12 4.81 L Cerebellum -30-60 -34 4.37 L Insula BA 48-28 33 9 4.05 L Medial frontal gyrus BA 6-14 -23 51 3.59 L Posterior cingulate BA 24-18 -17 3 3.20 R Posterior cingulate BA31/30/29 12-51 21 3.54 L Amygdala -24-6 -11 3.31 L Thalamus -24-19 10 3.26 L Anterior cingulate gyrus BA 32-12 19 34 3.04 R Precuneus BA 7/31 28-66 33 2.80 L Superior frontal gyrus BA 10-24 48-4 2.59 L Medial frontal gyrus BA 10-18 43-4 2.46 CDR 2/3 R Parahippocampal gyrus BA 37 32-37 -7 6.29 R Superior temporal gyrus BA 22 59 10 1 5.6 R Inferior frontal gyrus BA 11/47 26 34-22 5.24 R Posterior cingulate BA 23/30/31 16-54 6 5.17 R Middle frontal gyrus BA 10/11 32 40-19 5.08 R Fusiform gyrus BA 19/37 36-53 -7 5.06 R Lingual gyrus BA 18 28-72 -5 4.86 R Thalamus 14-27 3 4.56 L Anterior cingulate BA 32-12 13 36 4.53 R Red nucleus 8-25 -4 4.52 R Transverse temporal gyrus BA 41 57-19 10 4.51 L Cerebellum -36-58 -39 3.93 L Superior frontal gyrus BA 10-34 52 21 3.26 R Cerebellum 16-64 -29 3.23 L Precentral gyrus BA 4/6-34 -24 55 3.21 L Middle frontal gyrus BA 6-30 -13 47 3.19 L Putamen -24 11-7 3.19 L Insula BA 48-34 -2-5 2.63 L Paracentral lobule BA 5-16 -40 57 2.95 L Lingual gyrus BA 19-18 -43 0 2.86 L Inferior frontal gyrus BA 45-30 27 4 2.62 *Talairach coordinate (mm). L, left; R, right; BA, Brodmann s area.
112 조상수 김은주 강수진외 3 인 장을확인하였다 (Fig. 4, Table 3). 고찰이연구를통하여우리는 AD에서임상적손상에따른해마와대뇌다른영역들간의기능적상관의변화를살펴보고자하였다. 최경도 AD (CDR 0.5) 의경우다른영역으로의기능적연결성은보여지지않았으며중심영역인해마로의자기상관만이확인되었고, 좀더진행된경도 AD (CDR 1) 에서는좌, 우측해마모두주로중심영역의동측으로확장된해마의기능적연결성을관찰할수있었다. 중등도이상 AD (CDR 2/3) 에서는확장된해마의기능적연결패턴이우측해마의경우에만발견되었고, 이는동측외측측두엽및 2차시각영역으로의연결성확산은물론기저핵영역과안와전두와중전두엽을포함하는광범위한것이었다. 실제로 AD 환자를대상으로해마와다른뇌영역의기능적연결성의손상을확인한선행연구들에서는같은연령대의정상인에비하여 AD 환자에서좌우해마의기능적동시성의저하 [20] 가발견되었고뇌전체를분석대상으로한다른연구에서는정상집단에비하여 AD 환자의광범위한해마-피질 / 피질하영역의기능적연결손상이관찰되었는데, 특히전두엽과의연결결손이두드러졌다 [21]. AD 환자의일반적증상인일화기억손상은선행연구에서제안하였듯이양측해마간의연결단절로인한가용자원의저하나전두엽과의연결손실로인하여전두엽이담당하고있는것으로알려진기억의모니터링작용의저하 [21] 에의한것으로추측할수있다. 그러나정상성인을대상으로시행된 Lee 등 [13] 의연구에서안정상태포도당대사연결에서해마의경우자기상관만을보인결과를고려할때우리연구에서자기상관만을보인 CDR 0.5의해마연결성이 AD의병리와관련된기능적변화를제안하는지는확실치않다. 오히려병리의초기단계에서는해마이외의뇌내보상작용없이정상인과유사한해마연결성이인지기능수행저하의원인으로해석되는것이가능하다. CDR 1에서관찰된해마연결성의확장영역들은 AD 환자에서흔히보고되는뇌포도당대사의저하영역 [22, 23] 들로, 일화기억의처리와관련된피질영역들과도일치한다 [24, 25]. 그러나이러한연결성확장현상이좌측해마에서는오직 CDR 1에서만확인되는것은매우흥미로운결과이다. CDR 1은좌측해마의경우동측의측두-두정영역으로연결성이증가하였고우측해마는동측의측두-두정영역을포함하여동측및대측전두엽까지연결성의확장을보였다. CDR 2/3에서는좌우해마의연결성은대조를이루는데, 좌측해마가 CDR 1에비하여오히려해마연결성의현저한저하를보인반면우측해마의연결성은더욱확산된패턴을보이고있었다. 여기서자기상관을넘어선상관성을보이는결과들을신경원이보존된영역으로의연결성의증대로보긴어려운데, 그이유는본연구에서해마와확장된상관을가지는영역들이치매의진행과관련해확연히퇴행을보이는영역들이기때문이다 [26]. 일상생활에서주어진과제를수행하는데있어서항상정상적신경기능이나신경회로를사용할필요는없다. 특히뇌손상자나퇴행성질환환자에서구조적으로온전하게남아있는영역들이기능적으로고립되어작동하는것같지않은데 [27], 같은네트워크안에서작용하는뇌영역들이라도구조적병리의진행정도가각영역간기능적절충정도를조절하리라여겨진다. 한가지흥미로운결과는좌우해마가기능적연결에있어서 CDR단계에따라다른패턴을보인다는것이다. 일화기억의생성에있어서좌우해마의기능적차별성은활성화뇌영상연구 (i.e., 기능적자기공명영상연구 ) 를통해이미보고된바있다. 구체적으로살펴보면, 언어자극을이용한부호화 (encoding) 시주로좌측내측측두엽이활성화 [28, 29] 되는반면, 비언어자극의경우우측해마개입이더욱활발하였다 [30]. 더욱최근논문은부호화부하정도에따른좌우해마의역할을살펴보았는데주로우측해마가모든난이도의부호화동안일관적으로개입하고있는반면좌측해마는우측해마의과부화로인한기억기능의저하를막는기능적보상 (functional compensation) 을하는것으로보고하고있다 [31]. CDR 2/3에서우측해마는지속적으로다른영역과의연결성을증가시킴으로써일화기억을유지하기위하여노력하는반면, CDR 1에서우측해마의기능을보완하기위하여다른영역과의연결성을증가시켰던좌측해마가 CDR 2/3에접어들면서이러한보완기능을상실하고자기상관과해부학적으로직접적으로연결되어있는측두부로의연결성만을유지할가능성이있다. 일화기억의생성에있어서의좌우반구기능의차별성이외에도치매의진행동안나타나는좌우해마위축의차별성이기능적연결의패턴차이를가져오는또다른요인이라고볼수있는데, 좌우해마의비대칭적손상 [32] 과연결성의변화는이미 AD에서여러차례보고된바있다 [33]. 우리연구는방법론적제한점들또한가지고있다. 첫번째, 비록선행연구들이해마연결성에대한자료를축적했으나직접환자군과비교가능한정상인자료를포함하지못하였다. 두번째로이논문에서제시한상관분석결과가해마와다른뇌영
알츠하이머병진행에따른해마의기능적연결변화 : FDG-PET 을이용한뇌영역간상관분석 113 역간기능적연결성의존재여부에대한정보를제공하나해부학적연결정보나특정영역과의연결강도의변화에대한상세한정보는제공하지못한다는것이다. 추후연구들은대조군과환자군모두에서연결성의손상여부만이아니라연결강도의변화및방향성이 AD 환자에서나타나는인지적기능저하와상관을가지는지밝히는데초점을두어야할것으로보인다. 마지막으로, 영상획득의어려움으로인하여임상적증상의심각도가높은 CDR 3 이상의환자의데이터를포함하는데제한이있었다. 이분석에서 CDR 2와 CDR 3에속하는환자의영상을중등도이상의그룹으로통합하여분석하였으나추후, 인지기능의심각한붕괴를가진중증이상의환자에서도뇌영역간기능적상관변화가병리적진행과관련하여독립적으로분석되는것이요구된다. 국내제한적뇌기능영상관련데이터베이스의현실을고려할때, 충분한사례수의확보를위한센터간협력연구가한해결책이될수있을것이라본다. 결론적으로, 이연구는 AD에서치매의중증도에따른해마기능적연결성의변화를통계적정량화방법을적용해제안하였다. 손상된해마와다른뇌영역으로의기능적연결성은 AD 환자에서나타나는일련의기억기능저하는물론신경원의손상과퇴행에따른뇌의보상메커니즘과연결될가능성을시사하며, 이때아마도좌우해마의특정인지기능에대한비대칭적기능과신경원내의병리진행의특성이복합적으로관련될것으로보인다. 참고문헌 1. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. The Lancet 2005; 366(9503): 2112-7. 2. Greene JD, Hodges JR. Identification of famous faces and famous names in early Alzheimer s disease. Relationship to anterograde episodic and general semantic memory. Brain 1996; 119(Pt 1): 111-28. 3. Johnson JL. Episodic memory deficits in Alzheimer s disease: a behaviorally anchored scale. Arch Clin Neuropsychol 1994; 9: 337-46. 4. Greene JD, Baddeley AD, Hodges JR. Analysis of the episodic memory deficit in early Alzheimer s disease: evidence from the doors and people test. Neuropsychologia 1996; 34: 537-51. 5. Ballesteros S, Reales JM, Mayas J, Heller MA. Selective attention modulates visual and haptic repetition priming: effects in aging and Alzheimer s disease. Exp Brain Res 2008; 189: 473-83. 6. Hodges JR, Patterson K. Is semantic memory consistently impaired early in the course of Alzheimer s disease? Neuroanatomical and diagnostic implications. Neuropsychologia 1995; 33: 441-59. 7. Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al. Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer s disease, mild cognitive impairment, and elderly controls. Neuroimage 2009; 45(Suppl 1): S3-15. 8. Schmidt-Wilcke T, Poljansky S, Hierlmeier S, Hausner J, Ibach B. Memory performance correlates with gray matter density in the ento-/perirhinal cortex and posterior hippocampus in patients with mild cognitive impairment and healthy controls--a voxel based morphometry study. Neuroimage 2009; 47: 1914-20. 9. Schroeter ML, Stein T, Maslowski N, Neumann J. Neural correlates of Alzheimer s disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients. Neuroimage 2009; 47: 1196-206. 10. Reitz C, Honig L, Vonsattel JP, Tang MX, Mayeux R. Memory performance is related to amyloid and tau pathology in the hippocampus. J Neurol Neurosurg Psychiatry 2009; 80: 715-21. 11. Frisoni GB, Lorenzi M, Caroli A, Kemppainen N, Nagren K, Rinne JO. In vivo mapping of amyloid toxicity in Alzheimer disease. Neurology 2009; 72: 1504-11. 12. Mormino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, Miller BL, et al. Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain 2009; 132(Pt 5): 1310-23. 13. Lee DS, Kang H, Kim H, Park H, Oh JS, Lee JS, et al. Metabolic connectivity by interregional correlation analysis using statistical parametric mapping (SPM) and FDG brain PET; methodological development and patterns of metabolic connectivity in adults. Eur J Nucl Med Mol Imaging 2008; 35: 1681-91. 14. Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. International Psychogeriatrics 1997; 9(Suppl 1): 173-6. 15. 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 Services Task Force on Alzheimer s Disease. Neurology 1984; 34: 939-44. 16. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001; 58:
114 조상수 김은주 강수진외 3 인 1985-92. 17. 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. 18. Kwak Y, Cho DS. Usefulness of Seoul verbal learning test in differential diagnosis of Alzheimer s disease and subcortical vascular dementia. J Korean Neurol Assoc 2004; 22: 22-8. 19. Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain: 3-dimensional proportional system : an approach to cerebral imaging. Stuttgart: Thieme; 1988. 20. Li SJ, Li Z, Wu G, Zhang MJ, Franczak M, Antuono PG. Alzheimer disease: evaluation of a functional MR imaging index as a marker. Radiology 2002; 225: 253-9. 21. Allen G, Barnard H, McColl R, Hester AL, Fields JA, Weiner MF, et al. Reduced hippocampal functional connectivity in Alzheimer disease. Arch Neurol 2007; 64: 1482-7. 22. Sakamoto S, Ishii K, Sasaki M, Hosaka K, Mori T, Matsui M, et al. Differences in cerebral metabolic impairment between early and late onset types of Alzheimer s disease. J Neurol Sci 2002; 200: 27-32. 23. Buchert R, Wilke F, Chakrabarti B, Martin B, Brenner W, Mester J, et al. Adjusted scaling of FDG positron emission tomography images for statistical evaluation in patients with suspected Alzheimer s disease. J Neuroimaging 2005; 15: 348-55. 24. Miller SL, Celone K, DePeau K, Diamond E, Dickerson BC, Rentz D, et al. Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proceedings of the National Academy of Sciences 2008; 105: 2181-6. 25. Wheeler ME, Buckner RL. Functional-anatomic correlates of remembering and knowing. Neuroimage 2004; 21: 1337-49. 26. Kaye JA, Moore MM, Dame A, Quinn J, Camicioli R, Howieson D, et al. Asynchronous regional brain volume losses in presymptomatic to moderate AD. J Alzheimers Dis 2005; 8: 51-6. 27. Price CJ, Friston KJ. Functional imaging studies of neuropsychological patients: applications and limitations. Neurocase 2002; 8: 345-54. 28. Kelley WM, Miezin FM, McDermott KB, Buckner RL, Raichle ME, Cohen NJ, et al. Hemispheric specialization in human dorsal frontal cortex and medial temporal lobe for verbal and nonverbal memory encoding. Neuron 1998; 20: 927-36. 29. Fletcher PC, Stephenson CM, Carpenter TA, Donovan T, Bullmorel ET. Regional brain activations predicting subsequent memory success: an event-related fmri study of the influence of encoding tasks. Cortex 2003; 39: 1009-26. 30. Haxby JV, Ungerleider LG, Horwitz B, Maisog JM, Rapoport SI, Grady CL. Face encoding and recognition in the human brain. Proc Natl Acad Sci U S A 1996; 93: 922-7. 31. Ulrich M, Jonas C, Gron G. Functional compensation of increasing memory encoding demands in the hippocampus. Neuroreport 2010; 21: 59-63. 32. Shi F, Liu B, Zhou Y, Yu C, Jiang T. Hippocampal volume and asymmetry in mild cognitive impairment and Alzheimer s disease: Meta-analyses of MRI studies. Hippocampus 2009; 19: 1055-64. 33. Wang L, Zang Y, He Y, Liang M, Zhang X, Tian L, et al. Changes in hippocampal connectivity in the early stages of Alzheimer s disease: evidence from resting state fmri. Neuroimage 2006; 31: 496-504.