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1 ORIGINAL ARTICLE pissn: eissn: Korean J Clin Geri 2019;20(1): 혼합치매와알츠하이머병의국소뇌혈류차이 이명아 1, 정현석 2, 송인욱 1 1 가톨릭대학교인천성모병원신경과, 2 가톨릭대학교인천성모병원영상의학과 Differences in Regional Cerebral Blood Flow between Mixed Dementia and Alzheimer s Disease Myeong-A Lee 1, Hyeonseok Jeong 2, In-Uk Song 1 1 Department of Neurology, Incheon St. Mary s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea; 2 Department of Radiology, Incheon St. Mary s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea Background: Previous studies have suggested that mixed dementia (MD) has distinct characteristics of brain structure and function compared to other types of dementia such as Alzheimer s disease (AD). However, the patterns of altered regional cerebral blood flow (rcbf) in MD remain elucidated. This study aimed to investigate the differences in rcbf between MD and AD patients. Methods: Twent-seven MD patients and 27 AD patients in their early stages underwent brain technetium-99m hexamethylpropylene amine oxime single-photon emission computed tomography scans. Voxel-wise differences in rcbf between the two groups were examined using Statistical Parametric Mapping. Results: MD patients presented lower rcbf in the superior/inferior frontal and lateral orbital gyri compared to AD patients (P<0.005). On the other hand, AD patients demonstrated lower rcbf in the amygdala and hippocampus compared to their counterparts (P<0.005). Conclusion: The distinct characteristics of rcbf vary by underlying dementia pathology, MD and AD. Key Words: Alzheimer disease, Mixed dementia, Regional cerebral blood flow, Single-photon emission computed tomography 서론 혼합치매 (mixed dementia) 는치매의주요원인으로알려진알츠하이머병 (Alzheimer s disease) 과혈관치매 (vascular dementia) 가공존하는경우로정의된다 [1]. 신경병리학적연구들에따르면치매환자중혼합치매의비율은약 22% 로서비교적흔하게관찰되는것으로알려져있다 [2]. 세포외아밀로이드판 (amyloid plaque) 과세포내신 경원섬유매듭 (neurofibrillary tangles) 등의알츠하이머병관련뇌병변및허혈뇌경색증, 다발성열공뇌경색증, 뇌실주변백질병터등의혈관치매뇌병터가함께발생하는경우, 이들간의상승작용에의해인지기능의저하가발생할위험이유의하게높아질수있다 [3,4]. 혼합치매의진단및치료법개발을위해서는다른형태의치매와의비교연구가중요하고, 실제로이에대한다양한임상및뇌영상연구들이보고되고있다. 신경심 Received January 2, 2019; revised February 18, 2019; accepted February 25, Corresponding author: In-Uk Song, Department of Neurology, Incheon St. Mary s Hospital, College of Medicine, The Catholic University of Korea, 56 Dongsu-ro, Bupyeong-gu, Incheon 21431, Korea. siuy@catholic.ac.kr; or Hyeonseok Jeong, Department of Radiology, Incheon St. Mary s Hospital, College of Medicine, The Catholic University of Korea, 56 Dongsu-ro, Bupyeong-gu, Incheon 21431, Korea. hsjeong@catholic.ac.kr Copyright C 2019 The Korean Academy of Clinical Geriatrics This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which perm its unrestricted non-comm ercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 이명아외 : 혼합치매와알츠하이머병의국소뇌혈류차이 27 리학적특성을비교한연구들에서는알츠하이머병환자군에비하여혼합치매환자군의주의집중및실행기능등이유의하게낮은것으로나타났다 [5,6]. 또한치매에흔하게동반될수있는신경정신증상들의양상도알츠하이머병, 혈관치매, 혼합치매환자군사이에서차이가있는것으로알려졌다 [7]. 자기공명영상 (magnetic resonance imaging, MRI) 등을이용한뇌영상연구에서는혼합치매군에서전두엽-측두엽-두정엽의피질두께감소및백질의미세구조손상 [8], 알츠하이머병및혈관치매군에비하여 default mode network 및중앙집행기능네트워크 (central executive network) 에서휴지기기능적연결성 (resting-state functional connectivity) 의저하 [9], 혈관치매및정상대조군에비하여후두엽에서높은 myoinositol/creatine ratio [10] 등이확인되었다. 이와같은결과들은혼합치매의임상양상과뇌의구조및기능이다른형태의치매와차이를보인다는점을시사한다. 그러나혼합치매에대한뇌영상연구는다른형태의치매에비해상대적으로부족하여일관된결론을얻기위해서는추가적인연구가필요하다. 특히알츠하이머병에비해혈관치매에서이마관자엽, 마루엽, 시상에비대칭적으로산재된국소뇌혈류 (regional cerebral blood flow) 저하가관찰된것과는달리, 혼합치매의국소뇌혈류양상에대해서는잘알려지지않았다. 본연구는단일광자방출컴퓨터단층촬영 (single-photon emission computed tomography, SPECT) 을이용하여알츠하이머병환자군과혼합치매환자군간국소뇌혈류를비교분석하였다. 혼합치매군에서실행기능과전두엽의휴지기기능적연결성이저하되어있다고보고한선행연구에근거하여 [6,9], 알츠하이머병군에비하여혼합치매군에서전두엽의국소뇌혈류가유의하게낮을것으로가정하였다. 대상및방법 1. 연구대상자 가톨릭대학교인천성모병원에서모집한초기알츠하이머병및혼합치매환자를대상으로하였으며, 진단은 Diagnostic and Statistical Manual of Mental Disorders, Fourth edition [11] 및 National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer disease and Related Disorders Association 기준에 [12] 근거하였다. 임상치매척도 (Clinical Dementia Rating, CDR) [13] 점수는 0.5인경우로하였다. 두부외상, 뇌경색증, 뇌전증, 다른신경과적또는정신과적질환의과거력이있는환자는연구에서제외되었다. 본연구는인천성모병원임상연구심사위원회의승인을받았으며, 모든연구참여자로부터서면동의를받았다. 2. 임상적평가신경과전문의가병력청취, 신체검사, 실험실적검사등의임상적진찰을실시하였다. 인지기능및신경정신증상은각각간이정신상태검사 (Mini-Mental State Examination, MMSE) [14] 와 Neuropsychiatric Inventory (NPI) 로 [15] 평가하였다. 치매의전반적인심각도는 CDR [13], CDR-Sum of Boxes (CDR-SOB) 및치매단계평가척도 (Global Deterioration Scale, GDS) [16] 로평가하였다. 3. 뇌영상획득및분석대상자에게 550 MBq의 technetium-99m hexamethylpropylene amine oxime을정맥주사하고약 20분후에저에너지부채꼴빔조준기가탑재된 dual-head 감마카메라 (Discovery NM630, GE Healthcare, Milwaukee, WI, USA) 를이용하여 SPECT 뇌영상을획득하였다. 영상은 6 o 간격으로총 720 o 를회전하는카메라에의해획득되었으며, filtered back projection 기술을이용하여, matrix 및 mm의픽셀 (pixel) 크기 (field of view=250 mm, slice thickness=2.08 mm, 20% symmetric energy window at 140 kev) 로재구성되었다. 영상의전처리와통계분석에는 Statistical Parametric Mapping 12 (SPM; Wellcome Department of Cognitive Neurology, Institute of Neurology, London, UK) 가사용되었다. 전처리를위하여각영상을 SPM SPECT template 에공간정규화 (spatial normalization) 시킨다음, mm 3 의복셀 (voxel) 크기로 reslicing하였고, 12 mm fullwidth half-maximum Gaussian kernel을이용하여 smoothing 을적용하였다. 각복셀의국소뇌혈류값은 proportional scaling에의해뇌전체의평균혈류를기준으로정규화되었다. 4. 통계분석군간연속변수의비교를위하여독립 t 검정이이용되었다. 통계적유의성은 P<0.05 ( 양측검정 ) 을기준으로하였으며, 통계분석에는 Stata 13.1 (StataCorp., College

3 28 Korean J Clin Geri 2019;20(1):26-30 Station, TX, USA) 이사용되었다. 알츠하이머병군과혼합치매군의국소뇌혈류차이를분석하기위하여 SPM에서각복셀단위로두표본 t 검정 (two-sample t-test) 이실시되었으며, 나이, 성별, MMSE 총점이공변량으로포함되었다. 각복셀의 height threshold는 P<0.005로, extent threshold는 100 복셀이상으로설정하였다. Table 1. Demographic and clinical characteristics of the study participants Characteristic 결 과 총 27명의알츠하이머병환자와 27명의혼합치매환자가분석에포함되었으며, 이들의인구학적및임상적특성이 Table 1에정리되었다. 나이는알츠하이머병군이 75.1±4.6세, 혼합치매군이 76.7±5.1세로, 두집단간유의한차이가없었으며 (P=0.22), 성별은양군모두남성 Mixed dementia (n=27) AD (n=27) P value Age (year) 76.7± ± Sex (male:female) 9:18 9:18 Education status (year) 5.9± ± MMSE 22.4± ± CDR CDR-SOB 1.6± ± GDS 3.2± ± NPI 2.2± ± AD, Alzheimer s disease; CDR, Clinical Dementia Rating; CDR- SOB, Clinical Dementia Rating-Sum of Boxes; GDS, Global Deterioration Scale; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory. 9명과여성 18명으로동일하였다. 그밖에교육정도 (P= 0.32), MMSE (P=0.97), CDR (P=1.00), CDR-SOB (P= 0.65), GDS (P=0.49), NPI (P=0.30) 에도유의한차이는없었다. 두집단간국소뇌혈류비교결과는 Table 2와 Figure 1에제시되었다. 알츠하이머병군에비하여혼합치매군에서국소뇌혈류가유의하게낮았던영역은왼쪽위이마이랑, 왼쪽아래이마이랑, 오른쪽가쪽눈확이랑, 왼쪽위이마이랑, 오른쪽위이마이랑으로나타났다. 혼합치매군에비하여알츠하이머병군에서국소뇌혈류가유의하게낮았던뇌영역은오른쪽편도및왼쪽해마였다. 고찰 본연구는 SPECT 뇌영상을이용하여혼합치매와알츠하이머병환자군의국소뇌혈류차이를비교분석하였다. 그결과, 인구학적특성, 전반적인지기능, 치매의심각도, 신경정신증상등에는군간차이가유의하지않은가운데, 혼합치매환자군은위 / 아래이마이랑및가쪽눈확이랑에서상대적으로국소뇌혈류가낮았고, 알츠하이머병환자군은편도와해마에서낮았다. 이와같은결과는혼합치매와알츠하이머병의기저병태생리의차이에따라국소뇌혈류의분포가다를수있음을시사한다. 혼합치매군에서는전두엽여러영역에서국소뇌혈류가상대적으로낮게나타났다. 이와유사하게, 휴지기기능적 MRI를이용한선행연구에서도혈관치매및알츠하이머병군에비하여혼합치매군에서아래이마이랑을중심으로중앙집행기능네트워크내부의기능적연결성이감소한것으로나타났다 [9]. 또한혈관치매중가장흔한피질하혈관치매 (subcortical vascular dementia) 환자군 Table 2. Differences in regional cerebral blood flow between patients with mixed dementia and Alzheimer disease Brain region t P value Cluster size (voxels) Coordinates* Mixed dementia<alzheimer disease Left superior frontal gyrus 3.99 < , 58, 30 Left inferior frontal gyrus 3.73 < , 30, 0 Right lateral orbital gyrus , 40, 6 Left superior frontal gyrus , 10, 52 Right superior frontal gyrus , 8, 70 Mixed dementia>alzheimer disease Right amygdala 3.54 < , 4, 18 Left hippocampus , 42, 4 *The coordinates refer to the Montreal Neurological Institute coordinate system.

4 이명아외 : 혼합치매와알츠하이머병의국소뇌혈류차이 29 Figure 1. Brain regions with increases (red-yellow) or decreases (blue-green) in regional cerebral blood flow in patients with mixed dementia compared to those with Alzheimer s disease. The height threshold was P<0.005 and extent threshold was 100 or more contiguous voxels. Images are shown in neurological convention. Color bar represents voxel-level t-values. L, left; R, right. 에서도알츠하이머병환자군에비하여전두엽의인지기능및국소뇌혈류저하가보고되었다 [17]. 피질하혈관치매환자군에서는 T2-강조영상에서피질하열공경색과백질병터 (white matter hyperintensity) 가관찰되는경우가많은데, 이러한허혈병터는전두엽의피질과피질하부위를이어주는신경회로에손상을야기하고 [18], 수행기능에장애를초래할수있는것으로알려졌다 [19]. 또다른연구에서는백질병터가전두엽에더많이발견되며, 이는전두엽의포도당대사및수행기능저하와연관되는것으로보고되었다 [20]. 본연구에서나타난혼합치매환자군의전두엽국소뇌혈류저하는허혈성병태생리가반영된것으로생각되며, 혼합치매의특징적인전두엽기능저하 [6] 와연관되었을가능성을시사한다. 알츠하이머병군에서편도및해마의국소뇌혈류저하는기존의병리학및뇌영상연구결과들과잘부합한다. 알츠하이머병에대한병리학적연구들에서는내측두엽, 편도, 해마, 내후각피질, 해마곁이랑등의영역에서가장먼저손상이시작되는것으로알려져있다 [21]. 특히편도의덧기저편도핵 (accessory basal nucleus), 피질핵 (cortical nucleus) 와 cortical transition area 등해마투영 (hippocampal projection) 과연결된핵중심으로신경원섬유매듭과아밀로이드판이관찰되었고 [22], 해마의 CA1 영역에서도신경손상이보고된바있다 [23]. 관류강조 (perfusion-weighted) MRI를이용한연구에서는정상대조군과비교하여알츠하이머병군에서편도와해마의국소뇌혈류가저하된것으로나타났다 [24]. 본연구에포함된환자들은초기단계의치매였기때문에, 측두정엽등의영역에서는차이가유의하지않았던것으로생각된다. 본연구의제한점은다음과같다. 본연구에는정상대조군이포함되지않아알츠하이머병과혼합치매간국소뇌혈류의상대적인차이만을비교할수있었다. 국소뇌혈류의정상범위와비교한방향성을파악하기위하여향후정상대조군과의비교분석이필요하고, 추가적으로혈관치매와혼합치매간의비교도이루어진다면혈관치매와는다른혼합치매의특이적인국소뇌혈류양상을규명하는데도움이될것이다. 두번째, 종합적인신경심리학적검사가수행되지않아알츠하이머병과혼합치매간구체적인인지기능의차이및국소뇌혈류와인지기능사이의연관성을확인하지못하였다. 추후혼합치매군에서전두엽의국소뇌혈류저하가실행기능등의인지기능손상과연관관계를보이는지에대한연구가더필요할것이다. 결론적으로본연구는알츠하이머병과혼합치매환자군사이의 SPECT 뇌영상을비교분석해국소뇌혈류양상의차이를확인하고자하였다. 그결과혼합치매에서는전두엽의국소뇌혈류가상대적으로낮았고, 알츠하이머병군에서는피질하영역및내측두엽에서국소뇌혈류가낮았다. 앞서언급한제한점들을고려하여, 향후정상대조군및혈관치매환자군까지포함하고뇌영상과신경심리학적검사결과를추적하여연계분석한다면, 혼합치매의감별진단및예후예측등에도도움이될것으로기대된다. CONFLICTS OF INTEREST No potential conflict of interest relevant to this article was reported. ACKNOWLEDGEMENT This research was supported by Global Frontier Program through the National Research Foundation of Korea (NRF)

5 30 Korean J Clin Geri 2019;20(1):26-30 funded by the Ministry of Science and ICT (2018M3 A6A ). REFERENCES 1. Langa KM, Foster NL, Larson EB. Mixed dementia: emerging concepts and therapeutic implications. JAMA. 2004; 292: Custodio N, Montesinos R, Lira D, Herrera-Perez E, Bardales Y, Valeriano-Lorenzo L. Mixed dementia: A review of the evidence. Dement Neuropsychol 2017;11: Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997; 277: de la Torre JC. Vascular basis of Alzheimer's pathogenesis. Ann N Y Acad Sci 2002;977: Dong Y, Gan DZ, Tay SZ, Koay WI, Collinson SL, Hilal S, et al. Patterns of neuropsychological impairment in Alzheimer disease and mixed dementia. J Neurol Sci 2013;333: Kang HS, Kwon JH, Kim S, Na DL, Kim SY, Lee JH, et al. Comparison of neuropsychological profiles in patients with Alzheimer disease and mixed dementia. J Neurol Sci 2016; 369: Anor CJ, O'Connor S, Saund A, Tang-Wai DF, Keren R, Tartaglia MC. Neuropsychiatric symptoms in Alzheimer disease, vascular dementia, and mixed dementia. Neurodegener Dis 2017;17: Jang H, Kwon H, Yang JJ, Hong J, Kim Y, Kim KW, et al. Correlations between gray matter and white matter degeneration in pure Alzheimer disease, pure subcortical vascular dementia, and mixed dementia. Sci Rep 2017;7: Kim HJ, Cha J, Lee JM, Shin JS, Jung NY, Kim YJ, et al. Distinctive resting state network disruptions among Alzheimer disease, subcortical vascular dementia, and mixed dementia patients. J Alzheimers Dis 2016;50: Waldman AD, Rai GS, McConnell JR, Chaudry M, Grant D. Clinical brain proton magnetic resonance spectroscopy for management of Alzheimer's and sub-cortical ischemic vascular dementia in older people. Arch Gerontol Geriatr 2002;35: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric Association; McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer disease: Recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer disease. Alzheimers Dement 2011;7: Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, et al. The Consortium to Establish a Registry for Alzheimer disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer disease. Neurology 1989;39: Kang Y, Na DL, Hahn S. A validity study on the Korean Mini-Mental State Examination (K-MMSE) in dementia patients. J Korean Neurol Assoc 1997;15: Choi SH, Na DL, Kwon HM, Yoon SJ, Jeong JH, Ha CK. The Korean version of the neuropsychiatric inventory: a scoring tool for neuropsychiatric disturbance in dementia patients. J Korean Med Sci 2000;15: Reisberg B, Ferris SH, de Leon MJ, Crook T. Global Deterioration Scale (GDS). Psychopharmacol Bull 1988;24: Starkstein SE, Sabe L, Vazquez S, Teson A, Petracca G, Chemerinski E, et al. Neuropsychological, psychiatric, and cerebral blood flow findings in vascular dementia and Alzheimer disease. Stroke 1996;27: Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol 2002;1: O'Brien JT, Wiseman R, Burton EJ, Barber B, Wesnes K, Saxby B, et al. Cognitive associations of subcortical white matter lesions in older people. Ann N Y Acad Sci 2002;977: Tullberg M, Fletcher E, DeCarli C, Mungas D, Reed BR, Harvey DJ, et al. White matter lesions impair frontal lobe function regardless of their location. Neurology 2004;63: Braak H, Braak E. Neuropathological stageing of Alzheimerrelated changes. Acta Neuropathol 1991;82: Kromer Vogt LJ, Hyman BT, Van Hoesen GW, Damasio AR. Pathological alterations in the amygdala in Alzheimer disease. Neuroscience 1990;37: West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer disease. Lancet 1994;344: Luckhaus C, Fluss MO, Wittsack HJ, Grass-Kapanke B, Janner M, Khalili-Amiri R, et al. Detection of changed regional cerebral blood flow in mild cognitive impairment and early Alzheimer s dementia by perfusion-weighted magnetic resonance imaging. Neuroimage 2008;40:

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Dementia2 Today s Topics Memory Impairment & Dementia Age Associated Memory Impairment Dementia Definition of dementia Depression Schizophrenia Mental retardation Delirium : Not final diagnosis term, but symptomatologic