Original Article http://dx.doi.org/10.4235/jkgs.2012.16.4.200 뇌관류 Single Photon Emission Computed Tomography 에서초기알쯔하이머병과파킨슨병치매에서의뇌영역별혈류량의차이 가톨릭대학교의과대학신경과학교실 1, 핵의학과교실 2 나승희 1 송인욱 1 김영도 1 조현지 1 정성우 1 정용안 2 Differences of Regional Cerebral Blood Flow between Early Alzheimer s Disease and Parkinson s Disease Associated with Dementia on 99m Tc-Hexamethyl Propylene Amine Oxime Perfusion Single Photon Emission Computed Tomography Seung-Hee Na, MD 1, In-Uk Song, MD 1, Young-Do Kim, MD 1, Hyuin-Ji Cho, MD 1, Sung-Woo Chung, MD 1, Yong-An Chung, MD 2 Departments of 1 Neurology and 2 Nuclear Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Background: Alzheimer s disease (AD) and Parkinson s disease associated with dementia (PDD) are considered to be frequent types of cortical and subcortical dementia. Definitive diagnosis of neurodegenerative diseases is impossible without biopsy. Single photon emission computed tomography (SPECT) of the brain has long been used for years with cognitive disorders. Nevertheless, differential brain perfusion of patients with PDD and AD who exhibit mild dementia has not been reported. Therefore, we investigated the differences in the cerebral perfusional pattern using perfusion SPECT between mild AD and mild PDD to help clarify the diagnosis in the early stage of these dementias, since accurate diagnosis is crucial in decision regarding treatment, appropriate advice, management and prognosis. Methods: Thirty-one patients with mild PDD and 32 patients with mild probable AD were enrolled in this study. All subjects underwent 99m Tc-hexamethyl propylene amine oxime perfusion SPECT and general neuropsychological tests, and these data including perfusion images were analyzed. Results: Perfusion SPECT showed hypoperfusion in frontal, parietal and temporal regions in both PDD and AD patients with mild dementia. Hypoperfusion in the occipital and cerebellar regions was significantly apparent in only PDD patients. Conclusion: Comparison of mild PDD with mild AD showed a significantly decreased perfusion in the occipital and cerebellar region in patients with mild PDD. Cerebral perfusion in the occipital region and the cerebellum could be a crucial differential diagnostic method of these diseases in the early phase. Further studies are needed for a definitive conclusion. Key Words: Parkinson s disease, Alzheimer s disease, Dementia, Perfusion single photon emission computed tomography Received: July 3, 2012 Revised: October 28, 2012 Accepted: October 28, 2012 Address for correspondence: In-Uk Song, MD Department of Neurology, Incheon St. Mary s Hospital, The Catholic University of Korea College of Medicine, 56 Dongsu-ro, Bupyeong-gu, Incheon 403-720, Korea Tel: +82-32-280-5010, Fax: +82-32-280-5013, E-mail: siuy@freechal.com 서론 신경퇴행성질환중에서가장흔한질환은노인성치매로가장잘알려져있는알쯔하이머병 (Alzheimer's disease, AD) 이며, 두번째로흔한질환은운동완만증, 경축그리고안정시 200 J Korean Geriatr Soc 16(4) December 2012
나승희외 : 파킨슨병치매와알쯔하이머병의뇌혈류량차이 떨림으로발현되는파킨슨병 (Parkinson's disease, PD) 으로알려져있다 1). 최근고령사회로접어들면서이러한노인성신경퇴행성질환들이많은관심을받고있으나, 명확한진단은뇌조직검사를통해서만이루어지기때문에정확한진단및치료에많은어려움을가지고있다 2,3). PD 의경우는예전에는운동성질환으로만알려져왔으나, 최근 PD에서나타나는비운동성증상에대해많은관심을받게되었다. 흔히언급되는 PD에서의비운동성증상은정동장애, 충동장애, 감각장애, 인지기능장애등이있다. 이중인지기능장애에대해서는전체 PD 환자의약 40% 에서치매를동반하게되며, 정상인과비교하여 6배높은치매발병률을보인다고한다 2). 이처럼파킨슨병치매 (Parkinson's disease dementia, PDD) 가많음에도불구하고, 이에대한명확한진단은어려운실정이다. 뇌단일광자방출전산화단층촬영 (single photon emission computed tomography, SPECT) 은뇌혈류에 technetium을붙인 hexamethyl-prophylene-amine-oxime 또는 ethyl cysteinate dimer 를이용하여많이활용되고있는데, 최근치매환자에있어서진단에유용하게이용되고있다 3-5). 초기 AD에서는 SPECT 이정상인과비교하여내측측두엽, 두정엽, 후부띠이랑피질 (posterior cingulate cortex) 에혈류가저하된소견을보이게되고, 진행된 AD 환자에있어서는전두엽까지뇌혈류저하를보인다고알려져있다 4,5). 또한이전연구들에의하면 PDD 환자에있어서도 Brain SPECT 결과는선조체 (striatum) 에서의변화를의미있게보였다고보고하고있다 4,6). 하지만아직까지 PDD와 AD 사이의 Brain SPECT 소견으로감별이가능한지에대한연구보고는거의없는실정이다. 따라서저자들은본연구를통해뇌조직검사이외는명확히감별하기힘든 AD와 PDD 환자에서 Brain SPECT 을시행하여뇌관류의차이가두질환에서차이가있는지를확인하여초기에 AD 와 PDD의감별에도움을주고자한다. 대상및방법 2011년 7월부터 2012년 5월까지본원신경과에내원한치매를동반한 PDD 환자와 AD 환자를대상으로연구를본원임상윤리심의위원회의승인을받고진행하였다. 본연구에는 31명의 PDD 환자와 32명의 AD 환자가참여하였다. PDD 환자는영국파킨슨병학회뇌은행의임상진단기준 (United Kingdom Parkinson s Disease Society Brain Bank Clinical Diagnostic Criteria) 에맞는환자로본원 123 I-n-fluoropropyl- 2b-carbomethoxy-3b-(4-iodophenyl) nortropane positron emission tomography (FP-CIT PET) 상에서도도파민전달체의흡수가저하된환자를선택하였다. PD의진단을받은이후 12개월이후인지저하를호소하여인지검사상간이정신상태검사 (mini-mental state examination, MMSE) 20-24 점이면서임상적치매척도 (clinical dementia scale, CDR) 는 0.5 또는 1 그리고전반적퇴화척도 (global deterioration scale, GDS) 는 3 또는 4를충족시키는환자만을선택하였다. PDD 환자중에서 2차성파킨슨증을일으킬만한약물 ( 예, neuroleptic drug) 또는인지저하를일으킬약물 ( 예, anticholinergic agents) 을장기간복용한경우, 우울증이나정신과적이상증상이있는경우, 환시가보이며인지저하의변동이있는경우는본연구에서제외하였다. AD 환자의경우도 PDD 환자와같은인지검사를시행하여같은조건의결과에해당되는환자만선택하고, DSM-IV criteria와 NINCDS- ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer s Disease and Related Disorders Association) criteria 에합당한환자만을선택하였다. 이들선택된모든대상군은뇌관류 SPECT 을안전영상으로촬영하였다. 1. 99m Tc-Hexamethyl Propylene Amine Oxime (HMPAO) SPECT 영상획득 뇌영상연구를위해사용한 SPECT 를시행한다. 영상획득은 6 간격으로 360 회전하여저에너지고해상도조준기 (low energy high resolution collimator) 를사용하여 60 프레임을얻는다. 안정상태에서의영상을얻기위해 925 MBq 의 99m Tc- HMPAO 를정맥주사하고, 주사한후 20분경과후약 20-30분동안스캔하였다. 촬영하는동안피검자는편안한상태를유지하며, 머리의움직임을최소로하였으며, 촬영실은조용하고조명을어두운상태로유지하였다. 2. 영상분석및 SPM SPECT 영상은표준다이콤 (DICOM) 형태로변환되어마이크로소프트윈도우기반의컴퓨터에저장된다. 각각의파일은분석을위해 Analyze 형식으로변환된후모든영상을 SPECT 표준지도위에공간정규화한다. 뇌피질및내부구조의미세한차이는저주파함수들로미리정의된기저함수 (basis function) 들의가중합으로나타내는선형화된비선형적 (linearized nonlinear) 방법을사용하여제거한다. 신호 J Korean Geriatr Soc 16(4) December 2012 201
Seung-Hee Na, et al: Blood flow differences between AD and PDD 대잡음비를높이고미처보정되지않은뇌피질의차이를극복하기위하여공간정규화가된영상들을 16 mm 의 FWHM (full width at half maximum) 을갖는가우시안커널 (Gaussian kernel) 로중첩적분 (convolution) 한다. 이러한전처리과정으로서의편평화 (smoothing) 는통계분석결과에서크기가작은덩어리의생성을줄이므로위양성결과를보정하고고주파의잡음을제거해서예민도를높이는역할을한다. 그리고각복셀이가지는국소계수는뇌피질내의전체계수와개별적인내변이그리고불규칙한잡음의선형결합 ( 일반선형모델 : general linear model) 으로나타내어진다는가정하에선형회귀분석을이용하여각복셀에서의이러한변수들의가중치를찾아낸후국소계수의차이만을추출하였다. 3. 통계분석 양대상군의기본자료에대한통계분석은 SPSS ver. 17.0 (SPSS Inc., Chicago, IL, USA) 을이용하여연속변수는독립 t-test을시행하였고, 비연속변수에대해서는 Pearson chi-square analysis 를사용하였다. 뇌영상사진에대한분석은복셀별로통계분석하였다. 복셀별로각각의 SPECT 군사이의국소계수차이에대한귀무가설을검증하고자뇌영역내의모든복셀에대해 t-test를시행하고용이한해석을위해 t 값들을표준정규분포로변환하여 Z 값으로나타냈다. 이는위에서언급한일반선형모델을기본모델로하고, 각변수의효과가 Student s t 통계를따른다고보아그유의성을검정하는것으 로이렇게각복셀에서구해진 t 값들은그자체가뇌기능영상이포함된 3차원공간상에서또다른하나의확률변수 (random variable) 로써행동한다고생각하고, 그분포는고정가우시안랜덤영역 (stationary Gaussian random field) 을따른다고가정하였다. 이러한가정하에서각복셀의 t 값에대한통계적유의성은그값을 Z 값 [Z=(t-m)/SD; m, 평균 ; SD, 표준편차 ] 으로변환하여가우시안랜덤영역의행동과비교함으로써얻을수있다. 통계분석의결과를해석하고유의한관류차이와덩어리크기를갖는영역의 Z 값들을 magnetic resonance imaging 표준지도위에표현하여표준지도상에서의좌표와해부학적이름, 브로드만영역등을표시해준다. 또한각복셀의 Z 값에대한통계적매개변수영상 (statistical parametric image) 을구성하고 3차원으로렌더링 (rendering) 한표준지도위에투사하여관류차이를보이는부위를쉽게알아볼수있게한다. 이상의과정은 Matlab, ver. 5.3 (Mathworks Inc., Natick, MA, USA) 상에서구현된 SPM2 소프트웨어 (statistical parametric mapping software, Institute of Neurology, University College of London, London, UK) 를이용하였다. 결과 환자의성별, 평균나이, 교육정도, 인지저하의기간에대해서는양대상군사이에의미있는차이가없었다 (Table 1). PDD 군에서 PD 운동증상발현후치매로진단받기까지기간이 23.48 Table 1. Demographic data and cognitive functions in the AD and PDD groups and normal controls Variable AD PDD p value Subjects 32 31 Female sex 9 7 0.202 Mean age (yr) 76.26±6.20 74.69±3.90 0.337 Mean education (yr) 3.23±3.84 3.66±3.88 0.091 Mean duartion of dementia (mo) * 14.28±6.55 15.03±8.79 Mean duartion before PDD (mo) 23.48±12.58 MMSE score 21.25±1.50 22.06±1.86 0.576 CDR score 0.78±0.25 0.67±0.24 0.057 SOB score 4.45±1.60 4.06±2.84 0.508 GDS socre 3.59±0.76 3.23±0.92 0.088 Values are mean±standard deviation. AD. Alzheimer's disease; PDD, Parkinson's disease associated with dementia; ND, not done; MMSE, minimental state examination; CDR, clinical dementia scale; SOB, sum of box of CDR; GDS, global deterioration scale. * Duration of clinilcally notable cognitive impairment, Duration of Parkinson's disease prior to onset of mild dementia. 202 J Korean Geriatr Soc 16(4) December 2012
나승희외 : 파킨슨병치매와알쯔하이머병의뇌혈류량차이 ±12.58개월이었다. MMSE 는 AD군에서 21.25±1.50, PDD군에서 22.06±1.86, CDR 도각각 AD군에서 0.81±0.25, PDD 군에서 0.76±0.48 그리고 GDS의수치도 AD군에서 3.59±0.76, PDD군에서 3.23±0.92을보였으나, 통계적으로차이는보이지않았다. 양대상군에서뇌관류 SPECT 을통한혈류량의비교분석에서는의미있는차이를보였다 (Fig. 1, Table 2). 즉, PDD 환자군 에서양측소뇌의후엽 (posterior lobe of both cerebellum) 과우측후두엽의쐐기 (cuneus of right occipital lobe, 브로드만영역 23) 에서 AD군보다통계적으로유의한혈류량의저하를보였다. 하지만 AD군의혈류량보다의미있게증가된뇌부위는 PDD군에서찾을수없었다. 고찰 Fig. 1. Results obtained from group comparisons of Parkinson s disease associated with dementia (PDD) and Alzheimer's disease (AD) show brain regions (blue color) with decreased regional cerebral blood flow in trans-axial magnetic resonance fused images of PDD compared to AD. 최근에신경퇴행성질환중에서치매의치료및진단에많은관심이집중되고있으나, 여러종류의치매에대한정확한감별진단은어려운실정이다 2). PD 에동반되는인지저하는진행되는 PD에서흔히동반되는증상으로써환자및보호자의삶의어려움을증가시킬뿐만아니라, 환자의여생도단축시키게된다 7). 더욱이 PDD에있어서는초기에는자세한신경심리검사를통해서도감별진단하기가어려워초기 AD 와혼동되는경우가많아오진또한흔하다 2,8). 따라서뇌관류 SPECT 과같은뇌영상기법들을사용하여감별진단의정확성을위해노력하고있는실정이다 6,8). 이전보고들에의하면 AD는두정엽과측두엽, 전두엽에서특징적으로혈류저하를보인다고보고하고있으며, PDD 에서는두정엽, 전두엽, 소뇌, 후두엽에서영역별혈류량의저하를보이며, 치매를동반하지않는 PD에비해같은영역의혈류량저하가좀더심하게나타난다고보고하고있다 6,9-11). 추가적으로 PDD에서는기저핵의혈류저하가비대칭성으로주로나타난다고보고하고있으나, 이는치매를동반하지않는 PD에서의소견이므로서로같은맥락을가진다고볼수있겠다 12,13). 본연구는초기치매의감별진단에중점을둔연구로써초기 AD와초기 PDD 환자들의영역별뇌혈류량을뇌관류 SPECT 을통해비교분석하였다. 그결과초기 PDD에서의영역별뇌혈류량은초기 AD에비해후두엽과소뇌에서심한저혈류량을보였다. 이들부위는인지저하에영향을미치는부위가아님에도불구하고, PDD 에서 AD 보다초기에도의미있는저혈류량을보인것은아마도 PD의운동증상에의한 Table 2. Areas with significantly decreased regional cerebral blood flow in Parkinson's disease patients compared to the Alzheimer's disease patients ke T Z x, y, z Brain areas 721 721 473 3.68 3.05 3.19 3.43 2.90 3.02 4, 64, 32 12, 54, 14 6, 74, 8 Right cerebellum, posterior lobe Left cerebellum, posterior lobe Right occipital lobe, cuneus (BA 23) Height threshold, T=2.69; corrected p=0.005; extent threshold, k=50 voxels; ke, expected voxels per cluster. J Korean Geriatr Soc 16(4) December 2012 203
Seung-Hee Na, et al: Blood flow differences between AD and PDD 영향으로생각된다. 우선적으로소뇌영역의혈류량저하는 PD로인한소뇌- 시상-피질로 (cerebello-thalamo-cortical circuits) 영역, 특히소뇌의충부 (vermis/paravermis region in cerebellum) 의침범때문으로생각된다. 왜냐하면소뇌는운동을조절하는중요한역할을하며, 소뇌- 시상- 피질로를통해서뇌피질의운동영역에도영향을주기때문으로생각되나, 아직 PD에서소뇌의병리생태학적인역할에대해서는명확하게규명되지않았다 12,14). 초기 AD에비해 PDD에서혈류량감소를의미있게보인후두엽에대해서도이전에몇몇보고가되어있다 6,11). 즉 PD에서나타나는안구운동의장애, 공감각의장애그리고무시증상이후두엽의저혈류량소견을임상적으로반영한다고보고하고있다 6,15,16). 따라서본연구결과및이전보고들을통해초기 PDD 와 AD 사이의뇌관류영상을통한감별진단의가능성을엿볼수있었다. 즉, 초기에임상적으로는상기두질환의감별이어려울지라도 SPECT 같은뇌관류영상에서소뇌과후두엽의관류의차이로말미암아초기단계라할지라도두질환의감별진단에많은도움을줄수있으리라생각된다. 결론적으로 PDD 와 AD를초기단계에서감별하는것은자세한신경심리검사및뇌자기공명사진등을시행한다해도매우어렵다 2,17,18). 하지만본연구및참고문헌의고찰을통해저자들은초기임에도불구하고, AD 보다 PDD에서뇌관류 SPECT 의영역별혈류량의저하를의미있게보인소뇌와후두엽이두질환의감별에중요한역할을할수있다고조심스럽게제안하고자한다. 즉, 뇌관류 SPECT 소견만으로는 AD와 PDD 를진단및감별할수는없지만, 신경심리검사를바탕으로하여진단된상기질환에서감별진단에어려울때뇌관류 SPECT 같은영상검사들의소견이감별진단에많은도움을줄수있다고생각된다. 따라서이러한영상검사를통해상기질환의초기감별에도움이될수있다면초기단계에각각질환에맞는적절한치료및예방을가능하게되어향상된삶을영위하는데기여할수있으리라생각된다. 더욱이뇌관류 SPECT 은뇌자기공명사진이나, 뇌 PET 사진같이고가의검사가아니므로임상적으로도쉽게사용하여두질환의초기감별진단에적용할수있으리라생각된다. 하지만본연구의결과를좀더명확히하고객관화하기위해서는많은수의환자를통한다기관연구및추적검사를통한뇌관류에대한연구가향후에반드시진행되어야할필요성이있다고주장하는바이다. 요약 연구배경 : 알쯔하이머병과 PDD 는각각피질성그리고피 질하치매를대표하는퇴행성질환이다. 초기단계의두질환은뇌조직검사이외는명확한진단이어렵다. 하지만최근에영역별뇌혈류량의평가를뇌관류단일광자방출전산화단층촬영 (single photon emission computed tomography, SPECT) 을이용하여많이활용되고있는데, 치매와같은신경퇴행성질환의진단에도유용하게이용되고있다. 하지만아직까지초기단계의 PDD와알쯔하이머병사이의뇌관류 SPECT 으로의감별이가능한지에대한연구보고는거의없는실정이다. 따라서저자들은본연구를통해뇌조직검사이외는명확히감별하기힘든 PDD 와알쯔하이머병환자에서뇌관류 SPECT 을시행하여양군에서차이가있는지를확인하여초기에두질환을감별하고자한다. 방법 : 본연구에 31명의초기 PDD 와 32명의초기알쯔하이머병환자를선별하였다. 모든환자에게신경심리검사및뇌관류 SPECT 을시행하였고, 각각의대상군의임상및영상자료를비교분석하였다. 결과 : 뇌관류 SPECT 상알쯔하이머병및 PDD 환자모두에서전두엽, 두정엽, 측두엽의혈류량저하를보였다. 하지만알쯔하이머병보다 PDD 환자에서소뇌와후두엽만이통계적으로의미있는저혈류량소견을보였다. 결론 : 본연구결과를통해저자들은초기임에도불구하고, 알쯔하이머병보다 PDD 에서영역별혈류량의저하를통계적으로의미있게보인소뇌와후두엽이두질환의감별에중요한역할을할수있다고조심스럽게제안하고자한다. REFERENCES 1. Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen P. Risk of dementia in Parkinson's disease: a community-based, prospective study. Neurology 2001;56: 730-6. 2. Song IU, Kim JS, Yoo JY, Song HJ, Lee KS. Cognitive dysfunctions in mild Parkinson's disease dementia: comparison with patients having mild Alzheimer's disease and normal controls. Eur Neurol 2008;59:49-54. 3. Starkstein SE, Sabe L, Petracca G, Chemerinski E, Kuzis G, Merello M, et al. Neuropsychological and psychiatric differences between Alzheimer's disease and Parkinson's disease with dementia. J Neurol Neurosurg Psychiatry 1996;61: 381-7. 4. Markus HS, Costa DC, Lees AJ. HMPAO SPECT in Parkinson's disease before and after levodopa: correlation with dopaminergic responsiveness. J Neurol Neurosurg Psychiatry 1994;57:180-5. 204 J Korean Geriatr Soc 16(4) December 2012
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