Dementia and Neurocognitive Disorders 2014; 13: 37-41 ORIGINAL ARTICLE 초기다계통위축증에대한뇌관류 Single Photon Emission Computed Tomography 의임상적유용성 이종윤 * 송인욱 * 정성우 * 정용안 양영순 가톨릭대학교의과대학신경과학교실 * 핵의학과학교실, 보훈공단중앙보훈병원신경과 Received: May 16, 2014 Revision received: May 28, 2014 Accepted: May 28, 2014 Address for correspondence In-Uk Song, M.D. Department of Neurology, Incheon St. Mary s Hospital, The Catholic University College of Medicine, 56 Dongsu-ro, Bupyeong-gu, Incheon 403-720, Korea Tel: +32-280-5010 E-mail: siuy@cmcnu.or.kr Clinical Usefulness of 99mTc-Hexamethyl Propylene Amine Oxime Perfusion Single Photon Emission Computed Tomography for Early Phase Multiple System Atrophy Jong-Yoon Lee, M.D.*, In-Uk Song, M.D.*, Sung-Woo Chung, M.D.*, Yong-An Chung, M.D., YoungSoon Yang, M.D. Departments of Neurology* and Nuclear Medicine, College of Medicine, The Catholic University of Korea, Seoul; Department of Neurology, Veterans Hospital, Seoul Medical Center, Seoul, Korea Background: Clinical diagnosis of multiple system atrophy (MSA) relays on signs and symptoms that are often difficult to identify particularly at early stage. Indeed neuropathological studies have demonstrated that Parkinson variant of MSA (MSA-P) is the first cause of misdiagnosis in a cohort of patients presenting with parkinsonian features. But accurate diagnosis of these disorders is important for deciding on treatment, appropriate advice and prognosis since atypical parkinsonian disorders are characterized by poor response to dopaminergic treatment and more rapid disease progression. Therefore, we conducted this study to investigate difference of perfusion Single Photon Emission Computed Tomography (SPECT) in patients with the early phase of MSA-P using SPM program. Methods: We recruited consecutively 21 patients with MSA-P and 48 age-matched healthy controls. All subjects underwent Tc-99m HMPAO perfusion SPECT and this perfusion images were analyzed. Results: For MSA-P, only hypoperfusion was seen in the middle frontal gyrus of left frontal lobe, superior frontal gyrus of right frontal lobe, precentral gyrus of left frontal lobe, middle frontal gyrus of right frontal lobe and precentral gyrus of right frontal lobe with respect to healthy subjects. Conclusions: We cautiously assume that perfusion SPECT may offer significant advantages compared to other imaging techniques in the assessment of neuronal degeneration in MSA-P and may help the clinician in the diagnostic characterization of patients presenting with atypical parkinsonism. Key Words: Multiple system atrophy, Tc-99m HMPAO perfusion SPECT, Frontal lobe 서론특발파킨슨병과다계통위축증은대표적인파킨슨증을일으키는질환이다 [1]. 다계통위축증은임상적으로파킨슨증상과소뇌증상, 자율신경이상증상과추체외로증상을동반하는질환이다 [2]. 이러한다계통위축증의병리소견은흑질줄무늬체도파민로 (nigrostriatal dopaminergic pathway), 꼬리핵 (caudate) 과조가비핵 (putamen), 창백핵 (globus pallidus), 뇌간 (brain stem), 소뇌그리고척수에서신경퇴행성변화를보여주는질환으로특발파킨슨병과마찬가지로 확진은뇌조직검사뿐이므로다계통위축증도임상증상및신경학적검사를중심으로추정진단을내릴뿐이다 [2, 3]. 다계통위축증의조기진단은특발파킨슨병에비해진행이빠르고약물에반응을하지않아조기의증상조절및예후에대한명확한설명이반드시필요하다. 특발파킨슨병의경우는도파민전달체를이용한뇌기능영상기법과 iodine-123-meta-iodobenzylguanidine (I-123 MIBG) 신티그라피등으로인하여조기진단에많은도움을받고있으나다계통위축증에대해서는이러한영상기법이아직까지나와있지않는실정이다 [4]. 하지만뇌자기공명사진촬영으로다계통위축증을시 2014 Korean Dementia Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 37
38 이종윤 송인욱 정성우외 2 인 사하는소견들이보고되고는있으나어느정도진행된단계에서의소견이므로초기다계통위축증에서는적용되기힘들다. 물론이전연구들에의하면 statistical parametric mapping (SPM) 을이용한 fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) 영상으로인해특발파킨슨병과다계통위축증의특징적인소견을보였다고하나이는경제적인문제등으로인하여일반적으로사용하기어려운실정이다 [5, 6]. 이에반해뇌관류 brain perfusion singlephoton emission computed tomography (SPECT) 은일반적으로많이유용되는검사로서뇌혈류를 technetium을붙인 Hexamethyl-prophylene-amine-oxime 또는 ethyl cysteinate dimer를이용하여많이활용되고있으며, 최근신경퇴행성질환에있어서뇌혈류량에따른기능향상을평가하는데많이이용되고있다 [7, 8]. 특발파킨슨병에대해서는두정엽, 후두엽, 기저핵등에서관류저하를보이는특징적인소견이보고되고있으나뇌관류 SPECT의다계통위축증소견에대해서는아직까지확립되지않았을뿐만아니라이에대한연구도미미한실정이다 [6, 7, 9]. 더욱이다계통위축증은파킨슨증의임상증상을동반하기때문에조기에감별진단이더욱어려운실정이다. 하지만다계통위축증은특발파킨슨병에비해진행이빠르고약물에반응을하지않아조기의증상조절및예후에대한명확한설명이반드시필요하다. 따라서다계통위축증의뇌관류 SPECT 소견을객관적인방법인 SPM 프로그램을이용하여정상군과비교분석하여조기진단에도움이되고자본연구를시행한다. 방법본연구는 2012년 1월부터 12월까지본원신경과에내원한파킨슨증양상을주로보이는다계통위축증의파킨슨변형 (Parkinson variant of multiple system atrophy, MSA-P) 환자를대상하였고, 본원임상윤리심의위원회의승인을받고진행하였다. 모든연구대상자들은 Gilman 등 [2] 에의해제안된추정다계통위축증진단기능에맞는환자를선택하였다. 또한초기환자만을선정하기위해 Modified Hoehn-Yahr stage (H-Y stage) 3 미만환자만을선택하였고, 본원 123I-n-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane positron emission tomography (FP-CIT PET) 상에서도도파민전달체의흡수가저하되지않은환자만을선택하였다. 뇌자기공명사진상에서뇌의구조적병변이나허혈성병변등이있는환자는본연구에서제외하였다. 또한임상적으로의미있는신장, 간장, 심혈관계, 호흡기계, 뇌혈관계, 내분비계질환혹은기타심각한진행형신체질환이있는경우, 우울증이나정신과적장애를가졌거나과거력을가진경우, 2차성파킨슨증을일으킬만한약물및알코올의남용력이있는경우는본연구에서제외하였다. 이들선택된환자군은나이와성별을맞춘정상군과비교분석되었으며, 모든대상군은 뇌관류 SPECT를안정영상으로촬영하였다. 99m Tc-HMPAO SPECT 영상획득뇌영상연구를위해사용한단일광자방출전산화단층촬영 (Single Photon Emission Computed Tomographic, SPECT) 을시행했다. 영상획득은 6 간격으로 360 회전하여저에너지고해상도조준기 (low energy high resolution collimator) 를사용하여 60프레임을얻는다. 안정상태에서의영상을얻기위해 925 MBq의 99m Tc-HMPAO 를정맥주사하고, 주사한후 20분경과후약 20-30분동안스캔하였다. 촬영하는동안피검자는편안한상태를유지하며, 머리의움직임을최소로하였으며촬영실은조용하고조명을어두운상태로유지했다. 영상분석및 SPM SPECT 영상은표준다이콤 (DICOM) 형태로변환되어마이크로소프트윈도우기반의컴퓨터에저장되었다. 각각의파일은분석을위해 Analyze형식으로변환된후모든영상을 SPECT 표준지도위에공간정규화했다. 뇌피질및내부구조의미세한차이는저주파함수들로미리정의된기저함수 (basis function) 들의가중합으로나타내는선형화된비선형적 (linearized nonlinear) 방법을사용하여제거했다. 신호대잡음비를높이고미처보정되지않은뇌피질의차이를극복하기위하여공간정규화가된영상들을 16 mm의 full width at half maximum (FWHM) 을갖는가우시안커널 (Gaussian kernel) 로중첩적분 (convolution) 했다. 이러한전처리과정으로서의편평화 (smoothing) 는통계분석결과에서크기가작은덩어리의생성을줄이므로위양성결과를보정하고고주파의잡음을제거해서예민도를높이는역할을한다. 그리고각복셀이가지는국소계수는뇌피질내의전체계수와개인적인내변이그리고불규칙한잡음의선형결합 ( 일반선형모델 : general linear model) 으로나타내어진다는가정하에선형회귀분석을이용하여각복셀에서의이러한변수들의가중치를찾아낸후국소계수의차이만을추출했다. 양대상군의기본자료에대한통계분석은 SPSS ver. 17.0 (SPSS Inc., Chicago, IL, USA) 을이용하여연속변수는독립 t-test 을시행하였고, 비연속변수에대해서는 Pearson chi-square analysis를사용하였다. 뇌영상사진에대한분석은복셀별로통계분석하였다. 복셀별로각각의 SPECT군사이의국소계수차이에대한귀무가설을검증하고자뇌영역내의모든복셀에대해 t-test를시행하고용이한해석을위해 t값들을표준정규분포로변환하여 Z값으로나타냈다. 이는위에서언급한일반선형모델을기본모델로하고, 각변수의효과가 Student s t 통계를따른다고보아그유의성을검정하는것으로이렇게각복셀에서구해진 t값들은그자체가뇌기능영상
Perfusion SPECT and early MSA-P 39 이포함된 3차원공간상에서또다른하나의확률변수 (random variable) 로서행동한다고생각하고, 그분포는고정가우시안랜덤영역 (stationary Gaussian random field) 을따른다고가정하였다. 이러한가정하에서각복셀의 t값에대한통계적유의성은그값을 Z값 [Z = (t-m)/sd; m, 평균 ; SD, 표준편차 ] 으로변환하여가우시안랜덤영역의행동과비교함으로써얻을수있다. 통계분석의결과를해석하고유의한관류차이와덩어리크기를갖는영역의 Z값들을 magnetic resonance imaging 표준지도위에표현하여표준지도상에서의좌표와해부학적이름, 브로드만영역등을표시해주었다. 또한각복셀의 Z값에대한통계적매개변수영상 (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. 결과다계통위축증환자중에서파킨슨증상의변형 (MSA-P) 을가진 Table 1. Demographic and clinical characteristics of all subjects 환자 21명과 48명의정상군과의평균연령및성별의의미있는차이는없었다. MSA-P의평균 H-Y stage는 2.14 ± 0.63이고유병기간은 23.39 ± 14.64개월을보였다 (Table 1). 뇌관류 SPECT 분석상에서는 MSA-P를가진환자군과정상군을비교했을때좌측전두엽의중간전두이랑 (middle frontal gyrus of left frontal lobe; BA 6), 우측전두엽의상전두이랑 (superior frontal gyrus of right frontal lobe), 좌측전두엽의전중심이랑 (precentral gyrus of left frontal lobe; BA 4), 우측전두엽의중간전두이랑 (middle frontal gyrus of right frontal lobe; BA 6) 그리고우측전두엽의전중심이랑 (precentral gyrus of right frontal lobe) 에서 MSA-P에서관류저하소견을통계적으로의미있게보였다 (Table 2, Fig. 1). 고찰특발파킨슨병과 MSA-P의임상적인특징은파킨슨증양상을중심으로나타나기때문에초기단계에서는감별진단하기가매우어렵다 [7, 9, 10]. 특히 MSA-P가특발파킨슨병에비해약물에반응을보기가어려울뿐만아니라예후도좋지않음에도불구하고도진단및뇌기능에대한연구는특발파킨슨병에만초점이맞추어져있는실정이다. 이전초기단계에서임상적으로 MSA-P와비슷한소견을보이는특발파킨슨병에대한뇌관류를분석한연구에서는정상 MSA-P Healthy control p value Number of subject 21 48 Age 70.38 ± 6.94 66.23 ± 11.84 0.257 Gender (male/female) 8/13 11/37 0.089 Duration after diagnosis 19.52 ± 13.68 (months) Duration after symptom 23.39 ± 14.64 (months) Hoehn & Yahr stage 2.14±0.63 MMSE 27.92 ± 0.91 Levodopa dose/day (mg) 387.50±246.09 Dopamine agnoists/day (mg)* 1.09±1.42 *All patients have taken only pramipexole. MSA-P, Parkinson variant of multiple system atrophy; MMSE, mini-mental state examination. Table 2. Areas with significantly decreased regional cerebral blood flow in the MSA-P patients compared with the healthy controls ke T Z x, y, z Brain areas 1703 10.19 6.41-22, 2, 60 Left Frontal Lobe, Middle Frontal Gyrus, BA 6 1703 8.31 5.76 2, 8, 54 Right Frontal Lobe, Superior Frontal Gyrus 1703 7.02 5.21-34, -24, 60 Left Frontal Lobe, Precentral Gyrus, BA 4 687 7.60 5.47 24, -10, 62 Right Frontal Lobe, Middle Frontal Gyrus, BA 6 687 7.46 5.41 32, -10, 60 Right Frontal Lobe, Precentral Gyrus Height threshold, T=6.25, corrected p=0.01; Extent threshold, k=50 voxels. ke, Expected voxels per cluster. Left Z value corrected p<0.001 Right Fig. 1. Comparisons of patients with MSA-P compared with the healthy controls show cerebral regions (yellow color) with decreased regional cerebral blood flow in trans-axial MR fused images.
40 이종윤 송인욱 정성우외 2 인 군에비해전전두엽 (prefrontal lobe) 과외측전두엽 (lateral frontal lobe) 중심의전두엽과렌즈핵 (lentiform nucleus) 에서주로뇌관류저하를보인다고보고하면서이들영역에비해정도는약하지만측두엽과두정엽, 후두엽에서도약간의관류저하를보고하고있다 [7, 11-13]. 따라서이들보고들은이미잘알려진특발파킨슨병에서의전두엽기능저하를보이는뇌관류소견이라고볼수있겠다. 이에반해 MSA-P는신경병리학연구에의하면올리브교뇌소뇌계 (olivopontocerebellar system) 보다는흑질줄무늬체 (nigrostriatal system) 를주로침범하는양상을보인다고알려져있다 [3, 14]. 하지만 MSA-P 의뇌관류에대한최근연구들에의하면임상적으로소뇌증상은거의보이지않음에도불구하고소뇌에서주로저관류소견을보이면서전두엽, 섬이랑, 조가비핵그리고시상에서저관류소견을보인다고보고하였다 [8, 9, 14]. 하지만본연구에서는전두엽의저관류소견이이전의연구결과와비슷한소견을보였으나소뇌에서는정상군에비해서의미있는저관류소견을보이지않아이전의보고들과다른소견을보였다. 본연구의이러한결과는아마도이전의연구들과는달리본연구는초기단계의 MSA-P 환자의뇌관류소견만을분석하였기에기인되었을것이라고생각된다. 따라서저자들은본연구의결과및이전의연구들을통해서 MSA-P의초기단계의증상발현시기에는전두엽영역의침범으로시작하여증상이진행하면서소뇌를포함한다른뇌영역으로퇴행성변화가퍼져나간다는추정을할수있었다. 또한본연구에서는특발파킨슨병에서저관류를보이는후두엽에서는어떠한비정상적인뇌관류소견을보이지않아특발파킨슨병과 MSA-P의초기단계에서도두질환을감별할수있는뇌관류소견이될수도있을것이라는추정을할수있었다. 하지만이러한추정에대해서는향후두질환을가진환자들간의뇌관류에대한비교분석이반드시필요하다고생각한다. 결론적으로본연구는뇌관류 SPECT을통해서정상군에비해 MSA-P를가진환자군에서의미있는뇌관류변화의소견을알아보기위한연구로서이를통해정상군보다임상적초기단계의 MSA-P라할지라도전두엽중심으로의미있는저관류소견을보인것을알수있었다. 따라서본연구의결과를기초로초기단계의 MSA-P 환자의진단에도움이되는영상기법으로써 perfusion SPECT이유용하게사용될수있을가능성을본저자들은제시할수있었다. 따라서이러한영상검사를통해상기질환의초기감별에도움이될수있다면초기단계에각각질환에맞는적절한치료및예방을가능하게되어향상된삶을영위하는데기여할수있으리라생각된다. 더욱이뇌관류 SPECT은뇌자기공명사진이나, 뇌 PET 사진같이고가의검사가아니므로임상적으로도쉽게사용하여두질환의초기감별진단에적용할수있으리라생각된다. 하지만본연구의결과를좀더명확히하고객관화하기위해서는많은수의환자를통한다기관연구및추적검사를통한뇌관류에대한 연구가향후에반드시진행되어야할필요성이있다고주장하는바이다. 참고문헌 1. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic parkinson s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55: 181-4. 2. Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999; 163: 94-8. 3. Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 1997; 12: 133-47. 4. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features improve the accuracy of clinical diagnosis in parkinson s disease: a clinicopathologic study. Neurology 1992; 42: 1142-6. 5. Antonini A, Leenders KL, Vontobel P, Maguire RP, Missimer J, Psylla M, et al. Complementary pet studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and parkinson s disease. Brain 1997; 120(Pt 12): 2187-95. 6. Juh R, Kim J, Moon D, Choe B, Suh T. Different metabolic patterns analysis of parkinsonism on the 18f-fdg pet. Eur J Radiol 2004; 51: 223-33. 7. Feigin A, Antonini A, Fukuda M, De Notaris R, Benti R, Pezzoli G, et al. Tc-99m ethylene cysteinate dimer spect in the differential diagnosis of parkinsonism. Mov Disord 2002; 17: 1265-70. 8. Cilia R, Marotta G, Benti R, Pezzoli G, Antonini A. Brain spect imaging in multiple system atrophy. J Neural Transm 2005; 112: 1635-45. 9. Matsui H, Udaka F, Miyoshi T, Hara N, Tamura A, Oda M, et al. Brain perfusion differences between parkinson s disease and multiple system atrophy with predominant parkinsonian features. Parkinsonism Relat Disord 2005; 11: 227-32. 10. Tang CC, Poston KL, Eckert T, Feigin A, Frucht S, Gudesblatt M, et al. Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis. Lancet Neurol 2010; 9: 149-58. 11. Van Laere K, Santens P, Bosman T, De Reuck J, Mortelmans L, Dierckx R. Statistical parametric mapping of (99m)tc-ecd spect in idiopathic parkinson s disease and multiple system atrophy with predominant parkinsonian features: correlation with clinical parameters. J Nucl Med 2004; 45: 933-42. 12. Paschali A, Messinis L, Lyros E, Constantoyannis C, Kefalopoulou Z, Lakiotis V, et al. Neuropsychological functions and rcbf spect in parkin-
Perfusion SPECT and early MSA-P 41 son s disease patients considered candidates for deep brain stimulation. Eur J Nucl Med Mol Imaging 2009; 36: 1851-8. 13. Firbank MJ, Molloy S, McKeith IG, Burn DJ, O Brien JT. Longitudinal change in 99mtchmpao cerebral perfusion spect in parkinson s disease over one year. J Neurol Neurosurg Psychiatry 2005; 76: 1448-51. 14. Kimura N, Hanaki S, Masuda T, Hanaoka T, Hazama Y, Okazaki T, et al. Brain perfusion differences in parkinsonian disorders. Mov Disord 2011; 26: 2530-7.