Dementia and Neurocognitive Disorders 2007; 6: 7-11 원발성정상압수두증환자의국소뇌혈류변화 : Statistical Parametric Mapping을이용한 SPECT 분석 윤보라 양동원 심용수 김범생손영민 정성우 정용안 * 손형선

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1 Dementia and Neurocognitive Disorders 2007; 6: 7-11 원발성정상압수두증환자의국소뇌혈류변화 : Statistical Parametric Mapping을이용한 SPECT 분석 윤보라 양동원 심용수 김범생손영민 정성우 정용안 * 손형선 * 가톨릭대학교의과대학신경과학교실핵의학교실 * Analysis of Regional Cerebral Blood Flow Changes with SPECT in Idiopathic Normal Pressure Hydrocephalus: Statistical Parametric Mapping Analysis Bora Yoon, M.D., Dong-Won Yang, M.D., Yong-Soo Shim, M.D., Beum-Saeng Kim, M.D., Young-Min Shon, M.D., Sung-Woo Chung, M.D., Yong-An Chung, M.D.*, Hyung-Sun Sohn, M.D.* Departments of Neurology and Nuclear Medicine*, The Catholic University of Korea, Seoul, Korea Address for correspondence Dong-Won Yang, M.D. Department of Neurology, College of Medicine, The Catholic University of Korea, 62 Youido-dong, Yeongdeungpo-gu, Seoul , Korea Tel: Fax: neuroman@catholic.ac.kr *This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050079). Background and Objectives: Idiopathic normal pressure hydrocephalus (inph) is a reversible condition characterized by gait disturbance, urinary incontinence, and dementia. This study investigates the neuropsychological characteristics and changes of regional cerebral blood flow (CBF) in patients with inph. Methods: Ten patients with inph and thirteen normal control subjects were evaluated. The general cognitive function and detailed neuropsychological functions were measured by the Korean mini-mental status examination (K-MMSE) and a comprehensive neuropsychological battery. Patients who showed clinical improvement in at least one clinical domain after CSF drainage were included. 99m Tc-ECD (ethyl cysteinate dimmer) SPECT was performed to measure the regional CBF and the statistical parametric mapping (SPM) 99 software was applied for the objective analysis of SPECT data. Results: On the neuropsychological examination, all patients showed abnormalities in memory, psychomotor speed, and frontal executive function. SPM analysis of SPECT images revealed significantly decreased CBF in the bilateral thalami, right prefrontal area, anterior and posterior cingulate gyri, right caudate nucleus, and left parahippocampal gyrus in patients with inph compared to those of normal controls (uncorrected p=0.005). Conclusions: Neuropsychological abnormalities and CBF changes suggest that the prefrontal and subcortical areas may be associated with cognitive dysfunctions in patients with inph. Key Words: Idiopathic normal pressure hydrocephalus, SPECT, Statistical parametric mapping, Cerebral blood flow, Neuropsychological assessment 서론원발성정상압수두증 (idiopathic normal pressure hydrocephalus) 은주로노인에서발생하며서서히진행하는보행장애, 배뇨장애와인지기능장애를특징으로하는질환이다. 이질환은뇌척수액순환장애뿐만아니라뇌혈류의변화를동반하며, 병태생리를밝히기위해뇌혈류변화에대한다양한기능적뇌영상연구가수행되었다 [1-8]. 그러나이전연구들은영상위에직접관심영역 (region of interest, ROI) 을그려서수행한것이대부분이었으며, 관심영역을그리는대신영상에서얻는화소 (voxel) 볼륨의값을컴퓨터프로그램을이용하여서로직접비교하는 Statistical Parametric Mapping (SPM) 을이용한분석은매 우드물다 [7, 8]. 또한국소뇌혈류변화부위와임상증상과관련성에대한결과도일치하지않는다. 본연구는정상압수두증환자의뇌혈류변화를 SPECT 검사와 SPM 분석방법을통하여비교하고, 인지기능의장애와뇌혈류변화의연관성에대하여연구하였다. 대상및방법 1. 대상 2004년 6월부터 2005년 5월까지성모병원치매클리닉에내원 7

2 8 윤보라 양동원 심용수외 5 인 하여원발성정상수두압증환자로진단받은 10명의환자와 13명의정상대조군을대상으로하였다. 원발성정상수두압증환자진단은 1) 보행장애, 2) 인지기능장애, 3) 배뇨장애및 4) MRI상대뇌피질의위축을동반하지않은뇌실확장소견 (Evans 비율 >0.31)[9] 과, 5) 뇌척수압이 20 cmh 2 O 이하로정상범위인경우, 6) 뇌척수배액검사후에임상양상이호전되는환자들을대상으로, 7) 이차성정상수두압증을유발할만한원인이없고, 8) 임상증상이나영상소견을설명할만한다른질환도없으며, 9) 우울증, 두부손상, 약물남용의과거력이없는환자들로정하였다. 자기공명영상검사에서 2개이상의열공성경색이있거나열공성경색이 1개이더라도전략뇌경색치매를유발할수있는부위에있는경우, 10 mm 이상의심부백질의변성이동반된환자는배제하였고, 혈액검사, 혈액화학검사, 비타민 B12, 갑상선기능검사를시행하여갑상선기능이상이나기타인지기능에장애를줄수있는내과적인문제가있는경우도제외하였다. 정상대조군은 Christensen이정한인지기능에영향을미치는 28가지의질환 [10] 이없고, 환자나보호자에의하여기억장애나기타인지기능저하가없다고확인된사람들중환자군과나이와교육연령을맞춘 13명의건강한자원자를대상으로선정하였다. 2. 방법 1) 신경심리검사 (Neuropsychological assessments) 전반적인인지기능의상태의측정은 Korean Mini-mental Status Examination (K-MMSE)[11], Korean version of Hasegawa Dementia Scale (K-HDS)[12] 와 Clinical Dementia Rating (CDR)[13] 척도를이용하였다. 자세한인지기능의상태는 Seoul Neuropsychological Screening Battery (SNSB) [14] 를사용하였다. 2) 단광자방출단층촬영술 MBq의 99m Tc-ECD SPECT imaging ( 99m Tc-ECD) 를정맥주사하고 20분후저에너지, fan-beam collimator를이용한 multi-detector scanner (ECAM plus; Siemens, Erlangen, Germany) 를이용하여뇌 SPECT 영상을얻었다. 영상을얻는두부부착장치는 2줄의둥근원형의 59개의 probe-type detectors가장착되어있다. 신호잡음을없애기위하여 Butterworth 저역통과필터 (cutoff frequency 0.4 cycles/pixel, order 5) 를이용한여과후역투사 (filtered backprojection) 방법으로구성된횡단면영상 ( matrix) 들을얻어통계적분석을위하여워크스테이션으로옮겼다. 99m Tc-ECD SPECT 영상은표준화된상업적보정방법 (standard commertcial correction route) 으로감쇠보정을하였다. 3) Statistical parametric mapping 분석 Matlab, version 5.3 (Mathworks, Inc., Natick, MA) 과 SPM99 (Institute of Neurology, University College of London, UK)[15] 를이용하여이미지를분석하였다. SPECT 데이터를헤더정보와영상정보를분리하여 Analyze (Mayo Foundation, Baltimore, Md., USA) 소프트웨어형식으로변환시켜 SPM99 소프트웨어에입력하였다. 헤더정보는 348 바이트의헤더, 3.9 mm x, y pixel size, 3.9 mm의두께를가진다. 각대상에서얻은영상은공간정합 (registration) 을하여머리위치이동에따른오차를제거하고, 정합한영상을공간의뒤틀림과관계된 12개의 affine 벡터를최소한변형시키는방법으로얻은후, 이렇게얻은영상을 SPECT 틀 (template) 안에공간정규화 (spatial normalization) 시켰다 [15]. 각 SPECT 스캔에서주사된방사능과전체뇌의방사능의차이를배제하기위하여 SPM의비례변환에의하여뇌전체계수로각화소 (voxel) 를계수정규화 (global normalization) 하였다. 전체뇌의평균신호강도의 80% 보다낮은경우는 partial-volume error에의해서나타나는 brain-edge halo 라고생각하여제거하였다. 이영상은 SPM99 분석전신호대잡음비를높이기위하여 8 mm의 full-width at half-maximum (FWHM) 의가우시안커널 (Gaussian kernel) 을이용하여영상을평탄화시켰다. 이렇게얻은영상은 16-bit, 상의크기가 mm이고 mm 화소크기를가진다. SPM 분석으로얻은결과는평균 MR template (Montreal Neurological Institution, McGill University, CA)[15] 위에얹어서횡단면, 시상면으로표현하여뇌혈류의변화를알아볼수있게하였다. 4) 이미지분석원발성정상수두압증환자에서나타나는혈류의변화를보기위하여공간정규화시킨 10명의원발성정상수두압증환자와 13 명의대조군의 SPECT 영상을 two sample t-test를이용하여비교분석하였다. SPM 분석결과는 p 값을 corrected 0.05, uncorrected 0.001, uncorrected 0.01로변화시키면서의미있는결과를찾았고최소 100개이상의활성화된화소를보이는영역만분석하였다. Table 1. Demographic and clinical characteristics of NPH patients and control subjects NPH patients (n=10) Mean±S.D. Control subjects (n=13) Mean±S.D. p value Age 71.9± ± Sex (male/female) 6/4 8/ Education (years) 10.8± ± K-MMSE scores 22.5± ±0.63 <0.001 CDR scores 0.6±0.2 ND K-MMSE, Korean Mini-mental Status Examination; CDR, Clinical Dementia Rating scale; S.D., standard deviation, ND, not done.

원발성정상압수두증환자의국소뇌혈류변화 : SPM 을이용한 SPECT 분석 9 Table 2. Neuropsychological tests results in inph group (n=10) Neuropsychological tests Mean±SD Range Memory function SVLT free recall (total) 13.10±2.

30±3.20-1-8 Frontal/Executive function Contrasting program 2 (20%) Go-no-Go test 4 (40%) Fist-edge-palm test 7 (70%) Alternating hand movement 4 (40%) Alternating square&triangle 6 (60%) Luria loop 3

3 원발성정상압수두증환자의국소뇌혈류변화 : SPM 을이용한 SPECT 분석 9 Table 2. Neuropsychological tests results in inph group (n=10) Neuropsychological tests Mean±SD Range Memory function SVLT free recall (total) 13.10± SVLT 20 min recall 1.50± SVLT recognition index 5.40± RFC 17.75± RFC immediate recall 4.85± RFC 20 min recall 5.00± RFC recognition index 4.30± Frontal/Executive function Contrasting program 2 (20%) Go-no-Go test 4 (40%) Fist-edge-palm test 7 (70%) Alternating hand movement 4 (40%) Alternating square&triangle 6 (60%) Luria loop 3 (30%) Word fluency-animal 10.50± Word fluency test-supermarket 9.00± Word fluency test-ㄱ + ㅇ + ㅅ 11.40± Stroop test-color 52.83± L R A The number (percentage) on contrasting program, go-no-go test, fistedge-palm test, alternating hand movement, alternating square and triangle and Luria loop means the number of subjects who showed poor performance on the test. inph, idiopathic normal pressure hydrocephalus; SVLT, Seoul verbal learning test; RFC, Rey complex figure copy test. Table 3. Regions, P/T values of voxel and coordinates of the significant (uncorrected, p<0.005) clusters with decreased regional cerebral blood flow in patients with inph compared with healthy controls Regions (Decreased rcbf) Cluster Equi vk L Thalamus 2971 < , -8, 14 R Thalamus < , -10, 4 R Caudate < , 4, 0 L Cingulate gyrus, BA < , -8, 42 R Cingulate gyrus, BA , 0, 38 R Cingulate gyrus, BA 31 < , -30, 38 L parahippocampal gyrus , -20, -12 BA, Brodmann areas; L, left; R, right. 뇌표준지도위에덧씌워진결과들의정확한해부학적인위치를알기위하여각화소의 x, y, z 값을 Talairach Daemon Database 소프트웨어에넣어서최종적으로각영역의해부학적인위치와 Brodmann 영역들을구하였다. 결 과 Voxel T Voxel P (corrected) Co-ordinates x, y, z {mm} 원발성정상압수두증환자의평균연령은 71.9 세 ( 표준편차 ± 4.93, 범위 세 ), 평균증상발병기간은 28 개월 ( 표준편차 ± Fig. 1. Fusion of SPM99 results to axial (A) and sagittal (B) template of T1-weighted high-resolution brain MRI. Areas of decreased regional cerebral blood flow are noted in patients with NPH compared with controls. p=0.005 uncorrected. L: left, R: right. 22개월, 범위 12-78개월 ), 교육수준은 10.80±4.39년이었고, K- MMSE 점수와 K-HDS 점수는각각 22.50±3.89, 18.00±4.71 로정상대조군과비교해볼때연령, 교육수준은차이가없었으나 K-MMSE 점수는유의한차이를보였다 (p<0.001)(table 1). 자세한인지기능평가를보면, 원발성정상압수두증환자모두에서단기 장기언어기억검사 (Seoul Verbal Learning Test, 즉각회상, 지연회상, 재인검사 ) 와비언어적기억검사 ( 레이복합도형에대한즉각회상, 지연회상, 재인검사 ) 에서재인회상은비교적유지되었다. 반면, 즉각, 지연회상의뚜렷한저하소견을보여인출장애를특징으로하는전두엽성기억장애가관찰되었고, 전두엽기능검사 (contrasting program, Go-No Go Test, Fist-Edge-Palm, alternating hand movement, alternating square and triangle, Luria loop, 의미적언어유창성검사, Stroop 색깔읽기검사 ) 에서전두엽기능저하가뚜렷하게관찰되었다 (Table 2). 원발성정상압수두증환자와정상대조군사이의국소뇌혈류변화차이를 SPM99 으로분석하여그결과를컬러지도로표현하여 MRI 표준지도시상면위에옮긴그림 (Fig. 1) 에서양측시상 (thalamus), 전 후방띠다발 (anterior & posterior cingulate gyri), 우측전전두엽 (prefrontal area), 꼬리핵 (caudate nucleus) 과좌측부해마이랑 (parahippocampal gyrus) 에서의 B

4 10 윤보라 양동원 심용수외 5 인 미있게국소뇌혈류량이감소되었다 (uncorrected p=0.005). 원발성정상압수두증환자에서상대적으로혈류의흐름이떨어진영역의정확한해부학적인위치와 P, T 값과 x, y, z 좌표는 Table 3에표시하였다. 고찰 장애가뚜렷한환자들을선택하였다. 둘째, 대상환자수가적어서본연구의결과해석에유의해야하며, 향후대상환자군을늘려서연구를진행해야할것이다. 이러한한계점에도불구하고, 본연구는 SPM 분석을사용하므로써이전연구들보다좀더객관적인결과를얻었다는점과, 자세한인지기능검사와의관련성을찾으려고했다는점에서임상적의미가있을것으로생각된다. 원발성정상압수두증환자에대한이전의기능적뇌영상연구들은전두엽부위의뇌혈류감소를제외하고는다양한패턴의뇌혈류감소결과를보였고인지기능장애와같은증상과의관련성에대해서도일치된결과를보이지않았다. 본연구의결과에서전전두엽의뇌혈류감소는이전연구들과일치하는소견이었으나 [2, 6], 그외에양측전, 후방띠이랑, 시상과우측꼬리핵, 좌측부해마이랑의뇌혈류감소를보였는데, 양측시상과우측꼬리핵은뇌실주변구조물로서, 이들의뇌혈류감소는원발성정상압수두증에서나타나는뇌실확장의결과, 뇌실주변의미세순환감소에의한이차적변화로생각된다 [16, 17]. 비록뇌실확장의영향은양측으로발생하나대칭적으로나타나지는않기때문에더우세하게영향받는쪽이발생할수있어서일측뇌혈류감소가두드러져나타났을수있다 [18, 19]. Akai 등은정상압수두증환자의사후부검결과를통해심부대뇌백질내유수섬유의축돌기 (myelinated axon) 의수가현저하게감소되었음을보고하였는데, 이점을고려한다면가장길고굵은유수섬유다발로이루어진띠이랑이먼저영향받을수있음을예측해볼수있다 [20]. 또한 Mathew 등은뇌혈류감소가전대뇌동맥지배부위에가장두드러진다고발표하였는데, 이점또한띠이랑의뇌혈류감소를가능하게하는기전으로생각된다 [21]. 후방띠이랑의경우는삽화적기억력 (episodic memory) 과관련이있고 [22], 전방띠이랑은작업기억 (working memory) 을수행할때뇌의주의력과관련된여러영역을서로유기적으로통합하는중요한역할을수행한다고알려져있어 [23], 이곳의뇌혈류감소는전전두엽의뇌혈류저하와함께전두엽기능에영향을미친다고생각된다. 그외, 부해마이랑의뇌혈류감소는임상적으로정확한의미를알기는쉽지않으나기억회로를구성하는구조물로서기억장애와관련있을가능성이있다. 본연구에서환자들이인지기능검사에서보여주는전두엽기능저하와전두엽성기억장애는 SPECT SPM 분석에서나타난뇌혈류감소와어느정도일관된결과를보인다. 본연구의제한점은첫째, 원발성정상압수두증환자들중에는혈관성치매나알쯔하이머치매환자들이포함되었을가능성을완전히배제할수는없다. 그러나본연구에서는혈관성치매의감별을위해뇌자기공명영상검사를통해뇌경색이나허혈성변화를확인하였고, 알쯔하이머치매의경우병리학적으로확인할수는없지만임상양상에서기억장애보다보행장애나배뇨장애가선행했거나더심한경우를선택하였고자세한인지기능검사결과전두엽성 참고문헌 1. Meyer JS, Tachibana H, Hardenberg JP, Dowell RE, Kitagawa Y, Mortel KF. Normal pressure hydrocephalus: influences on cerebral hemodynamic and cerebrospinal fluid pressure-chemical autoregulation. Surg Neurol 1984; 21: Graff-Radford NR, Rezai K, Godersky JC, Eslinger P, Damasio H, Kirchner PT. Regional cerebral blood flow in normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 1987; 50: Larsson A, Bergh AC, Bilting M, Arlig A, Jacobsson L, Stephensen H, et al. Regional cerebral blood flow in normal pressure hydrocephalus: diagnostic and prognostic aspects. Eur J Nucl Med 1994; 21: Tanaka A, Kimura M, Nakayama Y, Yoshinaga S, Tomonaga M. Cerebral blood flow and autoregulation in normal pressure hydrocephalus. Neurosurgery 1997; 40: Chang CC, Kuwana N, Noji M, Tanabe Y, Koike Y, Ikegami T. Cerebral blood flow in patients with normal pressure hydrocephalus. Nucl Med Commun 1999; 20: Owler BK, Pickard JD. Normal pressure hydrocephalus and cerebral blood flow: a review. Acta Neurol Scand 2001; 104: Mataro M, Poca MA, Salgado-Pineda P, Castell-Conesa J, Sahuguilo J, Diez-Castro MJ, et al. Postsurgical cerebral perfusion changes in idiopathic normal pressure hydrocephalus: a statistical parametric mapping study of SPECT images. J Nucl Med 2003; 44: Dumarey NE, Massager N, Laureys S, Goldman S. Voxel-based assessment of spinal tap test-induced regional cerebral blood flow changes in normal pressure hydrocephalus. Nucl Med Commun 2005; 26: Wikkelso C, Andersson H, Blomstrand C, Matousek M, Syendsen P. Computed tomography of the brain in the diagnosis of and prognosis in normal pressure hydrocephalus. Neuroradiology 1989; 31: Christensen KJ, Multhaup KS, Nordstrom S, Voss K. A cognitive battery for dementia: development and measurement characteristics. Psychological Assessment 1991; 3: Kang YW, 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: Imai Y, Hasegawa K. The revised Hasegawa s dementia scale (HDS-R)-

5 원발성정상압수두증환자의국소뇌혈류변화 : SPM 을이용한 SPECT 분석 11 evlauation of its usefulness as a screening test for dementia. J Hong Kong Coll Psychiatr 1994; 4: Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993; 43: Kang YW. Samsung Neuropsychological Screening Battery. In: Current research in dementia. Seoul: The Korean Dementia Association 1998; Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frakowiak RS. Statisticcal Parametirc Maps in functional imaging: general approach. Human Brain Mapping 1995; 2: Hamlat A, And M, Sid-ahmed S, Askar B, Pasqualini E. Theoretical considerations on the pathophysiology of normal pressure hydrocephalus (NPH) and NPH-related dementia. Medical Hypotheses 2006; 67: Kimura M, Tanaka A, Yoshinaga S. Significance of periventricular hemodynamics in normal pressure hydrocephalus. Neurosurgery 1992; 30: Waldemar G, Schmidt JF, Delecluse F, Andersen AR, Gjerris F, Paulson OB. High resolution SPECT with [ 99m Tc]-d,l-HMPAO in normal pressure hydrocephalus before and after shunt operation. J Neurol Neurosurg Psychiatry 1993; 56: Tedeschi E, Hasselbalch SG, Waldemar G, Juhler M, Hogh P, Holm S, et al. Heterogenous cerebral glucose metabolism in normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 1995; 59: Akai K, Uchigasaki S, Tanaka U, Komatsu A. Normal pressure hydrocephalus. Neuropathological study. Acta Pathol Jpn 1987; 37: Mathew NT, Meyer JS, Hartmann A, Ott EO. Abnormal cerebrospinal fluid-blood flow dynamics. Implications in diagnosis, treatment, and prognosis in normal pressue hydrocephalus. Arch Neurol 1975; 32: Desgranges B, Baron JC, de la Sayette V, Petit-Taboue MC, Benali K, Landeau B, et al. The neural substrates of memory systems impairment in Alzheimer s disease. A PET study of resting brain glucose utilization. Brain 1998; 121: Posner MI. Attention: the mechanisms of consciousness. Proc Natl Acad Sci USA 1994; 91:

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( )Kju098.hwp 건강한젊은남성과중년남성에서성적자극에의한뇌의활성화비교 Difference of Brain Activation by Visual Erotic Stimuli in Young and Middle-aged Healthy Males Dong Wan Sohn, Kang June Cho, Hyo Sin Kim, Choong Bum Lee, Sung Hak Kang, Yong-Hyun