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1 원저 열공경색과파킨슨병환자의인지기능저하 국민건강보험공단일산병원신경과 a, 연구소정책연구부 b, 연세대학교의과대학신경과학교실 c 최선아 a 신수정 a,c 이준홍 a 조정희 a 김규식 a 지혜진 b 김종헌 a Lacunar Infarctions and the Cognitive Decline in Patients with Parkinson s Disease Sun-Ah Choi, MD, PhD a, Soo Jeong Shin, MD a,c, Jun Hong Lee, MD, PhD a, Jeong Hee Cho, MD, PhD a, Gyu Sik Kim, MD a, Hyejin Chi, MS b, Jong Hun Kim, MD a Departments of Neurology a and Health Policy Research, Institute of Health Insurance Research b, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea Department of Neurology c, Yonsei University College of Medicine, Seoul, Korea Background: The cause of dementia in Parkinson s disease (PD) remains incompletely understood. Cerebrovascular lesions (CVLs) are frequently found in the aging brain and may coexist with PD pathology. We hypothesized that lacunar infarction, which is one type of CVL, impacts on cognitive decline in patients with PD. Methods: The Mini Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) tools were applied to PD patients with lacunar infarction (<1.5 cm on brain MRI; PD-S) and PD patients with normal brain MRI (PD-NS). Results: Totals of 19 PD-S patients (9 males and 10 females) and 59 PD-NS patients (16 males and 43 females) took part in this study. Univariate analysis revealed that the gender distribution did not differ between the PD-S and PD-NS groups (p=0.1731), whereas age did differ significantly [79.1±5.0 years vs 73.0±7.8 years (mean±sd), respectively; p=0.0002]. There was no difference between the PD-S and PD-NS patients in either PD disease duration (6.9±3.2 vs 5.6±3.8 years, respectively; p=0.1790) or education duration (5.3±5.4 vs 6.4±5.3 years, respectively; p=0.4168). After adjustment for age in ANCOVA analysis, the MMSE score was significantly lower (p=0.0128) and the CDR score was significantly higher (p=0.0426) in the PD-S group than in the PD-NS group. Ten of the PD-S patients had a single lesion. The lacunar infarctions appeared in various locations in these patients, but they were most common in the basal ganglia, thalamus, and periventricular white matter. Conclusions: Lacunar infarction appears to be associated with cognitive decline in patients with PD even after adjustment for age. Analysis of larger age-matched cases for PD-S and PD-NS is required in order to validate these results. J Korean Neurol Assoc 30(2):88-92, 2012 Key Words: Cognition, Lacunar infarction, Parkinson s disease 서론 파킨슨병이진행하면서특히고연령에서드물지않게치매증세를보인다. 1,2 파킨슨병치매를일으키는원인으로최근피질레비소체 (Lewy Bodies) 의존재, 아밀로이드판 (amyloid Received July 18, 2011 Revised January 16, 2012 Accepted January 16, 2012 *Sun-Ah Choi, MD, PhD Department of Neurology, National Health Insurance Corporation Ilsan Hospital, 100 Ilsan-ro, Ilsandong-gu, Goyang , Korea Tel: Fax: sachoi0416@naver.com plaque), 신경원섬유매듭 (neurofibrillary tangles), 콜린부족 (cholinergic deficits) 등이있다. 3-6 레비소체양과치매정도사이에유의한상관관계가있다는연구와피질레비소체가파킨슨병치매에매우높은민감도를가졌다는결과를보인메타분석연구는파킨슨병치매에대한피질레비소체의주도적인역할을시사한다. 7-9 그러나현재까지보고된많은연구가레비소체의주도적역할을제시하였지만전통적으로알츠하이머병리소견은파킨슨병치매와매우연관이높다고알려졌다. 7 파킨슨병치매환자는치매가없는파킨슨병환자보다더심한알츠하이머병리가존재함이보고되었다. 10 파킨슨병치매환자의 1/3 에서심한알츠하이머병리가동반된반면, 피질레비소체가있 88 대한신경과학회지제 30 권제 2 호, 2012

2 열공경색과파킨슨병환자의인지기능저하 고다른병리소견이없던파킨슨병이최종단계까지진행해도극소수만이파킨슨병치매를보였다. 7,11,12 이는어느한병리만이파킨슨병치매의원인이된다고규정하기어려우며인지기능에영향을줄수있는다른병리도또한파킨슨병치매와연관이있을수있음을시사한다. 파킨슨병치매를일으키는병리에대해서여전히의견차이가많고아직도완벽하게병리기전을설명할수없다. 3,13,14 파킨슨병을가진고령의환자에게뇌혈관질환이드물지않게동반된다. 15 신경퇴행질환의대표적질환인알츠하이머병에서의뇌혈관질환의역할에대해서는이미많은보고가있었다 뇌혈관질환과알츠하이머병의병리는모두치매를일으킬수있다. 두질환의유병율도연령의증가와함께증가하며, 많은노인에서이두질환의병리가함께치매를초래하는원인이될수있고, 동시에존재할경우보다심각한치매를일으킬수도있다. 20,21 마찬가지로뇌혈관질환은나이가많은파킨슨병환자의뇌에서도드물지않게동반된다. 뇌혈관질환과파킨슨병병리가파킨슨증세와인지기능저하를함께악화시킬수있다. 15 파킨슨병치매환자에서뇌혈관질환의유병률은 94% 로, 치매가없는파킨슨병환자에서 44~58% 로보고되었다. 15,18 또한치매가없는파킨슨병환자에서알츠하이머병리또는레비소체와뇌혈관질환사이에상관관계는없으나, 치매를동반한파킨슨병환자에서는상관관계가있었다. 15,22 저자들은뇌혈관질환중하나인열공경색이있는파킨슨병환자가뇌졸중이없는파킨슨병환자보다인지저하가심한지규명하고자하였다. 대상과방법 1. 대상및방법 저자들은 2009 년 8월부터 2011 년 5월까지국민건강보험일산병원신경과에내원한파킨슨병환자중에서간이정신상태검사 (Mini Mental Status Examination; MMSE) 와임상치매척도 (Clinical Dementia Rating scale; CDR) 를시행한환자를대상으로의무기록을조사하여후향적으로연구하였다. 파킨슨병은 UK brain bank criteria 로진단하였고, 23 인지기능은 MMSE 와 CDR 로평가하였다. 열공경색은뇌자기공명영상 (Brain MRI) 에서액체감쇠역전회복영상 (Fluid-attenuated inversion recovery -FLAIR) 또는 T2 강조영상에서직경 1.5 cm 이하의뇌경색을보이는경우로정의하였다. 21 모든자기공명영상은 1.5 T MRI 장비 (Gyroscan Intera system, Philips Medical System, Best, Netherlands) 를사용하였으며, FLAIR 영상은반복시간 (TR)/ 에코시간 (TE)/ 역전시간 (TI) 을 7,000/100/2,000 msec, T2 강조영상은반복시간 (TR)/ 에코시간 (TE) 을 4,000/100 msec 으로하였다. 모든영상은절편두께 5 mm, 간격 1 mm, 격자크기 , 촬영시야 cm으로하였다. 열공경색을가진파킨슨병환자는파킨슨병- 열공경색군 (PD-S) 으로분류하였다. brain MRI 에서지름 1.5 cm보다큰뇌경색이있거나백질 (white matter) 변성이심하여넓은영역에걸쳐백질병변이융합된경우 (severe white matter lesion), 뇌실질내기타병변이있는경우, 치매나파킨슨증세를일으키는약물, 뇌종양, 대사질환등기타원인이있는이차치매나파킨슨증세를가진증례는제외하였다. 혈관위험인자를가지고있는지분석할때는고혈압, 당뇨, 심방세동, 심부전, 흡연등뇌졸중위험인자중적어도 1가지를가진경우로규정하였다. brain MRI 가정상인파킨슨병환자군 (PD-NS) 과 PD-S 환자군의나이, 성별, 유병기간, 혈관위험인자, 교육기간, MMSE, CDR, Hoehn & Yahr (H&Y) 병기, 레보도파등가용량 (L-dopa equivalent dose, LED) 을비교분석하였다. 또한 PD-S 군에서는열공경색의위치를분석하였다. DSM-IV criteria 에의해혈관치매로진단이가능한환자는본연구의대상에서제외하였다. 2. 통계분석 PD-S 와 PD-NS 환자의평균나이, 교육기간, Hoehn & Yahr 병기, 유병기간, 약물용량및 MMSE, CDR 분석에는단변량분석으로 t-test 를하여두집단간분포의차이가있는지검정하였고, 성별비교에는카이제곱검증 (Chi-square test) 을사용하였다. 단변량분석에서두집단의연령이통계적으로유의한차이를보였으므로 (Table 1), Analysis of Covariance (ANCOVA) 분석에서연령, 성별, 교육수준을통제하였다. 연령, 성별, 교육수준이통제된 MMSE 와 CDR 의평균점수를계산하였고, 두집단에서차이가있는지를검정하였다 (Table 2). 통계분석에서 SPSS (version 13.0) 프로그램을사용하였고, 통계적유의성은 p<0.05 로하였다. 결과 본연구는 19명의 PD-S 군에서남자와여자는각각 9명 /10 명이었고 59 명의 PD-NS 군에서남자와여자는각각 16명 /43 명으로두군간에성별차이는없었다 (p-value=0.1731). 평균연령 (± 표준편차 ; SD) 은두군간에통계학적으로의미있는차이를보였다 (PD-S 79.1±5.0 vs PD-NS 73.0±7.8, p-value=0.0002). J Korean Neurol Assoc Volume 30 No. 2,

3 최선아신수정이준홍조정희김규식지혜진김종헌 PD 유병기간은두군에서차이가없었고 (PD-S 6.9±3.2 vs PD-NS 5.6±3.8, p-value=0.1790) H&Y 병기는 PD-S 군에서더높은병기를보였다 (PD-S 3.8±1.2 vs PD-NS 2.7±1.2, p-value=0.0012). 교육정도는두군사이에차이가없었고 (PD-S 5.3±5.4 vs PD-NS 6.4±5.3, p-value=0.4168) LED 도역시두군에서차이가없었다 (PD-S 967.3±372.2 vs PD-NS 963.7±407.7, p-value=0.9730) (Tabel 1). PD-S 군이 PD-NS 군에비해 MMSE 점수가더낮았고 CDR 은 PD-S 군이더높았다 (MMSE; PD-S 16.8±6.9 vs PD-NS 21.9±5.2, p-value=0.0010) (CDR; PD-S 1.3 ±0.7 vs PD-NS 0.8±0.5, p-value=0.0120). ANCOVA 분석에서연령, 성별, 교육수준을통제한후에도 PD-NS 군에비해 PD-S 군에서통계학적으로의미있게 MMSE 점수는더낮았고 CDR 은더높았다 (MMSE; p-value=0.0128, CDR; p-value =0.0426) (Table 2). PD-S 군에서단일열공경색이있는경우는모두 10명으로그중 1명은우측소뇌, 3명은좌측기저핵, 1명은우측기저핵, 1명은좌측시상, 1명은우측시상, 3 명은좌측뇌실주변백질부에병변이있었다. 2개이상의병변을가진경우의위치는기저핵, 시상, 후두엽, 뇌실주변백질부, 뇌량에다양하게분포하였다. PD-S 군의 19명중기저핵또는시상또는뇌실주변백질부에열공경색이있는경우가 17 명으로열공경색이있는파킨슨병환자의대부분이이부위에열공경색이있었다. 혈관위험인자중적어도한가지를가지고있는경우가 19명의 PD-S 군에서는 14명, 59명의 PD-NS 군에서는 38명이었고두군간에통계학적인차이는없었다 (p-value=0.6410). 고찰 연령이증가할수록뇌졸중유병률이높아지고인지기능저하도심해진다. 본연구에서 PD-S 군의연령이 PD-NS 군보다더높았고, 연령은인지기능에영향을미치는매우중요한변수이므로통계방법으로 ANCOVA 분석을이용하여연령을보정하였다. 그결과연령을보정한후에도여전히 PD-S 군에서 PD-NS 군에비해더낮은 MMSE, 더높은 CDR 을보였으므로, 연령의영향을배제하더라도 PD-S 군에서 PD-NS 군에비해인지기능이더저하된것으로분석할수있다. 파킨슨병치매의위험인자로여러요인이있지만, 뇌졸중에대한연구는거의없다. 2,24 일반적으로뇌졸중이인지기능에영향을미치는것은이미알려졌고, 알츠하이머병에서뇌졸중의영향이나연관성은많은연구에서밀접한상관관계를보여주었다 ,25 신경퇴행질환인알츠하이머병과마찬가지로파킨슨병도연령이증가하면서그유병률이높아지고, 고연령에서뇌졸중과함께파킨슨병이존재할가능성이높다. 16,20 파킨슨병치매의위험인자로는고연령, 심한파킨슨증세, 특히경축, 체위불균형, 보행장애가심할경우, 질병시작시기에경도인지장애가있는경우가제시되고있다. 26 이외에도파킨슨병치매를일으키는위험요인으로고령에서의발병, 남자, 낮은교육수준, 환시, 우울증이제시되고있으나연구마다의견이일치하지는않는다. 2,11 따라서이미알려진위험요인이나원인병리외에도달리영향을미칠수있는다른조건을고려해볼수있다. 열공경색은알츠하이머병에서아밀로이드판또는신경원섬유매듭 (neurofibrillary tangle) 이비슷하게존재할때임상증 Table 1. Demographics for PD-S (PD with lacunar infarction) and PD-NS (PD with normal MRI) Demographic Data PD-S (N = 19) PD-NS (N = 59) p-value Age, yr (mean±sd) 79.1± ± a Sex, F/M 10/9 43/ PD duration, yr (mean±sd) 6.9± ± Education, yr (mean±sd) 5.3± ± Hoehn & Yahr 3.8± ± a LED (mg) 967.3± ± LED; L-dopa equivalent dose. a Significant difference between PD-S and PD-NS by t-test, chi-square, p<0.05. Table 2. Mean difference in cognitive test scores for PD-S (PD with lacunar infarction) and PD-NS (PD with normal MRI) Cognitive test Unadjusted mean±sd Adjusted mean±sd a PD-S PD-NS PD-S PD-NS MMSE 16.8± ± ± ±0.4 p-value a a CDR 1.3± ± ± ±0.005 p-value b b a adjusted for age, sex and education. b Significant difference between PD-S and PD-NS by ANCOVA analysis, p< 대한신경과학회지제 30 권제 2 호, 2012

4 열공경색과파킨슨병환자의인지기능저하 세를더발현시킨다고한다. 21 열공경색과연관된치매에대한연구에서열공경색이있는환자의 23.1% 가 4년이내치매가나타났고단일열공경색이치매로발현된경우도 13.5% 였다. 27 또한열공경색이인지기능에전략적으로중요한위치에있거나다수의열공경색이치매나인지기능저하를일으킨다는많은보고가있다 열공경색이시상과줄무늬체 (striatum)- 대뇌피질 (cortex) 경로의단절을초래하여인지기능저하를초래하는것으로추정한다 저자들은열공경색이파킨슨병의인지장애에영향을미치는지규명하고자하였다. 결과는열공경색을가진파킨슨병환자에서뇌경색이없는파킨슨병환자군에비해 MMSE 점수는낮고 CDR 점수는높아서인지기능저하가더뚜렷하다는것을알수있었다. 인지기능저하는파킨슨병치매로진행되거나이미치매로진단이될수있는중요한임상양상이다. 물론, MMSE 가인지기능을포괄적으로자세히평가할수있는것은아니며정확도가높지않은검사이지만, 연령을보정하였고유병기간, 교육기간또한차이가없는두군을비교했을때의 MMSE 점수는 CDR 과함께전반적인인지수준은제시할수있다고생각한다. 그러나본연구는환자의인지기능저하가단순히열공경색때문인지확신할수없다는한계가있다. 인지기능에영향을미치는일반적인원인, 예를들어해마위축, 열공경색의시기를명확히알수없어이전상태의인지기능수준을평가할수없었다. 또한병리나 Pittsburgh Compound-B (PiB) 양전자방출단층촬영 (Positron Emission Tomography, PET) 같은검사를시행하지못하여알츠하이머병리의존재나, 레비소체의피질분포가인지기능에영향을미쳤을가능성을배제할수없다. 또한저자들은열공경색이있는파킨슨병환자 (PD-S) 의 MMSE 중에서이상을보인항목을분석하였는데 19명의환자들중 17 명에서계산능력과오각형겹쳐그리기항목에서이상이있었고이는다른항목의이상보다더높은빈도를보였다. 포괄적인신경심리검사를시행하지않아 MMSE 이상이있는항목만으로판단하는것은한계가있으나, 문헌에보고된파킨슨병인지기능장애의특징인집행기능장애와주의집중력장애가 PD-S 군에서도뚜렷하게나타났다고추정할수있다. 26 추후이런환자군에서더종합적인신경심리종합검사를시행하여, 치매또는인지기능장애의원인이뇌졸중때문인지파킨슨병인지기능장애양상인지구분할수있을것이다. 본연구가의미있는것은파킨슨병환자에게드물지않게동반되는뇌졸중특히열공경색의임상적의미를평가하여파킨슨병치매를다양하게분석할수있는계기를제시하였기때문이다. 향후동일한연령의증례를더많이분석하여 MMSE 검사외 에도포괄적인신경심리종합검사에서영역별로평가하고, 열공경색의수에따른인지기능저하경향을분석한다면본연구의결과를정확히해석하는데도움이될것이다. REFERENCES 1. Emre M. Clinical features, pathophysiology and treatment of dementia associated with Parkinson's disease. Handb Clin Neurol 2007;83: Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord 2007;22: Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW. Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch Neurol 2002;59: Sabbagh MN, Lahti T, Connor DJ, Caviness JN, Shill H, Vedders L, et al. Functional ability correlates with cognitive impairment in Parkinson's disease and Alzheimer's disease. Dement Geriatr Cogn Disord 2007;24: Perry E.-K, Curtis M, Dick DJ, Candy JM, Atack JR, Bloxham CA, et al. Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease. J Neurol Neurosurg Psychiatry 1985;48: Emre M. Treatment of dementia associated with Parkinson's disease. Parkinsonism Relat Disord 2007;13:S457-S Farlow MR, Cummings J. A modern hypothesis: The distinct pathologies of dementia associated with Parkinson's disease versus Alzheimer's disease. Dement Geriatr Cogn Disord 2008;25: Mattila PM, Rinne JO, Helenius H, Dickson DW, Roytta M. Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease. Acta Neuropathol 2000;100: Mattila PM, Röyttä M, Torikka H, Dickson DW, Rinne JO. Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson's disease. Acta Neuropathol 1998;95: Braak H, Del Tredici K. Invited Article: Nervous system pathology in sporadic Parkinson disease. Neurology 2008;70: Emre M. Dementia associated with Parkinson's disease. Lancet Neurol 2003;2: Jellinger KA. The morphological basis of mental dysfunction in Parkinson's disease. J Neurol Sci 2006;248: Park KW, Kim HS, Cheon SM, Cha JK, Kim SH, Kim JW. Dementia with Lewy Bodies versus Alzheimer's Disease and Parkinson's Disease Dementia: A Comparison of Cognitive Profiles. J Clin Neurol 2011; 7: Choi SA, Evidente VG, Caviness JN, Shill HA, Sabbagh MN, Connor DJ, et al. Are there differences in cerebral white matter lesion burdens between Parkinson's disease patients with or without dementia? Acta Neuropathol 2010;119: Jellinger KA. Prevalence of cerebrovascular lesions in Parkinson's disease. A postmortem study. Acta Neuropathol 2003;105: Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 2002;109: Jellinger KA, Attems J. Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol 2008; J Korean Neurol Assoc Volume 30 No. 2,

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