Original Article J Korean Geriatr Soc 2013;17(1): 알츠하이머병과혈관치매에서고호모시스테인혈증의임상적의의 가톨릭대학교의과대학신경과교실 박형은 조현

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1 Original Article J Korean Geriatr Soc 2013;17(1): 알츠하이머병과혈관치매에서고호모시스테인혈증의임상적의의 가톨릭대학교의과대학신경과교실 박형은 조현지 송인욱 정성우 Clinical Significance of Hyperhomocysteinemia Between Alzheimer s Disease and Vascular Dementia Hyung-Eun Park, MD, Hyun-Ji Cho, MD, In-Uk Song, MD, Sung-Woo Chung, MD Department of Neurology, The Catholic University College of Medicine, Seoul, Korea Background: Recent research has shown that risk factors for cerebrovascular disorders are also causes of dementia. Of these risk factors, hyperhomocysteinemia is well known to be positively correlated with all types of dementias including Alzheimer s disease (AD) and vascular dementia (VaD). But it is not know if there is a difference in the concentration of homocysteine in AD and VaD. We analyzed the homocysteine concentrations in AD and VaD and investigated the relationship between homocysteine and the progression of these two dementias. Methods: A total of 193 patients to the dementia clinic at our hospital were enrolled. Fifty-four patients had AD and 48 patients had VaD. The remaining patients were the healthy control. Data for analysis consisted of the results of neuropsychological tests and homocysteine levels. Results: Homocysteine levels were higher in AD and VaD patients than in healthy subjects, and no statistical difference was seen between AD and VaD. With lower mini-mental state examination scores, the homocysteine concentration increased significantly in VaD, but not in AD. The homocysteine concentration and the sum of box of clinical dementia rating were positively correlated in both AD and VaD. Other neuropsychological tests had no correlation with the homocysteine level. Conclusion: This study suggests that hyperhomocysteinemia, resulting in inflammation of vessel walls and oxidative stress, is a risk factor for both AD and VaD. However, our results did not clarify if hyperhomocysteinemia is related to the progression of dementia symptoms. Key Words: Homocysteine, Alzheimer s disease, Vascular dementia 서 론 Received: October 17, 2012 Revised: January 12, 2013 Accepted: January 19, 2013 Address for correspondence: In-Uk Song, MD Department of Neurology, Incheon St. Mary s Hospital, The Catholic University College of Medicine, 56 Dongsu-ro, Bupyeong-gu, Incheon , Korea Tel: , Fax: siuy@cmcnu.or.kr 치매는점진적인인지기능의저하를보이는질환으로노인에게있어독립적인생활능력의저하를일으키며, 그로인한사망률에영향을미치는질환이다 1). 한국에서는노인인구의 10% 정도가치매진단을받았으며, 알츠하이머병은 %, 혈관치매는 % 로알려져있으며 2), 치매이환노인의경우에는사망률이유의하게높은것으로알려져있어 3) Copyright 2013 Korean Geriatric Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (

2 Hyung-Eun Park, et al: Hyperhomocysteinemia between AD and VaD 치매의빠른진단을위한생물표지자및위험인자발견의중요성이강조되고있다 4). 최근연구들에의하면뇌혈관질환의여러위험인자들이치매의발병원인들중에흔한원인중의하나로최근인식되고있어고혈압, 동맥경화증, 심방세동, 당뇨, 비만, 뇌졸중과같은혈관성질환들이알츠하이머병의발생에위험인자로써알려져있다 5). 더욱이호모시스테인은메티오닌의대사물질로혈관벽에산화성손상을일으키고혈관벽의증식을일으켜혈전생성이촉진되는상태를일으킬수있어여러혈관성질환의발생과의연관성도밝혀져있다 6,7). 특히혈중호모시스테인농도는건강한정상노인보다인지기능의저하가있는노인에게더높은혈중농도를보이는것으로여러연구에서밝혀졌고, 이는알츠하이머병과다른종류의치매에서도비슷한결과를보였다 8,9). 하지만알츠하이머병과혈관치매에혈중호모시스테인농도의차이및인지기능저하에어떠한역할을하는지에대해서는아직명확하게알려져있지않다. 따라서저자들은본연구에서알츠하이머병과혈관치매환자에있어서혈중호모시스테인농도의차이및임상적영향에대해알아보고자한다. 대상및방법 1. 대상 본연구는 2009년 8월 5일부터 2012년 5월 23일까지본원신경과치매클리닉을내원한 193명의환자 ( 여성 102 명, 남성 91명 ) 를대상으로하였으며, 이중치매환자 102 명 ( 여성 52명, 남성 50명 ) 과정상대조군 91명 ( 여성 50명, 남성 41명 ) 이었다. 이중알츠하이머병은 Neurological and Communicative Disorders and Stroke-Alzheimer s Disease and Related Disorders Association (NINCDS-ADRDA) 의 10) 추정알츠하이머병 (probable Alzheimer s disease) 진단기준을만족하는경우를선정하였고, 혈관치매는 National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'enseignement en Neurosciences (NINDS-AIREN) 11) 의추정혈관치매 (probable vascular dementia) 를만족시키면서 Hachinski 허혈성척도점수 7점이상인경우를선정하였다. 또한모든환자군에게뇌자기공명사진을시행하여뇌혈관질환과같은뇌의기질적병변을평가하였고, 한국형간이정신상태검 사 (Korean Mini-Mental State Examination, MMSE) 12) 24점이하면서임상적치매척도 (clinical dementia rating, CDR) 13) 0.5 이상인환자만을본연구에참여시켰다. 또한혈액검사를통해인지장애에영향을줄수있는갑상선기능이상증, 고혈당증, 저혈당증, 간또는신장기능장애와같은대사장애를가진환자들은본연구에서제외하였다. 정상대조군또한이전에어떠한내과적질환을가지지않고, 상기한혈액검사상이상소견을가지지않고, 인지저하를동반하지않는경우로써나이및성별을고려하여선정하였다. 본연구는본원임상윤리위원희의승인을받아시행하였다. 2. 방법 모든질환대상자에서교육연수를조사하였으며, 인지기능검사는 MMSE, CDR 과항목별점수의합산 (sum of box of CDR, SOB) 13) 그리고전반적인퇴화척도 (global deterioration scale, GDS) 14) 를시행하였다. 추가적으로 Barthel index 를이용하여일상생활의활동정도 (activities of daily living, ADL) 15) 를평가하였다. 모든대상군에서혈중호모시스테인농도를측정하였는데, 12시간이상공복후아침에환자의상박에서정맥채혈을하였다. 전혈은 citrate salts가포함된 vacutainer tube 에담아얼음으로냉각후즉시 3,000 rpm 으로 10분동안원심분리하여혈장을 -70 C로냉동보관하였다. 혈중호모시스테인농도는혈장에서 IMx kit (Abbott Laboratories, Abbott Park, IL, USA) 를사용하여형광편광면역검사법 (fluorescencepolarization immunoassay) 으로측정하였다. 따라서총 146명이본연구에포함되었으며, 그중알츠하이머병은 54명, 혈관치매는 48명, 대조군은 44명이었다. 성별은알츠하이머병에서남성이 27명, 혈관치매에서남성이 23명, 정상대조군에서남성이 21명이었다. 연령은알츠하이머병에서 77.39±1.62세, 혈관치매에서 77.19±4.64세, 그리고대조군에서 74.63±9.04세였다이들군간의통계분석은혈중호모시스테인농도가정규분포를정확히따르지않아연속변수에대해서는 Mann- Whitney U-test 와 Kruskal-Wallis test를사용하였고, 비연속변수에대해서는 chi-square 검정을사용하여통계분석을하였다. 혈중호모시스테인농도와 MMSE, CDR 와 SOB, 나이와의상관관계는 Spearman's rank order correlation coefficients을 42 J Korean Geriatr Soc 17(1) March 2013

3 박형은외 : 알츠하이병과혈관치매의호모시스테인 통해분석하였고, CDR 0.5와 1을가진군과 2 이상을가진군으로나누어 Mann-Whitney U-test 를이용해분석하였다. 유의수준은 p값이 0.05 이하인경우통계적으로의미있는것으로판정하였다. 모든통계학적분석은 IBM SPSS ver (IBM Co., Armonk, NY, USA) 를사용하였다. 결과 본연구에참여한환자및정상대조군의일반적인임상자료는 Table 1에정리하였다. 이중 MMSE 점수는알츠하이머병및혈관성치매군이정상대조군에비해서유의하게낮은점수를보였다 (p<0.001) (Table 1, Fig. 1). 또한각군별로혈중호모시스테인의농도를비교하였을때, 알츠하이머병 (16.12±13.26 umol/l) 과혈관치매군 (14.69±7.27 umol/l) 의혈중농도가정상대조군 (11.27±3.01 umol/l) 에비해서통계적으로유의하게높은것을확인할수있었다 (Table 1, Fig. 2). 하지만알츠하이머병과혈관치매군에서의혈중호모시스테인을비교하였을때는통계적으로유의한차이를보이지않았다 (p=0.178). 뿐만아니라교육연수, MMSE, CDR, SOB, GDS 그리고 ADL에서도양치매군에서의의미있는차이를보이지않았다 (Table 1). 알츠하이머병과혈관치매환자군에서혈중호모시스테인농도와인지기능저하의지표와의상관분석에서는 MMSE 가낮을수록혈관치매에서는혈중호모시스테인의농도가높은 것으로나타났으나 (Spearman's rank order correlation coefficients, 0.376; p=0.008), 알츠하이머병에서는통계적으로의미있는결과를보이지못했다. 하지만 CDR에서의 SOB의수치와혈중호모시스테인의농도는알츠하이머병과혈관치매모두에서통계적으로의미있는양의상관관계를보였다 (Spearman's rank order correlation coefficients: AD, 0.289; p=0.034/vd, 0.304; p=0.036). 하지만 CDR 와 GDS에서는어떠한치매군에서도통계적으로의미있는연관성을보이지못했다 (Table 2). 고찰 혈중호모시스테인의증가는노인인구에서비타민결핍과연관되어흔하게나타나며 16), 나이와연관하여증가하고 17) 인지기능의장애가있는노인에게서정상노인과비교할때의미있게높은수치임이알려져있다 18). 이와같은혈중호모시스테인의증가는뇌경색, 알츠하이머병, 우울증, 노인의인지기능저하, 간질등광범위한신경계질환들과연관이되어있는것으로보고되고있으며, 이는신경계가다른기관보다호모시스테인의흥분성신경독성에민감하기때문으로생각되고있다 19). 본연구에서도이전다른연구에서확인된바와같이알츠하이머병과혈관치매모두에서정상대조군에비해혈중호모시스테인농도가통계적으로유의하게증가함을알수있었다. Table 1. Clinical characteristics of subjects Characteristic AD (n=54) VaD (n=48) Control (n=44) p-value Gender (male) Age (yr) 77.39± ± ± Homocysteine (μmol/l) * 16.12± ± ± Vitamin B 12 (pg/ml) ± ± ± Folate (ng/ml) 16.61± ± ± Education (yr) 3.78± ± ± MMSE 16.61± ± ±2.00 <0.001 CDR 1.09± ±0.96 ND Sum of box of CDR 6.53± ±6.15 ND Global deterioration scale 4.0± ±1.39 ND Activities of daily living 17.13± ±6.03 ND Hachinski ischemic score 1.25± ±1.22 ND <0.001 Values were expressed mean±standard deviation. p-values were measured by Mann-Whitney U-test and Krusal-Wallis test. AD, Alzheimer's disease; VaD, vascular dementia; MMSE, Korean mini-mental state examination; CDR, cinical dementia scale; SOB, sum of box of CDR; ND, not done. * AD=VaD>Control. AD=VaD<Control. J Korean Geriatr Soc 17(1) March

Score for both AD and VaD patients were higher than healthy controls (AD, 16.61±5.56; VaD, 17.29±7.10; healthy control, 27.93±2.00).

4 Hyung-Eun Park, et al: Hyperhomocysteinemia between AD and VaD Fig. 1. Mean Korean mini-mental state examination (MMSE) score for patients with Alzheimer s disease (AD) and Vascular dementia (VaD) compared with normal controls. Score for both AD and VaD patients were higher than healthy controls (AD, 16.61±5.56; VaD, 17.29±7.10; healthy control, 27.93±2.00). The difference in scores between AD and VaD patients is not statistically significant (p=0.178). Error bar, 95% confidence interval. Table 2. Correlation coefficients for serum homocysteine and varables for each dementia Variable Alzheimer's disease Vascular dementia Age (yr) * 0.16 * MMSE * CDR SOB Values are Spearman's rank order Correlation coefficients. MMSE, Korean mini-mental state examination; CDR, clinical dementia scale; SOB, sum of box of CDR. * p-value >0.05 and p-value 0.05 by Spearman's correlation analysis. P-value of CDR by Mann-Whitney U test between two groups (CDR 0.5 and 1 & CDR 2). 혈중호모시스테인농도의증가가알츠하이머병에미치는영향으로는여러가지가설이설립되어있으며 20), 제시되고있는가설로는, 호모시스테인으로인한산화적손상 (oxidative stress) 21), 탈메틸화 (demethylation) 22), 아밀로이드베타 (Aβ) 의상승 23), 타우단백의인산화 24) 가원인으로꼽히고있으나아직까지명확하게확립되어있지는않은실정이다. 또한혈관성질환에대한혈중호모시스테인과의연관성도잘알려져있는사실이지만 25), 그병리기전에대해서는고혈중호모시스테인이혈관내피세포의기능저하를일으키고혈관평활근의증식을일으켜혈소판의응집을일으키고, 이로인한응고연쇄반응 (coagulation cascade) 를활성화시켜혈전반응을 Fig. 2. Mean homocysteine concentration for patients with Alzheimer s disease (AD) and vascular dementia (VaD) compared with healthy controls. Concentrations are higher in AD and VaD patients than in the normal controls (AD, 16.12±13.26; VaD, 14.69±7.27; healthy control, 11.27±3.01). The difference in homocysteine concentrations between AD and VaD patients is not statistically significant (p=0.768). Error bar, 95% confidence interval. 촉진시키며 26), 최근에는탈메틸화 (demethylation) 로인해혈전생성반응을촉진시킨다는보고가있으나, 아직까지정확한기전은알려져있지않다 25). 본연구에서는또한인지기능저하가있는환자에게혈중호모시스테인의농도가일반적으로다른기전으로발생하는것으로알려져있는대표적인치매종류인혈관치매와알츠하이머병의발병에미치는영향의차이를확인하고자하였으나, 알츠하이머병과혈관치매양군간의혈중호모시스테인농도는통계적으로의미있는차이를보이지않았다. 따라서이처럼두치매군에서혈중호모시스테인농도의의미있는차이가나지않았던이유로혈관치매와알츠하이머병사이에발병의공통적인기전이있음을생각해볼수있겠다. 더욱이알츠하이머병과혈관치매의양군에서모두염증반응이중요한기전으로작용함이알려져있으며 27), 고호모시스테인혈증이혈관내피세포의기능부전및만성염증반응을일으키는것으로알려져있어 28,29), 아마도고호모시스테인혈증으로인한염증반응이알츠하이머병과혈관치매에비슷한정도의영향을주었을가능성을고려해볼수있겠다. 본연구에서인지기능저하의진행정도에따른호모시스테인의혈중농도와의연관성에대한평가는혈관치매에서의 MMSE와알츠하이머병과혈관치매모두에서 SOB가의미있는상관관계를보였으나, CDR 자체와 GDS 및 ADL에서는 44 J Korean Geriatr Soc 17(1) March 2013

5 박형은외 : 알츠하이병과혈관치매의호모시스테인 통계적으로의미있는연관성을보이지못하였다. 더욱이 MMSE 와 SOB 에서도통계적으로는의미가있었으나, 상관계수가미미한수치를보여혈중호모시스테인농도가증상의진행정도와연관성에대해서는아직까지명확하게제시하기는어렵다고생각된다. 결론적으로저자들은본연구를통해서고농도의혈중호모시스테인이알츠하이머병과혈관치매의발생에영향을미칠수있다는것을확인할수있었다. 하지만두치매군에서의혈중호모시스테인농도의차이가보이지않아고호모시스테인혈증이영향을주는혈관내피세포의기능부전및만성염증이두질환의발병에공통적으로영향을줄것으로조심스럽게추정할수있었다. 하지만고농도의혈중호모시스테인이염증성질환과혈관질환에어떠한발병기전으로영향을주는지가아직까지명확하지않아임상의실제적용이현실화되고있지않는상태이므로이에대한지속되는대규모연구가향후에반드시필요하리라생각된다. 이에반해혈중호모시스테인농도가인지저하의심한정도를반영하거나치매의진행에임상적으로영향을보여주기에는미미한결과를보였다. 따라서치매의진행정도에영향을주는지에대한평가는향후많은대규모환자군을통한전향적인연구및추적관찰을통한연구분석이추가적으로필요하겠다. 가없었다. 또한 mini-mental state examination가낮을수록혈관치매에서는혈중호모시스테인의농도가높은수치를보인것에반해알츠하이머병에서는통계적으로유의하지않았다. 또한 clinical dementia rating (CDR) 에서의 sum of box of CDR (SOB) 의수치와혈중호모시스테인의농도는알츠하이머병과혈관치매모두에서통계적으로의미있는양의상관관계를보였지만, 이외다른신경심리검사에서는어떠한치매군에서도통계적으로의미있는연관성을보이지못했다. 결론 : 두치매군에서혈중호모시스테인농도의의미있는차이가나지않았던이유로혈관치매와알츠하이머병사이에발병의공통적인기전이있음을생각해볼수있으며, 고호모시스테인혈증으로인한염증반응이알츠하이머병과혈관치매에비슷한정도의영향을주었을가능성을고려해볼수있겠다. 인지기능저하의진행정도에따른호모시스테인의혈중농도와의연관성은 SOB 가통계적으로유의한관계를보였으나, 상관계수도미미한수치를보이고, 다른인지검사에서는통계적으로유의하지않아증상의진행정도와연관성에대해서는아직까지명확하게제시하기는어렵다고생각된다. 따라서향후대규모환자군을통한지속적인연구들이진행되어야할필요성이있다고생각한다. 요 약 REFERENCES 연구배경 : 치매는뇌혈관질환의여러위험인자들이발병원인으로알려져있고, 그중혈중호모시스테인농도는알츠하이머병과혈관치매같은치매에서도모두증가하는것으로잘알려져있다. 하지만알츠하이머병과혈관치매에서혈중농도의차이에대한연구는아직충분히시행되지않았다. 따라서저자들은알츠하이머병과혈관치매에서호모시스테인의임상적차이및진행에따른혈중호모시스테인의관련성에대해연구하고자한다. 방법 : 본원치매클리닉을내원한 193명의환자를대상으로알츠하이머병 54명, 혈관치매 48명, 대조군 44명을본연구에선정하였다. 모든군에서신경심리검사와혈중호모스시테인의농도를확인하였고, 알츠하이머병군과혈관치매군그리고정상군으로분류하여비교분석하였다. 결과 : 각환자군별로혈중호모시스테인의농도는알츠하이머병과혈관치매군의혈중농도가정상대조군에비해서통계적으로유의하게높게나타났으나, 두치매군에서는차이 1. van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol Neurosurg Psychiatry 2005;76 Suppl 5:v Cho MJ, Lee JY, Kim BS, Lee HW, Sohn JH. Prevalence of the major mental disorders among the Korean elderly. J Korean Med Sci 2011;26: Kane RL, Shamliyan T, Talley K, Pacala J. The association between geriatric syndromes and survival. J Am Geriatr Soc 2012;60: Garcia A, Zanibbi K. Homocysteine and cognitive function in elderly people. CMAJ 2004;171: Honig LS, Tang MX, Albert S, Costa R, Luchsinger J, Manly J, et al. Stroke and the risk of Alzheimer disease. Arch Neurol 2003;60: Loscalzo J. Homocysteine and dementias. N Engl J Med 2002;346: Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288: Lehmann M, Gottfries CG, Regland B. Identification of cogni- J Korean Geriatr Soc 17(1) March

6 Hyung-Eun Park, et al: Hyperhomocysteinemia between AD and VaD tive impairment in the elderly: homocysteine is an early marker. Dement Geriatr Cogn Disord 1999;10: Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004;80: McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34: Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43: 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, Lee BH, Hahm DS, Jeong JH, Yoon SJ, et al. Estimating the validity of the Korean version of expanded clinical dementia rating (CDR) scale. J Korean Neurol Assoc 2001;19: Choi SH, Na DL, Lee BH, Hahm DS, Jeong JH, Jeong Y, et al. The validity of the Korean version of global deterioration scale. J Korean Neurol Assoc 2002;20: Wade DT, Collin C. The Barthel ADL Index: a standard measure of physical disability? Int Disabil Stud 1988;10: Goodwin JS, Goodwin JM, Garry PJ. Association between nutritional status and cognitive functioning in a healthy elderly population. JAMA 1983;249: Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270: Bell IR, Edman JS, Selhub J, Morrow FD, Marby DW, Kayne HL, et al. Plasma homocysteine in vascular disease and in nonvascular dementia of depressed elderly people. Acta Psychiatr Scand 1992;86: Martignoni E, Tassorelli C, Nappi G, Zangaglia R, Pacchetti C, Blandini F. Homocysteine and Parkinson's disease: a dangerous liaison? J Neurol Sci 2007;257: Zhuo JM, Wang H, Pratico D. Is hyperhomocysteinemia an Alzheimer's disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol Sci 2011;32: Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 2001;78: Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D'Anselmi F, Coluccia P, et al. B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice. Mol Cell Neurosci 2008;37: Pacheco-Quinto J, Rodriguez de Turco EB, DeRosa S, Howard A, Cruz-Sanchez F, Sambamurti K, et al. Hyperhomocysteinemic Alzheimer's mouse model of amyloidosis shows increased brain amyloid beta peptide levels. Neurobiol Dis 2006;22: Sontag E, Nunbhakdi-Craig V, Sontag JM, Diaz-Arrastia R, Ogris E, Dayal S, et al. Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci 2007;27: Castro R, Rivera I, Blom HJ, Jakobs C, Tavares de Almeida I. Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. J Inherit Metab Dis 2006;29: Perna AF, Ingrosso D, Lombardi C, Acanfora F, Satta E, Cesare CM, et al. Possible mechanisms of homocysteine toxicity. Kidney Int Suppl 2003;(84):S Blasko I, Grubeck-Loebenstein B. Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease. Drugs Aging 2003;20: Karabag T, Kaya A, Temizhan A, Koc F, Yavuz S, Cam S. The influence of homocysteine levels on endothelial function and their relation with microvascular complications in T2DM patients without macrovascular disease. Acta Diabetol 2007; 44: Sohn JH, Lee SY, Kim HC, Lee SM, Choi HC. Relationship between homocysteine level, white matter lesion and cognitive decline. J Korean Geriatr Soc 2007;11: J Korean Geriatr Soc 17(1) March 2013

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