SPECIAL ARTICLE online ML Comm J Neurocrit Care 2008;1:137-142 ISSN 2005-0348 혈관성인지장애개념의논란과한국형혈관성인지장애표준화프로토콜을이용한다기관전향적관찰연구 한림대학교성심병원신경과, 한림대학교의과대학신경과학교실 오미선 이병철 Controversies in Concept of Vascular Cognitive Impairment and Korean Vascular Cognitive Impairment Harmonization Study Mi-Sun Oh, MD and Byung-Chul Lee, MD, PhD Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea The main controversies in the field of vascular dementia include the nosological classification and the concept of this disorder, the definition of dementia, specific neuropsycholotical test for vascular dementia, the differences between various diagnostic criteria, and early detection and diagnosis of vascular dementia. The concept of vascular dementia is a field in a state of profound change. Several consensus criteria are currently being used for the clinical diagnosis of vascular dementia, however the ability of these criteria to distinguish vascular dementia from Alzheimer s disease is limited. This review details the state of knowledge that we have now reached concerning the concept and the current diagnostic criteria of vascular dementia. Finally, we present the Korean vascular cognitive impairment harmonization study which is ongoing. J Neurocrit Care 2008;1:137-142 KEY WORDS: Vascular dementia Concept Diagnostic criteria. 서 론 혈관치매는 Alzheimer s disease(ad) 와더불어치매의주요한원인이며, 퇴행성치매와달리치료의여지가많다는점에서근래에들어활발한연구의대상이되고있다. 특히노인인구의급격한증가와더불어뇌혈관질환의증가를고려하면, 혈관치매는그자체로서혹은다른퇴행성치매의관여인자로서매우중요한질환이된다. 1 그러나아직도혈관치매의진단을둘러싼몇가지논란이있다. 첫째는혈관치매의병인분류 (nosological classification) 와개념 (concept) 의정립이이루어지지않았고둘째, 현재 Address for correspondence: Byung-Chul Lee, MD, PhD Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 896 Pyeongchon-dong, Dongan-gu, Anyang 431-070, Korea Tel: +82-31-380-3741, Fax: +82-31-381-4659 E-mail: ssbrain@hallym.ac.kr 본논문은보건복지부보건의료기술진흥사업및한국에자이의일부지원에의하여이루어진것임 (A06-0171-B51004-06N1-00060B). 사용되고있는혈관치매의진단기준은 AD의진단기준을기본틀로하기때문에기억력의장애없이전두엽 / 실행능력장애가주증상인혈관치매의진단에는제한이있다. 셋째는심한인지장애를보이는경우만을치매로규정함으로경증환자의조기진단이늦어져적절한시기의치료를놓칠수있으며넷째, 혈관치매의인지장애를효과적으로진단할수있는표준화된신경심리학적검사가부족하다는점이다. 이외에도뇌혈관질환과인지장애의인과관계의규명이나뇌혈관영상에서뇌병변의크기와위치를어떻게규정하느냐등의여러가지논란이있을수있다. 본논문에서는앞서기술한논란중혈관치매의개념정리와진단기준에대하여초점을맞추어논의하고자한다. 혈관치매의역사 혈관치매의개념정립을위한노력은 19세기후반에시작되어현재까지계속되고있다. 1672년 Thomas Willis 가 Copyright c 2008 The Korean Neurocritical Care Society 137
J Neurocrit Care 2008;1:137-142 뇌졸중후치매 의증례를최초로기술한후 17세기말부터혈관치매라는용어가사용되기시작하였다. 17세기말당시의의사들은뇌출혈과뇌경색의차이를알고있었으며혈관치매는증상이심한뇌출혈보다는상대적으로덜위증한뇌경색후에더많이동반된다고생각하였다. 2 1894년 Binswanger 는부검에서백색질의위축과심각한뇌동맥경화증 (arteriosclerotic cerebral arteries) 을특징으로하는피질하백질변성 (subcortical white matter change) 을보인치매를기술하였고이는혈관치매의한유형인 Binswanger 병 으로알려지게되었다. 3 1896년독일의 Emil Krapelin은 Bingwanger와 Alzheimer의임상병리학적인연구에기초하여노인성치매의주요형태로서죽상경화치매 (arteriosclerotic dementia) 를제안하고그의정신의학교과서에소개하였다. 3 그후 11년뒤 Marie 는다발성열공경색 (multiple lacuanr infarct) 즉, etat lacunaire 가인지기능저하의원인이된다는개념을발표하였다. 1970 년 Tomlison 은 50 cc 이상의뇌혈관병변의용량이인지장애를일으킬수있다고주장하기도하였다. 4 또한 1974 년 Hachinski 는뇌동맥경화만으로는치매를일으키지않으며다발성으로뇌경색이있어야한다고주장하며, 이를다발성경색치매 (multiple infarct dementia) 로부를것을제안하였다. 5 이후혈관치매를노인성치매의주요한원인으로생각한 20세기초까지의개념에서, 1970 년이후 AD 의병인론에관한연구가활발해지면서노인성치매의원인이죽상경화보다는 AD 형태의퇴행성변화가더중요하다고여겨져퇴행성치매가노인성치매의주요한질환으로대두되어집중연구가이루어졌다. 그러나뇌신경영상의눈부신발전과 1990년대경쟁적으로혈관치매의진단기준이발표된이후다시혈관치매에대한관심과연구가활발하게이루어지고있다. 혈관성인지장애의개념 (The Concept of Vascular Cognitive Impairment) 혈관치매 (Vascular dementia: VD) VD는기억력장애를포함한여러인지장애와이로인한일상생활기능의장애가뇌혈관질환으로발생하는경우로정의된다. VD는허혈성및출혈성뇌혈관질환, 혹은심혈관질환에의한뇌혈관병변으로초래되는치매를모두포함한다. 혈관성인지장애 (Vascular cognitive impairment: VCI) 혈관치매진단의가장주요한논란은치매에대한정의 로서, AD 진단기준처럼 기억력장애가반드시포함되어야하는가 에대한문제점이다. 기존의혈관치매의진단기준으로는기억력장애없이전두엽 / 실행능력 (frontal/executive function) 의장애와이로인한일상생활장애를갖는혈관성인지장애환자가진단에서빠지거나, 혼합성치매와순수혈관치매를감별하지못한다는문제가발생한다. 이러한문제의식을바탕으로 Hachinski 와 Bolwer 는허혈성뇌혈관질환과관련되어발생하는인지장애전반을포함할수있는포괄적인용어로 VCI의개념을제시하였다. 6-8 이들은기존의 VD의문제점으로기억력장애를기본인지장애로정의하는부적절한개념과경증인지장애를포함시키지않아조기진단과이차예방치료가불가능하다는점을꼽았다. Hachinski 의 VCI는뇌혈관성인지장애를 1) 혈관성위험인자단계 (brain-at-risk), 2) 증상전단계 (perisymptomatic stage), 3) 인지저하단계 (symptomatic stage) 로나누어혈관성인지장애의초기단계인 2차단계에서의적극적인치료를강조하였다. VCI 개념의정립은치매의예방적측면을강조한것으로치매에이르기전초기단계의인지장애환자를조기에발견하기위함이다. 그러나 Sachev 등은 VCI 개념에서경증의인지결손 (cognitive deficit) 과인지장애 (cognitive impairment) 의경계구분의어려움과우울증, 불안질환등의다른동반질환이미세한인지결손에미칠영향, 그리고임상또는신경영상학적으로초기뇌혈관질환의진단이어려울수있음을문제점으로지적하였다. 또한 VCI의진단을위한임상진단기준이아직제시되지않아 VCI는확립된개념이아니라는비평도있다. 캐나다의한연구팀 (Canadian Study on Health and Aging) 은 Vascular cognitive impairment with no dementia(vcind) 를 VCI 개념에서치매를제외시키는 cognitive impairment-no dementia 의축소된개념으로정의하고, 진단기준을제시하였다 (Table 1). 9 이진단기준에의한연구에서 VCIND 환자들중신경심리검사에서기억력과언어유창성점수가낮은경우추후혈관치매로진행할가능성이높은것으로나타났다. 9 TABLE 1. The criteria of vascular cognitive impairment with no dementia 1) The subject s cognitive impairment did not meet the DSM-III-R criteria for dementia (memory and other cognitive domain causing functional deficits) 2) Cognitive impairment was judged to have a vascular cause as based on presence of signs of ischemia/infarction 3) Operational functional deficits; global functional impairment was defined as having difficulty in any two of the following domains; performing household chores, managing money, feeding self, dressing, and incontinence 138
The Concept of Vascular Cognitive Impairment and K-VCIH Study MS Oh, et al. TABLE 2. Categories of vascular cognitive disorder Vascular cognitive disorder include Vascular cognitive impairment (VCI); the term is equivalent to cognitive impairment no dementia (VCI-ND) and to vascular mild cognitive impairment (vascular VCI). But it excludes isolated cognitive deficits resulting from stroke Vascular dementia (VD); Dementia is defined as executive control deficit producing loss of function for instrumental ADL Mixed AD+CVD; Preexisting AD worsened by stroke (assuming prestrike sub clinical disease, MCI, or overt AD) 혈관성인지질환 (Vascular cognitive disorder: VCD) Sachev 등에의해처음제안된혈관성인지질환은뇌혈관병변으로발생하는모든인지장애를아우르는개념으로 VCI 의개념과 VD 개념을통괄한다 (Table 2). 10 VCD의치매는이전의치매개념과다르게기억력장애를동반하지않아도집행기능의장애가있고이로의한기구사용일상생활장애 (instrumental activity daily living) 에이상이있는경우로정의하였다. 또한 VCD에는뇌졸중후인지장애 (poststroke cognitive impairment), 뇌졸중후치매 (poststroke dementia), CADASIL, Binswanger disease, 그리고혼합성치매도포함시키고있다. Diagnostic Criteria 혈관치매를진단하는핵심은일단치매가있어야하고, 뇌혈관질환의동반유무에대한진단, 그리고두질환의시간적-논리적연관성의확인이다. 1970년대 Hachinski Ischemic Score 가처음제안된후 1990년대에다수의혈관치매의임상진단기준이제시되어현재까지사용되고있다. 최근 10년동안에널리사용되고있는진단기준으로는 DSM-IV, ICD-10, ADDTC, NINDS-AIREN 이있다. DSM-IV(Diagnostic and statistical manual of mental disorders, 4 th edition) DSM-IV 의진단기준은기억장애와함께여러가지의인지장애중즉, 실어증, 실인증, 혹은실행능력중최소한한가지기능의장애를보이고이로인한일상생활의장애가초래되며이전에는정상적인인지기능을가지고있었던경우를 치매 라진단한다. 그리고치매환자가임상적으로치매와연관된국소신경학적증상및징후또는신경영상학적으로뇌졸중의증거가있고이로인하여인지기능의장애가유발된것으로판단될때 혈관치매 로진단한다. DSM-IV의진단기준은포괄적이고합리적이나, 진단범위가광범위하여혈관치매에대한특이성이떨어지고자세한 신경영상학적기준을제시하지않았다. ICD-10(International classification of disease 10 th revision) 1992 년 WHO에서제시된 ICD-10 진단기준에따르면혈관치매는비대칭적인지기능의장애와분명한뇌혈관질환을전제로한다. 이때뇌혈관질환은신경학적이상증상으로나타나는국소뇌손상의증거와치매증상과관련된뇌혈관질환의증거가있어야한다. ICD-10 의치매의정의는포괄적이고모호하며, DSM-IV 기준과마찬가지로신경영상학적진단기준이나임상증상에대한세부기준은제시되지않았다. ADDTC(Criteria of the state of california alzheimer s disease and treatment centers) ADDTC 진단기준은전적으로허혈성혈관치매만을규정하고있다. 병력청취나신경영상학적검사에서둘이상의허혈성뇌병변이보여야하지만, 치매와의시간적인과관계가반드시필요하지는않는다. 대신, 하나의뇌병변이치매발병시점과명확한인과관계가있는경우에는혈관치매로진단할수있다. ADDTC 진단기준은항상신경영상학적증거와더불어소뇌를제외한다른영역에적어도한개이상의뇌경색이동반되어있을것을요구한다. NINDS-AIREN(National institutes of neurological disorders and stroke-association internationalepour la recherche et l enseignement en neurosciences NINDS-AIREN 은혈관치매의임상연구목적으로만들어진진단기준으로치매와뇌혈관질환및양자의상관관계에대한정의를포함하고있다. 뇌혈관질환은국소신경학적징후와함께신경영상소견에서허혈성병변 ( 기저핵및백질열공성경색또는뇌실주위백질변성 ) 이관찰되어야한다. 치매와뇌혈관질환의시간적연계성이뚜렷하여뇌혈관질환발생 3개월이내에치매가발병하였을경우와, 인지기능의갑작스런변동이나계단양상으로악화되는인지기능의장애가있어야된다. NINDS-AIREN 기준은출혈성뇌졸중도혈관치매의원인에포함시켰으며, 전략적위치의뇌경색과피질하백질병변이혈관치매를일으킬수있다는점과치매와뇌혈관질환의시간적인과관계를강조하였다. 앞서언급한혈관치매의진단기준들은합의성기준으로 (consensus criteria) 로전향적인구대상연구 (prospective community-based study) 나자연적경과 (natural hi- 139
J Neurocrit Care 2008;1:137-142 TABLE 3. Comparison of clinical criteria for vascular dementia DSM-IV ICD-10 ADDTC NINDS-AIREN 1994 1993 1992 1993 Infarction/ischemic stroke + + + + Hemorrhage + + - + Memory impairment + + + + Stepwise deterioration - - - + Patchy distribution of cognitive deficits - + - - Focal neurological signs + + - + Focal neurological symptoms + - - - Evidence of significant stroke events + + + + Etiological relation to disturbance + + - + Temporal relationship - - + + Brain imaging - - + + ADDTC (n=93) 4 DSM IV NINDS (n=35) (n=98) 1 ICD-10 & DSM-III (n=39) 3 2 31 3 FIGURE 1. Subjects identified as having vascular dementia according to various diagnostic criteria. story) 에근거한것이므로서로교환해서사용이불가능하다. 11 또한각진단기준마다치매와뇌혈관질환을규정하는특징과차이점이있다 (Table 3). 따라서동일한환자군을대상으로적용했을때도많게는 4~5 배까지혈관치매의진단율이틀려진다 (Fig. 1). 12 또한이러한진단기준들이혈관치매를 AD와감별하기위한목적으로개발되었으나, 이두질환을정확하게이분화하여감별하지못한다는문제점을갖는다. 즉, 혈관치매로진단받는많은환자중에서순수혈관치매가아닌 AD와혈관치매의혼합성치매 (mixed dementia) 인경우가있다. 실제로노인환자에서혈관성병변과 AD의병리 (pathology) 가함께발견되며, 13 두질환이공통된위험인자를갖는다는최근의역학연구들을고려할때두질환이서로겹쳐서존재하는경우가많다. 14 따라서혈관치매의임상진료의정확도와유용성그리고임상연구의편의를모두만족시킬수있는새로운혈관치매의진단기준이필요하다는의견이모아지고있다. 3 국내혈관성인지장애연구 2006년미국 (NINDS) 과캐나다 (Canadian Stroke Network) 의연구자를중심으로혈관인지장애의개념정립을위해서는선행작업으로표준화된진단도구가필요하다는합의하에검사및진단도구의국제표준화작업이진행되었다. 15 이는혈관성인지장애의본격적인연구가시작될수있는국제적기반을마련하기위함이다. 이에따라국내에서도국제적기준에부합되는한국형혈관성인지장애의검사및진단도구를이용한국내혈관치매환자의다기관전향적관찰연구가 2007년에시작되어현재진행중에있다. K-VCIH study 의개요에대하여간략하게소개하고자한다. 뇌졸중후인지기능장애 ; 한국형혈관성인지장애표준화프로토콜에의한다기관전향적관찰연구 (Post-Stroke Cognitive Impairment; Prospective Multicenter Observational Study with Korean- Vascular Cognitive Impairment Harmonization Standards Protocol; K-VCIH Study) 역학적관점에서질병에관한연구의출발점은질병으로인한사회적부담의크기를평가하는데에서출발한다. 혈관성인지장애연구의출발점또한질환의유병률및발생률을밝히는것으로부터출발하여야할것이다. 뇌졸중이사망원인중 1위이며, 인구의노령화로가까운장래에발생률이급증할것으로생각되는우리나라에서는특히뇌졸중이후혈관성인지장애의빈도및자연경과에대한자료가소중하다. 이와같은취지로 K-VCIH study 는국내허혈 140
The Concept of Vascular Cognitive Impairment and K-VCIH Study MS Oh, et al. 뇌졸중환자의혈관성인지장애의발생률및유병률을구함으로써혈관성인지장애로인한뇌졸중환자의질병부담을평가하고국내혈관성인지장애의임상적특성과기초역학자료를마련하고자시행된연구이다. 본연구는한림대학교성심병원을중심으로전국 13개의주요대학병원이참여한다기관연구로, 연구기간동안연속적으로내원한급성기허혈뇌졸중환자중무작위배정전산시스템을이용하여전체환자의 50% 를추출하여이들을대상으로뇌졸중 3개월후의인지장애를평가하는전향적관찰연구로진행되었다 (Fig. 2). 2007년 10월부터 2008 년 10월까지총 520명의환자가연구에등록되었으며, 2008년 12월연구가종료되어현재자료를분석중에있다. 연구방법은발병 7일이내에내원한급성허혈뇌졸중환자중연구에참여동의를한환자들을대상으로내원당시의기초임상자료와신경학적결손을평가하였고, 급성기의인지기능상태를축약형의표준화된 5분 K-VCIH 프로토콜을이용해평가한다. 또한발병 3개월째, 표준화 K-VCIH 신경심리검사프로토콜과추가인기기능검사와신경학적장애및삶의질을평가하였다. 환자의병전기능적상태는보호자나환자를통해얻은 modified Rankin Disability Scale(m-RDS) 로평가하고병전인지기능상태는보호자용설문지인 Informant Questionnaire on Cognitive Decline in the Elderly(IQCODE) 를시행하여평가하였다. 허혈뇌졸중환자를대상으로표준화된 K-VCIH 신경심리검사가불가능한환자측의다양한원인을조사하고, K-VCIH 신경심리검사의 feasibility 평가를통해혈관치매의인지장애를효과적으로진단할수있는표준화된신경심리검사를마련하고자하였다. 본연구에사용된 K- VCIH 신경심리검사프로토콜은국제표준화에맞춘한국형신경심리검사들로구성되어있으며 (Table 4), 혈관치매환자의전두엽 / 실행능력장애를평가하기위한검사들이주 Center 건국대학교병원노원을지병원대전을지병원동국대학교병원동아대학교병원분당서울대학교병원서울대학교병원이화여자대학교목동병원인제대학교부산백병원울산대학교아산병원전남대학교병원한림대학교강동성심병원한림대학교성심병원 서울 6 center 경기 3 center 대전 1 center 광주 1 center 부산 2 center FIGURE 2. The centers of korean-vascular cognitive impairment harmonization study. 로포함되어있다. 본연구에서적용한혈관성인지장애의개념은기존의뇌졸중후치매 (post-stroke dementia: PSD) 의개념을변형한것으로, 허혈뇌졸중환자에서뇌졸중전인지장애의상태와관련없이뇌졸중후 3개월시점의인지기능을평가하였다 (Table 5). K-VCIH study 의혈관성인지장애는포괄적인 VCI 개념안에 PSD, 뇌졸중후인지장애 (Post- TABLE 4. Korean-vascular cognitive impairment harmonization standard protocol 인지영역 Frontal/Executive function Language, Lexical retrieval Visuospatial function Memory Neuropsychiatric/ Depressive symptoms Other 한국형혈관인지장애표준화 COWAT (controlled oral word association test) 동물이름대기, 음소이름대기 DSC (Digital symbol coding) TMT A, B (Trail making test A, B) SVLT (Seoul verbal learning test); Immediate BNT-short form (short version of the K-Boston naming test) Rey-copy SVLT (Seoul verbal learning test): delayed recall, recognition NPI-Q (neuropsychological inventory) GDS (geriatric depression scale) IQCODE-K (informant questionnaire on cognitive decline in the elderly) K-MMSE (Korean-mini mental state examination) K-IADL (Korean-instrumental activity of daily living) CDR (clinical dementia rating scale), Barthel index TABLE 5. The operating criteria of Korean-vascular cognitive impairment harmonization study Post-stroke dementia (PSD) Dementia after stroke regardless of pre-stroke cognitive status i. To avoid the impact of acute stroke, final diagnosis of dementia should be performed at 3 months after index stroke ii. Dementia defined by the criteria of DSM-IV Post-stroke cognitive impairment with no dementia (PSCI-ND) Cognitive impairment after stroke, does not meet the criteria of DSM-IV i. To avoid the impact of acute stroke, final diagnosis of cognitive impairment with no dementia should be performed at 3 months after index stroke ii. Cognitive impairment; one or more cognitive domains regardless of including memory domain Newly developed post-stroke dementia (ND-PSD) Newly developed dementia after index stroke which was meet the criteria of DSM-IV i. To avoid the impact of acute stroke, final diagnosis of dementia should be performed at 3 months after index stroke ii. No dementia before the index stroke, identified by K-IQCODE (<3.6) iii. Dementia defined by the criteria of DSM-IV 141
J Neurocrit Care 2008;1:137-142 Post-stroke dementia (PSD) Newly developed PSD PSD Degenerative dementia (especially) AD PSD with AD Stroke Cognitive Impairment with No Dementia: PSCI- ND), 그리고뇌졸중후새로발생한치매 (Newly Developed Post-Stroke Dementia: ND-PSD) 와인지장애 (Newly Developed Post-Stroke Vascular Cognitive Impairment with No Dementia: ND-PSCIND) 를모두포함한다 (Fig. 3). K-VCIH study 의결과는 2009년상반기에국내외관련학회에서발표될예정이며국내에서도이를통해국제적으로표준화된혈관치매환자의인지기능평가도구가확립되고혈관성인지장애의개념을새로이정립할수있을것이며또한국내혈관성인지장애의질병부담의기본적평가및역학자료가마련될수있을것으로기대된다. REFERENCES Vascular cognitive impairment (VCI) Post-stroke cognitive Impairment with no dementia (PSCI-ND) Newly developed PSCI-ND PSCI-ND MCI FIGURE 3. The concepts of vascular cognitive impairment of Korean-vascular cognitive impairment harmonization study. 1. Román GC. Vascular dementia may be the most common form of dementia in the elderly. J Neurol Sci 2002;203-204:7-10. 2. Román GC. On the history of lacunes, etat crible, and the white matter lesions of vascular dementia. Cerebrovasc Dis 2002;13 Suppl 2:1-6. 3. Román GC. A historical review of the concept of vascular dementia: Lessons from the past for the future. Alzheimer Dis Assoc Disord 1999; 13 Suppl 3:S4-8. 4. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11:205-42. 5. Hachinski VC, Iliff LD, Zilhka E, Du Boulay GH, McAllister VL, Marshall J, et al. Cerebral blood flow in dementia. Arch Neurol 1975; 32:632-7. 6. Hachinski VC, Bowler JV. Vascular dementia. Neurology 1993;43: 2159-60; author reply 2160-1. 7. Bowler JV. The concept of vascular cognitive impairment. J Neurol Sci 2002;203-204:11-5. 8. Bowler JV. Modern concept of vascular cognitive impairment. Br Med Bull 2007;83:291-305. 9. Ingles JL, Wentzel C, Fisk JD, Rockwood K. Neuropsychological predictors of incident dementia in patients with vascular cognitive impairment, without dementia. Stroke 2002;33:1999-2002. 10. Sachdev P. Vascular cognitive disorder. Int J Geriatr Psychiatry 1999; 14:402-3. 11. Erkinjuntti T, Bowler JV, DeCarli CS, Fazekas F, Inzitari D, O Brien JT, et al. Imaging of static brain lesions in vascular dementia: Implications for clinical trials. Alzheimer Dis Assoc Disord 1999;13 Suppl 3:S81-90. 12. Pohjasvaara T, Mantyla R, Ylikoski R, Kaste M, Erkinjuntti T. Comparison of different clinical criteria (dsm-iii, addtc, icd-10, nindsairen, dsm-iv) for the diagnosis of vascular dementia. National institute of neurological disorders and stroke-association internationale pour la recherche et l enseignement en neurosciences. Stroke 2000; 31:2952-7. 13. Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D, et al. Relative frequencies of alzheimer disease, lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the state of florida brain bank. Alzheimer Dis Assoc Disord 2002;16: 203-12. 14. AD K. Mixed dementia: the most common cause of dementia. Ann N Y Acad Sci 2002;977:129-34. 15. Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, et al. National institute of neurological disorders and strokecanadian stroke network vascular cognitive impairment harmonization standards. Stroke 2006;37:2220-41. 142