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1 2009 대한치매학회추계학술대회및보수교육 모시는말씀 사랑하고존경하는대한치매학회회원여러분들께, 가을이점차깊어지고있습니다. 들녘에서는가을걷이가한창입니다만날씨가추워지면서신종플루가맹위를떨치고있어한편으로는걱정스럽습니다. 모두들건강에유념하시기바랍니다. 오는 11월 27일 ( 금 )~28일( 토 ) 양일에걸쳐대한치매학회추계학술대회가개최됩니다. 회원여러분들이지난한해동안이룬연구의결실을소개하고그동안이루어진치매연구의최신지견에대한의견을교환하는장을마련하고자합니다. 또한파킨슨증상과관련한다양한치매에대하여학문적으로접근하는방법을다룰예정입니다. 이번학술대회가학문에대한목마름을해결함은물론회원여러분상호간에친목을도모할수있는화합의장이될수있기를기원합니다. 우리대한치매학회의학문적발전과단합된모습을보여주기위해여러분의적극적인참여가무엇보다중요합니다. 밝고건강한모습으로학술회의장에서여러분모두를뵙게되길진심으로고대합니다 년 11 월 대한치매학회이사장한설희드림

2 2009 대한치매학회추계학술대회및보수교육 Contents <November 27> Basic Neuropsychology for the Evaluation of Dementia 좌장 : 강연욱 ( 한림대학교심리학과 ) 18:00-18:20 Attention 류희진 ( 건국대학교병원 ) / 25 18:20-18:40 Motor Function 박아람 ( 한양대학교병원 ) / 10 18:40-19:00 Language 서미경 ( 삼성서울병원 ) / 15 19:00-19:20 Apraxia and Gerstmann Syndrome 백민재 ( 서울대학교병원 ) / 18 19:20-19:30 Q & A 19:30-19:50 Coffee Break 19:50-20:10 Visuospatial Function 오은아 ( 한림대학교강동성심병원 ) / 25 20:10-20:30 Memory 박재설 ( 한림대학교병원 ) / 31 20:30-20:50 Frontal Function 진주희 ( 삼성서울병원 ) / 38 20:50-21:10 Q & A Hot Topics in the Field of Dementia 좌장 : 한설희 ( 건국대학교병원신경과 ) 18:00-18:20 Neurodegenerative Proteinopathy 안성수 ( 경원대학교 ) / 49 18:20-18:40 Amyloid in AD 한설희 ( 건국대학교병원 ) / 55 18:40-19:10 Tau Function in AD 정용근 ( 서울대생명과학부 ) / 63 19:10-19:20 Q & A 19:20-19:40 Coffee Break 19:40-20:10 Neuronal Cell Death in AD 고재영 ( 서울아산병원 ) / 68 20:10-20:40 Genetic Markers in AD 기창석 ( 삼성서울병원 ) / 74 20:40-21:00 Neurovascular Pathogenesis of AD 이순태 ( 서울대학교병원 ) / 79 21:00-21:10 Q & A

3 2009 대한치매학회추계학술대회및보수교육 Contents <November 28> Parkinsonism & Dementia 좌장 : 김영현 ( 전북대학교병원신경과 ) 좌장 : 이재홍 ( 서울아산병원신경과 ) 08:30-09:00 Registration 09:00-09:30 Parkinsonism & Dementia 김상윤 ( 서울대학교병원 ) /087 09:30-10:00 Parkinson s Disease Dementia 김재우 ( 동아대학교병원 ) /091 10:00-10:30 Dementia with Lewy Bodies 박경원 ( 동아대학교병원 ) /095 10:30-11:00 Coffee Break 11:00-11:30 Parkinson-Related Dementia I (CBD, PSP, FTDP-17) 양동원 ( 가톨릭대학교서울성모병원 )/101 11:30-12:00 Parkinson-Related Dementia II (Vascular parkinsonism, NPH) 박기형 ( 가천의대길병원 ) /111 12:00-13:20 Lunch Case Discussion 좌장 : 나덕렬 ( 삼성서울병원신경과 ) 좌장 : 윤영철 ( 중앙대학교병원신경과 ) 13:20-13:50 Case I 13:50-14:20 Case II 14:20-14:50 Case III 14:50-15:10 Coffee Break 15:10-15:40 Case IV 15:40-16:10 Case V

4 2009 대한치매학회추계학술대회및보수교육 November 27 Basic Neuropsychology for the Evaluation of Dementia 좌장 : 강연욱 ( 한림대학교심리학과 ) Hot Topics in the Field of Dementia 좌장 : 한설희 ( 건국대학교병원신경과 ) 1

5 2009 대한치매학회추계학술대회및보수교육 Basic Neuropsychology for the Evaluation of Dementia 좌장 : 강연욱 ( 한림대학교심리학과 ) Attention 류희진 ( 건국대학교병원 ) Motor Function 박아람 ( 한양대학교병원 ) Language 서미경 ( 삼성서울병원 ) Apraxia and Gerstmann Syndrome 백민재 ( 서울대학교병원 ) Visuospatial Function 오은아 ( 한림대학교강동성심병원 ) Memory 박재설 ( 한림대학교병원 ) Frontal Function 진주희 ( 삼성서울병원 ) 3

6 Basic Neuropsychology for the Evaluation of Dementia November 27,

7 Attention Korean Dementia Association

8 류희진 7

9 Attention Korean Dementia Association

10 류희진 9

11 Basic Neuropsychology for the Evaluation of Dementia November 27, 2009 Why do we test motor function? Motor Functions Indicators of lesion lateralization Basic information for interpretation of higher cortical functions Quantitative information for motor function Aram Park Department of Neurology Hanyang College of Medicine Detection of neurodegenerative disease 2 Introduction Brain Structures Involved in Motor Control Brain Structures Involved in Motor Functions Motor System & Movement Disorder Neuropsychological Assessment of Motor Functions Handedness Gross / Fine / Complex Motor Function Subcortical regions Motor Tracts Cerebellum Basal Ganglia Cortical regions Primary Motor Cortex Supplementary and Premotor areas Anterior Cingulate Cortex Frontal Eye Field Parietal Lobe 3 4 The functional architecture of motor system: Functional hypotheses regarding how these different structures contribute to actions Motor system & Movement disorder Subcortical Areas Parkinson s disease Huntington s disease Tourette s syndrome Tardive dyskinesia Cortical Areas Hemiplegia Apraxia Alien limb syndrome Korean Dementia Association

12 박아람 Neuropsychological Assessment of Motor Functions Handedness Test Cerebral dominance Initiation and perseveration Manual dexterity Graphomotor skills Balance Ambulation Motor speed Speech regulation Motor strength Edinburgh Handedness Inventory (EHI; Oldfield, 1971) 1. 글씨를쓸때 2. 그림을그릴때 3. 종이를자를때가위를드는손 4. 칫솔질할때칫솔을드는손 5. 국을뜰때수저를뜨는손 6. 도마위에서야채나고기를썰때칼을쥐는손 7. 성냥불을켤때성냥을쥐는손 8. 상자의뚜껑을열때뚜껑을쥐는손 9. 목표를맞추기위해서어깨너머로작은공을던질때공을쥐는손 10. 대빗자루를두손으로잡고마당을쓸때빗자루의 ( 막대쪽 ) 끝을잡는손 7 8 Three Categories of Motor Function Three Categories of Motor Function Gross Motor Function Motor control involving strength, steadiness, or rapid body movements that place minimal demands on visual guidance Fine Motor Function Motor control involving rapid unimanual or symmetric bimanual placement of objects into precise locations, requiring eye-hand coordination Frontoparietal network Fine motor function Complex motor function Frontostriatal network Gross motor function Complex Motor Function Motor control involving tracking in two or more planes of space, alternating patterns of movements, or rapid asymmetric, bimanual constructions 9 10 Three Categories of Motor Function Gross Motor Function Gross Motor Speed Strength Steadiness Fine Motor Function Purdue / Grooved Pegboard Complete Minnesota Manual Dexterity Test Complex Motor Function Fist-edge-palm / Alternating Hand Movement Assembly Test of Purdue Pegboard Roeder Manipulative Aptitude Test Two-Arm Coordination Test Mirror Tracer A. Gross Motor Function Test Gross Motor Speed Finger Tapping Test Foot Tapping Test Tapping Board Test Strength Grip Strength Test JAMAR Hydraulic Hand Dynamometer Push/Pull Dynamometer Steadiness Groove Type Steadiness Tester Hold Type Steadiness Tester

13 Motor Functions Finger-Tapping Test (Finger Oscillation Test) Other test of Gross motor speed Halstead-Reitan Neuropsychological Test Battery (Halstead, 1947) Simple motor speed 10 sec x 5-10 trial on each hand Average tapping number Right-left hand discrepancy Age, sex, education effects Lateralized lesions, Diffuse brain injury, epilepsy, & Disease that involve the spinal cord Normal aging & AD Foot-Tapping Test Tapping Board Test (the electronic tapper) Using a metal tipped stylus A timer/counter can be used for data collection Grip Strength Test Other Tests of Strength Hand Dynamometer (Reitan and Wolfson, 1993; Spreen & Strauss, 1998) General body strength Two trials for each hand alternating between hands Average tapping number Right-left hand discrepancy Sex and age effect JAMAR Hydraulic Hand Dynamometer 400 Pound Push / Pull Dynamometer Steadiness Test B. Fine Motor Function Test Groove Type Steadiness Tester Hole Type Steadiness Tester Purdue Pegboard Test Grooved Pegboard Test O Connor Finger Dexterity Test O Connor Tweezer Dexterity Test Complete Minnesota Manual Dexterity Test Korean Dementia Association

14 박아람 Purdue Pegboard Test Grooved Pegboard Manual dexterity for employment selection(purdue research foundation, 1948; Tiffin, 1968). Test procedure Preferred hand > the other hand > both hands simultaneously Each condition lasts for 30 sec Sex, age, & practice effect Sensitive instrument for measuring general slowing Medication, diffuse brain dysfunction, toxic effects, or progression of disease processes such as parkinsonism or HIV infection Normal aging, MCI, & AD Complex coordination to the pegboard task (Klove, 1963) Board containing a 5x5 set of slotted holes angled in different directions Each peg has a ridge along one side Score is time to completion Age, sex, practice effect Other Tests of Fine Motor Function C. Complex Motor Function Test O Connor Finger Dexterity Test O Connor Tweezer Dexterity Test Fist-edge-palm Alternating Hand Movement Assembly Test of Purdue Pegboard Two-Arm Coordination Test Complete Minnesota Manual Dexterity Test Mirror Tracer Roeder Manipulative Aptitude Test Complex Motor Function Test Purdue Pegboard Test - Assembly Fist-edge-palm Alternating Hand Movement Procedure Pine (dominant H) Washer (non-dominant H) Collar (dominant H) Washer (non-dominant H) alternating procedure

15 Motor Functions Complex Motor Function Test Complex Motor Function Roeder Manipulative Aptitude Test Hand Tool Dexterity Test Auto Scoring Mirror Tracer Two-Arm Coordination Test Application of Motor Function Test Application of Motor Function Test Index of Laterality Finger Tapping, Purdue Pegboard, Grip Strength Test > Grooved Pegboard Test Standardized laterality index: 100 X (R-L)/(R+L) Average of intermanual discrepancies: 10% advantage for the dominant hand Motor slowing vs. cognitive problem Trail Making Test Digit Symbol Test Rey copy Detection of brain damage & neurodegenerative disease Quantitative information of motor function Medication effect, pre-post operation, disease progression Detection of malingering Extremely poor performance Physiological complexity gradient (Grip > Finger > Pegboard) Thank you for your attention Korean Dementia Association

16 Basic Neuropsychology for the Evaluation of Dementia November 27, 2009 Neurological model of oral communication Meitus & Weinberg(1983) Neurogenic language and speech disorders 삼성서울병원신경과 서미경 Ideation Symbolization Translation Execution When concepts we wish to express are generated When concepts are put into the symbolic system congruent to the speaker s language When linguistic units of symbols are translated into neuromotor commands that result in innervation of motor nerves Actual movement of speech mechanism Aphasia Aphasia Apraxia of speech Dysarthria Is a loss or impairment of previously, normally functioning language processing Is aquired through brain injury Not a perceptual disorder Not a movement disorder Not a disordered thought process Fluency: rate, quantity, ease of speech production Nonfluent speech Fluent speech ** language vs speech disorder Comprehension Word Word deafness Word meaning sentence simple complex (grammatical complexity) 15

17 Neurogenic Language and Speech Disorders Repetition Naming Confrontation naming Generative naming Reading Paraphgraph, sentence, words (words, nonwords, irregular words) Reading aloud, comprehension Writing Spontaneous writing Dictation Words (words /nonwords/irregular words) Sentence Fluency Comprehension Repetition Naming Aphasia type Apraxia of Speech Nonfluent Fluent Broca Transcortical Motor Mixed transcortical Global Wernicke Transcortical Sensory Conduction Anomic Phonetic-motoric disorder of speech production Inefficiencies in the translation of a well formed and filled phonological frame to previously learned kinematic parameters for intended movements Temporal, spatial displacement in intra and inter articulatory movements. Prosodic distortions Dysarthria Central and peripheral nervous system abnormalities Abnormalities in strength, speed, range, steadiness, tone, accuracy of muscle movements Speech subsystems Respiration Phonation Resonance Articulation Rate/prosody Korean Dementia Association

18 서미경 Screening for speech disorders Maximum phonation time Alternating motion rate (AMR)/ Sequenctial motion rate (SMR) /puh/, /tuh/, /kuh/, /puh-tuh-kuh/ Conversation/ reading passage Language and Speech disorders in Dementia FTLD FTD Progressive nonfluent aphasia Semantic Dementia AD VD 17

19 Basic Neuropsychology for the Evaluation of Dementia November 27, 2009 Gerstmann Syndrome (1930) 1. Agraphia ( 실서증 ) 2. Acalculia ( 실산증 ) 3. Right-left disorientation ( 좌우지남력장애 ) 4. Finger agnosia ( 손가락실인증 ) 분당서울대학교병원뇌신경센터 / 신경심리연구실백민재 4 가지증상이반드시같이나타나지않아도됨 Finger agnosia 가가장드문현상 Left hemisphere angular gyrus supramarginal gyrus (near the temporal & parietal lobe junction) Benton, 1992; Heimburger 등, 1964; Brusa 등, 1960; Santos 등 다양한신경질환에의해서발생 - 좌측의큰병변이나다양한병변에의해서발생 Roeltgen 등, 1983; Varney, 1984; Mazzoni 등, 1990; Morris 등, Left angulargyrus - 전기자극에의하여 Gerstmann syndrome만나타날수있음 Heimburger 등 (1964) - left hemisphere > right hemisphere (78% vs. 13%) - parietal lobe, temporal lobe, occipital lobe 에광범위하게분포 - Gerstmann syndrome 의 4 가지증상을보이는환자는다른뇌기능장애도같이동반됨 Agraphia: neurological disorder involving the loss of the ability to write (Benedikt, 1865) Brain areas responsible for writing - the left frontal lobe : Exner's Writing Area and Broca's Expressive Speech area : expressive aspects of writing - the left temporal lobe : Wernicke's receptive speech area : comprehension of written words - the superior and inferior parietal lobe : converting or visual images and sounds into written symbols linguistic & motor stages Linguistic stages (angular gyrus) - auditory and visual information syntactical-lexical units (the symbols for letters & written words) Motor components (Exner s writing area) - expression of graphemes Korean Dementia Association

20 백민재 Evaluating both linguistic & motor components Linguistic components 1. spelling 2. meaning Motor components 1. producing the correct letter form 2. producing the correct word form Spontaneous writing Writing to dictation copying 익숙한주제를가지고문장또는단어를쓰게함 ex) 오늘날씨에대해서써보세요. 그림을보여주고그림에대해서쓰게함 Assessment - generative abilities -selection -syntax - form the patient s writing 1. Parietal agraphia 2. Lesions of the left inferior parietal lobule (angular gyrus) 3. Disturbance with reading and writing 4. Difficulty with spelling (writing) 5. Alexia is a loss of the ability to read without motor abnormalities Frontal agraphia Pure agraphia Agraphia with alexia Apraxic agraphia Spatial agraphia 1. Lesions of the superior parietal lobule, the posterior perisylvian fissure, or Exner s area 2. loss of the ability select, from, and express words and sentences 3. misspelling words, inserting wrong letters 4. place letters in wrong order or sequence 5. unimpaired of reading or oral speech Dysfunction or inability to perform mathematical operations, recognize numbers, or count - Difficulty performing simple mathematical tasks (addition, subtraction, multiplication, or division) - difficulty in simply stating which of two numbers is larger Acquiring late in life due to neurological injury Lesions of the parietal lobe & the frontal lobe Early signs of dementia Double dissociations - lesions to the angular gyrus 1. greater impairment in memorized mathematical facts (multiplication tables) 2. relatively unimpaired subtraction abilities - lesions in the region of the intraparietal sulcus 1. greater deficits in subtraction 2. relatively preserved multiplication abilities (Dehaene and Cohen, 1997) 19

21 Gerstmann Syndrome & Apraxia > 31 or 31 > 28? (presenting verbally and visually) 2. Reading numbers aloud 3. Pointing to written numbers that are named by the examiner 4. Writing numbers to dictation 5. Writing numbers from copy 6. Counting out loud from 1 to 20, from 20 to 1, and from 1 to 20 by 2 s 7. Oral arithmetic calculation in which simple examples are given using each of the four basic operations 8. Written arithmetic calculation in which the examples are similar to those given orally 9. Arithmetic reasoning ability via the Arithmetic Reasoning subtest of the K-WAIS Loss of ability to indicate one s own or another s fingers Most often caused by lesion of or near the angular gyrus of the dominant hemisphere Benton (1959) and Benton et al. (1994) - developed finger localization test - 60-item test consisting of three parts 1. 손을볼수있는상태에서, 연필끝으로건드린손가락하나의위치를알아맞추기 ( 각손에 10 번 ) Patients with finger agnosia - loss of ability to name fingers - loss of ability to show fingers on verbal command - loss of ability to localize fingers following tactile stimulation 2. 손을볼수없는상태에서, 손가락하나의위치를알아맞추기 ( 각손에 10 번 ) 3. 손을볼수없는상태에서, 동시에자극되어진손가락두개의위치를알아맞추기 ( 각손에 10 번 ) Part A ( 손을볼수있는상태에서, 한손가락을확인 ) 오른손 : 1, 4, 2, 5, 3, 4, 1, 3, 5, 2 왼손 : 2, 5, 3, 1, 4, 3, 5, 2, 4, 1 Part B ( 손을볼수없는상태에서, 한손가락을확인 ) 오른손 : 2, 4, 1, 5, 3, 4, 2, 3, 1, 5 왼손 : 5, 1, 3, 2, 4, 3, 5, 1, 4, 2 Part C ( 손을볼수없는상태에서, 두손가락을동시에확인 ) 오른손 : 1-3, 3-4, 1-2, 2-5, 2-3, 3-4, 3-5, 2-4, 2-3, 1-4 왼손 : 1-4, 2-3, 2-4, 3-5, 3-4, 2-3, 2-5, 1-2, 3-4, 1-3 Disability to identify the right and left sides of one s own body Disability to identify the right and left sides of a person seated opposite or in a photo or drawing 좌 - 우지남력에대한가설 1. 공간적사고의결함 (Badal, 1888) 2. 자기신체에관한지남력의결함 (Pick, 1908) 3. 신체표상에대한결함 (Gerstmann, 1930) 4. 상징적사고에대한결함 (Head 1926) Korean Dementia Association

22 백민재 자기신체 에대한지남력 ex) 1. 왼쪽귀를지적하시오. 2. 왼손으로왼쪽귀를가리켜보시오. 3. 오른손으로왼쪽귀를가리켜보시오. 상대방 에대한지남력 ex) 1. 상대방의왼쪽귀를지적하시오. 2. 상대방의오른손을가리켜보시오. 자기신체 와 상대방 에대한복합지남력 ex) 1. 왼손으로상대방의오른쪽귀를가리켜보세요. Finger naming Body part identification 자 극 정반응 오반응 자 극 정반응 오반응 왼쪽팔목 엄지손가락 오른쪽팔꿈치 새끼손가락가운데손가락 오른쪽무릎왼쪽어깨 Right-left orientation 자 극 정반응 오반응 씨의왼손을보여주세요. 제 ( 검사자 ) 오른손을가리켜보세요. 씨오른손을제왼손위에놓으세요. Motor programming 의결손으로인하여이미반복하여학습된운동 (skilled movement) 이나몸짓 (gesture) 에대한장애 - not be caused by paralysis, sensory loss, incoordination, ataxia, movement disease, and poor comprehension (Liepmann, 1920; Heilman, 1993) Ideomotor apraxia - limb apraxia - buccofacial apraxia Ideational apraxia Callosal apraxia Verbal apraxia (Apraxia of speech) Constructional apraxia Oculomotor apraxia 간단한몸짓 ( 가위질, 망치질등 ) 을행하지못하는경우 검사는간단하지만, 반응내용을정확하게분석하여점수화하는것은어려움 1. Limb apraxia ( 사지실행증 ) - transitive items ( 도구를사용하는항목 ) - intransitive items ( 도구를사용하지않는항목 ) 2. Buccofacial apraxia ( 안면구강실행증 ) - transitive items ( 도구를사용하는항목 ) - intransitive items ( 도구를사용하지않는항목 ) Left inferior parietal lobe Left frontal lobe -premotorcortex - supplementary motor area Corpus callosum - 왼손에만 ideomotor apraxia 가나타남 Callosal apraxia 21

23 Gerstmann Syndrome & Apraxia Frontal operculum - 하부전두엽부위 ( 브로카영역 ) - 운동피질의실비우스열과만나는부위 Insula Centrum semiovale putamen Transitive Items 1. 망치질하는흉내 2. 드라이버를사용하는흉내 3. 가위질하는흉내 4. 열쇠로문을여는흉내 5. 김밥을써는흉내 Intransitive Items 1. 잘가라는손짓 2. 이리오라는손짓 3. ( 경찰또는군인들이하는 ) 거수경례 4. 당신이최고다 또는 제일이다 라는표시를할때사용하는손짓 5. 조용히하라고할때쓰는몸짓 ( 손가락과입술을사용 ) Transitive Items 1. 냄새맡는흉내 2. 휘파람부는흉내 3. 빨대로빠는흉내 4. 윙크 ( 한쪽눈만감기 ) 5. 촛불끄는흉내 Intransitive Items 1. 눈감기 2. 입벌리기 3. 혀내밀기 4. 기침하기 5. 혀를차는흉내 ( 남에게안타까운일이생겼을때 ) Content error - 내용적오류 Temporal error - 시간적오류 Spatial error - 공간적오류 Korean Dementia Association

24 백민재 Perseveration error ( 보속오류 ) - 앞에서실시한동작의일부나전부가다음동작에나타나는경우 Related content error ( 관련된동작오류 ) - 정확한몸짓이지만정답이아닌다른동작이며정답과의미적으로연관이있는경우 ex) 수저질 젖가락질 Non-related content error ( 무관한동작오류 ) - 정확한몸짓이지만정답이아닌다른동작이며정답과무관한동작을보이는경우 ex) 수저질 면도질 Sequencing error ( 순서오류 ) - 어떤동작은여러단계의구분동작으로구성되어있고, 이들이올바른순서로연결되어야함 ex) 열쇠로문여는동작 열쇠를쥐고, 넣고, 돌리고, 원위치로, 빼는동작으로구성됨 - 이동작들의순서중첨가, 탈락, 순서바뀜이나타나는경우 Timing error ( 속도오류 ) - 동작의속도가너무빠르거나, 느리거나불규칙한경우 Occurrence error ( 횟수오류 ) - 1 회성동작 ( 병따는흉내 ) - 동작을반복해야하는반복성동작 ( 톱질하기, 김밥써는흉내 ) - 1 회성동작을여러번반복하거나, 반복성동작의횟수가감소되는경우 Delayed error ( 지연오류 ) - 동작의시작이지연되는경우 Amplitude error ( 동작의크기오류 ) - 필요이상으로큰경우 - 지나치게작을경우 - 매우불규칙한경우 Internal Configuration Orientation error ( 내형오류 ) - 몸, 도구, 도구의목표가서로올바른공간적위치관계를가져야함 - 내적인형태 : 몸과도구와의관계 - 외적인형태 : 도구와도구의목표물과의관계 - 내형오류 (ICO): 손가락이나손의모양이도구를쥐고있는모양이아닌경우 ex) 망치를쥐었을때, 손을완전히쥐어서망치를든모양이되어야함 External Configuration Orientation error ( 외형오류 ) - 손에쥔도구와도구의목표물이올바르지않은공간적관계 ex) 망치의머리가책상위의못을치지못하고, 다른곳을향함 Body-Part-as-Object error ( 신체일부의도구화오류 ) - 손가락이나손을도구처럼사용 ex) 김밥썰기흉내 손을칼처럼사용함 Movement error ( 운동오류 ) - 목적동작의특징적인운동에오류를보이는경우 ex) 드라이버로나사를조이는경우 손목대신어깨나팔을돌림 가위질하는흉내를내보세요. - 만약손가락을가위날로사용하는행동을보이면, 실제로가위가손에있다고생각하고흉내를내보십시오. 정상인에게도흔히나타날수있는오류 한두번지침을반복해도동일한오류를보이는경우 실행증으로간주함 실제로가위질을하는경우에는문제가없음 Buccofacial apraxia에서도보임 23

25 Gerstmann Syndrome & Apraxia Inability to carry out a series of acts Inability to create ideational plan Inability to create idea of a specific movement due to impairment in the perception of its function or purpose (Marcus, 1904; Pick 1905) Patients with ideational apraxia -having difficulty sequencing acts in the proper order - not knowing the proper use of an object - no loss of motor movement or strength Korean Dementia Association

26 Basic Neuropsychology for the Evaluation of Dementia November 27, 2009 What is the visuospatial function? VISUOSPATIAL FUNCTION Over 50% of the human brain is involved with visual processing. 11% somatosensory function 3% auditory function Many of our daily expressions reflect our reliance on sight. 백문이불여일견 첫눈에반했다 강동성심병원치매예방센터오은아 What is the visuospatial function? Two visual pathways system Vision for action Spatial processing WHERE? Vision for action Vision for perception Visual recognition WHAT? Vision for perception Ventral visual system- WHAT? Object Recognition Not a template match between input image and stored representation, but flexibly accommodates considerable changes in images clue to changes in illumination, viewing angles, orientation, and so on. Failure of Object Recognition Visual Agnosia Individuals who demonstrate object recognition problems despite the fact that visual information continues to be registered at the cortical level Apperceptive agnosia Object Associative agnosia Prosopagnosia Face Pure alexia Written word Topographical agnosia Place 25

27 Visuospatial Function Failure of Object Recognition Apperceptive agnosia Elementary visual functions, such as acuity, brightness discrimination, depth perception, are normal or only mildly disordered but recognition is impaired. Failure to accommodate the perceptual constancies Cannot group elements into higher order configurations & cannot perceptually recognize or match objects Copying performance is very poor Failure of Object Recognition Lesion areas Diffuse across occipital regions Associative agnosia Impairment in the assignment of meaning to a normally perceived object Manifest as an inability to perform object naming, but the problem is not one of anomia per se Lesion areas Bilateral at the occipito-temporal border The typical lesion in associative agnosia is more anterior than the lesion in apperceptive agnosia Korean Dementia Association

28 오은아 Failure of Object Recognition Prosopagnosia Selective inability to recognize or differentiate among faces, although other objects in the visual modality can be correctly identified Can recognize a face as a face Even be able to determine the sex or relative age (old or young) of a person s face and the emotion that it is expressing Loss of the ability to recognize familiar individuals by face alone, irrespective of preservation or loss of the ability to discriminate between unfamiliar faces Prosopagnosia McCarthy et al. (1997) J. Cogn, Neurosci Fusiform Face Area (FFA; Rt. > Lt.) Engagement during face perception tasks Important for the perceptual processes that must be performed to create a configural representation of a face and to extract the invariants of the face that make it unique Failure of Object Recognition (Pure) Alexia Reading disorder It occurs in isolation from other visual & language disorder Ability to understand spoken language and recognize object is grossly intact Loss of visual word forms Lesion Left temporo-occipital region Visual Word Form Area (VWFA) Failure of Object Recognition Topographical agnosia The impairment is appropriately grouped with disorders of visual recognition rather than of spatial cognition Spatial abilities are preserved Patients develop a heavy dependence on their preserved spatial abilities to find their way around the environment and are able to use maps McCandiss et al. (2003) Topographical agnosia Ventral perception stream Parahippocampal Place Area (PPA) Posterior parahippocampal cortex & anterior lingual gyrus Respond strongly to complex visual scenes Perception or coding of the local scene Respond not just when scenes are visible, but also when scenes are cued or brought to mind (mental imagery) Familiarity effects are small FFA (faces) PPA (places) VWFA (Written words) area LO (Objects) 27

29 Visuospatial Function Two visual pathways system Vision for action Dorsal visual system- WHERE? Basic spatial processes Depth perception Orientation of Lines Motion Localization in space Vision for perception Dorsal visual system- WHERE? Macaque Monkey (single-unit studies) (reaching) Dorsal visual system- WHERE? LIP saccades Human (fmri studies) Separate regions of the dorsal stream are involved in the mediation of visually guided saccades, visually guided reaching movements, and visually guided grasping AIP grasping (saccades) (grasping) Cohen & Anderson (2002) Nature Reviews Connolly et al. (2002) Nature Neuroscience Connolly et al. (2003) EBR Culham et al. (2003) EBR PRR reaching Dorsal visual system- WHERE? Dorsal Visual system- WHERE? Balint s Syndrome Optic ataxia inability to point to a target under visual guidance Gaze apraxia Inability to voluntarily shift gaze toward a new visual stimulus Simultanagnosia Inability to perceive different pieces of information in the visual field simultaneously because the person cannot direct attention to more than one small location in the visual world at a time Simultanagnoisa 가가가가가가 가가가가가가가가가가가 Korean Dementia Association

30 오은아 Visuospatial output Constructional ability Ability to motorically produce or manipulate items so that they have a particular spatial relationship Visuospatial output Visuospatial Function in dementia Route-finding & Topographical Skills Navigation is often not simple We have a multiplicity of spatial frameworks with which to understand relationships between points Relationships between points in space that are within our range of view Relationships between points that are outside our rage of view (can be symbolized on maps) Relationships between points in space and our bodies Topographical orientation Topographical memory 물건을찾지못한다 물건을바로앞에두고도찾지못한다 가족들을잘알아보지못한다 길을잃거나헤맨다 집에서화장실이나자기방을잘찾지못한다 머리맡도알지못한다 Alzheimer s Dementia- 76/F, 6 년 Alzheimer s Dementia- 71/F, 12 년 2007/05/ /07/ /05/ /09/ /05/16 36/36(92.8%ile) 36/36(92.8%ile) 초등학교교사, 9 분 4 초 (<1%ile) 7 분 23 초 (<1%ile) 2009/08/06 29

31 Visuospatial Function Alzheimer s Dementia- 66/F, 12 년 2007/02/16 K-MMSE: 24/ /11/30 K-MMSE: 21/ /02/19 K-MMSE: 19/30 65/M, 초중퇴, 31/36 (77.9%ile) Parkinson s Disease 62/M, 대졸, 21.5/36(<1%ile) Vascular Dementia Korean Dementia Association

32 Basic Neuropsychology for the Evaluation of Dementia November 27,

33 Memory Korean Dementia Association

34 박재설 33

35 Memory Korean Dementia Association

36 박재설 35

37 Memory Korean Dementia Association

38 박재설 37

39 Basic Neuropsychology for the Evaluation of Dementia November 27, 2009 Frontal Lobe Functions 1 Neuropsychological tests for frontal lobe functions Attention Working memory Memory Visual construction Motor function Emotion and personality Concept formation Reasoning Executive function 27 th Nov Frontal lobes Functions 2 Prefrontal lobes Functions Patients with selective frontal lobe damage usually display deficits in judgment, insight, mental flexibility, reasoning, abstraction, planning, sequencing, comportment and the attentional matrix. S. Weintraub (2000) Executive function is an umbrella term comprising a wide range of cognitive processes and behavioral competencies Dorsolateral Prefrontal Cortex Poor organization strategies Poor memory search strategies Stimulus-bound behavior / environmental dependency Impaired set shifting and maintenance Verbal-manual dissociation Orbitofrontal Cortex Personality change Environmental dependency Obsession / compulsion Medial Frontal Cortex Impaired motivation Reduced creative thinking Poor response inhibition Frontal-subcortical circuits Dorsolateral prefrontal dysfunctions Executive dysfunction Dorsolateral Prefrontal Circuit Lateral Prefrontal Cortex Caudate dorsolateral GP VA, MD Thalamus Disinhibition Orbitofrontal Circuit Orbitofrontal Cortex Caudate ventromedial GP VA, MD Thalamus Apathy Anterior Cigulate Circuit Anterior Cingulate Gyrus Nucleus accumbens GP MD Thalamus Executive dysfunctions Disorganizing a volitional response to environmental contingencies Impairment of recalling past events and planning current actions in a temporally informed manner Problems with programming motor acts to follow volitional command Not able to implement programs to achieve the intended goal Not monitoring the results of the action to determine the success of the intervention Impairment of adjusting or stopping the action depending on the outcome of the assessment Korean Dementia Association

40 진주희 Orbitofrontal dysfunctions Medial frontal dysfunctions Disinhibition Poor social judgment Impulsive decision making Lack of consideration for the impact of their behavior Lack of empathy for others Personality change Emotional incontinence / Impulsivity / Irritability Antisocial behavior: Pseudopsychopathic Environmental dependency Utilization behavior / Imitation behavior Impaired motivation / apathy Akinetic mutism / Marked apathy Poverty of spontaneous speech Reduced creative thought Poor response inhibition Impaired Go/No-Go test performance Problem in Theory of mind Four functional domains within the frontal lobes Stuss, D.T. (2007) Executive cognitive functions Lateral prefrontal cortex (LPFC) Spatial and conceptual reasoning High-level cognitive functions: control and direction of lower level Planning, monitoring, energizing, switching, inhibiting Dorsolateral preforntal circuit Behavioral-emotional self-regulatory functions Ventro (medial) prefrontal cortex (VPFC) Emotional processing Acquisition and reversal of stimulus-reward associations Behavioral self-regulation Lateral orbitofrotnal circuit Energization regulating functions Superior medial frontal pathology disorder of energization and drive; clinically apathy or abulia Close relationship with self-regulation Medial frontal/anterior cingulate circuit Metacognitive processes Frontal polar region (right?) Integrating the higher-level executive cognitive functions, emotional or drive-related inputs Cold vs. Hot component of executive functions Chan, R.C.K. (2008) Cold component of executive functions Reasoning, problem-solving, planning, sequencing, ability to sustain attention, resistance to interference, utilization of feedback, multitasking, cognitive flexibility, ability to deal with novelty Relatively mechanistic or logical Hot component of executive functions Involving more emotional, belief, or desires such as the experience of reward and punishment, regulation of social behavior, decision-making involving emotional and personal interpretation Concept Formation Impairment of concept formation Concrete thinking Mental inflexibility Inability to think in useful generalization Difficulty in using categories Tests of concept formation focus on the quality or process of thinking more than the content of the response and provide the information about how the patent thinks

41 Neuropsychological Tests for Frontal Lobe Functions Concept Formation Tests Proverbs Concept formation tests in verbal formats Proverbs Similarity Concept formation tests in visual formats Category test Raven Progressive Matrices Sorting and shifting test Wisconsin Card Sorting Test Abstract thinking vs. concrete thinking Mental Status Examinations Proverbs test (Gorham,1956) California Proverbs Test (Delis et al, 2001) Wechsler Intelligence Scale Ex) Similarities Category Test 1 Tests calling for abstract comparisons between two or more words provide a sensitive measure of concrete thinking. Very dependent on the level of verbal skills WAIS-III or WISC-III Ex) Abstract generalization : two points Specific concrete likeness : one points Halstead (1947) Reitan and Wolfson (1983) Three versions original version / booklet / computer version Category test Abstraction Concept formation ability Flexibility in the face of complex and novel problem solving Capacity to learn from experience Category Test 2 Raven s Progressive Matrices 1 Total 7 sets and 208 visually presented items 1~6 sets: Each set is organized on the basis of a different principles 7 set: tests the subject s recall Scoring The number of errors Problems The amount of time Ability to maintain attention Visuospatial component Conceptualize spatial,design, and numerical relationships Standard Progressive Matrices (60) Colored Progressive Matrices (36) Advanced Progressive Matrices (36) Each item contains a pattern problem with one part removed and from six to eight pictured in sets of which one contains the correct pattern Korean Dementia Association

42 진주희 Raven s Progressive Matrices 2 Wisconsin Card Sorting Test 1 Culture fair test of general ability Requires neither language nor academic skills Education influences performance to a small degree Visuo-perceptual skill (right hemisphere) Reasoning by analogy (left hemisphere) The sorting and shifting test is the most common form of tests of abstraction and concept formation. Grant & Berg (1948) Heaton, Chelune, Talley, Kay, & Curtiss (1993) Total 64 cards x 2 packs 6 categories color, form, number, color, form, number Wisconsin Card Sorting Test 2 Wisconsin Card Sorting Test 3 Scoring index Number of categories completed Number of trials Correct Errors Perseverative Responses Perseverative errors Failure to maintain set The number of trial required to achieve the first category Dehaene & Changeus (1991) WCST 3 feedback (perseveration) (failure to maintain) (conceptual formation) Wisconsin Card Sorting Test 4 Reasoning Stuss, Levine, et al.(2000) More perseveration and errors Frontal lesions > posterior lesions Superior medial frontal lesions > inferior medial lesions Mountain and Snow (1993) Caution against using the WCST to identify lesion sites or as a marker of frontal dysfunctions Reasoning tests call for logical thinking, comprehension of relationships, and practical judgment. Verbal reasoning Comprehension Reasoning about visually presented material Picture completion Picture arrangement Picture problems

43 Neuropsychological Tests for Frontal Lobe Functions Comprehension Picture Completion Common-sense judgment and practical reasoning Discrepancy between the capacity to give right verbal responses to the structured questions and the judgment in the real-life situations Wechsler Intelligence Scales Wechsler Intelligence Scale Visual acuity and visual reorganization Judgments about both practical and conceptual relevancy Elicits concrete thinking Picture Arrangement Picture Problems Wechsler Intelligence Scale Failure most likely result from conceptual confusion, perceptual distortion, judgmental and reasoning problems. Social sophistication, socially appropriate thinking Stanford-Binet test Picture Absurdities Appreciation of humor Integration of all the elements, so that particular elements are taken out of the overall context and thus interpreted as inappropriate in some way Executive functions 1 Executive Functions 2 The executive functions can be conceptualized as having some components: Volition Planning Purposive action Effective performance All are necessary for appropriate, socially responsible, and effectively self-serving adult conduct. Frontal damage, subcortical damage, limbic structures, thalamic nuclei etc. A major obstacle to examining the executive function Paradoxical need to structure a situation in which patients can show whether and how well they can make structure for themselves. Most cognitive tests allow the subject little room for discretionary behaviors Korean Dementia Association

44 진주희 Component procedures of executive function Maze Tracing Volition Patient s Insight, verbal fluency, Stroop Planning and recalling Mental control task, tower test, complex figure test, maze task, clock drawing Memory task: temporal ordering, source memory, susceptibility to interference, strategy, metamemory, confabulation, false memory Motor programs Alternating program, reciprocal programs, Go/No-Go test Implementation of volitional activity Trail Making Test A, pegboard test, finger tapping Monitoring the effects of volitional activity Cancellation task, digit span, Continuous performance task Adjusting and Stopping Volitional activity Perseveration: multiple loop, motor programming task, WCST, Trail Making B Porteus Maze test (Porteus, 1959) WISC-III Mazes the process of choosing, trying, and rejecting or adopting alternative courses of conduct or thought. At a simple level, this is similar to solving a very complex maze. (Porteus, 1959) To achieve a successful trial, the subject must trace the maze without entering any blind alleys. Visuospatial and visuo-moter skills Tower Tests Tower of London, Tower of Hanoi Tower of Toronto Subjects must look ahead to determine the order of moves necessary to rearrange three colored rings of beads from their initial position to a new set of predetermined positions. Word generation Semantic word fluency: animal, supermarket items Phonemic word fluency: F/A/S, / / Design generation Design fluency test (Jones-Gotman and Milner, 1977) Free condition (5min)/fixed (four lines)condition (4min) Five-point test (Regard, 1991) Ruff Figural Fluency Test (RFFT) Use of Objects or Alternate Uses Test Convergent thinking; obvious and conventional responses Divergent thinking; different, unique, daring ideas Assessment of perseveration Copying the alternating letters or patterns Motor regulation Luria techniques: Repetitive sequential patterns of hand movements Withholding responses: Go-No Go Test Multiple loops Distractibility or impaired self-control Motor impersistence

45 Neuropsychological Tests for Frontal Lobe Functions Trail Making Tests Test of speed for attention, sequencing, mental flexibility, visual search, and motor speed. Part A & B Scoring: times, errors Color Trail Test (D Elia et al., 1996) Stroop Test Stroop (1935) The ability to shift between conflicting verbal response mood Interference effect / Inhibitory control ability Bench et al. (1993) Right anterior cingulate and right frontal polar cortex (PET study) Frontal Behavioral Inventory Kertesz, Davidson, & Fox (1997) 4 (0-3) points scale, total 24 items Apathy, Aspontaneity, Indifference, Inflexibility, Personal neglect, Disorganization, Inattention, Loss of insight, Logopenia, Semantic dementia, Verbal Apraxia, Alien hand, Perseveration/obsessions, Irritability, Excessive Jocularity, Impulsivity/Poor judgment, Hoarding, Inappropriateness, Restlessness, Aggression, Hyperorality, Hypersexuality, Utilization behavior, Incontinence, FTD>VaD>AD or PPA (Kertesz, Nadkarni, Davidson and Thomas, 2000) Behavior Rating Inventory of Exevutive Functions (BRIEF) Gioia, Isquith, Guy et al. (2000) An inventory designed to measure executive dysfunction in children aged Parent questionnaire & teacher questionnaire Global Executive Composite score & Two indexes The Behavioral Regulation Index Inhibition, Shift, and Emotional control subscales The Metacognition Index Initiate, Working memory, Plan/Organize, Organization of materials, and Monitor subscales Frontal Systems Behavior Scales (FrSBe) Grace and Malloy (2001) Behavioral Assessment of the Dysexecutive Syndrome (BADS) Total 46 items / 5 points scale Two rating forms Self-rating form / family rating form Total score & three subscales Apathy Disinhibition Executive dysfunction Age range: The purpose of test is to predict everyday problems arising from executive disturbance. The Rule Shift Cards Test The Action Program Test The Key Search Test The Temporal Judgment Test The Zoo Map Test The Modified Six Elements Test Dysexecutive Questionnaire (DEX) Total 20 items to measure four areas: emotional or personality changes, motivational changes, behavioral changes, cognitive changes Korean Dementia Association

46 진주희 Frontal Assessment Battery Dubois et al. (2000) A short bedside cognitive and behavior battery to assess frontal lobe functions Total 18 points (6 subtests x 0~3points) Subtests: Similarities Lexical fluency Motor series Conflicting instructions Go-No Go Prehension behavior

47 2009 대한치매학회추계학술대회및보수교육 Hot Topics in the Field of Dementia 좌장 : 한설희 ( 건국대학교병원신경과 ) Neurodegenerative Proteinopathy 안성수 ( 경원대학교 ) Amyloid in AD 한설희 ( 건국대학교병원 ) Tau Function in AD 정용근 ( 서울대생명과학부 ) Neuronal Cell Death in AD 고재영 ( 서울아산병원 ) Genetic Markers in AD 기창석 ( 삼성서울병원 ) Neurovascular Pathogenesis of AD 이순태 ( 서울대학교병원 ) 47

48 Hot Topics in the Field of Dementia November 27, 2009 Neurodegenerative Proteinopathy 2009 Korean Dementia Association 추계학술대회, Neurodegenerative Diseases Protein Misfolding Diseases: Protein Imbalance Protein Damage Production of Misfolded Proteins Haemostasis Factors Protein Clearance Clearance of Misfolded Proteins Aggregation Clearance Factors: Environments Genetic variations Aging Mitochondrial Function Diseases due to Degradation of Misfolded protein Diseases due to Accumulation of Misfolded protein Disease Protein involved Marfan syndrome Fibrillin Osteogenesis imperfecta Type 1 procollagen Gaucher s disease β? glucocerebrosidase Fabry Disease α -galactosidase A Cancer P53 α-1 anti trypsin deficiency α-1 antitrypsin Retinitis Pigmentosa 3 Rhodopsin Cystic fibrosis CFTR Disease Protein involved Creutzfeldt Jakob Disease Prion protein Parkinson s Disease α Synuclein Alzheimer s Disease Amyloid β-peptide, Tau Huntington disease Huntingtin Amyotrophic lateral sclerosis Superoxide dismutase Haemodialysis-related Amyloidosis β-2-microglobulin Primary Systemic Amyloidosis Immunoglobulin light chains Type II Diabetes Amylin Other systemic amyloidosis Amyloid A, Transthyretin, etc 49

49 Neurodegenerative Proteinopathy Transmissible spongiform encephalopathies (TSEs) Apoptosis of neurons, spongiform generation Symptoms anxiety, difficulty in walking and standing, whole body paralysis, slowly progressing neurodegenerative diseases, leading to death PrP C vs PrP SC Cause of TSE : abnormal prion Cellular prion protein PrP C Non-infectious Monomer Soluble (in detergents) Predominantly α-helical Proteinase K sensitive Scrapie-ass. prion protein PrP SC Infectious Aggregate Insoluble β-sheets rich Proteinase K resistant BSE Cattle Scrapie Sheep α- helices β-sheets Neuropathology Aggregated Scrapie-associated fibril (SAF) Neuronal Apoptosis Vacuolation Spongiform degeneration Spongiform Amyloid plaques (occasionally) HUMAN TSE TSE, Prion diseases in animals A. SPORATIC (CJD) 85-90% B. FAMILIAL 1. CJD 5-10% 2. Gerstmann-Straüssler- Scheinker Disease (GSS) 3. Fatal Familial Insomnia (FFI) C. IATROGENIC <1% (corneas, hgh, dural grafts) D. ORAL INGESTION 1. Kuru (ritual cannibalism) rare 2. New Variant CJD (vcjd) rare E. PK sensitive non-ad CJD-like dementia (2008) Showed that Kuru has an infectious etiology Passage to chimpanzees Scrapie Bovine spongiform encephalopathy (BSE - mad cow disease) Transmissible mink encepahlopathy (TME) Feline spongiform encephalopathy (FSE) Chronic wasting disease (CWD) Exotic ungulate encepahlopathy (EUE) sheep and goats cattle mink cats mule, deer, elk nyala, kudo Korean Dementia Association

50 Bead Bead 안성수 BSE link to vcjd: WESTERN BLOT OF CJDs PK _ Normal Abnormal 1. SPORATIC CJD 2. GSS 3. BSE 4-7 vcjd Problem of PK Digestion Fundamental characteristics of PrPsc aggregation C C Normal PrP PK-sensitive PrP PK-resistant PrP Limitation of current methods Normal Rogue C C C C S S S Binding C S S S C Conversion S S S S S Aggregation HamsterScrapieBH Existence of PK-sensitive PrP (Nature Medicine, Oct 1998) Possible to detect the accumulated PrPsc with PK (PrP res ) for the diagnosis Limitation of Blood detection S S S PrPsc aggregates (multimers) S S S S S S S S S S S S Platform Technology MDS (Multimer detection system) Concept: competition assay using capturing antibodies (conjugated with magnetic-beads) and epitope-overlapping detection antibodies (conjugated with HRP) for the detection of only multimers from monomers in protein-misfolding diseases. Normal Diseased HRP HRP m m HRP Bead HRP M m m Bead m HRP m Binding Binding m m HRP Bead m m HRP Bead m Magnetic field m HRP Bead HRP HRP M Magnetic field Bead Washing Washing m Bead Bead m HRP m HRP Bead M No Signal Signal Bead Western blot of rbovine PrP Proving the presence of PrP multimers in recombinant sample rec Bov PrP(200pg) m.w. 64 multimer monomer epitope-overlapping antibodies m Monomer M Multimer 51

51 Neurodegenerative Proteinopathy MDS with rbovine (a) & rmouse (b) PrP Detection of PrPsc in scrapie hamster brain homogenate by MDS 8.E+05 (a) 3.E+06 (b) PrP (RLU) 6.E+05 4.E+05 2.E+05 PrP (RLU) 2.E+06 2.E+06 1.E+06 5.E+05 PrP, OD (450nm) E rbovine PrP (µg/ml) 0.E rmouse PrP (µg/ml) 0 Normal Scrapie MDS detected the Multimers from rbovine & rmouse PrP Brain homogenate Detection of PrPc in normal and PrP Knock-out mouse plasmas Spiking test (spiked sample: mouse full length PrPsc) 2.0E+06 PrP control ELISA 2.0E+06 Multimer Detection System Full length Sc PrP27-30 recboprp (ng) 1.5E E+06 (µl) PrP (RLU) 1.0E E+05 normal PrP KO PrP (RLU) 1.0E E+05 normal PrP KO E Mouse Plasma (%) 0.0E Mouse Plasma (%) 14 * Normal: PrP Normal, PrP KO: PrP Knock-out Spiked Purified Mouse PrPsc from Brain Homogenate into plasma Hamster plasma test PrP (OD 450/600 nm Mouse plasma background Spiked PrP in plasma (µl) Scrapie: Pooled plasma from more than 5 hamsters with clinical symptoms. 4 different pooled batches. : ~ 60 days post inoculation at 45 days after birth, total of days Normal: Pooled plasma from more than 5 hamsters with age matched. 4 different pooled batches. : 100 days after birth Korean Dementia Association

52 안성수 Detection of PrPsc in Hamster plasma by MDS Experiment data with MDS on Prion Diseases RFU Scrapie Normal Luminescence (relative units) Scrapie blood results Scrapie plasmas: All showed clinical symptoms and the blood was collected before their death. Necropsy was done. Samples were provided by - Baltimore Research and Education Foundation (University of Maryland) - Ames Laboratories. Normal sheep plasmas: Healthy sheep without any neurological symptoms. Samples were provided by - NIAH: all AAQQ genotype, no spongiform in their brain sections by IHC. - Ames Laboratories - Hungary Academy of Sciences - Korean National Institute of Health/Center for Disease Control - Innovative Research - Rockland Laboratories Scrapie Normal Experiment data with MDS on Prion Diseases (preclinical stage) Similarities between Alzheimer s & Prion diseases Preclinical scrapie blood Preclinical scrapie plasmas: No clinical symptom was observed. All natural infected lambs at age of 8 month from their birth. Symptoms appear at age over 18 month. - All VRQ/VRQ genotypes - All parents had scrapie - Samples were provided by Ecole Nationale Veterinaire de Toulouse and EFS Pyrénées-Méditerranée (French Blood Transfusion Services), and tested at EFS Normal sheep plasmas: Healthy sheep without any neurological symptom. - All VRQ/VRQ genotypes - Samples were provided and tested at EFS Pyrénées-Méditerranée saβ Mainly α-helical Monomers Non-toxic Alzheimer s disease Neuronal loss Aβ plaque Neurofibrillary tangles Aβ oligomers Protofibrils / Fibrils Increased β-sheet Aggregated Toxic PrP C PrP SC Pathologic Chaperones Prion disease Neuronal loss Spongiosis ± PrP amyloid plaques R&D networks Amyloid-beta oligomer as AD biomarker < EUROPE > EFS Pyrénées-Méditerranée, France - The French vcjd surveillance authorities provides test samples of human blood donation as well as animal model. EFS gives us technology advices and EU policy info. We dispatch researchers for the tests. CJD Surveillance Center, U.K. - The U.K vcjd surveillance authorities provides vcjd animal/human samples to support clinical trial and approval. < JAPAN > National Institute of Animal Health - This world largest prion research institute is in charge of the prevention of prion disease (esp. BSE) prevalence in Japan. NIAH provides us animal samples, antibodies, facilities, etc. [ Scientific Advisory Board ] Dr. Paul Brown (former Director, US FDA) Dr. Joliette Coste (Directeur Scientifique, EFS France) Dr. Takasi Yokoyama (Director, NIAH Japan) Dr. SangYun Kim (Professor, SNU College of Medicinie) Dr. Aru Balachandran (Head, CFIA / OIE center) [Alzheimer s project team] SNU Bundang Hospital ChungAng University Hospital Bobath Memorial Hospital Hyoja Geriatric Hospital Incheon Christian Hospital Seoul National University Kyungwon University Collaborators BioChemed Services Covance Inc. The Genetics Company OBAMA study Oligomeric Beta Amyloid Detection by MDS in Alzheimer's Disease Patients Aβ oligomers α secretase β secretase γ secretase APP(Amyloid Precursor Protein) γ secretase α secretase β secretase Non-toxic proteins Soluble Aβ(1-40 & 1-42) monomer non-toxic Aggregation Detecting target Oligomer Neurotoxic AD is characterized by features : senile plaque and neurofibrillary tangle non-toxic Biomarker of AD NEUROTOXIC (Aβ monomers are non-toxic) Induce synaptic dysfunction and inhibits LTP (long term potentiation) Activate tau hyper-phosphorylation resulting in neurofibrillary tangle Induce oxidative stress leading to apoptosis 53

53 Neurodegenerative Proteinopathy Preliminary experiment (Detecting recombinant Aβ oligomers) Commercial kit: Detection of total Aβ in AD vs. non-ad CSF samples MDS-2, Detection of Aβ oligomers in AD vs. non-ad CSF samples MDS-2, Detection of Aβ oligomers in AD vs. non-ad CSF samples MDS-3D Korean Dementia Association

54 Hot Topics in the Field of Dementia November 27,

55 Amyloid in Alzheimer s Disease Korean Dementia Association

56 한설희 57

57 Amyloid in Alzheimer s Disease Korean Dementia Association

58 한설희 59

59 Amyloid in Alzheimer s Disease Korean Dementia Association

60 한설희 61

61 Amyloid in Alzheimer s Disease Korean Dementia Association

62 Hot Topics in the Field of Dementia November 27,

63 Tau Function in Alzheimer s Disease Korean Dementia Association

64 정용근 65

65 Tau Function in Alzheimer s Disease Korean Dementia Association

66 정용근 67

67 Hot Topics in the Field of Dementia November 27, 2009 Brain Zinc: Its Possible Role in Alzheimer s disease Alzheimer disease (AD) Jae-Young Koh NRL Neural Injury Research Center & Department of Neurology Asan Institute for Life Science Asan Medical Center / University of Ulsan College of Medicine 1907, Alois Alzheimer ( ) Age-dependent: 10% >60 years, 50% >85years More common among women than men by a ratio of 1.2 to 1.5. Auguste D. Some cases (5-10%) are familial (FAD) : βapp (Chr. 21), presenilin-1 (Chr. 14), presenilin-2 (Chr. 1) Accumulation of amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles Pathological Characteristics of AD Brain Cerebral amyloid angiopathy (CAA) Anti-Aβ antibody Thioflavin S Evidences for the role of zinc in AD Amyloid β Zinc-binding domain containing histidine residues within Aβ (Huang et al., 1997; Yang et al., 2000) Rapid aggregation of synthetic Aβ by zinc in an aqueous environment (Bush et al., 1994; Esler et al., 1996; Miura et al., 2000) Dissolution of Aβ aggregates by zinc chelators in vitro (Cherny et al., 1999) Elevated concentrations of the transition metals including zinc in AD brains, more so around plaques (Deibel et al., 1996; Danscher et al., 1997; Lovell et al., 1998) Inhibition of amyloid plaque accumulation by a zinc chelator (clioquinol) in happ transgenic mice (Cherny et al., 2000) Korean Dementia Association

68 고재영 Zinc in Plaques of APP Transgenic Mice (Tg2576) Anti-Aβ Congo red TSQ Neither zinc nor congophilic plaques in cerebellum of Tg2576 mice Anti-Aβ TSQ Congo red Lee et al., J. Neuroscience, 1999 Lee et al., J. Neuroscience, 1999 Zinc in amyloid plaques and CAA of AD brain non-demented elderly subject AD patient Zinc has been found at high levels in all the congophilic plaques of human AD brain (Suh et al., 2000) and human Swedish mutant APP 695 transgenic Tg2576 mice (Lee et al., 1999). So, where does zinc come from? Suh et al. Brain Res Synaptic zinc and AD Abundance of synaptic zinc in olfactory bulb, cerebral cortex and the limbic area, and its scarcity in thalamus and cerebellum (Perez-Clausell, 1996; Danscher et al., 1997; Frederickson et al., 2000; Jo et al., 2000), correlates with the regional distribution of amyloid plaques (Games et al., 1995; Zhan et al., 1995; Hsiao et al., 1996). (Frederickson, Koh, Bush, 2005) Although the cerebellum contains abundant diffuse (soluble) Aβ deposits (Joachim et al., 1989), this structure lacks amyloid plaques (Styren et al., 1998; Lee et al., 1999). 69

69 Brain Zinc: Its Possible Role in Alzheimer s Disease Human APP transgenic Tg2576 mouse that lacks Znt3 genes No labile zinc in Znt3-null brain Znt3 -/- (knockout) happ +/- (Tg2576) ZnT3 +/- ;happ +/- happ + ;Znt3 +/+ happ + ;Znt3 -/- Reduced deposition of amyloid plaques in Tg2576/Znt3-null mice Gender and Znt3 dependence of amyloid plaque deposition happ + Znt3 +/+ happ + Znt3 -/- Lee et al., PNAS, 99 (2002) Soluble/insoluble Aβ ratio Linear correlation between zinc content and insoluble Aβ Zn Zn Zn Soluble Aβ Insoluble Aβ Aggregation Amyloid plaque Zn Zn Zn Lee et al., PNAS, 99 (2002) Lee et al., PNAS, 99 (2002) Korean Dementia Association

70 고재영 Reduced CAA in Tg2576/Znt3-null mice Plaque formation in real-time (Meyer-Luehmann et al., Nature, 2008) happ + /Znt3 +/+ happ + /Znt3 -/- Friedrich et al. J. Neurosci (2004) Neuritic changes follow plaque formation Targets for Alzheimer s Disease Therapy Clioquinol (iodochlorhydroxyquin) and PBT2 CQ-treated Membrane active metal chelator DP-109 (D Pharm) Reduction of amyloid plaque deposition by oral DP-109 Vehicle DP-109 Control Cherny et al., Neuron, 2001 Lee et al. Neuroiol. Aging, 25 (2004) 71

71 Brain Zinc: Its Possible Role in Alzheimer s Disease Membrane active metal chelator DP-109 A Possible Scenario Amelioration of CAA by oral DP-109 or chelators Additional mechanism?: activation of autophagy by clioquinol Zinc in autophagic vacuoles induced by oxidative stress CQ, a weak zinc chelator and membrane permeator, functions as a zinc ionophore Hence, while CQ can remove zinc from Abeta, it also can introduces labile zinc inside cells Increases in intracellular zinc has been shown to activate autophagy, which can remove intracellular Ab and other abnormal proteins Lee et al., GLIA, 2009 Levels of labile zinc modulate autophgagy induced by oxidative stress CQ is a zinc ionophore Korean Dementia Association

72 고재영 CQ activates autophagy CQ reduces accumulation of mhttq74 A C uM Anti - LC3 I/II A Anti-LC3 I/II CTL Clioquinol P M M C uM Clioquinol dose P C CQ+3MA 6h A Anti - LC3 I/II P M C CQ +TPEN Conclusion 1. Synaptic zinc (ZnT3-dependent) plays a large role in the accumulation of amyloid plaques and CAA 2. Synaptic zinc levels change with aging in a genderdependent manner (female>male) 3. Zinc chelators such as CQ reduce plaques and CAA in Tg2576 mice likely by removing zinc from plaques 4. CQ and other weak zinc chelators may also activate autophagy, which can additionally contribute to reduction in plaque load 73

73 Hot Topics in the Field of Dementia November 27, 2009 Prevalence of AD The incidence of AD Affecting million people yrs : 2.8/1,000 person years > 90 yrs : 56.1/1,000 person years > 85 years Suffer from either dementia or mild cognitive impairment (MCI) In Japan (2003) > 65 years of age 10% suffer from dementia and 7% from MCI TRENDS in Genetics Vol.17 No.5 May &type=1&EBV1 Nature vs. Nurture Genetic? Pre-determined? Tends to run in families? Identical twins? Pre-disposition? Environment? How much can be attributed to environment? Types of Genetic Diseases Monogenic Huntington disease HD on 4p16.3 Myotonic dystrophy 1 DMPK on 19q13.3 Polygenic/Multifactorial Stroke Diabetes Myopia Questions Is AD a genetic disorder? How do we know the AD is genetically determined? If AD is not a single gene disorder, why are we searching for AD-associated genes? How can we find AD-associated genes, not AD-causing genes? Are there any clinical implications of ADassociated genes? Is AD a genetic disorder? How Do We Know a phenotype is genetically determined? Runs in families Recurrence risk increases as relatedness increases Concordance in monozygotic twins is high Heretability is high Runs in particular ethnic groups Korean Dementia Association

74 기창석 Familial Aggregation of Disease Genetic Diagnosis Flowchart Genetic disorders usually show familial aggregation Clinical Diagnosis Phenotype Pattern Recognition +/- Laboratory Tests λ R = prevalence (risk) of the disease in a relative R of an affected person population prevalence (risk) Myotonic dystrophy 1 - Risk in sibs = ~0.5; risk in population = ~ λ R = 4,000 Alzheimer disease - Risk in sibs = ~ ; risk in population = ~ λ R = 3-4 Mendelian? YES Gene Mapped? YES YES Gene Cloned? Mostly the Same Few Mutations? NO NO NO NO Empiric Risks Mendelian Principles May be possible by Imaging Chromosome Analysis Biochemical Tests Indirect Tests by Gene Tracking Direct Tests by Mutation Scanning or Indirect Tests YES Direct Tests for Specific Mutations Molecular Diagnosis Do we know the causative gene(s)? Check the mutation spectrum Genetic Disease DB OMIM Online Mendelian Inheritance in Men GeneReviews in GeneTests Select the right technique Perform genetic test and interpret the results Importance of Genetic Marker P. vera No definite diagnostic tools JAK2 gene mutations Papillary thyroid cancer USG and pathologic diagnosis BRAF gene mutations H1N1 Flu Confirmation of infection by real-time RT- PCR detection of viral RNA Case 남 /45 세 주소 : 심한건망증 현병력 신학교교수 4 년전 (41 세 ) 부터건망증이생김 현재는일상생활유지불가능 가족력 아버지 : 치매증상, 50 세사망 여동생 : 38 세경부터심한건망증호소 형 : 약사, 약간의건망증만호소 C/W EOFAD 75

75 Genetic Markers in Alzheimer s Disease Mutation Analysis Target Gene PSEN1 ~20-70% of EOAD Previous report in Koreans (PSEN1 H163R) Methods Fibroblast culture RT-PCR Direct sequencing Ref Seq Ref Seq Forward Reverse Forward Reverse PSEN1 gene Exon 8 c.697 A>C (M233L) Mutation Confirm Mutation Destroys a NlaIII Site Amplification of Genomic DNA Exon 8 region M233L TM-V g.44716a>c c.697a>c Spanish: Aldudo J, et al Canadian: Rogaeva EA, et al bp C M 344 bp 233 bp 111 bp Pre C M Korean Dementia Association

76 기창석 Classification of AD Gene Ch. Journal Auth SORL1 11q23 Nat Genet. Rogaeva et al 2007 A2M 12 Nat Genet. Neurology. Neurosci Lett. Blacker et al 1998, Dodel et al 2000, Depboylu et al 2006 GST01, GST02 10 Hum Mol Genet Li et al 2003 GAB2 11q14 Neuron. Reiman et al 2007 CALHM1 10q24 Cell. Dreses et al 2008 Several other potential genes are under investigation Contribution and Interaction Pattern of Known and Putative AD Genes AD1 AD3 AD4 AD2 GWAS 2032 AD pts. / 5328 controls CLU (APOJ), chromosome 8 (rs ) OR = 0.86, p = 7.5 x 10-9 CR1, chromosome 1 (rs ) OR = 1.21, p = 3.7 x 10-9 (Lambert et al., Nature 2009) : CLU, CR1 in the clearance of amyloid (Aβ) peptide Pharmacological Research 50 (2004) GWAS AD pts. / 3941 (7848) controls CLU (APOJ), chromosome 8 (rs ) OR = 0.86, p = 8.5 x 10-9 PICALM, chromosome 11 (rs ) OR = 0.86, p = 1.3 x 10-9 (Harold et al., Nature 2009) : PICALM in the endocytic pathway, APP processing 77

77 Genetic Markers in Alzheimer s Disease Gene Refseq ID dbsnp ID ch Position (g.) Allele OR (95% c.i.) APOE (ε2/3/4) NP_ apoe ε2/3/ * ( ) CLU NM_ rs T>C PICALM NT_ rs T>C CR1 NM_ rs A>G TNK1 NM_ rs T>A 0.84 ( ) ACE NT_ rs C>T?0.79 ( ) TFAM NM_ rs A>G 0.78 ( ) CST3 NM_ rs G>A?1.15( ) IL1B NT_ rs G>A 1.18 ( ) hcg NT_ rs G>A 1.23 ( ) SORL1 NT_ rs C>T 1.21 ( ) CHRNB2 NT_ rs G>T 0.67 ( ) DAPK1 NT_ rs C>T 0.88 ( ) PRNP NT_ rs A>G 0.89 ( ) MTHFR NT_ rs C>T 0.85 ( ) LOC NT_ rs A>G 0.86 ( ) BDNF NT_ rs G>A 1.09 ( ) CH25H NT_ rs C>T 1.44 ( ) TF NT_ rs C>T 1.26 ( ) LOC NT_ rs C>T 1.15 ( ) TNF NT_ rs C>T 1.37 ( GAPDHS NT_ rs C>G 0.87 ( ) GALP NT_ rs C>G 1.21 ( ) PSEN1 NT_ rs A>C 0.92 ( ) Korean Dementia Association

78 Hot Topics in the Field of Dementia November 27, 2009 Neurovascular Pathogenesis of Alzheimer Disease(AD) 서울대학교의과대학신경과학교실 이순태 Vascular Risk Factors in AD Alzheimer disease(ad) 의발생, 진행과관련된여러 epidemiologic, laboratory factor 들을도식화하면 Figure 1 과같다. Neurovascular Unit in Alzheimer Disease 1. Neurovascular unit Neurovascular unit(nvu) 은 endothelial cells, astrocyte, neuron, vascular smooth muscle cells, pericyte로이루어지며, neural activity 에따른 cerebral blood flow(cbf) 의조율과 BBB transporter 를통해뇌내환경을조절하는기능적단위이다. neurovascular coupling 현상은 neural activity 증가에따라 CBF 를증가시키는기전으로, neuronal active excitatory synapse에서유리된 glutamate가 post-synaptic neuron과 astrocyte foot process, endothelial cell에작용하여 intracellular calcium 을증가시키고, nitric oxide(no), potassium(k), adenosine, prostanoids, neurotransmitter 등여러이차물질의분비를일으켜 endothelial cell 과 smooth muscle cell 을통해 vasodilation을유발한다. Endothelial tight junction 은 BBB 를이루면서, 각종 endothelial transporter 를통한선택적물질교환을통해뇌내환경을조절한다. Cognitive activity, Stroke Low education Female Social engagement Physical activity Head-trauma Depression Atherosclerosis Small head-size Diet Fish Low serum cystatin C Statin, anti-ht High plasma Abeta40 (Middle life) HT X MCI/AD Homocysteine Smoking NSAIDS Dyslipidemia Obesity DM MCI vs. CTR Cerebral hypoperfusion White matter hyperintensity Metabolic syndrome ApoE4 MCI AD Cortical, hippocampal, entorhinal atrophy Heart failure Atrial fibrillation AD vs. CTR Low angiogenic cells CSF biomarker: High p-tau, Tau, Low Abeta42 AD Prog Vasomotor reactivity PiB-PET FDG-PET CSF high isoprostane Inflammation/Proteomics markers 위험인자혹은양의상관성억제인자혹은음의상관성부분적관계 Figure 1. AD 와연관된각종인자들. X MCI/AD: 정상인이 MCI/AD 로발전하는것과관련된예측인자. MCI vs. CTR: MCI 와 control 군에서차이를보인인자. MCI AD: MCI to AD conversion 에관련된예측인자. AD vs. CTR: AD 와 control 군에서차이를보이는인자. AD prog: AD 환자의질병진행에관련된예측인자. 79

79 Neurovascular Pathogenesis of Alzheimer Disease(AD) 2. Vascular morphology in AD AD 환자뇌조직의병리소견에서는다양한혈관변화가관찰되며, 정리하면다음과같다. - Large cerebral artery: atherosclerotic plaques - Pial arteries: amyloid lesions, thin smooth muscle layer(=cerebral amyloid angiopathy) - Capillary: decreased capillary density, endothelial senescence, thickening of basement membrane, amyloid lesions, microglial activation, gliosis, disturbed connections of perivascular neurons and synapse, dysfunctional pericytes 이러한혈관병변은 neurovascular unit 의본래기능을저하시키고, AD 환자의 MRI, fmri, TCD, SPECT 연구들에서관찰되는 CBF 저하의원인이되며, 뇌내 Aβ clearance 를떨어뜨리는데, 이에따른 Aβ 병리기전의가속은다시혈관계를손상시킴으로써악순환이유발되는것으로보인다. Aβ Homeostasis through BBB Brain interstitial fluid의 Soluble Aβ는주로 degradation enzyme, microglia, BBB를통한 efflux에의해제거된다 (Figure 2). 1. Aβ influx through BBB endothelial cells RAGE(receptor for advanced glycation endproducts) 는 BBB endothelial cell 을통해 Blood 에서 Brain 쪽으로 Aβ influx 를일으키는주요 transporter 로써, Aβ의 binding 과함께각종 neuroinflammation의기전 (NF-kB, Cytokine, ROS) 도활성화하여, 질병에다양하게관여한다. AD brain 에서는 RAGE 의발현이증가되어있으면서, Aβ influx 를통한질병의가속화와 neuroinflammation 에관여하고있는것으로보인다 (Figure 3). 2. Aβ efflux through BBB endothelial cells Aβ를 Brain 에서 Blood 내로제거하는 efflux 에관여하는 transporter 로는 LRP(lipoprotein receptor related protein 1) 가주요기능을담당하며 P-gp(p-glycoprotein) 도관여한다. LRP는 endothelial cell 과 vascular smooth muscle cell 에존재하면서 transcytosis 를통해 interstitial fluid 의 Aβ를 Blood 로 pumping-out 하는역할을하며, Plasma내에는 solouble LRP(sLRP) 가존재하여 Aβ와 binding하고 peripheral sink에관여한다. AD 환자의 brain 에서는 LRP의발현이감소되어있고혈중 slrp 의변성도관찰되는데, Aβ efflux 가제한되고, 뇌내 Aβ homeostasis 의장애를유발하여, 질병을가속화하는것으로보인다. Plasma 와 interstitial fluid의 Aβ는 ApoE, ApoJ, α2-macroglobulin(α2m) 와같은 chaperone proteins과도 binding하며, microglia, efflux system과상호작용하여 Aβ homeostasis에관여한다. 예를들어 ApoE4는 ApoE2나 ApoE3 보다 Aβ binding affinity 가낮아뇌내 Aβ clearance 의효율이떨어지는것으로보인다. 3. Enzymatic degradation of Aβ by neurovascular unit cells Neurovascular unit 의세포들은 insulin degrading enzyme, neprilysin를발현하여 Aβ의 enzymatic degradation 에도관여한다. 4. Clearance of Aβ by blood-born microglia/macrophage Perivascular space를중심으로 blood-born microglia/macrophage가존재하며, 이들세포는 Aβ clearance 에관여한다. 5. Vascular pulsatile clearance of Aβ Aβ는 vascular pulsatile flow 에의한 passive clearance도가능한데, AD에서의 vasoconstriction 은이들거기능의장애를일으키는것으로보인다 Korean Dementia Association

80 이순태 Brain APP Degradation enzyme Aβ Microglia Influx though BBB Efflux through BBB Figure 2. Aβ homeostasis 에관여하는 input 과 output. Blood BBB Brain srage slrp RAGE Aβ Neuronal APP processing ApoE ApoJ α2m Aβ LRP α2m-aβ Aggregation ApoJ-Aβ ApoE-Aβ Peripheral APP processing Aβ P-gp Microglia Figure 3. Influx and efflux of Aβ through BBB. Therapeutic Implications Neurovascular unit 을기반으로한 Aβ homeostasis의개념은 disease-modifying treatment 개발에다양하게활용될수있다 (Figure 4). soluble LRP/RAGE 를이용한 Aβ의 sink method 를개발하거나, endothelial regeneration 을통해 neurovascular coupling 과 Aβ homeostasis를개선할수있고, immunization 을통한 Aβ제거의효과를이해하는데있어서중요한지식기반이된다. 또한 growth factors, RNAi 치료제와같은신치료기술개발의타깃을개별세포개념에서 Cell-to-Cell, Blood-to-Brain interaction 의확장된개념으로제시해줄수있다. Suggested readings and references 1) Benarroch EE. Neurovascular unit dysfunction: a vascular component of Alzheimer disease? Neurology May 15;68(20): ) Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica- Worms D, Holtzman DM. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest 2005 Nov;115(11): ) Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003 Jul;9(7): ) de la Torre JC. Is Alzheimer s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol 2004 Mar;3(3): ) Lee ST, Chu K, Jung KH, Park HK, Kim DH, Bahn JJ, Kim JH, Oh MJ, Lee SK, Kim M, Roh JK. Reduced circulating angiogenic cells in Alzheimer disease. Neurology 2009 May 26;72(21): ) Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ, Wu Z, Zarcone T, Goate A, Mayo K, Perlmutter D, Coma M, Zhong Z, Zlokovic BV. Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med 2007 Sep;13(9): ) van Oijen M, de Jong FJ, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM. Atherosclerosis and risk for dementia. Ann Neurol 2007 May; 61(5): ) Zlokovic BV. Neurovascular mechanisms of Alzheimer s neurodegeneration. Trends Neurosci 2005 Apr;28(4):

81 2009 대한치매학회추계학술대회및보수교육 November 28 Parkinsonism & Dementia 좌장 : 김영현 ( 전북대학교병원신경과 ) 좌장 : 이재홍 ( 서울아산병원신경과 ) Case Discussion 좌장 : 나덕렬 ( 삼성서울병원신경과 ) 좌장 : 윤영철 ( 중앙대학교병원신경과 ) 83

82 2009 대한치매학회추계학술대회및보수교육 Parkinsonism & Dementia 좌장 : 김영현 ( 전북대학교병원신경과 ) 좌장 : 이재홍 ( 서울아산병원신경과 ) Parkinsonism & Dementia 김상윤 ( 서울대학교병원 ) Parkinson s Disease Dementia 김재우 ( 동아대학교병원 ) Dementia with Lewy Bodies 박경원 ( 동아대학교병원 ) Parkinson-Related Dementia I (CBD, PSP, FTDP-17) 양동원 ( 가톨릭대학교서울성모병원 ) Parkinson-Related Dementia II (Vascular parkinsonism, NPH) 박기형 ( 가천의대길병원 ) 85

83 Parkinsonism & Dementia November 28, 2009 Dementia & Parkinsonism Cognitive impairment Alzheimer s disease Subjective & Objective Sx Dementia SangYun Kim Department of Neurology Seoul National University College of Medicine Clinical Neuroscience Center Seoul National University Bundang Hospital Parkinsonism Parkinson s disease Copyright c SangYun Kim. All Rights Reserved Dementia & Parkinsonism Diagnosis of Cognitive impairment & Parkinsonism Parkinsonism and Dementia Dx of Parkinsonism in the patients with Cognitive impairment Parkinson s disease and Dementia Parkinson s disease Dementia Parkinsonism related Dementia Dx of Cognitive impairment in the patients with Parkinsonism Parkinsonism and Cognitive impairment Copyright c SangYun Kim. All Rights Reserved Dementia & Parkinsonism Parkinsonism of pt. with dementia Dementia of pt. with parkinsonism Onset & Course Insidious onset with slow progression Diagnosis Clinical decision of diagnosis Pick up the Sx Usually by clinical observation Usually by caregiver s report Diagnosis by Suspected by observation & Suspected by simple test Dx with neurologic exam Dx with neuropsychometry Symptomatology Relatively simple Relatively complex (multiple stages & multiple pattern) In practice Easily detected Active consideration needed Caregiver report Less frequent More frequent Patient report Possible only in early stage Possible but not frequent Impact on ADL Great Delayed Dx Impact (+) Greater impact (++) Tx trial Easy start & easy stop Problematic Totally Easily controlled Challenging *** Copyright c SangYun Kim. All Rights Reserved Proteinopathy of Neurodenerative diseases Presenting Cognitive Impairment & Parkinsonism Amyloidopathies Synucleinopathies PD PDD DLB MSA AD CBD/CBS PSP FTDP-17-MAPT FTDP-17-PGRN TDP-43 Tauopathies Copyright c SangYun Kim. All Rights Reserved 87

84 Dementia & Parkinsonism Dementia & Parkinsonism Dementia & Parkinsonism Parkinson s disease & Dementia PD PDD DLB MSA AD CBD PSP FTDP-17 Parkinson-related Dementia Synucleinopathy Parkinson s disease Parkinson s disease dementia Dementia with Lewy bodies Multiple system atrophy Copyright c SangYun Kim. All Rights Reserved Dementia & Parkinsonism Dementia & Parkinsonism Tauopathy Amyloidopathy Corticobasal degeneration Progressive supranuclear palsy Frontotemporal dementia Alzheimer s disease Alzheimer s disease TDP-43 Frontotemporal dementia Amyotrophic lateral sclerosis Diagnosis of Parkinsonism in Dementia Comparison of parkinsonian findings 보다정확한진단을위해서 Dementia vs. Dementia with parkinsonism 환자의증상을호전시키기위해서 Parkinsonism control Improved cognitive function Planning of long-term care Disorder Specific parkinsonian findings L-dopa Rx AD Tends to be later in course; rigidity, bradykinesia, tremor Masked facies, stooped posture, reduced arm swing, PD asymmetric rigidity, bradykinesia, resting tremor, and postural instablility Good Same as in PD, but over time, bilateral involvement, marked PDD postural instability Similar to PD and PDD, but tremor is less asymmetric and DLB more postural than at rest Markedly asymmetric rigidity and apraxia, often with coexisting CBS jerky tremor, myoclonus, dystonia, alien limb phenomenon, cortical sensory loss; Wide-eyed stare, reduced eye blink frequency, axial greater PSP than appendicular rigidity, moves en bloc Rigidity less asymmetric; ataxia & spasticity prominent in OPCA MSA variant; orthostatic hypotension prominent in SDS variant FTDP-17 Parkinsonism variable, often similar findings to those in CBS Over time, loss of effect Good Minimal Minimal on SND type Often Korean Dementia Association

85 김상윤 Patterns of Cognitive impairment Patterns of Cognitive impairment Disorder Learning & memory Attention / concentration Executive function Language function Visuospatial function Disorder Learning & memory Attention / concentration Executive function Language function Visuospatial function AD to to to to +++ PD Nl to + Nl to ++ Nl to ++ Nl Nl PDD Nl to to to +++ Nl to ++ + to +++ DLB Nl to to to +++ Nl to ++ + to +++ CBS Nl to ++ Nl to +++ Nl to ++ Nl to ++ Nl to ++ PSP Nl to ++ + to to +++ Nl to ++ Nl MSA Nl to + + to ++ + to Nl FTDP-17 Nl to to to +++ Nl to +++ Nl to ++ AD to to to to +++ PD Nl to + Nl to ++ Nl to ++ Nl Nl PDD Nl to to to +++ Nl to ++ + to +++ DLB Nl to to to +++ Nl to ++ + to +++ CBS Nl to ++ Nl to +++ Nl to ++ Nl to ++ Nl to ++ PSP Nl to ++ + to to +++ Nl to ++ Nl MSA Nl to + + to ++ + to Nl FTDP-17 Nl to to to +++ Nl to +++ Nl to ++ Patterns of Neuroimaging studies Dementia & Parkinsonism Disorder MRI SPECT or FDG-PET Maximal in hippocampi, generalized AD cortical atrophy evolves over time Maximal in T-P cortex Normal or minimally PD Min. to no abnormal PDD significant cortical or hippocampal Maximal in F-P-O cortex DLB atrophy Maximal in P-O cortex Max. in the parietal & posterior Maximal in P-F cortex CBS frontal cortex; asymmetric BG thalamus; asymmetric PSP Max. in the frontal cortex & midbrain Maximal in frontosubcortical regions Normal or minimally MSA Max. in the pons or cerebellum abnormal FTDP-17 Max. in the F-T cortex or amygdala Maximal in the F-T ± amygdala ± basal ganglia Definite dementia of CBD Dementia of MSA Parkinsonism of AD without Lewy body Clinical AD progress to DLB Dementia & Parkinsonism Dementia & Parkinsonism Criteria of dementia in the patients with Parkinsonism Criteria of parkinsonism in the patients with dementia Research or Clinical purpose Neurodegenerative proteinopathy Cognitive impairment Parkinsonism Vascular cognitive impairment Depression Neurodegenerative disorders Neurovascular coupling Prionopathy 89

86 Dementia & Parkinsonism Dementia & Parkinsonism Bundang Neurodegenerative Cooperation Lewy body spectrum PD PDD DLB AD CBD PSP FTDP-17 Amyloidopathy Brain necropsy Geriatric neurology MSA Tauopathy Synucleinopathy Copyright c SangYun Kim. All Rights Reserved Copyright c SangYun Kim. All Rights Reserved SangYun Kim, MD. PhD. Department of Neurology Seoul National Univ. College of Medicine Clinical Neuroscience Center Seoul National Univ. Bundang Hospital Korean Dementia Association

87 Parkinsonism & Dementia November 28, 2009 파킨슨병치매 (Parkinson s Disease Dementia) 동아대학교의과대학신경과학교실 김재우 서 론 파킨슨병은노인에서알츠하이머병다음으로흔한신경퇴행성질환이다. 임상적으로떨림증, 근육의경직, 운동완만및자세불안정등의운동장애가대표적인주된증상이나자율신경계이상과감각신경계장애그리고치매를포함한다양한정도의인지기능장애가관찰된다. 파킨슨병의초기에는치매가잘나타나지않으나신경심리검사를통하여자세히들여다보면질환의초기에도인지기능의장애가흔하다. 이것은파킨슨병환자의생존율이증가되고치매에대한연구가많이이루어게됨에따라파킨슨병과연관된인지기능의변화를발견할수있는가능성이증가되었기때문이라고할수있다. 파킨슨병환자의약 20~40% 에서치매가동반되며, 건강한사람에비해파킨슨병환자에서는치매의발병률이 6배에달하는것으로알려져있다. 임상적으로파킨슨병치매의전형적인양상은피질하성치매양상과집행기능의장애 (executive dysfunction) 로나타난다. 즉, 집중력장애, 사고과정의완만, 정신운동지체, 기억력장애, 그리고시공간능력장애등이특징적으로나타난다. 역 학 파킨슨병치매의유병률은약 2% 에서최대 81% 까지매우다양한결과를보고하고있는데, 이것은치매를어떻게정의했느냐에따른차이, 인지기능의평가방법차이, 그리고연구대상집단의차이등에따라서매우다르게나타나는것으로생각된다. Cummings 등은 27개연구를분석한결과파킨슨병치매의유병률을약 40% 정도로보고하고있다. 국내에서의파킨슨병치매유병률조사는거의없는데안산시에서시행된파킨슨증후군의역학조사결과중파킨슨증후군으로진단된환자의약 50% 에서인지기능장애가관찰되었음을보고하고있다. 치매의발생률이일반정상인에비해파킨슨병환자에서높은것은잘알려진사실이다. 여러연구자들은일반적으로파킨슨병환자에서치매가발생할확률이 4~6 배가량높은것으로보고하고있다. 전향적인연구에따르면파킨슨병환자에서정상대조군에비해치매발생률이 10년동안 38%, 14년동안 53% 로각각나타났다. 파킨슨병환자에서치매의위험인자로서는나이, 질병의유병기간, 임상양상즉, akinetic-rigid type, 우울증동반유무등을들수있다. 임상양상 전형적인파킨슨병치매환자에서나타나는임상적특징은집행기능장애라고할수있다. 치매가없는파킨슨병환자에서도자세한인지기능검사를시행하면이상소견을쉽게발견할수있다, 집행기능장애외에도주의집중능력과기억력, 시공간능력과언어기능과같은다양한형태의인지영역에서기능장애가관찰되고, 감정변화와이상행동증상이동반된다. 1. 주의집중능력과기억력주의집중능력장애는인지반응시간및각성검사에서의미있는감소소견으로나타난다. 루이체치매에서흔히나타나는주의집중능력의변동소견이파킨슨병치매에서도나타날수있다. 파킨슨병치매환자에서는알츠하이머병환자에서보이는새로운정보를학습하는능력의결여로인한심한단기기억장애보다는저장된정보에접근하고인출하는능력의장애를주로보인다. 따라서정보를저장하는능력의어려움이라기보다는기억의표지에접근하는데장애를보이는형태라고할수있고, 내재적인신호를탐색하는데어려움이있어언어유창성이나기억의인출장애를보인다. 91

88 파킨슨병치매 (Parkinson s Disease Dementia) 2. 집행기능집행기능이란목표를세우고그목표를효과적으로수행해가는능력을지칭한다. 파킨슨병치매환자에서는집행기능의손상으로인해개념을정립하거나규칙을발견하고, 문제를해결하고계획을수립하며상태변화에적응하는능력이부족하다. 파킨슨병치매환자는외부에서단서가주어지는경우에는수행을잘하지만, 스스로단서를찾아내어야하는경우에는일을수행하는데많은어려움을보인다. 3. 시공간능력과언어능력시공간능력장애는파킨슨병치매환자에서특징적으로나타나는데비슷한정도의알츠하이머병환자에비해서그정도는심한것으로알려져있다. 시감각능력과시각재인항목을제외한시공간분석과방향감각을보는검사항목에서심한장애가관찰된다. 언어능력과행동능력과같은도구적기능들은알츠하이머병환자에비해파킨슨병치매환자에서비교적보존되어있다. 그러나언어유창성검사에서는파킨슨병치매환자에서현저한장애를보인다. 4. 감정및행동변화파킨슨병치매환자에서다양한이상행동및심리증상이나타나는것으로알려져있다. 그중대표적인증상이불안과우울증이다. 환시는파킨슨병치매환자의약 70% 에서나타날수있다. 알츠하이머병에서는반복적인행동, 초조, 탈억제, 흥분성, 다행감, 그리고무감동등이흔하게관찰되지만파킨슨병치매에서는환각현상이상대적으로심하게나타난다. 뇌영상소견 파킨슨병치매를진단하기위하여뇌영상소견이꼭필요한것은아니다. 뇌 MRI 영상소견에서는특이한구조적이상소견을보이지않는다는보고가많다. SPECT 를이용한기능적영상소견에서파킨슨병치매환자는양측측두- 두정엽부위의관류저하를보이는경우가많다. PET 연구에서는전반적인당대사저하소견이관찰되면서특히외측두정부, 측두부, 전두연합피질부 (frontal association cortex), 그리고후방띠이랑부위에서현저하여알츠하이머병과의감별이쉽지않다. 한편, 파킨슨병치매환자에서시각피질부위에서실질적인당대사소견이나타나지만알츠하이머병에서전형적으로보이는내측두엽부위의대사저하증은덜나타나는것으로알려져있다. 병리소견 파킨슨병의주된병리소견은루이체이고이것은 α-synuclein 이주성분이다. Braak 에의하면파킨슨병의운동증상이나타나기이전부터하부뇌간과 olfactory bulb 등에서루이체가시작하여상부로퍼져나가고질환이상당히진행되면뇌의피질부와변연계에도침착이되어치매가발생된다고주장하였다. 이러한가설은파킨슨병에서치매가질환의말기에잘생기는이유를설명할수있다. 그러나최근의연구에의하면루이체의침착이 Braak 의가설대로항상그런순서로뇌에발생하는것은아니라는의견들이속속제기됨으로써향후더많은환자들을대상으로체계화된병리연구가필요하리라생각된다. 루이체와더불어공존하는알츠하이머형병리소견이파킨슨병에서치매를유발하는데기여할것이라는연구도끊임없이나오고있다. 이와더불어신경전달물질의변화도인지기능장애의중요한요인으로알려져있다. 이중아세틸콜린기능의감소는알츠하이머병에서보다파킨슨병치매에서더욱심하고파킨슨병의초기부터감소되어있다는보고도있어파킨슨병의초기에나타나는인지기능의장애를설명하는데도움을주고있다. 또한메이너트기저핵에서의아세틸콜린신경세포의소실은아세틸콜린기능의감소의주된병리소견이되고파킨슨병의치매에서콜린분해효소억제제가치료효과를보이는이유를설명해주고있다. 이외에도도파민, 노르아드레날린및세로토닌신경세포의감소도인지기능의부분적인감소에기여할것으로생각된다. 진 단 파킨슨병치매는다음의몇가지이유로인해정확한진단이어려울수있다. 우선, 치매진단에있어서필수적인항목인일상생활수행능력의저하가인지기능의장애로인한것인지아니면파킨슨병의운동기능장애의한것인지판단하기가어 Korean Dementia Association

89 김재우 렵다. 그리고환시나망상등과같은정신적인증상이복용중인약물에의한부작용인지아니면파킨슨병치매에의한것인지를구별하기가힘들다. 이전에는 DSM 4를진단기준으로많이사용하였으나그내용이모호하여유병율및발생율이보고자에따라변화가심하였다. 최근에는 Movement Disorders Society 에서새로운진단기준을제정하여사용을권고하고있다. 파킨슨병치매와루이체치매가같은질환인지서로다른질환인지에대해서는아직확실하지않다. 병리소견과뇌영상소견은같으나임상양상은다르다. 루이체치매의경우에는일반적으로파킨슨증상에선행해서치매증상이나타나는경우가더흔하지만파킨슨병의운동증상이선행하는경우루이체치매로진단하기위해서는파킨슨병의운동증상이시작된후 1년이내에치매가나타나야한다. 파킨슨병치매에서는운동증상이나타나고수년이경과한후에인지저하증상이나타나는경우가대부분이다. 치 료 파킨슨병치매에서레보도파를비롯한도파민약제들은각성을증가시키고도파민성신경전달에의한정보처리과정과작업기억등에서일부유용한효과를보인다는보고가있으나극히제한적이다. 오히려치매환자에서혼돈상태나정신증상을야기할수있기때문에사용에주의를요한다. 파킨슨병치매에서인지기능의개선을위해서는콜린분해효소억제제를이용한임상시험들이시행되었고어느정도그효과가입증되었다. 대표적으로 Rivastigmine 을이용한대규모의이중맹검약물시험연구에서파킨슨병치매환자의인지기능이향상되었다. 파킨슨병치매에서환각이나망상과같은정신병증상이나타난다면우선복용하고있는약물의부작용을먼저생각하고레보도파를제외한약물들을차례로줄이거나끊어보아야한다. 그래도증상의변화가없으면비전형적인신경이완제를투여해본다. 추체외로증상이가장적게나타나는것으로알려진 quetiapine 을먼저투여해보고효과를보지못하면 clozapine 을조심스럽게투여한다. 이때정기적인혈액검사를통하여백혈구감소증을확인하는것을잊어서는안된다. REFERENCES 1) 고성범, 권도영, 이종문, 한진규, 김병조, 박민규, 박건우, 이대희. 안산시에서의파킨슨증후군의역학조사. 대한신경과학회지 2003; 21(5): ) 김재우, 박경원, 차재관, 김상호, 강도영. 루이체치매의임상양상, 약물반응및뇌영상소견. 대한신경과학회지 2003;21(3): ) Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen P. Risk of dementia in Parkinson s disease: a community-based, prospective study. Neurology 2001;56(6): ) Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil for cognitive impairment in Parkinson s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2002;72(6): ) Ballard CG, Aarsland D, McKeith I, O Brien J, Gray A, Cormack F, Burn D, Cassidy T, Starfeldt R, Larsen JP, Brown R, Tovee M. Fluctuations in attention: PD dementia vs DLB with parkinsonism. Neurology 2002;59(11): ) Bissessur S, Tissingh G, Wolters EC, Scheltens P. rcbf SPECT in Parkinson s disease patients with mental dysfunction. J Neural Transm Suppl 1997;50: ) Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson s disease. Neurobiol Aging 2003;24: ) Cummings JL. Intellectual impairment in Parkinson s disease: clinical, pathologic, and biochemical correlates. J Geriatr Psychiatry Neurol 1988; 1(1): ) Dubois B, Pilon B, Lhermitte F, Agid Y. Cholinergic deficiency and frontal dysfunction in Parkinson s disease. Ann Neurol 1990;28(2): ) Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson s disease. NEJM 2004;351: ) Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson s disease. Mov Disord 2007;22: ) Goetz CG, Koller WC, Poewe W, Rascol O, Sampaio C. Drugs to treat dementia and psychosis. Mov Disord 2002;17(suppl 4): ) Hietanen M, Teravainen H. The effect of age of disease onset on neuropsychological performance in Parkinson s disease. J Neurol Neurosurg Psychiatry 1988;51(2): ) Huber SJ, Shuttleworth EC, Freidenberg DL. Neuropsychological differences between the dementias of Alzheimer s and Parkinson s diseases. Arch Neurol 1989;46(12): ) Hughes TA, Ross HF, Musa S, Bhattacherjee S, Nathan RN, Mindham RH, Spokes EG. A 10-year study of the incidence of and factors predicting dementia in Parkinson s disease. Neurology 2000;54(8): ) Jellinger KA, Paulus W. Clinico-pathological correlations in Parkinson s disease. Clin Neurol Neurosurg 1992;94 Suppl:S ) Litvan I, Mohr E, Williams J, Gomez C, Chase TN. Differential memory and executive functions in demented patients with Parkinson s and Alzheimer s disease. J Neurol Neurosurg Psychiatry 1991;54(1): ) Mattila PM, Roytta M, Torikka H, Dickson DW, Rinne JO. Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson s disease. Acta Neuropathol (Berl) 1998;95(6): ) McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB 93

90 파킨슨병치매 (Parkinson s Disease Dementia) international workshop. Neurology 1996;47(5): ) Perry EK, Irving D, Kerwin JM, McKeith IG, Thompson P, Collerton D, Fairbairn AF, Ince PG, Morris CM, Cheng AV. Cholinergic transmitter and neurotrophic activities in Lewy body dementia: similarity to Parkinson s and distinction from Alzheimer disease. Alzheimer Dis Assoc Disord 1993;7(2): ) Pillon B, Boller F, Levy R, Dubois B. Cognitive deficits and dementia in Parkinson s disease. 2 ed. Amsterdam: Elsevier Science; ) Stern Y, Richards M, Sano M, Mayeux R. Comparison of cognitive changes in patients with Alzheimer s and Parkinson s disease. Arch Neurol 1993;50(10): ) Vander Borght T, Minoshima S, Giordani B, Foster NL, Frey KA, Berent S, Albin RL, Koeppe RA, Kuhl DE. Cerebral metabolic differences in Parkinson s and Alzheimer s diseases matched for dementia severity. J Nucl Med 1997;38(5): Korean Dementia Association

91 Parkinsonism & Dementia November 28, 2009 루이체치매 동아대학교의과대학신경과학교실 박경원 김재우 Dementia with Lewy Bodies Kyung Won Park, MD, PhD, Jae Woo Kim, MD, PhD Department of Neurology, Dong-A University College of Medicine, Busan, Korea ABSTRACT Dementia with Lewy bodies (DLB) is the second common degenerative dementia and has several characteristics including fluctuating cognition, visual hallucination and parkinsonism. DLB should be first considered as one of possible diagnosis in patients showing dementia in the early stage of parkinsonism. Clinical presentation, unlike Parkinson s disease, is with progressive cognitive decline with significant deficits of visuospatial ability as well as frontal executive function accompanied by mild to moderate Parkinsonism. Several potential biomarkers for the differential diagnosis of probable DLB and AD have shown modest diagnostic accuracy in the research setting. Responsiveness of parkinsonism to levodopa seems favorable. Cholinesterase inhibitors were thought promising in enhancing cognition in short term periods. We review the clinical characteristics with differential diagnosis, biomarkers, treatment and prognosis in patients with DLB. KEY WORDS: Dementia with Lewy bodies Parkinsonism Neuropsychological test Neuroimaging Biomarker Treatment. 서 론 루이체치매 (dementia with Lewy bodies, 이하 DLB) 는노인에서관찰되는퇴행성치매의신경병리학적원인중알쯔하이머병 (Alzheimer s disease, 이하 AD) 다음으로흔한치매의원인질환으로약 20% 정도를차지하는것으로알려져있다. 1) DLB 란임상적으로치매를보이면서뇌조직병리소견에서뇌간과피질부위에서루이체가광범위하게관찰되는모든치매를말한다. DLB 의임상양상과뇌조직병리소견은 AD와는다르며, 임상적, 병리학적진단기준이제안되어전향적인연구에의해그타당성이조사되었다. 2-4) 신경병리학적으로 DLB 에서는루이체가흑질뿐만아니라변연피질 (limbic cortex) 을비롯한뇌의신피질부위에광범위하게분포되어있으며, 콜린성신경세포가밀집해있는 nucleus basalis of Meynert 에도존재하여콜린성신경기능의장애를초래하는것으로생각된다. 2) 파킨슨증상에선행해서치매의증상이나타나거나파킨슨증상의초기에치매증상이있으면반드시 DLB 의가능성을생각하여야한다. 최근루이체의주요성분인 α-synuclein 의면역조직화학 (immunohistochemistry) 방법이개발된이후에관심이증대되고있다. 5) DLB 환자중많은수 (66%) 에서 AD 병리소견을동반하는것으로알려져있다. DLB 에서는루이체가흑질부위뿐만아니라변연계피질 (limbic cortex) 을비롯한뇌의신피질 (neocortex) 부위에광범위하게분포함으로써치매를유발하는것으로생각된다. 6) 본종설에서는 DLB 의임상양상과진단기준, 생체지표및약물치료등에관한전반적인고찰을하고자한다. 임상양상및감별진단 1. 임상증상및진단기준 DLB의평균발병연령은 75세전후이고남자에서더흔하다. McKeith 등이 2005년에제시한개정판임상적진단기준 (Table 1) 4) 에서, 진행하는인지기능장애이외에임상적으로세가지핵심증상 (core feature) 이관찰될수있는데변동하는인지기능 (fluctuating cognition) 과반복되는환시 (recurrent hallucination) 그리고파킨슨증상 (parkinsonism) 이핵 95

92 루이체치매 Table 1. Revised clinical diagnostic criteria for DLB (from Mc Keith et al. 2005) 4) Criteria Central feature Core features (any 2=probable DLB; any 1=possible DLB) Suggestive features (1 or more+ a core feature=probable DLB, any 1 alone=possible DLB) Supportive features (common but lacking diagnositic specificity) Details Progressive cognitive decline that interfere with social and occupational function Fluctuating cognition Recurrent visual hallucinations Spontaneous parkinsonism REM sleep behavior Severe neuroleptic sensitivity Decreased tracer uptake in striatum on SPECT dopamine transporter imaging or on MIBG myocardial scintigraphy Repeated falls and syncope Transient, unexplained loss of consciousness Systemized delusion Hallucinations in other modalities Relative preservevation of medial temporal lobe on CT or MRI scan Decreased tracer uptake on SPECT or PET Prominent slow waves on EEG with temporal lobe transient sharp waves Table 2. The mayo fluctuation scale (from Ferman et al, 2004) 9) Four items significantly differ from AD 알츠하이머병과감별할수있는 4가지항목 1) drowsiness and lethargy all the time or several times a day despite getting enough sleep the night before 간밤에충분한수면에도불구하고하루종일혹은하루중여러번졸려하거나기면상태를보인다. 2) daytime sleep of 2 or more hours (before 7 pm) 저녁 7시이전에 2시간이상낮잠을잔다. 3) staring into space for long periods 오랜기간동안일정공간을멍하니주시한다. 4) times when the patient s flow of ideas seem 환자생각의흐름이지리멸렬하거나, 명백하지않고, 비이성적이다. disorganized, unclear, not logical 심증상을이룬다. 변동하는인지기능은다양한형태를가진다. 7) 의식이명료한가운데산발적인혼미증상 (sporadic confusion) 을보이는정도에서부터의식의각성정도가현저히저하되어있거나심지어낮에도기면상태 (somnolence) 를보이는정도까지나타날수있다. 지속시간도수분에서수시간혹은수주간으로다양하며, 이러한증상은섬망 (delirium) 을연상케하므로독성물질이나약제에대한철저한병력조사가필요하다. 이와같은형태의의식변화는다른유형의치매에서도나타나지만 DLB 에서약 75% 의빈도로가장흔히관찰된다. 8) 이증상은보호자를통한문진과기록에의존해야하는제한성때문에판단이어려운경우가많다. 최근에는변동하는인지기능을객관적으로점수화한척도를사용하여인지변동의정도를제시하기도한다 (Table 2). 9,10) 환시는동물이나사람에관한내용이흔한데전형적인경우는아주구체적인형상이나색깔등을생생하게표현한다. 치매가심하지않으면환자는헛것을보았다는사실을대개인정한다. 변동하는인지기능과반복적인환시와같은핵심증상을임상적으로쉽게진단하기어려운점이있다. 그이유는임상적진단과병리학적진단이일치하는경우는 45% 정도로높지않으며, 핵심증상의빈도또한높지않기때문으로설명하고있다. AD 병리소견을동반하는환자에서는핵심증상이서로혼합되어구분이쉽지않다. 11) DLB 의핵심증상중하나인파킨슨증상의경우, 신경이완제와같은약제유발성이아니고자발적으로발생하는경우를말한다. DLB에서파킨슨증상의특징은파킨슨병과임상적으로크게다르지않으나안정떨림 (resting tremor) 이상대적으로드물다. 운동증상중에는경직 (rigidity) 과운동완만 (bradykinesia) 이흔하게나타나지만파킨슨병과비교하여대칭적이다. 안정떨림이비교적드문대신운동및체위성떨림 (action or postural tremor) 과보행장애가흔히동반된다. 12) 파킨슨병과는달리운동에관여하는선조체에서의콜린성신경기능이함께감소되어있어서 DLB에서진전이상대적으로드문게아닌가생각된다. 레보도파에대한반응에대해서는연구자마다달리보고하나파킨슨병에서와같이아주현저하지는않으나비교적좋은편이다. 약 25% 정도의환자에서는파킨슨증상이없을수있으나파킨슨증상이선행하는경우에는 DLB 의진단을위하여치매가 12개월내에시작되어야한다. 13) 2005년임상진단기준 4) 에는핵심증상이외에진단부주증상 (suggestive features) 을추가하여중요한증상으로간주하고있다. 렘수면행동장애 (REM sleep disturbance), 심한신경이완제감수성, 그리고 PET/SPECT 검사에서선조체에 Korean Dementia Association

93 박경원 Brainstem Lewy bodies Limbic/Cortical Lewy bodies Amyloid Plaques Neurofibrillary Tangles Parkinson s Disease Lewy Body Dementias Alzheimer s Disease Figure 1. Clinicopathologic relations among Alzheimer s disease and Lewy body disorders (from Troster et al. 2008). 14) 도파민운반체 (dopamine transporter) 의낮은섭취율측정이여기에속한다. 한가지의핵심증상과한가지이상의진단부주증상이동반된경우를 probable DLB 로, 한가지진단부주증상만있는경우를 possible DLB 로진단한다 (Table 1). 보조적증상 (supportive features) 으로는반복적인넘어짐 (repeated fall) 과실신 (syncope), 일시적원인미상의의식소실, 체계화된망상, 혹은다른유형의환각등이있을수있다. 이외에뇌 MRI에서비교적보존된안쪽관자엽 (medial temporal lobe), PET 이나 SPECT 검사상후두엽에서추적자섭취율감소 (low rate of tracer uptake), 뇌파검사상저명한서파활동과관자엽에일시적예파 (transient sharp wave) 등의소견을보일수있다. 그러나이들증상과소견은다른질환에서도비교적흔한것으로서진단적특이성을갖지는않는다. 2. 신경심리소견신경심리소견으로서 DLB 는 AD에서관찰되는기억장애와비교하여병초기부터전두엽기능장애와시공간및시각적구성인지기능의장애를보인다. 또한인지과정이느려지고주의력저하및변동증상이나타난다. 비슷한인지장애정도를가진 AD와비교해서상대적으로기억력저하는경미한것으로알려져있지만, AD와대등하게기억력저하를보인다는연구결과도있다. 중등도및심한상태의 AD에서도주의력변동은나타나지만주의력저하에의한인지반응시간의현저한지연은 DLB 에서비교적특이한소견이다. 14) 치매와파킨슨병의증상이공존한다는점에서 DLB와치매가동반된파킨슨병이궁극적으로동일한질환일가능성에대해서는논란의여지가있으나파킨슨병에서는초기에치매가동반되는경우는거의없다는점이중요한차이점으로생각된다. 파킨슨증상이치매에선행하는경우 DLB 로진단하기위해서는파킨슨증상의시작후 1년이내에치매가시작되어야한다. 그러나실제로파킨슨병에서 5년이내에치매가동반되는경우는드물기때문에파킨슨병의초기에치매가나타날경우에는파킨슨병자체에의한경우보다도 DLB를먼저생각하여야하고, 약물이나우울증에의한인지장애가아닌지를반드시고려해야한다. 12,13) DLB 의주요증상인인지기능의변화와환각증상은파킨슨병의초기에는거의관찰되지않는증상들이다. 파킨슨병에서관찰되는치매는파킨슨병이진행될수록그리고파킨슨병의증상이시작될당시에나이가많을수록또한이전에환각을경험한경우가있을때가그렇지않은경우에비하여발생될가능성이커진다. 3. 감별질환치매와파킨슨병의증상이공존하는여러질환들과의감별이필요하다. AD 환자들의약 30% 에서도파킨슨병의운동증상이동반될수있다고보고하고있으나대개는 AD의말기에관찰되며레보도파에대한반응도미미한편이다. 그리고 AD의초기에는변동성인지장애와반복적인환시증상은비교적드물다. 파킨슨병의증상이시작되고얼마되지않아서치매가동반될수있는질환의경우감별이용이하지않을수도있다. 15) 진행성핵상마비 (progressive supranuclear pa- 97

94 루이체치매 lsy) 와피질기저핵변성 (corticobasal degeneration) 에서초기에치매증상이동반되는경우 DLB와의감별이어려울수있는데전자의경우에는파킨슨병의증상이외에도안구의상하운동의장애와잘넘어지는증상 (falling) 을흔히동반한다. 후자의경우에는피질감각증상과실행증이한동안한쪽팔다리에국한되고그반대편뇌피질의위축이흔히관찰된다. 두경우모두레보도파에대한반응이 DLB 보다못하다. 12) DLB 와가장감별이어렵고항상고려해야할질환이파킨슨병치매이다. DLB 의경우에는일반적으로파킨슨증상에선행해서치매증상이나타나는경우가더흔하지만파킨슨병의운동증상이선행하는경우 DLB 로진단하기위해서는파킨슨병의운동증상이시작된후 12개월이내에치매가나타나야한다. 4) 그러나파킨슨병치매에서는대개운동증상이나타나고수년이경과한후에인지저하증상이나타나는경우가대부분이다. 15) 생물지표 (Biomarkers) 1. 영상소견 DLB 환자에서 MRI 영상소견에관한연구는많지않다. 일반적으로 AD와의미있게구분되는특징적인뇌영상소견은없다. 다만 AD에비해해마부위와내측두엽부위용적이상대적으로보존되어있다는점이다를뿐이다. 16) SPECT 를이용하여뇌혈류분포를살펴보면 AD에서와같이측두엽, 두정엽을비롯하여전두엽에서의혈류감소가관찰되나 AD에서와는달리많은환자들에서후두엽에서도혈류의감소가관찰되는점이특징이다. 17,18) 이러한후두엽에서의혈류감소가 DLB 의주요증상인환시와연관이있을것으로생각되나그이유에대해서는아직알려진바가없다. 도파민운반체 (transporter) 에특이하게반응을하는물질을이용한 SPECT 를시행하여보면선조체에서의섭취율이감소되어파킨슨병에서와같이흑질-선조체도파민경로의소실을확인할수있다. 이러한소견은 AD와의구별에도움이될수있다. 19) 심혈관자율신경계기능저하는 DLB 에서비교적흔한것으로알려져있고, 123 I-MIBG Scintigraphy를이용하여 postganglionic cardiac sympathetic innervation 을정량적으로측정할수있다. 123 I-MIBG Scintigraphy 를이용한여러연구에서 AD와비교해서 DLB 에서현저하게 cardiac uptake 감소를보고하고있다. 20) 최근에발표된뇌영상연구에의하면, 베타아밀로이드축적을반영하는 Pittsburgh Compound B(PIB) PET 영상에서 DLB 환자는 AD와비슷한양상의소견을보여주고있고, 이는 DLB 에서 AD 병리소견이상당히공존하고있음을시사한다고할수있다. 21) 2. 뇌파소견뇌파검사를이용한여러연구에서 AD와비교해서 DLB 환자에서서파가관찰됨을보고하고있고, 특히후두부와전두엽에서서파가현저하게나타남을알수있다. 또다른연구에서간헐적인델타파가 AD 환자에서는 22% 정도관찰되지만 DLB 에서는 70% 까지발견됨을보고하고있다. 한연구에서는정량적뇌파검사 (quantitative EEG) 를이용한어느연구에서느린델타파의변동성 (variability in the slow δ wave) 이 AD와비교해서 DLB 에서의미있게관찰됨을제시하였다. 그러나뇌파검사의민감도나특이도에관한연구는아직부족하여두질환을감별하는 biomaker 로사용하기에는불충분하다고할수있다. 16) 3. 뇌척수액및혈액검사소견 AD의생체표지인자로사용되는 CSF β amyloid 와 phosphorylated tau 양과달리 DLB 에서생체표지인자에대한연구는부족하다. 최근한실험적연구에서 αβ peptide 와 α-synuclein 간의상호작용결과로 oxidaised α-helical form of αβ 1-40(αβ-ox) 이 DLB환자에서의미있게증가됨을보고하였다. 22) DLB 와 PD의병태생리적원인물질로알려지고있는 α-synuclein 은주로세포내형태로관찰되지만세포외형태로 CSF 나혈액에서도발견될수있다. 따라서 α-synuclein 양의감소가파킨슨병환자에서파킨병증상의정도와연관된다는연구결과가있지만아직까지더욱많은증거가필요하다. 16) 약물치료와예후 DLB 에서의치료는크게세가지관점에서고려되어야한다. 즉, 인지기능의개선과신경정신증상그리고파킨슨증상의개선이다. 그러나이들개별증상에대한치료가쉽지않을수있다. 왜냐하면한가지증상에대한치료는다른증상에나 Korean Dementia Association

95 박경원 쁜영향을미칠수있기때문이다. 예를들면환시나망상같은정신증상을치료하기위하여사용하는신경이완제가대부분도파민수용체에길항작용을가지고있으므로환자가가지고있는파킨슨증상을악화시킬수있다. 그리고파킨슨증상의개선을위하여사용하는약제들이반대로환시나망상을초래할수도있고인지기능의개선을위하여사용하는아세틸콜린분해효소억제제도드물게는파킨슨증상을악화시킬수있기때문이다. 15) 1. 아세틸콜린분해효소억제제및메만틴일반적으로아세틸콜린분해효소억제제에대한인지기능개선효과는 AD보다 DLB 에서더나은것으로알려져있다. 이는 AD에서와는달리 DLB 에서뇌피질에존재하는무스카린수용체의기능이보존되어있기때문으로생각된다. 아세틸콜린분해효소억제제는인지기능의개선이외에도여러신경정신증상들에도효과가있는것으로알려져있는데, 최근유럽에서 120명의 DLB환자들을대상으로한연구에서무관심, 불안, 망상과환시가좋은반응을보이는것으로보고되었다. 그러나우려하였던파킨슨증상의악화는거의관찰되지않았고단지일부환자들에서만진전이관찰되었다. 23,24) 최근에파킨슨병치매와 DLB 환자를대상으로메만틴을이용한이중맹검다기관임상시험에서메만틴을복용한환자군에서위약군에비해전반적인인지기능과집중력에서의미있게호전됨을증명하였다. 25) 2. 항파킨슨약제 DLB 에서도도파민이정상보다많이감소되어있기때문에파킨슨운동증상의호전을위해서는레보도파를투여하는것이효과적이다. 그러나파킨슨운동증상이심하지않을경우에는레보도파의투여를서두를필요가없다. 레보도파에의한여러정신증상이나타날가능성이우려되기때문이다. DLB 에서레보도파에대한반응은보고자마다차이가있으나파킨슨병에서와같이아주현저하지는않으나비전형적인파킨슨증 (atypical parkinsonism) 보다는훨씬좋은것으로생각한다. 3. 신경이완제 DLB 환자에서도 AD에서와같이정신증상을개선시키는것이매우중요하다. 그이유는정신증상은환자자신이나보호자모두에게가장큰짐으로작용하고조기에입원을해야하는요인일뿐만아니라사망률을증가시키는원인이기때문이다. 신경이완제가정신증상을개선시키는데에는가장중요한역할을한다. 그러나일반적으로 DLB 환자에게신경이완제는매우조심스럽게사용하여야하는데그이유는신경이완제에민감한반응 (neuroleptic sensitivity) 을보일수있기때문이다. 이경우파킨슨증상의심한악화뿐만아니라의식저하와자율신경계의기능까지마비시켜심하면사망에이를수있기때문이다. 4) 한연구에서는신경이완제를사용한 DLB 환자의 40~50% 에서이러한반응을보일수있는것으로보고하였고이와관련하여사망률도 2~3 배증가할수있는것으로주장하였다. 26) 비전형적인신경이완제 (atypical neuroleptics) 가이러한부작용을줄일수있다는보고와이들약제들도비슷한부작용을초래한다는상반된보고들이동시에나오고있다. 26,27) 신경이완제를사용할경우지나친진정작용과정신착란의부작용과더불어파킨슨증상이악화되지않는지조심스럽게관찰하여야한다. DLB 의예후에관하여, McKeith 등은평균생존기간은 2년에서 6.4 년으로다른치매보다평균유병기간이짧다고하였다. 25) 그러나최근전향적연구결과에의하면 AD나혈관성치매와비교하여발생나이, 유병기간및사망나이가크게다르지않았다. 28) 결 론 DLB 는 AD 다음으로흔한퇴행성치매의원인이지만진단시상대적으로과소평가 (underestimation) 되는경향이있고, 초기증상이 AD와구분이매우어려워약물치료시점을놓치거나지연될수있다. 따라서 DLB 에대한다양한임상증상과병태생리에대하여충분한지식과경험이축적되어야만적절한치료와중재를시행할수있다. 그동안 DLB 의진단기준에대한타당도를평가하는작업들이몇몇있어왔지만앞으로도더많은 DLB 환자들을대상으로임상양상과병리소견의상관관계를통해서구체적인진단기준을제시하고질환의개념을발전시켜나가야할것으로생각한다. 아울러병의진행상태를초기에발견하고진단할수있는유용한생물지표 (biomarker) 의발견과이에대한연구가시급하다고할수있다. 99

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97 Parkinsonism & Dementia November 28, 2009 Pathology of AD Neurofibrillary Tangles Bielschowsky-stained section from the Auguste D. s brain, showing neurofibrillary tangles, and a diagram of the tangles from a 1911 research paper by Alois Alzheimer. Paired Helical Filament(PHF) 1963 Michael Kidd, PHF Longitudinal spacing 80nm Width 30, 15 nm Tau, molecular composition of PHF 1985 Jean-Pierre Brion Tau like immunoreactivity in Neurofibrillary tangle or PHF 101

98 Tauopathies with Parkinsonism Tau Protein Microtubule Microtubule Associated Protein Tau(MAPT) Function of Tau Protein Kinesin and Dynein Korean Dementia Association

99 양동원 Tau synthesis Tau Isoforms Choromosom 17 q21 Microtuble-binding domain(mbds)- C terminal AA, 3 or 4 repeated sequence 3 R, 4 R Bind to β-tubulin in microtubule Projection domain-n terminal 29 AA, 1 or 2 sequence Phosphorylation affect binding ability of tau 6isoforms Human Chromosome Tau and chromosome Microtubule Associated Protein Tau - MAPT - 17q % familial FTD - tau-positive inclusions DNA (Idea) RNA (blue print) A B Tau (House) N3R 2N4R 103

100 Tauopathies with Parkinsonism FTDP-17 mutation Different Isoforms of Tau Fetal tau isoforms: 0N3R Different neurons have different tau isoforms: hippocampal granule cells of dentate gyrus have only 3R tau Different tauopathies have different isoform ratio FTDP-17: affect splicing of exon 10 4R Pick disease: 3R AD: 3R/4R =1 3R and 4R tau 4R tau binds with more affinity to tubulin dimers, and increase microtubule stability, enable to render the microtubules stiffer, longer and to modify the morphology of neurites, as well as to control neuronal plasticity Tau phosphorylation Tau phosphorylation Sites Abnormal hyperphosphorylation of tau in AD Phosphorylation of tau by kinase (GSK-3, MARK, CDK5) detaches tau from microtubule Dephosphorylation by phosphatase(?) attaches tau to microtubule. Microtubule binding domain Korean Dementia Association

101 양동원 Tau hyper-phosphorylation Dynamic Equilibrium of Tau Binding Aβ Oxidative stress Inflammation Phenotypical spectrum of tauopathies with pakinsonism Predominant tau pathology/prominent parkinsonism Progressive supranuclear palsy Corticobasal degeneration Postencephalitic parkinsonism (encephalitis lethargica) Parkinsonism dementia complex of Guam (Kii, Papua) Guadeloupean parkinsonism Miscellaneous cases tangle parkinsonism, LRRK2 mutations Predominant tau pathology/variable parkinsonism FTDP-17 Predominant tau pathology/parkinsonism uncommon Pick disease Argyrophilic grain disease Progressive Suprnuclear Palsy NINDS/SPSP diagnostic inclusion criteria Probable(clinically definite) Gradual progressive Age onset > 40yrs Vertical supranuclear palsy and prominent postural instability with falls in first year of disease onset Down gaze is affected before up gaze Lateral gaze is usually preserved Preserved vestibulo-occular reflex Falls gait apraxia, loss of righting reflex, ataxia No evidence of other disorder 105

102 Tauopathies with Parkinsonism Progressive Suprnuclear Palsy Pseudobulbar palsy-weak voice, dysphagia Axial rigidity Cognitive impairment-inattentive, apathy, decreased word fluency, dysexecutive function, faster than PD or MSA Visual symptoms blurred vision, diplopia, photophobia, blepharospasm, slow saccade, Correct diagnosis is usually made years after the onset of clinical signs. Median survival 6 yrs Progressive Suprnuclear Palsy Two forms of PSP PD like forms Bradykinesia, rigidity, levodopa responsiveness, asymmetric onset, tremor Pure akinetic form Gait freezing, apraxia of speech with delayed or even absent core PSP feature DDx with PD More axial, dystonic, less tremor(10-20%), symmetric, retrocollis, scloliosis of the lower spine Progressive Suprnuclear Palsy Pathologic distribution of PSP Neuropathology Gross Pathology Midbrain prominent Pallidum, thalamus, subthalamic nucleus, mild frontal atrophy Histopathology Neuron-globoe and flame-shaped NFT, neuropil threads Glial cell-tufted astrocyte, thorn-shaped astrocyte, oligodentrial coiled bodies 4 repeat tau Clinical and anatomical correlations of PSP Region Frontal cortex Parietal cortex Substantia nigra Periaqueductal grey and raphe nucleus Dentate nucleus Pontine and medullary nuclei rimlf (premotor burst neurons) Cholinergic neurons of the lower pontine reticular formation Clinical features Dysexecutive syndrome; progressive non-fluent aphasia; perseveration; impulsivity Alien limb Rigidity; bradykinesia; postural instability; dystonia Sleep disturbances Gaze fixation (excess of square wave jerks) Dysarthria; dysphagia Slow saccades No startle response; oculomotor dysfunction Normal PSP MSA-P Korean Dementia Association

103 양동원 Progressive Suprnuclear Palsy FDG-PET SPM Corticobasal degeneration -clinical presentation Movement asymmetric!! sever in the arm Parkinsonism: rigidity, tremor, bradykinesia, akinesia Limb dystonia Focal reflex myoclonus Postural instability Cortical features Cortical sensory loss Apraxia-ideomotor, bilateral, imitation of meaningless hand gesture Alien limb-has a will of its won intermanual conflict Frontal releasing sign Dementia, aphasia(motor) Others Cortico-spinal tract sign Oculomotor dysfunction Dysarthria Dysphasia Neuropsychiatric Depression(73%) Apathy (40%) Agitation(20%) Irritability(20%) Delusion Corticobasal degeneration FDG-PET SPM Corticobasal degeneration -clinical presentation Cognitive dysfunctions Frontal lobe involvement Non-fluent aphasia Frontal executive dysfunction Parietal lobe involvement Abnormal calculation and visuospatial function Lack of temporal lobe involvement Less affected semantic memory, episodic memory Corticobasal degeneration Neuropathology Gross Pathology Posterior frontal and parietal atrophy Sparing of temporal and occipital regions Assymetic Histopathology Neuron-cortical and strial Ballooned neuron-eccentrically located nucleus Globose NFT Glial cell Astrocytic plaque 4 repeat tau Corticobasal degeneration One third of CBD patients, underlying pathology dose not correspond to CBD Corticobasal syndrome was observed in PSP, Pick disease, AD, FTD with parkinsonism, FTLD with ubiquitin-positive inclusion CBD pathology was found in several clinical syndromes, PNFA, PSP, FTLD 107

104 Tauopathies with Parkinsonism Frontotemporal dementia with parkinsonism linked to chromosome 17 FTD + parkinsonism First reported in 1994 Autosomal dominant, 100% penetrance Chromosome 17-MAPT or progranulin gene Age of onset Mean duration to death 3-10 years Clinical syndrome-can vary within the same family FTD with or without parkinsonism Progressive nonfluent aphasia Semantic dementia Probable AD CBD FTDP 17-clinical presentation Age of onset between the third and fifth decades Neuropsychiatric syndrome including personality and behavioral abnormalities Parkinsonism-plus syndrome (bradykinesia, rigidity, postural instability, paucity of resting tremor, and poor or no response to dopaminergic therapy) frequently associated with falls and supranuclear gaze palsy and less commonly associated with apraxia, dystonia, and lateralization Progressive speech difficulties from the onset Seizure disorder poorly controlled by medication Family history suggestive of AD inheritance FTDP-17-clinical presentation Pathologic features of FTLD Neuropsychiatric dysfunctions Disinhibition, apathy, defective judgment, compulsive behavior, hyper-religiosity, neglect of personal hygiene, alcoholism, drug addiction, verbal and physical aggressiveness, family abuse, poor hygiene, echolalia, palilalia, verbal and vocal perseverations FTLD-tau: FTLD-U: FTLD-null: tau protein(+), ubiquitin(+) tau protein (-), ubiquitin(+) tau protein (-), ubiquitin(-) Cognitive dysfunction Memory, orientation, visuospatial function are relatively preserved in early stage Progressive speech difficulties with non-fluent aphasia and disorders of executive functions, DLDH: Dementia Lacking distinctive histology Pathological features of FTLD Role of TDP-43 nucleus cytoplasm nucleus U: Ubiquitin TDP-43: TAR DNA binding protein 43 (TARDBP) DLDH: Dementia Lacking distinctive histology Transactive response(tar) DNA binding protein(tardbp) 43KDa, 414 amino acid Chromosome 1, TARDBP gene First cloned in human immunodeficiency virus type 1 Localized in nucleus, regulation of transcription and splicing, micro RNA synthesis, apoptosis, cell division, mrna stabilization, neuronal plasticity, interact with survival motor neuron protein Shuttling effect between the nucleus and cytoplasm Korean Dementia Association

105 양동원 Progranulin Role of Progranulin In 2006, discovery of mutation of progranulin in FTDP-17 with no MAPT mutation. Multifunctional protein with neurotrophic growth or survival factor, with functions in wound healing and inflammation. 66 mutations in 199 families ( FTDP-17 MAPT, 44 mutations) 5% of all FTD and 4-10% of familiar FTD Clinical feature of mutation: FTD, AD, PD, CBD, PNFA Mechanism of progranulin mutation : unknown 1. Mutation produce premature stop codons mutant mrna nonsense mediated decay no mutant protein and reduction of functional progranulin cell damage. 2. Accumulation of hyperphospholylated c- terminal fragment of TDP-43 in cytoplasm toxic effect 3. Loss of TDP-43 function in the nucleus Accumulation of TDP-43 in progranulin mutation Mechanism is unknown C-terminal TDP-43 fragment in cytoplasm TDP-43 normally present in nucleus, not in cytoplasm Suppression of progranulin favors caspasedependent cleavage of TDP-43, leading to the accumulation of TDP-43 Accumulation of TDP-43 in cytoplasm suggests a loss of nuclear function of TDP-43 MAP-tau Progranulin Frequency among FTD 6 5 Inheritance AD AD Sex M=F M=F Onset age Duration of illness Clinical features Personality/behavior change Executive dysfunction Aphasia Amnesia Parkinsonism Motor neuron disease + 0 Clinical syndromes Probable AD + ++ CBD ALS ++ 0 Tauopathies- vulnerability Corticobasal degeneration Alzheimer s disease Pick s disease FTDP-17 Progressive supranuclear palsy 109

106 Tauopathies with Parkinsonism Understanding of neurodegenerative disease Clinical syndrome FTD PSP CBD FTDP-17 Pathology Tau TDP43 Clinical Syndrome and Proteinopathy FTDP-17 CBD PSP PNFA FTD-MND SD Tauopathy (With Extra pyramidal features) TDP-43opathy > 90% of FTLD Korean Dementia Association

107 Parkinsonism & Dementia November 28,

108 Parkinson-Related Dementia II Korean Dementia Association

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110 Parkinson-Related Dementia II Korean Dementia Association

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