1. Alzheimer’s Disease: 진단과 치료
울산의대 서울아산병원 신경과
이 재 홍

2. 베타아밀로이드 단백( Aβ42)
타우 단백
(Tau)
유해라디칼
( free radical) 노화
( Aging)
Gene
( ApoE ..)
신경세포손상, 신경전달물질 저하, 시냅스약화
인지기능 저하, 행동이상, 일상활동저하
Normal
Alzheimer’s disease

4. A, B, C: The key symptom domains affected in AD
ADL
Cognition
Behavior

5. A, B, C, D of Dementia A: Activities of daily living
B: Behavioral and psychological symptoms of dementia (BPSD)
C: Cognition
D: Differential diagnosis

6. Diagnosis of Dementia 상세한 병력 가족력 신경학적 검사 신경심리(인지)검사 혈액검사
뇌영상검사 - CT, MRI

7. Causes of Dementia
퇴행성 뇌질환
뇌혈관 질환
기타 질환 (2차 치매)

8. 알츠하이머 치매
혈관성 치매
루이체 치매
파킨슨병 치매
전두측두엽 치매
외상성 치매
알코올성 치매
. . .
2008년

9. 베타아밀로이드 단백( Aβ42)
타우 단백
(Tau)
유해라디칼
( free radical) 노화
( Aging)
Gene
( ApoE ..)
신경세포손상, 신경전달물질 저하, 시냅스약화
인지기능 저하, 행동이상, 일상활동저하
Normal
Alzheimer’s disease

10. Amyloid Cascade
from Pangalos et al. 2005

12. Generation of beta amyloid
Gamma secretase가 작동하기 위해서는 PS1 이 필요
PS1 이 gamma secretase라는 설과 gamma secretase의 한 part라는 설이 다 있다
PS1에 binding하는 다른 protein으로 nicastrin이라는 것이 최근에 발견, PS1으로 하여금 APP processing아 가능하게
Intramembranous cleavage of APP가가능하게 하기 위해서는 PS, nicastrin, additional proteins form a complex with gamma-secretase 12

13. Pathology in Alzheimer’s Disease

14. Diagnostic tests of AD Neuropsychological tests Neuroimaging studies
- structural
- functional

16. Seoul Neuropsychological Screening Battery
시행 시간: 약 1시간 30분
병력 청취: 약 30분-1시간
표준화
정상 노인 447명 (여자 258명, 남자 189명)
무학– 대학 졸업
Computerized scoring

17. Structural imaging markers
Medial temporal atrophy (volumetric MRI)
hippocampus
entorhinal cortex
medial temporal lobe as a whole
Medial temporal atrophy (visual rating scale)

18. Hippocampus size in Aging, MCI and Alzheimer’s Disease
Mild Cognitive
Impairment
Alzheimer’s
Disease
Normal
Normal
25 Years
75 Years
75 Years
75 Years
National Institute on Aging

19. Hippocampus volume

20. Functional imaging markers
Offers potential insights into all of the
main pathological features of AD –
neuronal loss, tangle & plaque deposition,
cholinergic depletion
PET – regional glucose metabolism
SPECT – cerebral blood perfusion

21. Temporoparietal glucose hypometabolism on FDG-PET21

22. C-11 PIB PET Normal Alzheimer’s disease
Figure. (Left) 정상 노인의 PIB-PET 소견. 대뇌 피질에 PIB 결합(PIB binding)이 보이지 않음. (Right) 알츠하이머병 환자의 PIB-PET 소견. 후두엽을 제외한 전두엽, 측두엽, 두정엽 등 대뇌 피질 전반에 PIB 결합이 관찰됨.
PIB, Pittsburgh compound B

23. PIB vs CSF biomarkers Fagan et al. EMBO, 2009
금방 발표에서 본 PIB pet과의 연관성을 알아본 논문에서는 세가지 marker모두 연관성이 커서 상호 보완적으로 사용할 수 있을 것 같습니다.
그러나, PIB는 fibrillar form만 detection하므로, 간혹 PIB (-)인 경우
Fagan et al. EMBO, 2009

24. Cholinergic systems in the brain
Selden NR et al., Brain 1998;121

26. 신경연접(시냅스)
아세틸콜린
아세틸콜린 분해효소

27. Acetylcholinesterase inhibitors
Tacrine (Cognex) 1993
Donepezil (Aricept) 1997
Rivastigmine (Exelon) 2000
Galantamine (Reminyl) 2001

29. Memantine (Ebixa) NMDA-receptor antagonist 1982
organic brain syndrome treatment (Memantine hydrochloride)
1989
Merz Pharmaceuticals-drug study for the AD and vascular dementia (Axura®)
2003 FDA approved memantine (Namenda®) for the treatment of moderate to severe AD

31. Memantine (Ebixa®)- NMDA receptor antagonist
Neuroprotection with Memantine
Cell death 31

32. Unmet needs for AD
Currently available Alzheimer’s drugs are only beneficial for symptomatic improvement and no good for arresting or slowing the disease progression
There is an urgent need for disease modifying therapy for Alzheimer’s disease

33. Treatment of Alzheimer’s Disease
N5-067 Dem Con Template
4/28/2017 6:17 AM
Treatment of Alzheimer’s Disease
Cognitive Function
Disease-Modifying Therapy
Symptomatic Therapy
Natural History of AD
Years 33

34. Therapeutic interventions in AD
Antiamyloidogenic agent
Amyloid
Neuronal loss
Neurotropic agent
Neurochemical deficiency
Cholinesterase inhibitor
Symptoms
Psychotropic agent

35. 면역요법-항체를 이용한 아밀로이드 제거 뇌 혈관

36. Immunotherapy for reducing Aβ in the brain

38. Clearance Ab immunotherapy IDE Neprilysin γ - secretase b - secretase
inhibitors
Tramiprosate (Alzhemed)
Metal chelator/Zinc ionophore
(PTB-2)

41. Possible reasons from failed trials
Drugs are inefficient
Poor sensitive outcome measure
Relatively short period of follow-up
The target is wrong (e.g., Ab)
Incorrect timing of intervention

42. Alzheimer’s Disease Course, Treatment, and Prevention
Primary
Prevention
Secondary
Prevention
Treatment
Intervention
Normal
Pre- symptomatic AD
Mild Cognitive Impairment AD
Clinical
State
Brain
Pathologic
State
Early Brain
Changes
No Symptoms
AD Brain
Changes
Mild Symptoms
Moderate to
Severe
Impairment
No Disease
No Symptoms
Disease Progression
National Institute on Aging, USA

43. Conclusions
Combined algorithms comprising clinical, neuropsychological and imaging modalities are necessary at present to detect early AD
Disease modifying therapy and prevention strategies are being actively explored in the earliest phase of Alzheimer’s disease