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

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

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

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

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

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

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

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

Amyloid Cascade from Pangalos et al. 2005

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

Pathology in Alzheimer’s Disease

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

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

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

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

Hippocampus volume

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

Temporoparietal glucose hypometabolism on FDG-PET 21

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

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

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

신경연접(시냅스) 아세틸콜린 아세틸콜린 분해효소

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

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

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

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

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

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

면역요법-항체를 이용한 아밀로이드 제거 뇌 혈관

Immunotherapy for reducing Aβ in the brain

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

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

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

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