Vol.21 No AD Japanese-ADNI J-ADNI 2015 AMED AD NA-ADNI 400 AD AD 2. NA-ADNI 研究の主な成果 NA-ADNI 2004 NA-ADNI ADNI, ADNI-GO ADNI-2 phase

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1 アルツハイマー型認知症のバイオマーカーの現状と課題 Biochemical biomarkers for Alzheimer s disease: present status and awaiting solution 京都府立医科大学分子脳病態解析学 / 教授 * 1. はじめに Alzheimer s disease AD AD 460 MCI 6000 AD National Plan to Address Alzheimer s Disease 2025 AD AD AD ADL AD disease-modifying agent= ADL AD 2004 ADNI Alzheimer s Disease Neuroimaging Initiative ADNI: NA-ADNI ADNI AD MRI Positron Emission Tomography: PET * Takahiko Tokuda, M.D., Ph.D. Department of Molecular Pathobiology of Brain Diseases, Kyoto Prefectural University of Medicine, Professor

Vol.21 No.4 2017 AD 2 3 2007 38 Japanese-ADNI J-ADNI 2015 AMED AD NA-ADNI 400 AD AD 2.

2 Vol.21 No AD Japanese-ADNI J-ADNI 2015 AMED AD NA-ADNI 400 AD AD 2. NA-ADNI 研究の主な成果 NA-ADNI 2004 NA-ADNI ADNI, ADNI-GO ADNI-2 phase Tau imaging ADNI-3 ADNI MCI 192 AD 2 MCI MRI PET 2 MCI AD AD Aβ42 PET AD preclinical stage AD 5 6 AD CLU CR1 PICALM 7 ADNI 8 ADNI 図 1 AD Aβ PIB-PET Aβ42 Aβ NIA/AA MCI AD preclinical AD stage

3 3. NIA/AA による新臨床診断基準 20 ADNI NIA/AA the National Institute on Aging/ the Alzheimer s Association AD 27 AD AD preclinical stages of AD AD mild cognitive impairment MCI due to AD AD MCI dementia due to AD AD 3 preclinical AD Alzheimers Dement. 2011; 7(3): AD Aβ 図 1 probable AD dementia probable AD 1984 NINCDS- ADRDA AD dementia unlikely due to AD Aβ42 PET t- / p- FDG -PET MRI 4. AD の診断バイオマーカー AD 1) 生化学的バイオマーカー :AD signature 表 1 Aβ42 t- p- AD B AD AD AD Aβ Aβ42 t- /p- p- AD ELISA p- 181 p Innogenetics ELISA 36 AD t- 81% 90% Innogenetics ELISA 13 AD Aβ42 86% 90% ELISA 11 AD p- 80% 92% Humpel 2011 internationally established biomarkers in CSF used to diagnose AD AD Aβ42 t- p- Innogenetics ELISA 表 2A 表 1 ( 認知症疾患治療ガイドライン 2010 コンパクト版 2012 より ) 1 髄液 Aβ42 の低下 t- タウ値あるいは p- タウ値の上昇は AD の診断マーカーとして推奨される ( グレード B) 2 認知症が疑われる場合血液検査は認知症および認知症様症状をきたす内科疾患との鑑別に重要である一般血液生化学検査血糖アンモニア甲状腺ホルモンビタミン B1 B12 梅毒血清反応等の検査項目が推奨される ( グレード C1)

4 Vol.21 No 表 2A Aβ42, t-tau, p-tau Biomarker 対照群 (pg/ml) AD 群 (pg/ml) Aβ ± 20 <500 # t-tau 136 ± 89 (21-50 歳 ) / 243 ± 127 (51-70 歳 ) 341 ± 171 (>71 歳 ) >450 >600 # p-tau ± 2 >60 # # p<0.001 β 表 2B Aβ42, t-tau, p-tau 疾患アルツハイマー病 Aβ42 表 2B NA-ADNI Aβ42 t- p- Innogenetics INNO-BIA AlzBio3 kit Luminex assay ADNI NA-ADNI 2009 historical paper 56 AD 52 Non-ADNI cohort Aβ1-42 =192 pg/ml AD ROC AUC t- /Aβ42 = 0.39 Aβ42 AUC= Aβ1-42 t-tau p-tau AD signature AD p t-tau p-tau181 急性期脳梗塞 - アルコール性認知症クロイツフェルトヤコブ病うつ病前頭側頭型認知症レビー小体型認知症中枢神経系の炎症正常加齢パーキンソン病脳血管性認知症 - : 変化なし,: 増加, : 減少 (Humpel 2011 を著者改変 ) 表 3 バイオマーカー AD NA-ADNI Beckett 2010 正常群年率変化の平均値 (SD) MCI 群 AD 群 CSF Aβ (18) 1.4 (17) 0.1 (14) CSF t-タウ 3.45 (13) 2.34 (21) 1.24 (24) PIB # (0.18) (0.18) (0.25) FDG-PET # (0.06) (0.064) (0.067) MRI: 海馬容積 40 (84) 80 (91) 116 (93) MRI: 脳室容積 848 (973) 1551 (1520) 2540 (1861) ADAS-cog 合計点 # (3.05) 1.05 (4.40) 4.37 (6.60) MMSE (1.14) 0.64 (2.5) 2.4 (4.1) CDR 合計点 # (0.33) 0.63 (1.16) 1.62 (2.20) RAVLT 5 回の合計点 # (7.8) 1.37 (6.6) 3.62 (5.6) #1: PIB: 前部帯状回頭頂葉楔前部前頭葉を通る断面での Standard uptake value ratio (SUVR) #2: FDG ( 18 F-fluorodeoxyglucose)-PET: 両側角回頭頂葉後部帯状回の平均糖代謝 #3: ADAS-cog = Alzheimer s disease assessment scale-cognitive subscale #4: CDR = Clinical dementia rating #5: RAVLT = Rey auditory-verbal learning test ADNI cohort AD signature MCI AD conversion ADNI cohort NA-ADNI t- /Aβ42 p- 181/ Aβ AD PIB-PET NA-ADNI PIB-PET Aβ42 Aβ40 t- p- 181 Aβ42 91% Aβ42 PIB-PET MMSE MCI AD conversion NA-ADNI 2 Walhovd t- / Aβ42 MCI AD conversion Aβ42 PIB-PET MRI

5 NA-ADNI MCI AD 1 表 3 AD CSF Aβ42 AD MCI FDG-PET AD AD 図 1 Aβ42 preclinical MCI AD AD dementia AD MRI Aβ42 AD AD p- AD t- Aβ42 ELISA Luminex assay Gothenburg Blennow The Alzheimer Association QC Program validation 2012 Bateman New England journal AD 128 CSF Aβ42 PIB-PET Aβ CSF t- MRI FDG-PET MMSE/CDR CSF Aβ42 PIB-PET AD AD AD AD 2) 新しい AD biomarker 候補 : 髄液中 Aβ オリゴマーについて Aβ42 Hampel Blennow 2010 Core CSF candidate biomarkers for AD 表 4 Aβ バイオマーカー ( 測定法 ) Aβ42/Aβ40 比 (ELISA) APP isoform: sappα, sappβ (ELISA) BACE1 (enzyme activity assay) Aβ oligomers (Bio-Barcode assay, ELISA) (#1) 脳 Aβ 代謝 (#2) 表 4 AD Hampel 2010 AD での変化評価コメント AD での Aβ42/Aβ40 比の減少は Aβ42 単独よりも高度 AD では変化がみられない BACE1 蛋白レベルと酵素活性は AD および MCI で増加 AD での増加が異なる検出法による 2 つの研究で報告報告なし限られた数の研究による data 限られた数の研究による data 異なる方法を用いた報告による data 測定法の開発段階健常な volunteer での検討 Aβ42 単独よりもアミロイド原性 Aβ 代謝のより正確な尺度である可能性 AD 診断には有用ではないが BACE1 阻害薬などの臨床試験には有用かもしれない有用性は更に検討が必要 BACE1 阻害薬などの臨床試験には有用かもしれない非常に有望なバイオマーカーであるが髄液中に極少量しか存在しないために定量法開発が困難臨床試験で脳の Aβ 産生とクリアランスを計量するのには有用かもしれない p-tau231 (ELISA) AD および AD/MCI での著明な増加が報告されている数多くの報告で一貫した結果髄液の p-tau は臨床試験で tau のリン酸化状態をモニターするための最も重要なバイオマーカー #1: 1 Bio-Barcode assay 2010 ELISA Fukumoto, Tokuda 2010 #2: isotope

6 Vol.21 No AD β Aβ 1 Aβ AD APP AD AD Aβ Aβ42 AD AD Aβ Aβ AD Aβ Aβ AD Aβ Aβ Aβ AD / Aβ Aβ42 AD Aβ Aβ Aβ ELISA single-antibody sandwich ELISA AD Aβ Aβ AD AD Aβ AD Aβ Aβ 6. おわりに 1984 Aβ AD 15 AD 21 AD 文献 1 Weiner MW, et al. Alzheimer s Disease Neuroimaging Initiative. The Alzheimer s Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement 2012; 8 Suppl 1: S Sperling RA, et al. Toward defining the preclinical stages of Alzheimer s disease: Recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement 2011; 7: Albert MS, et al. The diagnosis of mild cognitive impairment due to Alzheimer s disease: recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement 2011; 7: McKhann GM, et al. The diagnosis of dementia due to Alzheimer s disease: recommendations from the National Institute on Aging-Alzheimer s Association

7 workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement 2011; 7: McKhann G, et al. Clinical diagnosis of Alzheimer s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer s Disease. Neurology 1984; 34: Blennow K, et al. CSF markers for incipient Alzheimer s disease. Lancet Neurol 2003; 2: Humpel C. Identifying and validating biomarkers for Alzheimer s disease. Trends Biotechnol 2011; 29: Shaw LM, et al. Alzheimer s Disease Neuroimaging Initiative. Cerebrospinal fluid biomarker signature in Alzheimer s disease neuroimaging initiative subjects. Ann Neurol 2009; 65: De Meyer G, et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol 2010; 67: Jagust WJ, et al. Relationships between biomarkers in aging and dementia. Neurology 2009; 73: Weigand SD, et al. Alzheimer s Disease Neuroimaging Initiative. Transforming cerebrospinal fluid Aβ42 measures into calculated Pittsburgh Compound B units of brain Aβ amyloid. Alzheimers Dement 2011; 7: Jack CR Jr, et al. Alzheimer s Disease Neuroimaging Initiative. Brain β-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer s disease. Brain 2010; 133: Beckett LA, et al. Alzheimer s Disease Neuroimaging Initiative. The Alzheimer s Disease Neuroimaging Initiative: Annual change in biomarkers and clinical outcomes. Alzheimers Dement 2010; 6: Mattsson N, et al. The Alzheimer s Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. 2011; 7: Mattsson N, et al. Alzheimer s Association QC Program Work Group. CSF biomarker variability in the Alzheimer s Association quality control program. Alzheimers Dement. 2013; 9: Bateman RJ, et al. Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer s disease. N Engl J Med. 2012; 367: Sutphen CL, et al. Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age. JAMA Neurol. 2015; 72: Hampel H, et al. Biomarkers for Alzheimer s disease: academic, industry and regulatory perspectives. Nat Rev Drug Discov 2010; 9: Fukumoto H, et al. High-molecular-weight β-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. FASEB J 2010; 24:

PET n = 7 AD n = 20 図 3 PiB AD A 3. わが国のアミロイド PET の現状 PET 100 PiB 15 BF 図 4 J-ADI 105 図 5 20%MCI 60% AD 90% MCI AD AD E ApoE 4 AD 4 図 6 4.

PET n = 7 AD n = 20 図 3 PiB AD A 3. わが国のアミロイド PET の現状 PET 100 PiB 15 BF 図 4 J-ADI 105 図 5 20%MCI 60% AD 90% MCI AD AD E ApoE 4 AD 4 図 6 4. 病態理解と薬剤開発におけるアミロイド PET 検査の現状 Current Status of Amyloid PET in Pathophysiological Research and Drug Development for Alzheimer s Disease 東京都健康長寿医療センター研究所附属診療所 / 所長 * 1. はじめに PET A A AD 図 1 AD AD PET 2. アミロイド