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 460 65 10 1 85 3 1 Alzheimer s disease AD 5 7 2500 AD 460 MCI 6000 AD 21 2012 5 National Plan to Address Alzheimer s Disease 2025 AD AD 2015 1 2008 10 2018 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 - 39 -
Vol.21 No.4 2017 AD 2 3 2007 38 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 229 398 MCI 192 AD 2 MCI 3 2009 1 MRI PET 2 MCI AD 3 1 4 AD Aβ42 PET AD preclinical stage AD 5 6 AD CLU CR1 PICALM 7 ADNI 8 ADNI 図 1 AD 70 25 Aβ PIB-PET Aβ42 Aβ NIA/AA MCI AD preclinical AD stage - 40 -
3. NIA/AA による新臨床診断基準 20 ADNI 2011 4 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):280-92 3 AD Aβ 図 1 probable AD dementia probable AD 1984 NINCDS- ADRDA 40 90 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- 181 2003 Innogenetics ELISA 36 AD 2500 1400 t- 81% 90% Innogenetics ELISA 13 AD 600 450 Aβ42 86% 90% ELISA 11 AD 800 370 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) - 41 -
Vol.21 No.4 2017 表 2A Aβ42, t-tau, p-tau Biomarker 対照群 (pg/ml) AD 群 (pg/ml) Aβ42 792 ± 20 <500 # t-tau 136 ± 89 (21-50 歳 ) / 243 ± 127 (51-70 歳 ) 341 ± 171 (>71 歳 ) >450 >600 # p-tau181 23 ± 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 96.4 76.9 ROC AUC 0.913 t- /Aβ42 = 0.39 Aβ42 AUC=0.917 85.7 84.6 80 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 Aβ42 0.94 (18) 1.4 (17) 0.1 (14) CSF t-タウ 3.45 (13) 2.34 (21) 1.24 (24) PIB #1 0.098 (0.18) 0.008 (0.18) 0.004 (0.25) FDG-PET #2 0.006 (0.06) 0.015 (0.064) 0.055 (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 0.54 (3.05) 1.05 (4.40) 4.37 (6.60) MMSE 0.0095 (1.14) 0.64 (2.5) 2.4 (4.1) CDR 合計点 #4 0.07 (0.33) 0.63 (1.16) 1.62 (2.20) RAVLT 5 回の合計点 #5 0.29 (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/ Aβ42 94 68 64 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 - 42 -
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 2012 4 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 25 15 15 15 10 10 5 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 - 43 -
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