蛋白特異的PETイメージングによる神経回路破綻機序の解明

2015 Fiscal Year Annual Research Report

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 26117003
• Research Institution: Tohoku University
• Principal Investigator: 谷内 一彦 東北大学, 医学系研究科, 教授 (50192787)
• Co-Investigator(Kenkyū-buntansha): 田代 学 東北大学, サイクロトロンRIセンター, 教授 (00333477)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: 老化 / 脳神経疾患 / 認知症 / トランスレーショナルリサーチ / イメージング

Outline of Annual Research Achievements

我々はタウ蛋白蓄積と神経変性、脳機能障害との関連性を明らかにするため、独自に開発したタウPET プローブ[18F]THK-5351を用いて健常高齢者や各種神経変性疾患の患者を対象とした臨床研究を実施した。ADではタウ病変好発部位に一致した[18F]THK-5351の集積を認め、軽度認知障害（MCI）から認知症へと進行するにつれて、[18F]THK-5351の集積量が上昇し、側頭葉下部から頭頂葉や前頭葉などの他の皮質へと集積範囲が拡大する傾向を認めた。ADの非典型例とされる後部皮質萎縮症の症例では、外側後頭―頭頂領域におけるTHK-5351集積が顕著であり、記憶障害を主体とする典型的AD症例とは集積パターンが異なっていた。大脳皮質におけるTHK-5351の集積分布は脳萎縮の分布ともよく一致し、特に脳萎縮に左右差のみられる症例では萎縮の優位側でTHK-5351の集積を顕著に認めた。またアミロイドPET陰性の認知症患者においても、側頭葉の萎縮部位に一致した[18F]THK-5351集積を確認した。進行性核上性麻痺、皮質基底核症候群（CBS）における病変検出性能についても検討を行ったところ、タウ病変好発部位で顕著な[18F]THK-5351集積を認めた。特にCBS症例ではトレーサー集積の左右差が目立ち、淡蒼球症状優位側の対側の中心前回付近で高度な[18F]THK-5351集積を観察したことから、トレーサー集積によって反映されるタウ病変の局在が臨床症候に強い影響をもたらすことが示唆された。上記臨床研究と並行して、αシヌクレイン蛋白を検出するための新しいPETプローブ候補化合物の探索も昨年度に引き続き実施し、パーキンソン病患者脳切片におけるレビー小体を明瞭に染色する低分子化合物を見出した。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本年度は、前年度に引き続き申請者が独自に開発した改良型タウPETプローブ[18F]THK-5351を用いて健常高齢者や各種神経変性疾患の患者を対象とした臨床研究を実施した。当初の計画通り、本年度はアルツハイマー患者だけでなく非アルツハイマー病である進行性核上性麻痺、皮質基底核症候群も対象として各種PET検査を施行し、ADとは異なる特徴的な集積が認められ、期待通りの結果が得られている。
α-シヌクレイン、TDP-43を標的としたPETプローブの開発は、スクリーニングの評価系の構築は完了し、候補化合物の探索が進行中であり、病変に対する結合性を有し、脳血液脳関門透過性を有する候補化合物が見出されており、当初の計画通りプローブ開発作業が進行中である。

Strategy for Future Research Activity

来年度以降も、[18F]THK-5351と[11C]PiBを用いてタウ蛋白質、βアミロイドの脳内蓄積量の評価を進める。これまでに検査を実施済の被験者において、フォローアップ検査を実施し、タウ蛋白質、βアミロイドの経時変化および相互作用を調べる予定である。また、αシヌクレイン、TDP-43に対して結合親和性を有するPETプローブ化合物について標識化合物を合成し、オートラジオグラフィーによる結合選択性評価、体内動態など詳細評価を行っていく予定である。

Research Products

• [Int'l Joint Research] メルボルン大学(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: メルボルン大学
• [Int'l Joint Research] ハバナ大学(キューバ)
  • Country Name: CUBA
  • Counterpart Institution: ハバナ大学
• [Journal Article] microPET Imaging of Tau Pathology with [18F]THK5117 in two Transgenic Mouse Models. (2016)
  • Author(s): Brendel M, Jaworska A, Probst F, Overhoff F, Korzhova V, Lindner S, Carlsen J, Bartenstein P, Harada R, Kudo Y, Haass C, van Leuven F, Okamura N, Herms J, Rominger A.
  • Journal Title: Journal of Nuclear Medicine Volume: 印刷中 Pages: 印刷中
  • DOI: 10.296/jnumed.115.163493.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Advances in the development of tau PET radiotracers and their clinical applications. (2016)
  • Author(s): Okamura N, Harada R, Furukawa K, Furumoto S, Tago T, Yanai K, Arai H, Kudo Y.
  • Journal Title: Ageing Research Reviews Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.arr.2015.12.010.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Introduction and overview of the special issue "Brain imaging and aging": The new era of neuroimaging in aging research. (2016)
  • Author(s): Furukawa K, Ishiki A, Tomita N, Onaka Y, Saito H, Nakamichi T, Hara K, Kusano Y, Ebara M, Arata Y, Sakota M, Miyazawa I, Totsune T, Okinaga S, Okamura N, Kudo Y, Arai H
  • Journal Title: Ageing Research Reviews Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.arr.2016.02.005.
  • Peer Reviewed
• [Journal Article] Characteristics of Tau and Its Ligands in PET Imaging. (2016)
  • Author(s): Harada R, Okamura N, Furumoto S, Tago T, Yanai K, Arai H, Kudo Y
  • Journal Title: Biomolecules Volume: 6(1) Pages: 1-15
  • DOI: 10.3390/biom6010007.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis and characterization of 18F-interleukin-8 using a cell-free translation system and 18F-fluoro-L-proline (2016)
  • Author(s): Harada R, Furumoto S, Yoshikawa T, Ishikawa Y, Shibuya K, Okamura N, Ishiwata K, Iwata R, Yanai K.
  • Journal Title: Journal of Nuclear Medicine Volume: 57(4) Pages: 634-639
  • DOI: 10.2967/jnumed.115.162602.
  • Peer Reviewed
• [Journal Article] Structure-Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer's Disease. (2016)
  • Author(s): Tago T, Furumoto S, Okamura N, Harada R, Adachi H, Ishikawa Y, Yanai K, Iwata R, Kudo Y.
  • Journal Title: Journal of Nuclear Medicine Volume: 57(4) Pages: 608-614
  • DOI: 10.2967/jnumed.115.166652.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer's Disease. (2016)
  • Author(s): Harada R, Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, Tago T, Hiraoka K, Watanuki S, Shidahara M, Miyake M, Ishikawa Y, Matsuda R, Inami A, Yoshikawa T, Funaki Y, Iwata R, Tashiro M, Yanai K, Arai H, Kudo Y.
  • Journal Title: Journal of Nuclear Medicine Volume: 57(2) Pages: 208-214
  • DOI: 10.2967/jnumed.115.164848.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Preclinical Evaluation of [18F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer. (2016)
  • Author(s): Tago T, Furumoto S, Okamura N, Harada R, Adachi H, Ishikawa Y, Yanai K, Iwata R, Kudo Y.
  • Journal Title: Molecular Imaging and Biology Volume: 18 Pages: 258-266
  • DOI: 10.1007/s11307-015-0879-8.
  • Peer Reviewed
• [Journal Article] Tau imaging in the study of ageing, Alzheimer's disease, and other neurodegenerative conditions. (2016)
  • Author(s): Villemagne VL, Okamura N.
  • Journal Title: Current Opinion in Neurology Volume: 36 Pages: 43-51
  • DOI: 10.1016/j.conb.2015.09.002.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Longitudinal Assessment of Tau Pathology in Patients with Alzheimer's Disease Using [18F]THK-5117 Positron Emission Tomography. (2015)
  • Author(s): Ishiki A, Okamura N, Furukawa K, Furumoto S, Harada R, Tomita N, Hiraoka K, Watanuki S, Ishikawa Y, Tago T, Funaki Y, Iwata R, Tashiro M, Yanai K, Kudo Y, Arai H.
  • Journal Title: Plos One Volume: 10(10) Pages: e0140311
  • DOI: 10.1371/journal.pone.0140311.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Amyloid deposits and response to shunt surgery in idiopathic normal-pressure hydrocephalus. (2015)
  • Author(s): Hiraoka K, Narita W, Kikuchi H, Baba T, Kanno S, Iizuka O, Tashiro M, Furumoto S, Okamura N, Furukawa K, Arai H, Iwata R, Mori E, Yanai K
  • Journal Title: Journal of the Neurological Sciences Volume: 356(1-2) Pages: 124-128
  • DOI: 10.1016/j.jns.2015.06.029.
  • Peer Reviewed
• [Journal Article] Quantitative kinetic analysis of PET amyloid imaging agents [11C]BF227 and [18F]FACT in human brain. (2015)
  • Author(s): Shidahara M, Watabe H, Tashiro M, Okamura N, Furumoto S, Watanuki S, Furukawa K, Arakawa Y, Funaki Y, Iwata R, Gonda K, Kudo Y, Arai H, Ishiwata K, Yanai K.
  • Journal Title: Nuclear Medicine and Biology Volume: 42(9) Pages: 734-744
  • DOI: 10.1016/j.nucmedbio.2015.05.001
  • Peer Reviewed
• [Journal Article] Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue (2015)
  • Author(s): Lemoine L, Saint-Aubert L, Marutle A, Antoni G, Eriksson JP, Ghetti B, Okamura N, Nennesmo I, Gillberg PG, Nordberg A
  • Journal Title: Acta Neuropathologica Communications Volume: 3 Pages: 40
  • DOI: 10.1186/s40478-015-0220-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] [18F]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer's disease. (2015)
  • Author(s): Harada R, Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, Hiraoka K, Watanuki S, Shidahara M, Miyake M, Ishikawa Y, Matsuda R, Inami A, Yoshikawa T, Tago T, Funaki Y, Iwata R, Tashiro M, Yanai K, Arai H, Kudo Y
  • Journal Title: European Journal of Nuclear Medicine and Molecular Imaging Volume: 42 Pages: 1052-1061
  • DOI: 10.1007/s00259-015-3035-4.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Tau imaging. (2016)
  • Author(s): Okamura N
  • Organizer: AONeuro Symposium - Neurotrauma
  • Place of Presentation: 仙台市立病院講堂（宮城県・仙台市）
  • Year and Date: 2016-02-28
  • Invited
• [Presentation] Tau PET Imaging. Current status and future directions. (2016)
  • Author(s): Okamura N.
  • Organizer: Mind Brain Conference "From Molecules to the Universe: Advancing Biomedical Sciences and Engineering"
  • Place of Presentation: グランドホテル浜松（静岡県・浜松市）
  • Year and Date: 2016-02-24
  • Int'l Joint Research / Invited
• [Presentation] Distinct patterns of [18F]THK-5351 retention in AD and non-AD tauopathies. (2016)
  • Author(s): Okamura N, Kikuchi A, Furukawa K, Ishiki A, Harada R, Hasegawa T, Takeda A, Furumoto S, Iwata R, Tashiro M, Yanai K, Aoki M, Arai H, Kudo Y.
  • Organizer: The 10th Human Amyloid Imaging (HAI) meeting
  • Place of Presentation: Miami, USA
  • Year and Date: 2016-01-13 – 2016-01-15
  • Int'l Joint Research
• [Presentation] Metabolite analysis of tau PET tracer [18F]THK-5351. (2016)
  • Author(s): Harada R, Okamura N, Furumoto S, Tago T, Furukawa K, Ishiki A, Iwata R, Tashiro M, Arai H, Yanai K, Kudo Y.
  • Organizer: The 10th Human Amyloid Imaging (HAI) meeting
  • Place of Presentation: Miami, USA
  • Year and Date: 2016-01-13 – 2016-01-15
  • Int'l Joint Research
• [Presentation] Experience with Tau PET (2015)
  • Author(s): Okamura N
  • Organizer: Busan Paik Hospital Neurodegenerative Disease Symposium
  • Place of Presentation: Busan, South Korea
  • Year and Date: 2015-11-27
  • Int'l Joint Research / Invited
• [Presentation] Tau PET imaging with THK tau tracers. (2015)
  • Author(s): Okamura N.
  • Organizer: 2015 IPA 17th International Congress
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2015-10-15
  • Int'l Joint Research / Invited
• [Presentation] Molecular PET imaging of tau pathology in Alzheimer disease using THK tracers (2015)
  • Author(s): Yanai K, Okamura N
  • Organizer: 1st International Symposium of Brain Protein Aging and Dementia Control
  • Place of Presentation: 野依記念ホール（愛知県・名古屋市）
  • Year and Date: 2015-10-10
  • Int'l Joint Research
• [Presentation] PET imaging of misfolded proteins in Alzheimer’s disease. (2015)
  • Author(s): Okamura N.
  • Organizer: Tohoku Forum for Creativity: Frontier of Brain Science Satellite Symposium “Neuroimaging and its impact on our lives”
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] Validation of the binding specificity of tau PET tracer [18F]THK-5351 on postmortem human brain samples. (2015)
  • Author(s): Harada R, Okamura N, Furumoto S, Ishiki A, Furukawa K, Tomita N, Tago T, Iwata R, Yanai K, Arai H, Kudo Y
  • Organizer: AAIC 2015
  • Place of Presentation: Washington D.C., USA
  • Year and Date: 2015-07-22
  • Int'l Joint Research
• [Presentation] Distribution of tau pathology in the patients with mild cognitive impairment and Alzheimer’s disease measured with [18F]THK-5351 PET. (2015)
  • Author(s): Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, Harada R, Tashiro M, Yanai K, Arai H, Kudo Y.
  • Organizer: AAIC2015
  • Place of Presentation: Washington D.C., USA
  • Year and Date: 2015-07-22
  • Int'l Joint Research
• [Presentation] PET imaging of tau pathology in mild cognitive impairment and Alzheimer's disease with [18F]THK-5351. (2015)
  • Author(s): Okamura N, Furumoto S, Furukawa K, Ishiki A, Harada R, Iwata R, Tashiro M, Yanai K, Arai H, Kudo Y.
  • Organizer: SNMMI 2015 Annual Meeting
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2015-06-08
  • Int'l Joint Research
• [Presentation] Tau imaging in dementia. (2015)
  • Author(s): Okamura N.
  • Organizer: Molecular Imaging of Dementia: Beyond Amyloid PET, SNMMI 2015 Annual Meeting,
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2015-06-06
  • Int'l Joint Research / Invited
• [Presentation] Preclinical characterization of [18F]THK-5117 enantiomers as a PET tau probe for tau pathology in Alzheimer’s disease (2015)
  • Author(s): Tago T., Furumoto S., Okamura N., Harada R., Adachi H., Ishikawa Y., Yanai Y., Iwata R., Kudo Y.
  • Organizer: 21st International Symposium on Radiopharmaceutical Sciences
  • Place of Presentation: Columbia, USA
  • Year and Date: 2015-05-23 – 2015-05-26
  • Int'l Joint Research