Development of novel imaging biomarker using highly-sensitive tau PET probes

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15H04900
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: 岡村 信行 東北医科薬科大学, 医学部, 教授 (40361076)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 認知症 / 画像診断 / タウ / アストロサイト

Outline of Annual Research Achievements

THK-5351 PET画像所見の病的意義を検証する目的で、THK-5351 PET検査を生前に実施した3剖検例（アルツハイマー病1例、進行性核上性麻痺2例）において、生前の画像所見と死後の病理所見との対応を検討した。剖検にてアルツハイマー病の確定診断が得られた患者では、生前のTHK-5351 PET画像で側頭頭頂皮質におけるTHK-5351高集積を認めた。大脳皮質におけるTHK-5351局所集積量は、剖検脳で測定したPHF-tau濃度と正の相関を示した。THK-5351の集積は、タウ蛋白蓄積のみられない線条体においても観察されたことから、トレーサーのオフターゲット結合と判断された。その結合標的を確認するため、剖検脳を用いてオートラジオグラフィー実験を実施したところ、線条体におけるTHK-5351結合は過剰量のモノアミン酸化酵素（MAO-B）阻害剤によって完全に置換された。また剖検脳におけるTHK-5351局所集積量はMAO-B濃度およびGFAP濃度と正の相関を示したことから、THK-5351はMAO-Bへのオフターゲット結合を有し、その結合はMAO-Bが局在する反応性アストロサイトの存在を反映している可能性が考えられた。進行性核上性麻痺、進行性非流暢性失語と診断された2例の画像病理相関も検討した。これらの患者の剖検脳では進行性核上性麻痺に特有の4リピートタウの病理像が観察され、THK-5351集積量はタウ蛋白蓄積量、MAO-B濃度の両者と正の相関を示した。以上の結果からMAO-BはTHK-5351の主要な結合標的の一つであり、THK-5351集積所見はタウ病理像に共局在するアストログリオーシスを併せて反映していると判断された。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] カロリンスカ研究所/ウプサラ大学(スウェーデン)
  • Country Name: SWEDEN
  • Counterpart Institution: カロリンスカ研究所/ウプサラ大学
• [Int'l Joint Research] ミュンヘン大学(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: ミュンヘン大学
• [Int'l Joint Research] 嘉泉大学校(韓国)
  • Country Name: KOREA (REP. OF KOREA)
  • Counterpart Institution: 嘉泉大学校
• [Int'l Joint Research] ウィスコンシン大学/ニューヨーク大学(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: ウィスコンシン大学/ニューヨーク大学
• [Int'l Joint Research] 長庚紀念医院(台湾)
  • Country Name: その他の国・地域
  • Counterpart Institution: 長庚紀念医院
• [Int'l Joint Research]
  • # of Other Countries: 2
• [Journal Article] Correlations of 18F-THK5351 PET with post-mortem burden of tau and astrogliosis in Alzheimer's disease. (2018)
  • Author(s): Harada R, Ishiki A, Kai H, Sato N, Furukawa K, Furumoto S, Tago T, Tomita N, Watanuki S, Hiraoka K, Ishikawa Y, Funaki Y, Nakamura T, Yoshikawa T, Iwata R, Tashiro M, Sasano H, Kitamoto T, Yanai K, Arai H, Kudo Y, Okamura N.
  • Journal Title: J Nucl Med. Volume: 59 Pages: 印刷中
  • DOI: 10.2967/jnumed.117.197426.
  • Peer Reviewed
• [Journal Article] [18F]-THK5351 PET Imaging in Patients With Semantic Variant Primary Progressive Aphasia. (2018)
  • Author(s): Lee H, Seo S, Lee SY, Jeong HJ, Woo SH, Lee KM, Lee YB, Park KH, Heo JH, Yoon CW, Kang JM, Cho J, Okamura N, Furumoto S, Yanai K, Na DL, Ido T, Villemagne VL, Noh Y.
  • Journal Title: Alzheimer Dis Assoc Disord. Volume: 32 Pages: 62-69
  • DOI: 10.1097/WAD.0000000000000216.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] [18F]-THK5351 PET correlates with topology and symptom severity in progressive supranuclear palsy. (2018)
  • Author(s): Brendel M, Schonecker S, Hoglinger G, Lindner S, Havla J, Blautzik J, Sauerbeck J, Rohrer G, Zach C, Vettermann F, Lang AE, Golbe L, Nubling G, Bartenstein P, Furukawa K, Ishiki A, Botzel K, Danek A, Okamura N, Levin J, Rominger A.
  • Journal Title: Front Aging Neurosci. Volume: 9 Pages: 440
  • DOI: 10.3389/fnagi.2017.00440.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Case of progressive supranuclear palsy detected by tau imaging with [18F]THK-5351 before the appearance of characteristic clinical features. (2018)
  • Author(s): Shimizu S, Imabayashi E, Takenoshita N, Okamura N, Furumoto S, Kudo Y, Matsuda H, Hanyu H.
  • Journal Title: Geriatr Gerontol Int. Volume: 18 Pages: 501-502
  • DOI: 10.1111/ggi.13229.
  • Peer Reviewed
• [Journal Article] In vivo comparison of tau radioligands 18F-THK-5351 and 18F-THK-5317. (2017)
  • Author(s): Betthauser T, Lao PJ, Murali D, Barnhart TE, Furumoto S, Okamura N, Stone CK, Johnson SC, Christian BT.
  • Journal Title: J Nucl Med. Volume: 58 Pages: 996-1002
  • DOI: 10.2967/jnumed.116.182980.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prediction of the clinical SUV ratio in amyloid PET imaging using a biomathematical modeling approach towards the efficient development of a radioligand. (2017)
  • Author(s): Arakawa Y, Nai Y, Shidahara M, Furumoto S, Seki C, Okamura N, Tashiro M, Kudo Y, Yanai K, Gonda K, Watabe H.
  • Journal Title: J Nucl Med. Volume: 58 Pages: 1285-1292
  • DOI: 10.2967/jnumed.116.183566.
  • Peer Reviewed
• [Journal Article] Brain imaging: Applications of tau PET imaging. (2017)
  • Author(s): Okamura N, Yanai K.
  • Journal Title: Nat Rev Neurol. Volume: 13 Pages: 197-198
  • DOI: 10.1038/nrneurol.2017.38.
• [Journal Article] Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. (2017)
  • Author(s): de Leon MJ, Li Y, Okamura N, Tsui WH, Saint Louis LA, Glodzik L, Osorio RS, Fortea J, Butler T, Pirraglia E, Fossati S, Kim HJ, Carare RO, Nedergaard M, Benveniste H, Rusinek H.
  • Journal Title: J Nucl Med. Volume: 58 Pages: 1471-1476
  • DOI: 10.2967/jnumed.116.187211.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biodistribution and radiation dosimetry for the tau tracer 18F-THK-5351 in healthy human subjects. (2017)
  • Author(s): Hsiao IT, Lin KJ, Huang KL, Huang CC, Chen HS, Wey SP, Yen TC, Okamura N, Hsu JL.
  • Journal Title: J Nucl Med. Volume: 58 Pages: 1498-1503
  • DOI: 10.2967/jnumed.116.189126.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A comparison of five partial volume correction methods for Tau and Amyloid PET imaging with [18F]THK5351 and [11C]PIB. (2017)
  • Author(s): Shidahara M, Thomas BA, Okamura N, Ibaraki M, Matsubara K, Oyama S, Ishikawa Y, Watanuki S, Iwata R, Furumoto S, Tashiro M, Yanai K, Gonda K, Watabe H.
  • Journal Title: Ann Nucl Med. Volume: 31 Pages: 563-569
  • DOI: 10.1007/s12149-017-1185-0.
  • Peer Reviewed
• [Journal Article] Regional tau deposition and subregion atrophy of medial temporal structures in early Alzheimer's disease: A combined positron emission tomography/magnetic resonance imaging study. (2017)
  • Author(s): Sone D, Imabayashi E, Maikusa N, Okamura N, Furumoto S, Kudo Y, Ogawa M, Takano H, Yokoi Y, Sakata M, Tsukamoto T, Kato K, Matsuda H.
  • Journal Title: Alzheimers Dement (Amst) Volume: 9 Pages: 35-40
  • DOI: 10.1016/j.dadm.2017.07.001.
  • Peer Reviewed
• [Journal Article] Tau positron emission tomography using [18F]THK5351 and cerebral glucose hypometabolism in Alzheimer's disease. (2017)
  • Author(s): Kang JM, Lee SY, Seo S, Jeong HJ, Woo SH, Lee H, Lee YB, Yeon BK, Shin DH, Park KH, Kang H, Okamura N, Furumoto S, Yanai K, Villemagne VL, Seong JK, Na DL, Ido T, Cho J, Lee KM, Noh Y.
  • Journal Title: Neurobiol Aging. Volume: 59 Pages: 210-219
  • DOI: 10.1016/j.neurobiolaging.2017.08.008.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of the radiosynthesis and purification of [18F]THK-5351, a PET ligand for neurofibrillary tau. (2017)
  • Author(s): Betthauser TJ, Ellison PA, Murali D, Lao PJ, Barnhart TE, Furumoto S, Okamura N, Johnson SC, Engle JW, Nickles RJ, Christian BT.
  • Journal Title: Appl Radiat Isot. Volume: 130 Pages: 230-237
  • DOI: 10.1016/j.apradiso.2017.10.002.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Histamine N-methyltransferase regulates aggression and the sleep-wake cycle. (2017)
  • Author(s): Naganuma F, Nakamura T, Yoshikawa T, Iida T, Miura Y, Karpati A, Matsuzawa T, Yanai A, Mogi A, Mochizuki T, Okamura N, Yanai K.
  • Journal Title: Sci Rep. Volume: 7 Pages: 15899
  • DOI: 10.1038/s41598-017-16019-8.
  • Peer Reviewed
• [Journal Article] Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains. (2017)
  • Author(s): Lemoine L, Gillberg PG, Svedberg M, Stepanov V, Jia Z, Huang J, Nag S, Tian H, Ghetti B, Okamura N, Higuchi M, Halldin C, Nordberg A.
  • Journal Title: Alzheimers Res Ther. Volume: 9 Pages: 96
  • DOI: 10.1186/s13195-017-0325-z.
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Structure-binding relationship of quinoline derivatives on monoamine oxidase B. (2018)
  • Author(s): Okamura N.
  • Organizer: The 12th Human Amyloid Imaging (HAI) meeting
  • Int'l Joint Research
• [Presentation] Amyloid and Tau Imaging in Neurodegenerative Diseases. (2017)
  • Author(s): Okamura N.
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research / Invited
• [Presentation] THK5351 PET imaging in Alzheimer’s disease and non-AD tauopathies. (2017)
  • Author(s): Okamura N.
  • Organizer: International tau symposium
• [Presentation] Imaging tau and astrocyte with 18F-THK5351 - analysis of autopsy cases -. (2017)
  • Author(s): Okamura N.
  • Organizer: Society of Nuclear Medicine and Molecular Imaging
  • Int'l Joint Research
• [Presentation] 認知症を標的とした分子イメージングプローブ開発の現状 (2017)
  • Author(s): 岡村信行
  • Organizer: 第32回日本老年精神医学会
  • Invited
• [Presentation] THK5351-PETイメージングの有用性と課題 (2017)
  • Author(s): 岡村信行
  • Organizer: 第36回日本認知症学会学術集会
• [Presentation] 認知症を標的とした分子イメージングプローブ開発の現状 (2017)
  • Author(s): 岡村信行
  • Organizer: 第60回日本脳循環代謝学会学術集会
• [Book] Neuroimaging Diagnosis for Alzheimer’s Disease and Other Dementias. (2017)
  • Author(s): Okamura N, Harada R, Furumoto S, Kudo Y.
  • Total Pages: 279
  • Publisher: Springer
  • ISBN: 978-4-431-55133-1