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

2016 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: 痴呆 / 神経科学 / 放射線 / 脳神経疾患 / 老化

Outline of Annual Research Achievements

[18F]THK-5351を用いたPET検査の画像バイオマーカーとしての臨床的意義を確立する目的で、PET計測値の再現性を評価した。健常高齢者2名、アルツハイマー病患者2名においてPET検査を短期間（2週間以内）に2度実施し、投与40-60分後のPET画像をcoregistrationした後、脳各領域の集積値を計測した。その結果、2回の検査における[18F]THK-5351集積量は、健常高齢者（r = 0.989）、アルツハイマー病患者（r = 0.993）ともに高い相関を示した。またtest-retest variabilityは大脳皮質領域で平均2%前後であり、既存のアミロイドPETプローブと遜色ない結果が得られた。参照領域による計測値の安定性も評価したところ、小脳皮質よりも橋を参照領域とした場合に、信頼度が改善する傾向を認めた。前年度に引き続き、健常人、軽度認知障害、アルツハイマー病の各症例でPET検査を実施し、前年度に検査済の症例では、一年後の縦断的追跡評価を実施した。その結果、軽度認知障害では内側側頭葉で、アルツハイマー病患者では大脳皮質で[18F]THK-5351集積量の経時的上昇がみられた。このような大脳皮質における集積変化は、アミロイドPET陽性の健常認知機能高齢者においても観察された。アミロイドPET陽性例において、外側側頭葉における[18F]THK-5351集積量が高い症例ほど、頭頂皮質における集積量上昇が顕著であり、アミロイド病理の存在が大脳皮質におけるタウ関連病理の進展を加速させていると考えられた。

Current Status of Research Progress

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

Reason

前年度にPET検査を実施した計22名の被検者で、縦断的追跡評価を実施した。症例数の蓄積とフォローアップは順調に進んでおり、アミロイドβとタウの相互作用を示唆するデータが得られた。またPET計測値の再現性を確認することもできた。

Strategy for Future Research Activity

引き続きTHK5351-PET撮像を実施して、検査実施済の被検者で追跡撮像と神経心理機能の評価を行う予定である。またPET検査を実施した剖検例の脳切片を使用して、結合選択性をより詳細に評価する予定である。

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] マギル大学(カナダ)
  • Country Name: CANADA
  • Counterpart Institution: マギル大学
• [Int'l Joint Research] UC Berkeley/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: UC Berkeley/ウィスコンシン大学/ニューヨーク大学
• [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] 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]
  • # of Other Countries: 2
• [Journal Article] 18F-Labeled 2-Arylquinoline Derivatives for Tau Imaging: Chemical, Radiochemical, Biological and Clinical Features. (2017)
  • Author(s): Furumoto S, Tago T, Harada R, Kudo Y, Okamura N.
  • Journal Title: Curr Alzheimer Res. Volume: 14 Pages: 178-185
  • Peer Reviewed
• [Journal Article] Tau imaging with [18F]THK-5351 in progressive supranuclear palsy. (2017)
  • Author(s): Ishiki A, Harada R, Okamura N, Tomita N, Rowe CC, Villemagne VL, Yanai K, Kudo Y, Arai H, Furumoto S, Tashiro M, Furukawa K.
  • Journal Title: Eur J Neurol. Volume: 24 Pages: 130-136
  • DOI: 10.1111/ene.13164.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A report of the automated radiosynthesis of the tau positron emission tomography radiopharmaceutical, [18F]-THK-5351. (2017)
  • Author(s): Neelamegam R, Yokell DL, Rice PA, Furumoto S, Kudo Y, Okamura N, El Fakhri G.
  • Journal Title: J Labelled Comp Radiopharm. Volume: 60 Pages: 140-146
  • DOI: 10.1002/jlcr.3482.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of [11C]/[3H]THK-5351 - A potential novel carbon-11 tau imaging PET radioligand. (2017)
  • Author(s): Stepanov V, Svedberg M, Jia Z, Krasikova R, Lemoine L, Okamura N, Furumoto S, Mitsios N, Mulder J, Langstrom B, Nordberg A, Halldin C.
  • Journal Title: Nucl Med Biol. Volume: 46 Pages: 50-53
  • DOI: 10.1016/j.nucmedbio.2016.12.004.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain. (2017)
  • Author(s): Ng KP, Pascoal TA, Mathotaarachchi S, Therriault J, Kang MS, Shin M, Guiot MC, Guo Q, Harada R, Comley RA, Massarweh G, Soucy JP, Okamura N, Gauthier S, Rosa-Neto P.
  • Journal Title: Alzheimers Res Ther. Volume: 9 Pages: 25
  • DOI: 10.1186/s13195-017-0253-y.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Preclinical Evaluation of [(18)F]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: Mol Imaging Biol. Volume: 18 Pages: 258-166
  • DOI: 10.1007/s11307-015-0879-8.
  • Peer Reviewed
• [Journal Article] Structure-Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease. (2016)
  • Author(s): Tago T, Furumoto S, Okamura N, Harada R, Adachi H, Ishikawa Y, Yanai K, Iwata R, Kudo Y.
  • Journal Title: J Nucl Med. Volume: 57 Pages: 608-614
  • DOI: 10.2967/jnumed.115.166652.
  • Peer Reviewed
• [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 Res Rev. Volume: 30 Pages: 107-113
  • DOI: 10.1016/j.arr.2015.12.010.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Small-Animal PET Imaging of Tau Pathology with 18F-THK5117 in 2 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: J Nucl Med. Volume: 57 Pages: 792-798
  • DOI: 10.2967/jnumed.115.163493.
  • Peer Reviewed / Int'l Joint Research
• [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 Res Rev. Volume: 30 Pages: 1-3
  • DOI: 10.1016/j.arr.2016.02.005.
  • Peer Reviewed
• [Journal Article] Dynamic PET Measures of Tau Accumulation in Cognitively Normal Older Adults and Alzheimer's Disease Patients Measured Using [18F] THK-5351. (2016)
  • Author(s): Lockhart SN, Baker SL, Okamura N, Furukawa K, Ishiki A, Furumoto S, Tashiro M, Yanai K, Arai H, Kudo Y, Harada R, Tomita N, Hiraoka K, Watanuki S, Jagust WJ.
  • Journal Title: PLoS One. Volume: 11 Pages: e0158460
  • DOI: 10.1371/journal.pone.0158460.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of the radiolabeled metabolite of tau PET tracer 18F-THK5351. (2016)
  • Author(s): Harada R, Furumoto S, Tago T, Katsutoshi F, Ishiki A, Tomita N, Iwata R, Tashiro M, Arai H, Yanai K, Kudo Y, Okamura N.
  • Journal Title: Eur J Nucl Med Mol Imaging. Volume: 43 Pages: 2211-2218
  • DOI: 10.1007/s00259-016-3453-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Untangling tau imaging. (2016)
  • Author(s): Villemagne VL, Okamura N, Rowe CC.
  • Journal Title: Alzheimers Dement (Amst) Volume: 4 Pages: 39-42
  • DOI: 10.1016/j.dadm.2016.05.001.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Applied multimodal diagnostics in a case of presenile dementia. (2016)
  • Author(s): Schonecker S, Brendel M, Huber M, Vollmar C, Huppertz HJ, Teipel S, Okamura N, Levin J, Rominger A, Danek A.
  • Journal Title: BMC Neurol. Volume: 16 Pages: 131
  • DOI: 10.1186/s12883-016-0647-7.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In vivo visualization of tau deposits in corticobasal syndrome by 18F-THK5351 PET. (2016)
  • Author(s): Kikuchi A, Okamura N, Hasegawa T, Harada R, Watanuki S, Funaki Y, Hiraoka K, Baba T, Sugeno N, Oshima R, Yoshida S, Kobayashi J, Ezura M, Kobayashi M, Tano O, Mugikura S, Iwata R, Ishiki A, Furukawa K, Arai H, Furumoto S, Tashiro M, Yanai K, Kudo Y, Takeda A, Aoki M.
  • Journal Title: Neurology. Volume: 87 Pages: 2309-2316
  • DOI: 10.1212/WNL.0000000000003375
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Longitudinal analysis of [18F]THK5351 tau PET images in patients with Alzheimer's disease and corticobasal syndrome. (2016)
  • Author(s): Okamura N, Harada R, Ishiki A, Furukawa K, Kikuchi A, Hasegawa T, Aoki M, Furumoto S, Tashiro M, Yanai K, Arai H, Kudo Y.
  • Organizer: CTAD 2016
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-10
  • Int'l Joint Research
• [Presentation] タウPETイメージングの現状と可能性 (2016)
  • Author(s): 岡村信行、原田龍一
  • Organizer: 第35回日本認知症学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-12-02
• [Presentation] 認知症患者における神経原線維変化の画像化に関する研究 (2016)
  • Author(s): 岡村信行
  • Organizer: 第35回日本認知症学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-12-01
• [Presentation] Impact of tau PET on dementia research. (2016)
  • Author(s): 岡村信行
  • Organizer: 第56回日本核医学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2016-11-05
  • Invited
• [Presentation] Novel PET Probes for Imaging of Tau in Alzheimer's Disease. (2016)
  • Author(s): Okamura N.
  • Organizer: Symposium of Medical Imaging; PET/MR and Molecular Images
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2016-10-29
  • Int'l Joint Research / Invited
• [Presentation] Development of THK tau tracers. (2016)
  • Author(s): Okamura N.
  • Organizer: Tau PET Futures Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2016-10-13
  • Int'l Joint Research / Invited
• [Presentation] [F-18]THK5351 retention is associated with the progression of brain atrophy in patients with Alzheimer's disease. (2016)
  • Author(s): Okamura N, Ishiki A, Furukawa K, Harada R, Tomita N, Furumoto S, Tashiro M, Yanai K, Arai H, Kudo Y.
  • Organizer: AAIC 2016
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2016-07-22 – 2016-07-28
  • Int'l Joint Research
• [Presentation] タウPETイメージング：最近の進歩 (2016)
  • Author(s): 岡村信行
  • Organizer: AAJ関東甲信越エリアシンポジウム
  • Place of Presentation: 大手町サンケイプラザ（東京都千代田区）
  • Year and Date: 2016-07-03
  • Invited
• [Presentation] アルツハイマー病の分子イメージング (2016)
  • Author(s): 岡村信行、長沼史登、中村正帆
  • Organizer: 第32回日本DDS学会学術集会
  • Place of Presentation: 静岡県コンベンションアーツセンター（静岡市駿河区）
  • Year and Date: 2016-06-30
  • Invited
• [Presentation] 認知症におけるタウPETイメージング (2016)
  • Author(s): 岡村信行
  • Organizer: 第12回認知症ファイヤーカンファレンス
  • Place of Presentation: 愛知県産業労働センター（愛知県名古屋市）
  • Year and Date: 2016-06-18
  • Invited
• [Presentation] Recent clinical studies with THK tau tracers. (2016)
  • Author(s): Okamura N.
  • Organizer: SNMMI 2016 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-06-13
  • Int'l Joint Research / Invited
• [Presentation] アルツハイマー病のPET診断 (2016)
  • Author(s): 岡村信行
  • Organizer: 第11回日本分子イメージング学会総会・学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2016-05-28