高感度タウPETプローブによる新規画像バイオマーカーの創出

2015 Fiscal Year Annual Research Report

• Project/Area Number: 15H04900
• Research Institution: Tohoku University
• Principal Investigator: 岡村 信行 東北大学, 医学(系)研究科(研究院), 准教授 (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

申請者らが独自に開発した高感度タウPETプローブの有用性を確認する目的で、計41名の被検者で[18F]THK-5351および[11C]PiB PET検査を実施した。[18F]THK-5351投与後90分間のダイナミック撮像を実施した結果、投与40分後以降でSUV対小脳比（SUVR）が一定値となったことから、本プローブの最適な撮像時間帯は投与40分以降と判断された。同一被検者で[18F]THK-5351、[18F]THK-5117を投与して得られたPET画像を比較したところ、[18F]THK-5351の方がシグナル対ノイズ比の高い画像が得られ、皮質下白質や脳幹部からのクリアランスも良好であった。PMODソフトウェアを用いた自動関心領域設定によって、脳各領域における[18F]THK-5351 SUVR値を健常高齢者、軽度認知障害、アルツハイマー病患者の三群間で比較した結果、中下側頭回におけるSUVR値によってアルツハイマー病群と健常高齢者の二群を感度・特異度90%以上で鑑別可能であった。軽度認知障害群のSUVR値は健常高齢者とアルツハイマー病患者の中間的な値を示し、タウ病理像の形成が過渡期にあると考えられた。PiB-PETで高集積所見を示した健常高齢者（Preclinical AD）においても大脳皮質におけるSUVR値上昇を認めたことから、アミロイドβ病理像がタウ蛋白病変の大脳皮質への進展を加速させている可能性が示唆された。当初の予想通り、下部側頭葉における[18F]THK-5351集積量は認知症重症度の指標となるADAS-cogスコアと有意な正の相関を示した。上記臨床研究と並行して、ヒト病理脳標本を用いてオートラジオグラフィーや結合アッセイ試験を実施した結果、[18F]THK-5351がタウ病変に高い親和性および選択性を有することが確認された。

Current Status of Research Progress

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

Reason

本年度は計41名の被検者で[18F]THK-5351を用いたPET検査を実施した。臨床研究における症例数の蓄積は順調に進んでおり、アルツハイマー病診断における臨床的有用性とタウ蛋白病理像への選択性を確認することができた。また暫定的な解析ながらもアミロイドβとタウの相互作用を示唆するデータも得られている。

Strategy for Future Research Activity

引き続きPET撮像を実施して、健常高齢者、軽度認知障害の症例数を増やすほか、既に検査を実施済の被検者で一年後の追跡撮像を実施する計画である。In vitroでの評価では、アルツハイマー病以外の神経疾患の脳切片も使用して、結合選択性をより詳細に評価する予定である。さらにタウ蛋白が自然蓄積するタウトランスジェニックマウスを用いて、[18F]THK-5351のin vivoでの細胞内タウ病変への結合能力も検証したいと考えている。

Research Products

• [Int'l Joint Research] Karolinska Institutet/Uppsala University/Lund University(Sweden)
  • Country Name: Sweden
  • Counterpart Institution: Karolinska Institutet/Uppsala University/Lund University
• [Int'l Joint Research] University of Munich(Germany)
  • Country Name: Germany
  • Counterpart Institution: University of Munich
• [Int'l Joint Research] University of Melbourne(Australia)
  • Country Name: Australia
  • Counterpart Institution: University of Melbourne
• [Int'l Joint Research] University of Wisconsin/New York University/Columbia University(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: University of Wisconsin/New York University/Columbia University
  • # of Other Institutions: 5
• [Int'l Joint Research] Chang Gung Memorial Hospital(Taiwan)
  • Country Name: その他の国・地域
  • Counterpart Institution: Chang Gung Memorial Hospital
• [Int'l Joint Research]
  • # of Other Countries: 8
• [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] 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] 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: J Nucl Med Volume: 印刷中 Pages: 印刷中
  • DOI: 10.2967/jnumed.115.163493
  • Peer Reviewed / Int'l Joint Research
• [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 Pages: 1-15
  • DOI: 10.3390/biom6010007
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer 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: J Nucl Med Volume: 57 Pages: 208-214
  • DOI: 10.2967/jnumed.115.164848
  • Peer Reviewed / Acknowledgement Compliant
• [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: Curr Opin Neurobiol 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 Pages: e0140311
  • DOI: 10.1371/journal.pone.0140311
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Visualization of regional tau deposits using (3)H-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 Neuropathol Commun. 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: Eur J Nucl Med Mol Imaging. Volume: 42 Pages: 1052-1061
  • DOI: 10.1007/s00259-015-3035-4.
  • Peer Reviewed
• [Presentation] Tau imaging. (2016)
  • Author(s): Okamura N
  • Organizer: AONeuro Symposium - Neurotrauma
  • Place of Presentation: 仙台市立病院（宮城県仙台市）
  • Year and Date: 2016-02-28 – 2016-02-28
  • Int'l Joint Research / 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 – 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 – 2016-01-13
  • 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 – 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 – 2015-10-15
  • Int'l Joint Research / Invited
• [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: AAIC 2015
  • Place of Presentation: Washington D.C. (USA)
  • Year and Date: 2015-07-22 – 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 – 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
  • Place of Presentation: Baltimore (USA)
  • Year and Date: 2015-06-06 – 2015-06-06
  • Int'l Joint Research / Invited