High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies

Kenji Tagai¹, Maiko Ono², Manabu Kubota³, Soichiro Kitamura⁴, Keisuke Takahata⁵, Chie Seki², Yuhei Takado⁶, Hitoshi Shinotoh⁷, Yasunori Sano⁵, Yasuharu Yamamoto⁵, Kiwamu Matsuoka⁴, Hiroyuki Takuwa², Masafumi Shimojo², Manami Takahashi², Kazunori Kawamura², Tatsuya Kikuchi², Maki Okada², Haruhiko Akiyama⁸, Hisaomi Suzuki⁹, Mitsumoto Onaya¹⁰, Takahiro Takeda¹¹, Kimihito Arai¹¹, Nobutaka Arai¹², Nobuyuki Araki¹¹, Yuko Saito¹³, John Q Trojanowski¹⁴, Virginia M Y Lee¹⁴, Sushil K Mishra¹⁵, Yoshiki Yamaguchi¹⁶, Yasuyuki Kimura¹⁷, Masanori Ichise², Yutaka Tomita¹⁸, Ming-Rong Zhang², Tetsuya Suhara¹, Masahiro Shigeta¹⁹, Naruhiko Sahara², Makoto Higuchi²⁰, Hitoshi Shimada²

Affiliations

¹ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, The Jikei University Graduate School of Medicine, Tokyo 105-8461, Japan.
² National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
³ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
⁴ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Nara Medical University, Nara 634-8521, Japan.
⁵ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Keio University School of Medicine, Tokyo 160-0016, Japan.
⁶ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address: takado.yuhei@qst.go.jp.
⁷ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Neurology Clinic Chiba, Chiba 263-8555, Japan.
⁸ Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
⁹ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Keio University School of Medicine, Tokyo 160-0016, Japan; National Hospital Organization Shimofusa Psychiatric Medical Center, Chiba 266-0007, Japan.
¹⁰ National Hospital Organization Shimofusa Psychiatric Medical Center, Chiba 266-0007, Japan.
¹¹ Department of Neurology, National Hospital Organization Chibahigashi National Hospital, Chiba 260-8712, Japan.
¹² Laboratory of Neuropathology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
¹³ National Center of Neurology and Pathology Brain Bank, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
¹⁴ Center for Neurodegenerative Disease Research and Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁵ Glycoscience Group, National University of Ireland, Galway H91 W2TY, Ireland.
¹⁶ Laboratory of Pharmaceutical Physical Chemistry, Tohoku Medical and Pharmaceutical University, Miyagi 981-8558, Japan.
¹⁷ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan.
¹⁸ Tomita Hospital, Aichi 444-3505, Japan.
¹⁹ Department of Psychiatry, The Jikei University Graduate School of Medicine, Tokyo 105-8461, Japan.
²⁰ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address: higuchi.makoto@qst.go.jp.

PMID: 33125873
DOI: 10.1016/j.neuron.2020.09.042

Free article

High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies

Kenji Tagai et al. Neuron. 2021.

Free article

. 2021 Jan 6;109(1):42-58.e8.

doi: 10.1016/j.neuron.2020.09.042. Epub 2020 Oct 29.

Authors

Affiliations

¹ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, The Jikei University Graduate School of Medicine, Tokyo 105-8461, Japan.
² National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
³ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
⁴ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Nara Medical University, Nara 634-8521, Japan.
⁵ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Keio University School of Medicine, Tokyo 160-0016, Japan.
⁶ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address: takado.yuhei@qst.go.jp.
⁷ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Neurology Clinic Chiba, Chiba 263-8555, Japan.
⁸ Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
⁹ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Psychiatry, Keio University School of Medicine, Tokyo 160-0016, Japan; National Hospital Organization Shimofusa Psychiatric Medical Center, Chiba 266-0007, Japan.
¹⁰ National Hospital Organization Shimofusa Psychiatric Medical Center, Chiba 266-0007, Japan.
¹¹ Department of Neurology, National Hospital Organization Chibahigashi National Hospital, Chiba 260-8712, Japan.
¹² Laboratory of Neuropathology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
¹³ National Center of Neurology and Pathology Brain Bank, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
¹⁴ Center for Neurodegenerative Disease Research and Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁵ Glycoscience Group, National University of Ireland, Galway H91 W2TY, Ireland.
¹⁶ Laboratory of Pharmaceutical Physical Chemistry, Tohoku Medical and Pharmaceutical University, Miyagi 981-8558, Japan.
¹⁷ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan.
¹⁸ Tomita Hospital, Aichi 444-3505, Japan.
¹⁹ Department of Psychiatry, The Jikei University Graduate School of Medicine, Tokyo 105-8461, Japan.
²⁰ National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address: higuchi.makoto@qst.go.jp.

PMID: 33125873
DOI: 10.1016/j.neuron.2020.09.042

Abstract

A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of ¹⁸F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of ¹⁸F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of ¹⁸F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.

Keywords: Alzheimer’s disease; PET; Pick's disease; corticobasal degeneration; frontotemporal lobar degeneration; in vivo imaging; progressive supranuclear palsy; tauopathies; tauopathy mouse model; translational research.

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Conflict of interest statement

Declaration of Interests H. Shimada, M.-R.Z., T.S., and M.H. hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672).

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High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies

Affiliations

High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies

Authors

Affiliations

Abstract

Conflict of interest statement

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