title: A new method to quantify tau pathologies with (11)C-PBB3 PET using reference tissue voxels extracted from brain cortical gray matter.
abstract: BACKGROUND
  Quantitative in vivo imaging of tau pathologies potentially improves diagnostic accuracy of neurodegenerative tauopathies and would facilitate evaluation of disease-modifying drugs targeting tau lesions in these diseases. Tau pathology can be quantified by reference tissue models without arterial blood sampling when reference tissue devoid of target binding sites is available. The cerebellar cortex has been used as a reference region in analyses of tau positron emission tomography (PET) data in Alzheimer's disease (AD). However, in a significant subset of tauopathies such as progressive supranuclear palsy and corticobasal degeneration, tau accumulation may occur in diverse brain regions including the cerebellar cortex. This hampers selection of a distinctive reference region lacking binding sites for a tau PET ligand. The purpose of this study was to develop a new method to quantify specific binding of a PET radioligand, (11)C-PBB3, to tau deposits using reference voxels extracted from cortical gray matter, which have a low likelihood of containing tau accumulations.
  
  
  METHODS
  We reanalyzed (11)C-PBB3 PET data of seven mild AD patients (ADs) and seven elderly healthy control subjects (HCs) acquired in a previous study. As a standard method, parametric images of binding potential ([Formula: see text]) were initially generated using reference tissue manually defined on the cerebellar cortex. We then constructed a frequency histogram of [Formula: see text] values in these parametric images and selected cortical gray matter voxels contained in a certain range of the histogram with a low likelihood of having (11)C-PBB3 binding sites. Finally, these reference voxels were used for generating new [Formula: see text] parametric images.
  
  
  RESULTS
  Reference tissue voxels defined by the histogram analysis spread throughout the cortical gray matter of AD and HC brains. The [Formula: see text] values determined by our new method correlated very well with those estimated by the standard method (r (2) = 0.94), although the binding estimates by the current method were slightly higher by ~0.14 than those by the standard method.
  
  
  CONCLUSIONS
  We developed and validated a new method enabling quantification of tau lesions that can accumulate in the cerebellum and other extensive brain areas. This method may be applicable to all tauopathy subtypes and various tau PET ligands besides (11)C-PBB3.
  
  
  BACKGROUND
  The number is UMIN000009052.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan. y-kimura@nirs.go.jp.
authors.forename: Yasuyuki
authors.identifier: http://orcid.org/0000-0002-7927-9483
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.|Division of Neurology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Endo
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan. ichisem@nirs.go.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichise
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Seki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ikoma
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shinotoh
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
keywords: 11C-PBB3; Alzheimer’s disease; PET quantification; Reference tissue; Tau