@misc{oai:repo.qst.go.jp:00071620,
 author = {Suhara, Tetsuya and Shimada, Hitoshi and Maruyama, Masahiro and Shinotoh, Hitoshi and Maeda, Jun and Zhang, Ming-Rong and Sahara, Naruhiko and Aoki, Ichio and Ito, Hiroshi and Higuchi, Makoto and 須原 哲也 and 島田 斉 and 丸山 将浩 and 篠遠 仁 and 前田 純 and 張 明栄 and 佐原 成彦 and 青木 伊知男 and 伊藤 浩 and 樋口 真人},
 month = {Dec},
 note = {Background and aims:
Senile plaques and deposition of intracellular tau fibrils are neuropathological hallmarks in Alzheimer’s disease (AD). Tau pathology is considered to be closely related with neural dysfunction in AD and non-AD tauopathy, and could accordingly be an important target for both therapeutic intervention and diagnostic imaging. Here, we developed a novel positron emission tomographic (PET) ligands, phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums (PBBs), for visualizing diverse tau inclusions in brains of living patients with AD or non-AD tauopathies and animal models of these disorders. In vivo optical and PET imaging of a transgenic mouse model demonstrated high affinity and selectivity for tau deposits by PBBs. Based on results from preclinical studies, a pyridinated PBB, [11C]PBB3 was next applied in a clinical PET study.
 Therefore, the aim of the present study was to investigate characteristics of [11C]PBB3 in cognitively normal elderlies and patients with cognitive impairments.
Methods:
Participants were 13 patients with AD, 6 patients with PIB-positive (amyloid positive) mild cognitive impairments (MCI) and 10 age-matched healthy controls (HCs). One patient with corticobasal syndrome (CBS) was also included as a preliminary examination. Their cognitive functions were assessed by Mini-Mental State Examination (MMSE).
PET images were acquired by a Siemens ECAT EXACT HR+ scanner. A dose (about 10 mCi) of [11C]PBB3 was intravenously injected and sequential PET scans were performed for 70 min. Standardized uptake value ratio (SUVR) was calculated using the cerebellar cortex as reference region, and SUVR images were visually assessed in each subject. We also performed PET scan with a plaque-binding agent, [11C]PIB (about 10 mCi), for 70 min and three-dimensional T1-weighted MRI. Cerebral plaque depositions were estimated using SUVR images at 50-70 minute after [11C]PIB injection. Parahippocampal grey matter volumes were estimated by voxel-based morphometry. Correlation analysis between MMSE score and mean cortical [11C]PBB3 or [11C]PIB bindings estimated by WFU pickatlas was performed among MCI and AD patients.
Results:
All HCs and a patient with CBS were PIB-negative, and all MCI and AD patients were PIB-positive. SUVR images of [11C]PBB3-PET demonstrated high accumulation of [11C]PBB3 in the medial temporal cortex of all AD patients, in which binding of [11C]PIB was minimal. Distribution of [11C]PBB3 accumulation observed in AD patients extended to the entire limbic system and subsequently to the neocortex as a function of the disease severity. Interestingly, a subset of HCs also showed noticeable accumulation of [11C]PBB3 confined to the medial temporal cortex, and exhibited mild parahippocampal atrophy. Significant correlation was shown between mean cortical [11C]PBB3 binding and MMSE score among MCI and AD patients, whereas there was no significant correlation between [11C]PIB and MMSE score. Furthermore, increased [11C]PBB3 signals were found in a CBS patient negative for [11C]PIB-PET.
Discussion:
The present study supported the utility of [11C]PBB3-PET for detecting tau deposition in vivo, in light of distinct spatial distributions of [11C]PBB3 and [11C]PIB retentions in AD patients. Furthermore, the spread of [11C]PBB3 binding may reflect the dementia severity, resembling progression of Braak tau stages. Moreover, the present study also provided the first evidence for in vivo detection of tau lesions in plaque-negative tauopathies. Our next stage clinical study with expanded sample size and wider range of MMSE scores including non-AD tauopatheis is currently ongoing to pursue tau accumulation in normal controls and subjects with mild cognitive impairments, AD and non-AD tauopathies at diverse stages, and will bring more compelling insights into the significance of tau PET imaging in early diagnosis and prediction of AD and non-AD tauopathies., 52nd Annual Meeting of ACNP},
 title = {In vivo PET imaging of tau pathology in Alzheimer patients compared to normal controls},
 year = {2013}
}