Article Text

Download PDFPDF

Research paper
Tau-induced focal neurotoxicity and network disruption related to apathy in Alzheimer’s disease
  1. Soichiro Kitamura1,2,
  2. Hitoshi Shimada1,
  3. Fumitoshi Niwa3,
  4. Hironobu Endo4,
  5. Hitoshi Shinotoh1,5,
  6. Keisuke Takahata1,
  7. Manabu Kubota1,
  8. Yuhei Takado1,
  9. Shigeki Hirano6,
  10. Yasuyuki Kimura1,7,
  11. Ming-Rong Zhang8,
  12. Satoshi Kuwabara6,
  13. Tetsuya Suhara1,
  14. Makoto Higuchi1
  1. 1 Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
  2. 2 Department of Psychiatry, Nara Medical University, Kashihara, Japan
  3. 3 Department of Neurology and Gerontology, Kyoto Prefectural University of Medicine, Kyoto, Japan
  4. 4 Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Japan
  5. 5 Neurology Chiba Clinic, Chiba, Japan
  6. 6 Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
  7. 7 Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan
  8. 8 Department of Radiopharmaceutics Development, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
  1. Correspondence to Dr Hitoshi Shimada, Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-0024, Japan; shimada.hitoshi{at}


Objective Apathy is a common neuropsychological symptom in Alzheimer’s disease (AD), and previous studies demonstrated that neuronal loss and network disruption in some brain regions play pivotal roles in the pathogenesis of apathy. However, contributions of tau and amyloid-β (Aβ) depositions, pathological hallmarks of AD, to the manifestation of apathy remain elusive.

Methods Seventeen patients with AD underwent positron emission tomography (PET) with 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) and 11C-Pittsburgh compound-B (11C-PiB) to estimate tau and Aβ accumulations using standardised uptake value ratio (SUVR) images. 11C-PBB3 and 11C-PiB SUVR were compared between AD patients with high and low Apathy Scale (AS) scores. Additionally, volumetric and diffusion tensor MRI was performed in those areas where any significant difference was observed in PET analyses. Correlation and path analyses among AS and estimated imaging parameters were also conducted.

Results AD patients with high AS scores showed higher 11C-PBB3 SUVR in the orbitofrontal cortex (OFC) than those with low AS scores, while 11C-PiB SUVR in any brain regions did not differ between them. Elevated 11C-PBB3 SUVR in OFC, decreased OFC thickness and decreased fractional anisotropy (FA) in the uncinate fasciculus (UNC), which is structurally connected to OFC, correlated significantly with increased scores of the AS. Path analysis indicated that increased 11C-PBB3 SUVR in OFC affects apathy directly and through reduction of OFC thickness and subsequent decrease of FA in UNC.

Conclusions The present findings suggested that tau pathology in OFC may provoke focal neurotoxicity in OFC and the following disruption of the OFC-UNC network, leading to the emergence and progression of apathy in AD.

  • Alzheimer’s disease
  • apathy
  • tau
  • PET
  • cortical thickness
  • DTI

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

View Full Text

Statistics from


  • Contributors Authors’ contributions are as follows: (1) substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data: SKi and HS; (2) drafting the article or revising it critically for important intellectual content: all authors; (3) final approval of the version to be published: all authors.

  • Funding This work was partly supported by JSPS KAKENHI Grant-in-Aid for Young Scientists (B) (JP15K19756) to SoK from the Japan Society for the Promotion of Science; the Young Scientists (A) (26713031) to H Shimada from the Ministry of Education, Culture, Sports, Science and Technology, Japan; the Kashiwado Memorial Foundation to H Shimada; the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) and AMED under Grant Number JP17dm0207007.

  • Competing interests H Shimada, M-RZ, TS and MH hold a patent on compounds related to the present report (JP 5422782/EP 12 884 742.3).

  • Patient consent Not required.

  • Ethics approval This study was approved by the Institutional Review Board of the National Institute of Radiological Sciences (NIRS), in accordance with the ethical code of NIRS and the ethical guidelines for clinical studies presented by the Ministry of Health, Labour and Welfare in Japan, as well as the Declaration of Helsinki. Written informed consent was obtained from all patients and from their spouses or other close family members. The study was registered with UMIN Clinical Trials Registry (UMIN-CTR; number 000009863).

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.