PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury

Keisuke Takahata, Yasuyuki Kimura, Naruhiko Sahara, Shunsuke Koga, Hitoshi Shimada, Masanori Ichise, Fumie Saito, Sho Moriguchi, Soichiro Kitamura, Manabu Kubota, Satoshi Umeda, Fumitoshi Niwa, Jin Mizushima, Yoko Morimoto, Michitaka Funayama, Hajime Tabuchi, Kevin F. Bieniek, Kazunori Kawamura, Ming Rong Zhang, Dennis W. DicksonMasaru Mimura, Motoichiro Kato, Tetsuya Suhara, Makoto Higuchi

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter.

Original languageEnglish (US)
Pages (from-to)3265-3279
Number of pages15
JournalBrain
Volume142
Issue number10
DOIs
StatePublished - 2019

Keywords

  • Chronic traumatic encephalopathy (CTE)
  • PET
  • Post-traumatic psychosis
  • Tau
  • Traumatic brain injury (TBI)

ASJC Scopus subject areas

  • Clinical Neurology

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    Takahata, K., Kimura, Y., Sahara, N., Koga, S., Shimada, H., Ichise, M., Saito, F., Moriguchi, S., Kitamura, S., Kubota, M., Umeda, S., Niwa, F., Mizushima, J., Morimoto, Y., Funayama, M., Tabuchi, H., Bieniek, K. F., Kawamura, K., Zhang, M. R., ... Higuchi, M. (2019). PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury. Brain, 142(10), 3265-3279. https://doi.org/10.1093/brain/awz238