Affiliations: [a] National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| [b] Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| [c] Institute of Biomedical Engineering/Institute for Pharmaceutical Sciences ETH Zurich, Switzerland
Correspondence:
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Correspondence to: Naruhiko Sahara, Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institute for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Tel.: +81 43 206 3251; Fax: +81 43 253 0396; E-mail: sahara.naruhiko@qst.go.jp.
Abstract: Background:Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood. Objective:We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model. Methods:rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [11C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [11C]AC-5216 were used to visualize tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry. Results:PET studies revealed age-dependent increases in [11C]PBB3 and [11C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [11C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [11C]AC-5216 disappeared after age 7 months. In contrast, [11C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia. Conclusion:Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [11C]PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.
