Abstract
Introduction The accumulation of neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, starts spreading early in specific regions in the course of Alzheimer’s disease (AD), correlating with the progression of memory dysfunction. The non-invasive imaging of tau could therefore facilitate the early diagnosis of AD, differentiate it from other dementing disorders and allow evaluation of tau immunization therapy outcomes. In this study we characterized the in vitro binding properties of THK5117, a tentative radiotracer for positron emission tomography (PET) imaging of tau brain deposits.ResultsSaturation and competition binding studies of 3H-THK5117 in post-mortem AD brain tissue showed the presence of multiple binding sites. THK5117 binding was significantly higher in hippocampal (p < 0.001) and temporal (p < 0.01) tissue homogenates in AD compared to controls. Autoradiography studies with 3H-THK5117 was performed on large frozen brain sections from three AD cases who had been followed clinically and earlier undergone in vivo18F-FDG PET investigations. The three AD cases showed distinct differences in regional THK5117 binding that were also observed in tau immunohistopathology as well as in clinical presentation. A negative correlation between in vivo18F-FDG PET and in vitro3H-THK5117 autoradiography was observed in two of the three AD cases.ConclusionsThis study supports that new tau PET tracers will provide further understanding on the role of tau pathology in the diversity of the clinical presentation in AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0220-4) contains supplementary material, which is available to authorized users.
Highlights
The accumulation of neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, starts spreading early in specific regions in the course of Alzheimer’s disease (AD), correlating with the progression of memory dysfunction
This study supports that new tau positron emission tomography (PET) tracers will provide further understanding on the role of tau pathology in the diversity of the clinical presentation in AD
In this study we explored the binding properties and regional distribution of the novel PET tau tracer THK5117 in autopsy brain tissue homogenates and autoradiography on whole frozen brain hemisphere. 3H-THK5117 showed a high affinity for tau, as observed in competition binding studies where 3H-THK5117 demonstrated up to three binding sites
Summary
The accumulation of neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, starts spreading early in specific regions in the course of Alzheimer’s disease (AD), correlating with the progression of memory dysfunction. In this study we characterized the in vitro binding properties of THK5117, a tentative radiotracer for positron emission tomography (PET) imaging of tau brain deposits. In order to visualize and increase our understanding of the time course of NFT deposition during the development of AD and other dementia disorders, there is currently an attempt to develop PET tracers that are specific for tau protein [5]. A negative correlation between 18F-FDDNP binding and episodic memory has been reported in patients with AD and patients with mild cognitive impairment (MCI) [11], but this tracer showed limitations with low levels of specific binding [12]. Clinical studies with 18F-THK5117, 11C-PBB3, and 18F-T807 are currently in progress [14,15,16,17]
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