Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study.

Ines Moreno-Gonzalez,Paul E Schulz,Jonathan E Schulz,Juan Jose Fernandez-Valenzuela,George A Edwards,Omar Hasan,Claudio Soto,Nazaret Gamez,Antonia Gutierrez

doi:10.3390/diagnostics11101874

Abstract

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer’s disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

Highlights

Introduction iationsTau protein aggregation and deposition occurs in several neurodegenerative dementias that are collectively called tauopathies
We found that the tau radiotracer was able to reach the brain and cross the blood–brain barrier, binding to the cortical and brain stem areas in P301S animals stronger than in WT controls
To determine whether results obtained in positron emission tomography (PET) imaging correlated with clinical signs observed in the animal model, we evaluated transgenic tau P301S and age-matched WT

Summary

Introduction

Tau protein aggregation and deposition occurs in several neurodegenerative dementias that are collectively called tauopathies. AD is an age-related, progressive dementia characterized by extracellular amyloid-beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, inflammation, synaptic impairment, and neuronal loss. These result in macroscopic brain atrophy and cognitive function demise. Amyloid deposition can be detected up to 15–20 years before the onset of symptoms [2]. According to the amyloid cascade hypothesis, Aβ aggregation is followed by hyperphosphorylated p-tau protein deposition [3]. Other dementias have p-tau deposition, and include frontotemporal dementia (FTD), progressive supranuclear

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