TAU PET IMAGING IN ANIMAL MODELS AND HUMANS

Abstract

Accumulation of tau aggregates has been implicated in Alzheimer's disease (AD) and a subset of non-AD dementias. Pathogenetic signaling cascade of AD is supposedly triggered by deposition of amyloid-β peptide (Aβ), while initiation of tau pathologies may not be necessarily secondary to Aβ abnormalities. Prion-like intracranial transmission of tau fibrillogenesis in these tauopathies and modulation of this spreading by other pathogenic molecules such as Aβ and TDP-43 have also been of paramount interest. These issues could be examined by visualization of tau inclusions in tauopathy patients and animal models. We developed an imaging agent, PBB3, applicable to in vivo detection of tau aggregates in patients with AD and diverse other tauopathies and tau transgenic mice. Binding of PBB3 along with various tau-binding fluorescent compounds to tau inclusions in sliced human and mouse brains was comparatively assessed. Preclinical characterization of PBB3 was performed in tau transgenic mice using imaging optics and PET. Clinical PET studies were conducted with [11 C]PBB3 and Aβ ligand, [11 C]PIB. Tested tau ligands differentially reacted with tau inclusions in AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease, familial FTLD-tau and two tau transgenic mouse lines (PS19 and rTg4510), presumably due to structural diversities of tau fibril strains. Two-photon laser microscopic and microPET imaging enabled kinetic assessments of PBB3 in mouse models. Clinical PET assays demonstrated [11 C]PBB3-positive tau aggregates in the hippocampal formation of a subpopulation of [11 C]PIB-negative non-demented elderly subjects. Tau deposits spread to extensive brain areas in transition from normal aging to severe AD, supporting the utility of [11 C]PBB3-PET for objectively determining severity of AD from a preclinical stage. Increases of [11 C]PBB3 signals in patients with PSP, CBD and other FTLDs were also consistent with local atrophies and reported postmortem distribution of tau lesions in these illnesses, and were intimately associated with their characteristic symptoms. [11 C]PBB3-PET would serve for clarification of mechanisms by which tau accumulates and spreads and for differential diagnosis and pathological staging of tauopathies. Differential use of PBB3 and other tau ligands would help translational research and drug development targeting specific tau strains.