The Sensitivity of Tau Tracers for the Discrimination of Alzheimer’s Disease Patients and Healthy Controls by PET

Abstract

Hyperphosphorylated tau aggregates, also known as neurofibrillary tangles, are a hallmark neuropathological feature of Alzheimer’s disease (AD). Molecular imaging of tau by positron emission tomography (PET) began with the development of [18F]FDDNP, an amyloid β tracer with off-target binding to tau, which obtained regional specificity through the differing distributions of amyloid β and tau in AD brains. A concerted search for more selective and affine tau PET tracers yielded compounds belonging to at least eight structural categories; 18F-flortaucipir, known variously as [18F]-T807, AV-1451, and Tauvid®, emerged as the first tau tracer approved by the American Food and Drug Administration. The various tau tracers differ concerning their selectivity over amyloid β, off-target binding at sites such as monoamine oxidase and neuromelanin, and degree of uptake in white matter. While there have been many reviews of molecular imaging of tau in AD and other conditions, there has been no systematic comparison of the fitness of the various tracers for discriminating between AD patient and healthy control (HC) groups. In this narrative review, we endeavored to compare the binding properties of the various tau tracers in vitro and the effect size (Cohen’s d) for the contrast by PET between AD patients and age-matched HC groups. The available tracers all gave good discrimination, with Cohen’s d generally in the range of two–three in culprit brain regions. Overall, Cohen’s d was higher for AD patient groups with more severe illness. Second-generation tracers, while superior concerning off-target binding, do not have conspicuously higher sensitivity for the discrimination of AD and HC groups. We suppose that available pharmacophores may have converged on a maximal affinity for tau fibrils, which may limit the specific signal imparted in PET studies.

FibrilPaint to determine the length of Tau amyloids in fluids

“…The development of tracer diagnostics for early diagnosis of neurodegenerative diseases remains crucial. To date, Tauvid is the only FDA approved PET tracer for AD (Commissioner, 2020; Jie et al, 2021; Mohammadi et al, 2023). Cryo EM data reveals Tauvid does not bind in a regular stochiometric manner to AD fibrils, but it does to CTE Type I filaments (Shi et al, 2022).…”

“…In 2020, imaging agent Tauvid ([18F]-flortaucipir) was approved by the FDA (Commissioner, 2020; Jie et al, 2021; Ossenkoppele et al, 2018; Xia et al, 2013). Tauvid is currently the only PET tracer approved for diagnosing living patients, with results that can discriminate disease as well as stage of the disease (Jie et al, 2021; Leuzy et al, 2020; Merz et al, 2023; Mohammadi et al, 2023). Tracers for other aggregating proteins are also in development.…”

Recent progress of nanomedicine in the treatment of Alzheimer’s disease

“…It primarily affects the distal end of axons, preserving the stability and flexibility of microtubules while also regulating axonal transport and promoting actin filament formation ( Venkatramani and Panda, 2019 ). Normal Tau carries multiple phosphate groups in its microtubule assembly domain, but phosphorylation of tau reduces its affinity for microtubules and begins to aggregate in its hyperphosphorylated form ( Mohammadi et al, 2023 ). Elevated phosphorylation and aggregation of Tau are widely considered pathological hallmarks in AD ( Wegmann et al, 2021 ).…”

Cryo-EM structures reveal variant Tau amyloid fibrils between the rTg4510 mouse model and sporadic human tauopathies

“…Considering the pivotal role of Tau aggregation in AD and other tauopathies, mouse models such as rTg4510 and PS19 overexpressing disease-associated Tau mutations have been developed and widely used to investigate the disease mechanism as well as for drug development 6 , 7 . These models manifest symptoms such as age-correlated memory loss, specific brain region Tau accumulation, and neuron degeneration, which effectively echo the clinical and pathological facets of tauopathies 8 .…”

“…Our finding suggests that the rTg4510 mouse model could not precisely mirror sporadic human tauopathies on atomic and molecular fronts. Hence, when probing into the disease mechanism of AD and other tauopathies, or in the development of Tau-targeting drugs, caution is advised in using this model 6 , 7 . Thus, for mechanistic study and drug development of tauopathies, it is important to refine animal models that not only resonate with human disease manifestations, but also mimic the specific Tau fibril structures associated with each disease.…”