Tau imaging in neurodegenerative diseases

Abstract

Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike β-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [18F]THK523, [18F]THK5117, [18F]THK5105 and [18F]THK5351, [18F]AV1451(T807) and [11C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with β - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future.

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

“…In a recent debate on CSF, some researchers acknowledged the need for more systematic validation 88,89 ), while others regarded the currently available evidence as sufficient to support their use in the clinic 90 . If experts do not agree, it is not surprising that health care payers are reluctant to reimburse.…”

Tau Imaging in Alzheimer's Disease Diagnosis and Clinical Trials

“…Several quinolone and benzimidazole derivatives have been created, the first of which was [ 18 F-THK523] which had several limitations, including high white matter retention and only 12-fold selectivity of tau over amyloid, preventing its clinical utility [36]. [38].…”

Preclinical Evaluation of18F-JNJ64349311, a Novel PET Tracer for Tau Imaging

“…However, it has some off-target binding (7) and exhibits a problematic kinetic profile, clearing slowly and failing to reach steady state in some brain regions (8)(9)(10)(11). On the other hand, some reports demonstrated that 18 F-AV1451 may also have some affinity for non-AD tauopathies (5). The aim of the present study was to develop a tau PET ligand with a pharmacokinetic profile superior to that of 18 F-AV1451 but with similar or better affinity to and selectivity for b-amyloid plaque.…”

“…Because tau exists in six different isoforms, tau is subject to various posttranslational modifications, and tangles can have many ultrastructural conformations, the development of a specific tau PET tracer able to target tau pathology in AD remains daunting (4). Nonetheless, several tau-specific PET ligands have been developed in the past decade, and they were recently discussed in a review by Dani et al (5). Among the first of these identified was T807, a tracer developed by Siemens and then licensed to Eli Lilly, now known as 18 F-AV1451.…”