Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer’s disease in the context of a structured 5-phase biomarker development framework

Abstract

Purpose In 2017, the Geneva Alzheimer’s disease (AD) Biomarker Roadmap initiative adapted the framework of the systematic validation of oncological diagnostic biomarkers to AD biomarkers, with the aim to accelerate their development and implementation in clinical practice. With this work, we assess the maturity of [18F]flortaucipir PET and define its research priorities. Methods The level of maturity of [18F]flortaucipir was assessed based on the AD Biomarker Roadmap. The framework assesses analytical validity (phases 1–2), clinical validity (phases 3–4), and clinical utility (phase 5). Results The main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. [18F]Flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties and excellent discriminative accuracy for AD. The majority of secondary aims of phase 2 were fully achieved. Multiple studies showed high correlations between ante-mortem [18F]flortaucipir PET and post-mortem tau (as assessed by histopathology), and also the effects of covariates on tracer binding are well studied. The aims of phase 3 (early detection ability) were only partially or preliminarily achieved, and the aims of phases 4 and 5 were not achieved. Conclusion Current literature provides partial evidence for clinical utility of [18F]flortaucipir PET. The aims for phases 1 and 2 were mostly achieved. Phase 3 studies are currently ongoing. Future studies including representative MCI populations and a focus on healthcare outcomes are required to establish full maturity of phases 4 and 5.

Diagnostic value of amyloid-PET and tau-PET: a head-to-head comparison

“…In fact, this explains why two patients changed diagnosis from non-AD to AD after a tau-PET Braak stage = I-III, which was negative according to the study operationalization, but considered as already positive by one of the raters. Further research is needed to understand whether a dichotomous tau-PET result has a greater clinical value than a stage classification, and to validate visual assessment methods [7].…”

“…The first study on humans involving an amyloid-PET ligand was published 17 years ago [4], and converging evidence suggests that amyloid-PET is a helpful support for clinicians, leading to changes of diagnoses and treatment plan based on traditional work-up and increase of confidence on etiological diagnosis [5]. Tau-PET was more recently introduced [6], and 18F-Flortaucipir, the most widely used firstgeneration tau-PET tracer, has shown partial analytical validity and preliminary evidence of clinical validity [7] and has recently been approved by the FDA for estimating density and distribution of tau neurofibrillary tangles in vivo [8], but evidence on the diagnostic value of tau-PET is not available yet.…”

The strategic biomarker roadmap for the validation of Alzheimer’s diagnostic biomarkers: methodological update

“…This work is part of a wider initiative, aimed to use the SBR and assess the validation status of biomarkers of tau pathology [25][26][27][28][29]. The initiative consisted of a workshop held in Geneva, November 11-12, 2019.…”

“…In 2017, we used this framework to assess the validation status of the neuropsychological assessment (viz., episodic memory test) as a gateway to biomarker-based diagnosis [19], and of most consolidated AD biomarkers at that time, i.e., amyloid imaging [20], CSF [21], hippocampal atrophy [22], FDG-PET [23], and biomarkers for dementia with Lewy bodies [24], based on evidence published until 2015. In the present work, we revised the SBR to update it to the current A/T/N framework for research on AD and related disorders [1] and to enable proper assessment of biomarkers of tau pathology [25][26][27][28][29]. Such update was required, in that the diagnostic criteria adopted in 2017 entailed a relatively unclear role of Tau in the diagnostic procedure of AD.…”

Molecular imaging and fluid biomarkers of Alzheimer’s disease neuropathology: an opportunity for integrated diagnostics

“…In parallel, a number of new ligands (second-generation tracers), purportedly with greater sensitivity and specificity, are currently under evaluation. Their level of maturity within the Strategic Biomarker Roadmap structure is summarized in the contributions by Wolters, Chiotis, and Bischof [5][6][7].…”