Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer\u2019s disease in the context of a structured 5-phase biomarker development framework

E E Wolters,A Dodich,A Drzezga,O Hansson,J Corre,M Boccardi,G B Frisoni,R Ossenkoppele,A Nordberg,V Garibotto

doi:10.1007/s00259-020-05118-w

Abstract

PurposeIn 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.MethodsThe 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).ResultsThe 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.ConclusionCurrent 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.

Highlights

In 2017, a methodological framework for the systematic assessment of biomarker validation was imported from oncology [94] and adapted to Alzheimer’s disease (AD) [10]
The target population consists of patients with mild cognitive impairment (MCI) referring to memory clinics for ascertained cognitive complaints, attributed to possible sporadic and not familial neurodegenerative disorders leading to dementia
Neurofibrillary tau tangles are one of the main pathological hallmarks of AD [11, 37, 45]. [18F]Flortaucipir binds to paired helical filaments (PHFs) of tau with a 25-fold higher affinity than for amyloid-β in AD patients [15, 68, 75, 126]

Summary

Introduction

In 2017, a methodological framework for the systematic assessment of biomarker validation was imported from oncology [94] and adapted to Alzheimer’s disease (AD) [10] This framework assesses analytical validity (phases 1–2), clinical validity (phases 3–4), and clinical utility (phase 5) in steps to be fulfilled sequentially to prevent conveying uncontrollable variability in downstream validation studies (Fig. 1). Within this “Biomarker Roadmap” initiative, we assessed the validation status of consolidated AD biomarkers at that time [30]: episodic memory [14], cerebrospinal fluid (CSF) [78], medial temporal atrophy [111], FDG-PET [32], amyloid PET [16], and 123I-ioflupane brain single-photon emission tomography and 123I-MIBG cardiac scintigraphy [109]. We have developed a methodological framework to assess biomarkers of brain tauopathy [8]

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