Nordberg Translational Molecular Imaging Lab, Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo 7th floor, 141 83, Stockholm, Sweden.
Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
Eur J Nucl Med Mol Imaging. 2021 Jul;48(7):2086-2096. doi: 10.1007/s00259-021-05277-4. Epub 2021 Mar 15.
The research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer's disease (AD). In 2017, the Geneva AD Biomarker Roadmap initiative adapted the framework for the systematic validation of oncological biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. The aim of this work was to assess the validation status of tau PET ligands of the THK family and PBB3 as imaging biomarkers for AD, based on the Biomarker Roadmap methodology.
A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of clinical validity of tau PET ligands of the THK family and PBB3 was assessed based on the 5-phase development framework before the meeting and discussed during the workshop.
PET radioligands of the THK family discriminate well between healthy controls and patients with AD dementia (phase 2; partly achieved) and recent evidence suggests an accurate diagnostic accuracy at the mild cognitive impairment (MCI) stage of the disease (phase 3; partly achieved). The phases 2 and 3 were considered not achieved for PBB3 since no evidence exists about the ligand's diagnostic accuracy. Preliminary evidence exists about the secondary aims of each phase for all ligands.
Much work remains for completing the aims of phases 2 and 3 and replicating the available evidence. However, it is unlikely that the validation process for these tracers will be completed, given the presence of off-target binding and the development of second-generation tracers with improved binding and pharmacokinetic properties.
研究界一直致力于定义可靠的生物标志物，以早期发现阿尔茨海默病（AD）的病理标志。2017 年，日内瓦 AD 生物标志物路线图倡议采用了用于系统验证肿瘤生物标志物的框架，以加速其在临床实践中的开发和实施。本工作旨在根据生物标志物路线图方法评估 THK 家族和 PBB3 的 Tau PET 配体作为 AD 成像生物标志物的验证状态。
2019 年 11 月，在日内瓦举行的为期两天的研讨会上，召集了一组 AD 生物标志物专家。在会议之前，根据 5 阶段开发框架评估了 THK 家族和 PBB3 的 Tau PET 配体的临床有效性水平，并在研讨会上进行了讨论。
THK 家族的 PET 放射性配体可很好地区分健康对照者和 AD 痴呆患者（阶段 2；部分实现），最近的证据表明该配体在疾病的轻度认知障碍（MCI）阶段具有准确的诊断准确性（阶段 3；部分实现）。由于没有关于配体诊断准确性的证据，因此认为 PBB3 的阶段 2 和 3 未实现。所有配体都有初步证据表明每个阶段的次要目标。
完成阶段 2 和 3 的目标并复制现有证据还有很多工作要做。然而，鉴于存在非靶标结合以及具有改善的结合和药代动力学特性的第二代示踪剂的开发，这些示踪剂的验证过程不太可能完成。
