| 1. |
- Bischof, Gérard N., et al.
(författare)
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Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2110-2120
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Forskningsöversikt (refereegranskat)abstract
- Purpose: In 2017, the Geneva Alzheimer’s disease (AD) strategic biomarker roadmap initiative proposed a framework of the systematic validation AD biomarkers to harmonize and accelerate their development and implementation in clinical practice. Here, we use this framework to examine the translatability of the second-generation tau PET tracers into the clinical context. Methods: All available literature was systematically searched based on a set of search terms that related independently to analytic validity (phases 1–2), clinical validity (phase 3–4), and clinical utility (phase 5). The progress on each of the phases was determined based on scientific criteria applied for each phase and coded as fully, partially, preliminary achieved or not achieved at all. Results: The validation of the second-generation tau PET tracers has successfully passed the analytical phase 1 of the strategic biomarker roadmap. Assay definition studies showed evidence on the superiority over first-generation tau PET tracers in terms of off-target binding. Studies have partially achieved the primary aim of the analytical validity stage (phase 2), and preliminary evidence has been provided for the assessment of covariates on PET signal retention. Studies investigating of the clinical validity in phases 3, 4, and 5 are still underway. Conclusion: The current literature provides overall preliminary evidence on the establishment of the second-generation tau PET tracers into the clinical context, thereby successfully addressing some methodological issues from the tau PET tracer of the first generation. Nevertheless, bigger cohort studies, longitudinal follow-up, and examination of diverse disease population are still needed to gauge their clinical validity.
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| 2. |
- Chiotis, Konstantinos, et al.
(författare)
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Clinical validity of increased cortical binding of tau ligands of the THK family and PBB3 on PET as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2086-2096
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Forskningsöversikt (refereegranskat)abstract
- Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.
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| 3. |
- Nordberg, Agneta, et al.
(författare)
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A European multicentre PET study of fibrillar amyloid in Alzheimer's disease
- 2013
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 40:1, s. 104-114
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer's disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies. In this study 238 [C-11]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [C-11]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69 +/- 8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5 +/- 8 years) and 51 healthy controls (mean age 67.4 +/- 6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28 +/- 15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype. [C-11]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [C-11]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [C-11]PIB retention was observed in MCI ApoE epsilon 4 carriers compared to non-ApoE epsilon 4 carriers (p < 0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted. This study demonstrated the robustness of [C-11]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.
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