ABSTRACT
Several studies have demonstrated the high agreement between routine clinical visual assessment and quantification, suggesting that quantification approaches could support the assessment of less experienced readers and/or in challenging cases. However, all studies to date have implemented a retrospective case collection and challenging cases were generally underrepresented.
Methods In this prospective study, we included all participants (N=741) from the AMYPAD Diagnostic and Patient Management Study (DPMS) with available baseline amyloid-PET quantification. Quantification was done with the PET-only AmyPype pipeline, providing global Centiloid (CL) and regional z-scores. Visual assessment was performed by local readers for the entire cohort. From the total cohort, we selected a subsample of 85 cases 1) for which the amyloid status based on the local reader’s visual assessment and CL classification (cut-off=21) was discordant and/or 2) that were assessed with a low confidence (i.e. ≤3 on a 5-point scale) by the local reader. In addition, concordant negative (N=8) and positive (N=8) scans across tracers were selected. In this sample, (N=101 cases: ([18F]flutemetamol, N=48; [18F]florbetaben, N=53) the visual assessments and corresponding confidence by 5 certified independent central readers were captured before and after disclosure of the quantification results.
Results For the AMYPAD-DPMS whole cohort, the overall assessment of local readers highly agreed with CL status (κ=0.85, 92.3% agreement). This was consistently observed within disease stages (SCD+: κ=0.82/92.3%; MCI: κ=0.80/89.8%; dementia: κ=0.87/94.6%). Across all central reader assessments in the challenging subsample, global CL and regional z-scores quantification were considered supportive of visual read in 70.3% and 49.3% of assessments, respectively. After disclosure of quantitative results, we observed an improvement in concordance between the 5 readers (κbaseline=0.65/65.3%; κpost-disclosure=0.74/73.3%) and a significant increase in reader confidence (Mbaseline=4.0 vs. Mpost-disclosure=4.34, W=101056, p<0.001).
Conclusion In this prospective study enriched for challenging amyloid-PET cases, we demonstrate the value of quantification to support visual assessment. After disclosure, both inter-reader agreement and confidence showed a significant improvement. These results are important considering the arrival of anti-amyloid therapies, which utilized the Centiloid metric for trial inclusion and target-engagement. Moreover, quantification could support determining Aβ status with high certainty, an important factor for treatment initiation.
Competing Interest Statement
DISCLOSURESDA, IB, DVG, ILA, AP, and GBF report no relevant disclosures.LEC has received research support from GE Healthcare and Springer Healthcare (funded by Eli Lilly), both paid to institution. Dr. Collij s salary is supported by the MSCA postdoctoral fellowship research grant (#101108819) and the Alzheimer Association Research Fellowship (AARF) grant (#23AARF-1029663).GNB is funded by the Deutsche Forschungsgemeinschaft (DFG) Project ID 431549029 - SFB 1451 and partially by DFG, DR 445/9 1.MB is employed by GE HealthCare.RW is employed by IXICO ltd.RG is employed by Life Molecular ImagingAWS is employed by Life Molecular ImagingZW has received research support from GE Healthcare.PS is employed by EQT Life Sciences team.AN has received consulting fee from H Lundbeck AB, AVVA pharmaceuticals and honoraria for lecture from Hoffman La Roche.JDG has received research support from GE HealthCare, Roche Diagnostics and Hoffmann La Roche, speaker/consulting fees from Roche Diagnostics, Esteve, Philips Nederlands, Biogen and Life Molecular Imaging and serves in the Molecular Neuroimaging Advisory Board of Prothena Biosciences.AD has received research support from: Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, Sofie, Eisai, Novartis/AAA, Ariceum Therapeutics, speaker Honorary/Advisory Boards: Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Invicro, Novartis/AAA, Bayer Vital, Lilly Stock: Siemens Healthineers, Lantheus Holding, Structured therapeutics, Lilly. Patents: Patent for 18F JK PSMA 7 (Patent No.: EP3765097A1; Date of patent: Jan. 20, 2021).SM received speaker honoraria from GE Healthcare, Eli Lilly and Life Molecular Imaging.CB is employed by GE HealthCare.VG is supported by the Swiss national science foundation (project n.320030_185028 and 320030_169876), the Aetas Foundation, the Schmidheiny Foundation, the Velux Foundation, the Fondation privee des HUG. She received support for research and speakers fees from Siemens Healthineers, GE HealthCare, Janssen, Novo Nordisk, all paid to institution.GF is employed by GE HealthCare.FB is supported by the NIHR biomedical research centre at UCLH. Steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai and Prothena. Advisory board member for Combinostics, Scottish Brain Sciences. Consultant for Roche, Celltrion, Rewind Therapeutics, Merck, Bracco. Research agreements with ADDI, Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD.
Funding Statement
ACKNOWLEDGMENTSThe project leading to this paper has also received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115952. This Joint Undertaking receives the support from the European Union s Horizon 2020 research and innovation programme and EFPIA. This communication reflects the views of the authors and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
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All participants gave written informed consent. The trial was registered with EudraCT (2017-002527-21). The study was approved by the CCER (Commission Cantonale d Ethique de la Recherche) in Geneva Switzerland (#2017-01408).
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