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Randomized Controlled Trial
. 2023 Jun 1;80(6):548-557.
doi: 10.1001/jamaneurol.2023.0997.

Clinical Effect of Early vs Late Amyloid Positron Emission Tomography in Memory Clinic Patients: The AMYPAD-DPMS Randomized Clinical Trial

Daniele Altomare  1   2   3 , Frederik Barkhof  4   5 , Camilla Caprioglio  1   2 , Lyduine E Collij  4 , Philip Scheltens  6 , Isadora Lopes Alves  4 , Femke Bouwman  6 , Johannes Berkhof  7 , Ingrid S van Maurik  6   7 , Valentina Garibotto  8   9 , Christian Moro  1   2 , Julien Delrieu  10   11 , Pierre Payoux  12   13 , Laure Saint-Aubert  12   13 , Anne Hitzel  12 , José Luis Molinuevo  14   15 , Oriol Grau-Rivera  14   16   17 , Juan Domingo Gispert  14   16   18 , Alexander Drzezga  19   20   21 , Frank Jessen  20   22   23 , Philip Zeyen  22 , Agneta Nordberg  24   25 , Irina Savitcheva  26 , Vesna Jelic  27 , Zuzana Walker  28   29 , Paul Edison  30 , Jean-François Demonet  31 , Rossella Gismondi  32 , Gill Farrar  33 , Andrew W Stephens  32 , Giovanni B Frisoni  1   2 ; Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Consortium
Collaborators, Affiliations
Randomized Controlled Trial

Clinical Effect of Early vs Late Amyloid Positron Emission Tomography in Memory Clinic Patients: The AMYPAD-DPMS Randomized Clinical Trial

Daniele Altomare et al. JAMA Neurol. .

Abstract

Importance: Amyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect.

Objective: To assess the clinical effect of amyloid PET in memory clinic patients.

Design, setting, and participants: The AMYPAD-DPMS is a prospective randomized clinical trial in 8 European memory clinics. Participants were allocated (using a minimization method) to 3 study groups based on the performance of amyloid PET: arm 1, early in the diagnostic workup (within 1 month); arm 2, late in the diagnostic workup (after a mean [SD] 8 [2] months); or arm 3, if and when the managing physician chose. Participants were patients with subjective cognitive decline plus (SCD+; SCD plus clinical features increasing the likelihood of preclinical Alzheimer disease), mild cognitive impairment (MCI), or dementia; they were assessed at baseline and after 3 months. Recruitment took place between April 16, 2018, and October 30, 2020. Data analysis was performed from July 2022 to January 2023.

Intervention: Amyloid PET.

Main outcome and measure: The main outcome was the difference between arm 1 and arm 2 in the proportion of participants receiving an etiological diagnosis with a very high confidence (ie, ≥90% on a 50%-100% visual numeric scale) after 3 months.

Results: A total of 844 participants were screened, and 840 were enrolled (291 in arm 1, 271 in arm 2, 278 in arm 3). Baseline and 3-month visit data were available for 272 participants in arm 1 and 260 in arm 2 (median [IQR] age: 71 [65-77] and 71 [65-77] years; 150/272 male [55%] and 135/260 male [52%]; 122/272 female [45%] and 125/260 female [48%]; median [IQR] education: 12 [10-15] and 13 [10-16] years, respectively). After 3 months, 109 of 272 participants (40%) in arm 1 had a diagnosis with very high confidence vs 30 of 260 (11%) in arm 2 (P < .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%]; P < .001; MCI: 45/108 [42%] vs 9/102 [9%]; P < .001; dementia: 39/80 [49%] vs 16/80 [20%]; P < .001).

Conclusion and relevance: In this study, early amyloid PET allowed memory clinic patients to receive an etiological diagnosis with very high confidence after only 3 months compared with patients who had not undergone amyloid PET. These findings support the implementation of amyloid PET early in the diagnostic workup of memory clinic patients.

Trial registration: EudraCT Number: 2017-002527-21.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Barkhof reported grants from the EU Innovative Medicines Initiative (IMI) AMYPAD project during the conduct of the study; consulting fees from Combinostics, Roche, and IXICO; grants from Biogen; serving on a steering committee, data and safety monitoring board, or advisory board for Merck, Prothena, and Biogen outside the submitted work; and being a cofounder and shareholder of Queen Square Analytics. Dr Collij reported research support from GE Healthcare (paid to their institution). Dr Scheltens reported employment with EQT Lifesciences; grants from Alzheimer’s Drug Discovery Foundation and Cure Alzheimer; consultancy fees (paid to the university) from Alzheon, Brainstorm Cell, and Green Valley; and serving as a principal investigator or on steering committees for Vivoryon, Novo Nordisk, FujiFilm Toyama Chemical, Alzheon, Novartis Cardiology, AC Immune, UCB, and ImmunoBrain Checkpoint outside the submitted work. Dr Bouwman reported financial and nonfinancial support (paid to their institution) from Biogen, Optina Dx, and Roche outside the submitted work and being a committee member or chair for the European Academy of Neurology, Atypical Alzheimer’s Disease Professional Interest Area, and Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART). Dr Berkhof reported grants from the EU IMI during the conduct of the study. Dr van Maurik reported grants from Health Holland, Top Sector Life Sciences & Health (LSHM18075). paid to their institution outside the submitted work. Dr Garibotto reported financial support for research and/or speaker fees through her institution from Siemens Healthineers, GE Healthcare, Life Molecular Imaging, Cerveau Technologies, Roche, and Merck and grants to her institution from the Swiss National Science Foundation and Velux Foundation outside the submitted work. Dr Delrieu reported serving on a data and safety monitoring board for Roche and receiving lecture fees from Biogen outside the submitted work. Dr Molinuevo reported being a full-time employee of Lundbeck; receiving grants from the EU IMI and La Caixa Foundation; and having served as a consultant or on advisory boards for or given lectures in symposia sponsored by Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, and ProMIS Neurosciences. Dr Gispert reported grants from the EU IMI during the conduct of the study and nonfinancial study support from GE Healthcare, grants from Roche Diagnostics and Hoffmann La Roche, and personal fees from Biogen, Roche, and Philips Nederlands outside the submitted work. Dr Drzezga reported research support from Siemens Healthineers, Life Molecular Imaging, GE Healthcare, Avid Radiopharmaceuticals, Eisai, and SOFIE; speaker and advisory board fees from Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Novartis, Bayer, and Invicro; owning stock in Siemens Healthineers, Lantheus Holding, and Biogen; having a patent pending for 18F-PSMA7 (PSMA PET imaging tracer); providing expert testimony in a local court; and participating on a data and safety monitoring board or advisory board for GE Healthcare, Siemens Healthineers, Novo Nordisk, Invicro, and Biogen. Dr Jessen reported payment/honoraria from Roche and Lilly and participating on a data and safety monitoring board or advisory board for AC Immune, Biogen, Roche, Eisai, and Grifols. Dr Nordberg reported consulting fees from Hoffman La Roche, having a US patent for alpha 7 nicotinic PET tracer, and being deputy chairman of Wennergren Foundations. Dr Walker reported grants from the EU IMI during the conduct of the study and grant support and consulting fees from GE Healthcare outside the submitted work. Dr Edison reported receiving grants from Alzheimer’s Research UK, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Society UK, Alzheimer’s Association US, Medical Research Council UK, Novo Nordisk, Piramal Life Sciences, and GE Healthcare; being a consultant to Roche, Pfizer, and Novo Nordisk; receiving speaker fees from Novo Nordisk, Pfizer, Nordea, and Piramal Life Science; receiving educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals, and Eli Lilly; being an external consultant to Novo Nordisk and Cytodyn and a member of their scientific advisory boards; and being editor in chief of Brain Connectivity and serving on editorial boards of other journals. Dr Demonet reported a patent (European Patent Office 19705763.1-1132) and participating on an advisory board for Biogen Switzerland. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Design for Early vs Late Positron Emission Tomography (PET)
Tan boxes indicate features of the study design not presented in the current work. The 13-month visit, the follow-up amyloid PET (to test the hypothesis that amyloid load is stable over 12-18 months), and the corresponding 18-month visit for arm 1 were made optional for logistic reasons. These measures were put in place to keep the end of the study timeline despite a prolonged recruitment (originally planned to be completed by June 30, 2020), which was granted to the recruiting memory clinics when in spring 2020 the COVID-19 pandemic brought recruitment to a complete halt.
Figure 2.
Figure 2.. Flowchart for the Amyloid Imaging to Prevent Alzheimer’s Disease Diagnostic and Patient Management Study (AMYPAD-DPMS)
Reasons for not undergoing the baseline or 3-month visit included the following: incident comorbidity (n = 6), concerns about radiation exposure (n = 5), emigration (n = 4), COVID-19 lockdown (n = 3), insufficient cost/benefit ratio (n = 3), managing physician’s advice (n = 3), death (n = 2), inability to understand the study design (n = 1), and participation in a competing clinical trial (n = 1), while the remaining participants (n = 18) did not give any explanation. ITT indicates intention to treat; PET, positron emission tomography; PP, per protocol.
Figure 3.
Figure 3.. Proportions of Participants Receiving an Etiological Diagnosis With Very High Diagnostic Confidence (≥90%) After 3 Months
MCI indicates mild cognitive impairment; SCD+, subjective cognitive decline plus clinical features increasing the likelihood of preclinical Alzheimer disease.
Figure 4.
Figure 4.. Change in Etiological Diagnosis After 3 Months in the Whole Sample
AD indicates Alzheimer disease; PET, positron emission tomography.
See this image and copyright information in PMC

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