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Review
. 2023 Jan 20:13:1063598.
doi: 10.3389/fneur.2022.1063598. eCollection 2022.

The amyloid imaging for the prevention of Alzheimer's disease consortium: A European collaboration with global impact

Lyduine E Collij  1   2 , Gill Farrar  3 , David Valléz García  1   2 , Ilona Bader  1   2 , Mahnaz Shekari  4 , Luigi Lorenzini  1   2 , Hugh Pemberton  5 , Daniele Altomare  6 , Sandra Pla  7 , Mery Loor  7 , Pawel Markiewicz  5 , Maqsood Yaqub  1 , Christopher Buckley  3 , Giovanni B Frisoni  6 , Agneta Nordberg  8 , Pierre Payoux  9 , Andrew Stephens  10 , Rossella Gismondi  10 , Pieter Jelle Visser  1 , Lisa Ford  11 , Mark Schmidt  11 , Cindy Birck  12 , Jean Georges  11 , Anja Mett  3 , Zuzana Walker  5 , Mercé Boada  13   14 , Alexander Drzezga  15 , Rik Vandenberghe  16 , Bernard Hanseeuw  17 , Frank Jessen  15 , Michael Schöll  18 , Craig Ritchie  19 , Isadora Lopes Alves  20 , Juan Domingo Gispert  1 , Frederik Barkhof  1   2   5
Affiliations
Review

The amyloid imaging for the prevention of Alzheimer's disease consortium: A European collaboration with global impact

Lyduine E Collij et al. Front Neurol. .

Abstract

Background: Amyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and 'Small and Medium-sized enterprises' (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population.

The amypad studies: In the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [18F]flutemetamol or [18F]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method.

Results: AMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BP ND ), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging Aβ burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine.

Future steps: The AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.

Keywords: Alzheimer's disease; amyloid; consortium; diagnosis; positron emission tomography (PET); prognosis.

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Conflict of interest statement

LC has received research support from GE Healthcare (paid to institution). GF is an employee of GE Healthcare. HP is an employee of GE Healthcare. DA received funding by the Fondation Recherche Alzheimer and the Swiss National Science Foundation (project CRSK-3_196354/1). PM received consulting fees from Oncovision. CB is an employee of GE Healthcare. GBF reports grants from Avid Radiopharmaceuticals, Biogen, GE International, Guerbert, IXICO, Merz Pharma, Nestlé, Novartis, Eisai, Piramal, Roche, Siemens, Teva Pharmaceutical Industries, and Vifor Pharma; he has received personal fees from AstraZeneca, Avid Radiopharmaceuticals, Biogen, Roche, Diadem, Neurodiem, Elan Pharmaceuticals, GE International, Lundbeck, Pfizer, and TauRx Therapeutics. AN received consulting fees from Hoffman La Roche. Patent: US patent alpha 7 nicotinic PET tracer. She is deputy chairman of Wennergren Foundations. PP has received research support from GE Healthcare (paid to institution). AS is an employee of Life Molecular Imaging GmbH. RG is an employee of Life Molecular Imaging GmbH. PV has served as member of the advisory board of Roche Diagnostics and received nonfinancial support from GE Healthcare, research support from Biogen and grants from Bristol-Myers Squibb, EU/EFPIA Innovative Medicines Initiative Joint Undertaking, EU Joint Programme–Neurodegenerative Disease Research (JPND and ZonMw). LF is an employee of Janssen Pharmaceuticals. Mark Schmidt is an employee of Janssen Pharmaceuticals. CB is an employee of Alzheimer Europe which has received grant support from Horizon2020, EU/EFPIA Innovative Medicines Initiative Joint Undertaking and the Luxembourg National Research Fund under the aegis of the EU Joint Programme - Neurodegenerative Disease Research (JPND) and sponsorship from AbbVie, Biogen, Danone, Eisai, GE Healthcare, Grifols, Janssen, Lilly, NovoNordisk, Roche and TauRx. JG is an employee of Alzheimer Europe which has received grant support from Horizon2020, EU/EFPIA Innovative Medicines Initiative Joint Undertaking and the Luxembourg National Research Fund under the aegis of the EU Joint Programme - Neurodegenerative Disease Research (JPND) and sponsorship from AbbVie, Biogen, Danone, Eisai, GE Healthcare, Grifols, Janssen, Lilly, NovoNordisk, Roche and TauRx. AM is an employee of GE Healthcare. MB has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, Biogen, and Servier; and received fees for lectures and funds for research from Araclon, Esteve, Grifols, Janssen, Novartis, Nutricia, Piramal, Pfizer-Wyett, Roche, and Servier. RV institution has Clinical Trial Agreements (RV as PI) with Alector, Biogen, Janssen Pharmaceuticals, NovoNordisk, Prevail, Roche, UCB. RV's institution has consultancy agreements (RV as DSMB member) with AC Immune and Novartis. RV was global PI of the Phase 1 and 2 18F-flutemetamol trials. RV's institution had a material transfer agreement (RV as PI) with GEHC for free tracer delivery of the FPACK cohort baseline scans and with Avid Pharmaceuticals, an EliLilly subsidiary. AD Research support: Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, Sofie, Eisai, Novartis/AAA. Speaker Honorary/Advisory Boards: Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Invicro, Novartis/AAA, Bayer Vital. Stock: Siemens Healthineers, Lantheus Holding. Patents: Patent pending for 18F-PSMA7 (PSMA PET imaging tracer). BH received consulting fees from Biogen and Roche. The Belgian Foundation for Scientific Research supports his salary (FNRS CCL grant #40010417). He has received grants from the FNRS (including the WELBIO fund #0010035), the Belgian Alzheimer Research Foundation (SAO-FRA), the Louvain and Saint-Luc Foundations, and the Queen Elizabeth Medical Foundation (QEMF-FMRE). FJ received payment/honoraria from Roche and Lilly. He has participated on a Data Safety Monitoring Board or Advisory Board for AC Immune, Biogen, Roche, Eisai, and Grifols. MS has received fees for contributions to Advisory Boards from Biogen, Eisai, Eli Lilly, Roche, Roche Diagnostics, Actinogen, Alchemab, Merck, Kyowa Kirin and Signant. His research has been supported by Janssen and Biogen. He was Chief Investigator of the IMI Funded EPAD project that had multiple EFPIA and SME partners. CR has received fees for contributions to Advisory Boards from Biogen, Eisai, Eli Lilly, Roche, Roche Diagnostics, Actinogen, Alchemab, Merck, Kyowa Kirin, and Signant. His research has been supported by Janssen and Biogen. He was Chief Investigator of the IMI Funded EPAD project that had multiple EFPIA and SME partners. JG has received research support from GE Healthcare, Roche Diagnostics, F. Hoffmann – La Roche and speaker's fees from Biogen and Philips. In addition, he holds a “Ramón y Cajal” fellowship (RYC-2013-13054), has received research support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD grant agreement no 115952, and from Ministerio de Ciencia y Universidades (grant agreement RTI2018-102261). FB Steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Network of study cohorts and sites that contribute to the AMYPAD consortium. Sites affiliated with the DPMS study are shown in yellow, sites affiliated with the PNHS are shown in blue, and sites affiliated with both trials are shown in green. EPAD: European Prevention of Alzheimer's Dementia; ALFA+ for Alzheimer and Families; FPACK Flemish Prevent AD Cohort-KU; FACEBHI Fundació ACE Healthy Brain Initiative; UCL-2010-412 University College Louvain 2010-412 study; DELCODE Longitudinale Studie zu Kognitiven Beeinträchtigungen und Demenz; H70 Gothenburg H70 Birth cohort study; EMIF-AD 60++ and 90+ Medicine Initiative European Medical Information Framework for AD Twin60++ and 90+ study from the Alzheimercenter Amsterdam; DPMS Diagnostic and Patient Management Study from AMYPAD.
Figure 2
Figure 2
Centiloid distributions across DPMS and populations. (A) Centiloid distribution across patient populations, reflecting a bi-modal distribution. (B) Centiloid distribution across per-dementia subjects, mostly cognitively unimpaired, skewed toward lower amyloid burden.
Figure 3
Figure 3
Visual illustration of amyloid PET harmonization results. Example images of the Hoffman phantom were acquired on four different scanners before (left panel) and after (right panel) harmonization. Coefficient of variance (COV%), which is an indication of image noise, is shown for each scan. Before harmonization, the COV% difference was more than 22, while after harmonization this ranged only ~1.
Figure 4
Figure 4
Graphic illustration of ExploreQC toolbox. Overview of the quality control workflow. QC features are computed in the feature estimation module and cover 5 image features domains. Feature distributions can then be interactively inspected between-sites (5A) and within-sites (5B). Single-subject scans can be opened by clicking on the scatterplots (5C). Adapted from Lorenzini et al. (39).
Figure 5
Figure 5
Infrastructure for standalone PET image reconstruction and analysis of PET/MR brain data using amyloid PET tracer. Stages (A–C) involve processing of input data (raw acquisition and image data), while in stages (D, E) image reconstruction is performed followed by image analysis in stages (F–H).
Figure 6
Figure 6
Schematic representation of data-flow within the PNHS trial.
See this image and copyright information in PMC

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