Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study

Ariane Bollack; Lyduine E Collij; David Vállez García; Mahnaz Shekari; Daniele Altomare; Pierre Payoux; Bruno Dubois; Oriol Grau-Rivera; Mercè Boada; Marta Marquié; Agneta Nordberg; Zuzana Walker; Philip Scheltens; Michael Schöll; Robin Wolz; Jonathan M Schott; Rossella Gismondi; Andrew Stephens; Christopher Buckley; Giovanni B Frisoni; Bernard Hanseeuw; Pieter Jelle Visser; Rik Vandenberghe; Alexander Drzezga; Maqsood Yaqub; Ronald Boellaard; Juan Domingo Gispert; Pawel Markiewicz; David M Cash; Gill Farrar; Frederik Barkhof; AMYPAD consortium

doi:10.1002/alz.13761

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study

Alzheimers Dement. 2024 May;20(5):3429-3441. doi: 10.1002/alz.13761. Epub 2024 Apr 4.

Authors

Ariane Bollack¹, Lyduine E Collij^{2

3

4}, David Vállez García², Mahnaz Shekari^{5

6

7}, Daniele Altomare⁸, Pierre Payoux^{9

10}, Bruno Dubois¹¹, Oriol Grau-Rivera⁵, Mercè Boada^{12

13}, Marta Marquié^{12

13}, Agneta Nordberg^{14

15}, Zuzana Walker^{16

17}, Philip Scheltens¹⁸, Michael Schöll^{19

20

21}, Robin Wolz²², Jonathan M Schott²³, Rossella Gismondi²⁴, Andrew Stephens²⁴, Christopher Buckley²⁵, Giovanni B Frisoni⁸, Bernard Hanseeuw^{26

27

28}, Pieter Jelle Visser^{2

14

29}, Rik Vandenberghe³⁰, Alexander Drzezga^{31

32

33}, Maqsood Yaqub², Ronald Boellaard^{2

34}, Juan Domingo Gispert^{5

6

35}, Pawel Markiewicz^{1

36}, David M Cash^{37

38}, Gill Farrar²⁵, Frederik Barkhof^{1

2

37}; AMYPAD consortium

Affiliations

¹ Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, University College London, London, London, UK.
² Department of Radiology and Nuclear Medicine, Amsterdam UMC, Amsterdam, The Netherlands.
³ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁴ Amsterdam Neuroscience, Brain Imaging, VU University Amsterdam, Amsterdam, The Netherlands.
⁵ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
⁶ Universitat Pompeu Fabra, Barcelona, Spain.
⁷ Instituto de investigaciones médicas Hospital del Mar (IMIM), Barcelona, Spain.
⁸ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁹ Department of Nuclear Medicine, Imaging Pole, Toulouse University Hospital, Toulouse, France.
¹⁰ Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, CHU Purpan, Pavillon Baudot, Place du Docteur Joseph Baylac, Toulouse, France.
¹¹ Department of Neurology, Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France.
¹² Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.
¹³ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
¹⁴ Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Theme Inflammation and Aging, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Division of Psychiatry, University College London, London, UK.
¹⁷ Essex Partnership University NHS Foundation Trust, The Lodge, Wickford, UK.
¹⁸ Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Alzheimercentrum Amsterdam, Amsterdam, The Netherlands.
¹⁹ Wallenberg Centre for Molecular and Translational Medicine, The University of Gothenburg, Gothenburg, Sweden.
²⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
²¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²² IXICO Plc, London, UK.
²³ Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
²⁴ Life Molecular Imaging, GmbH, Berlin, Germany.
²⁵ GE HealthCare, Buckinghamshire, UK.
²⁶ Department of Neurology, Institute of Neuroscience, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
²⁷ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁸ WELBIO Department, WEL Research Institute, Wavre, Belgium.
²⁹ Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
³⁰ Laboratory for Cognitive Neurology, LBI - KU Leuven Brain Institute, Leuven, Belgium.
³¹ Department of Nuclear Medicine, University Hospital Cologne, Universitätsklinikums Köln, Köln, Germany.
³² Molecular Organization of the Brain, Institute for Neuroscience and Medicine, INM-2), Forschungszentrum Jülich GmbH, Jülich, Germany.
³³ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
³⁴ Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³⁵ Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, Spain.
³⁶ Computer Science and Informatics, School of Engineering, London South Bank University, London, UK.
³⁷ Queen Square Institute of Neurology, University College London, London, UK.
³⁸ UK Dementia Research Institute at University College London, London, UK.

Abstract

Introduction: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-β (Aβ) accumulation based on Centiloids (CL) in pre-dementia populations.

Methods: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [¹⁸F]flutemetamol, [¹⁸F]florbetaben or [¹⁸F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95^th percentile of longitudinal measurements in sub-populations (N_PNHS = 101/750, N_Insight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models.

Results: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aβ-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education.

Discussion: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Keywords: Alzheimer's; Centiloid; amyloid; longitudinal PET; quantification; reliable accumulation.

MeSH terms

Aged
Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / metabolism
Amyloid beta-Peptides* / metabolism
Aniline Compounds*
Benzothiazoles
Brain / diagnostic imaging
Brain / metabolism
Female
Humans
Longitudinal Studies
Male
Middle Aged
Positron-Emission Tomography*
Prognosis
Stilbenes

Abstract

MeSH terms

Grants and funding