Multicenter Study

. 2025 Oct;21(10):e70732.

doi: 10.1002/alz.70732.

Calibration of multisite raters for prospective visual reads of amyloid PET scans

David N Soleimani-Meigooni^{1

2}, Stefania Pezzoli¹, Ganna Blazhenets¹, Renaud La Joie¹, Zoe Lin¹, Carol L Soppe¹, Derek R Johnson³, Mary Ellen I Koran⁴, Jonathan E McConathy⁵, Ilya M Nasrallah⁶, Maria Rosana Ponisio⁷, Jeremy A Tanner⁸, Victor L Villemagne⁹, Charles C Windon¹, Michael Zeineh¹⁰, Sarah Biber¹¹, Walter A Kukull^{11

12}, Heather O'Connell¹¹, Daniel J Peterson¹¹, Elizabeth C Mormino¹⁰, Sterling C Johnson¹³, Gil D Rabinovici^{1

14}; LEADS Consortium; PREVENT‐AD Research Group; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
² Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Lab, Berkeley, California, USA.
³ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Department of Radiology, Mayo Clinic, Phoenix, Arizona, USA.
⁵ University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶ Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
⁸ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas, USA.
⁹ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
¹⁰ Stanford University School of Medicine, Stanford, California, USA.
¹¹ National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA.
¹² Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁴ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

PMID: 41030129
PMCID: PMC12484700
DOI: 10.1002/alz.70732

Multicenter Study

Calibration of multisite raters for prospective visual reads of amyloid PET scans

David N Soleimani-Meigooni et al. Alzheimers Dement. 2025 Oct.

. 2025 Oct;21(10):e70732.

doi: 10.1002/alz.70732.

Authors

Affiliations

¹ Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
² Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Lab, Berkeley, California, USA.
³ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Department of Radiology, Mayo Clinic, Phoenix, Arizona, USA.
⁵ University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶ Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
⁸ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas, USA.
⁹ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
¹⁰ Stanford University School of Medicine, Stanford, California, USA.
¹¹ National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA.
¹² Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁴ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

PMID: 41030129
PMCID: PMC12484700
DOI: 10.1002/alz.70732

Abstract

Introduction: In multicenter Alzheimer's disease studies, amyloid positron emission tomography (PET) visual reads are typically performed centrally by a few experts. Incorporating a broader reader network enhances scalability and generalizability.

Methods: Ten neuroimaging experts from eight Alzheimer's Disease Research Centers (ADRCs) visually read 180 amyloid PET scans (30 scans and 15 duplicate scans for each of four tracers, imaged across a wide variety of scanners), using preferred reading software without anatomical imaging or quantitation. Scans were classified as elevated or non-elevated per tracer-specific criteria. Inter- and intra-rater agreement was assessed.

Results: Inter-rater agreement was substantial (Fleiss' κ = 0.78), with full consensus on 69% of scans. Inter-rater reliability was substantial to perfect across tracers (Fleiss' κ = 0.70-0.87). Intra-rater agreement was substantial to perfect (Cohen's κ = 0.79-1). Scans with intermediate (10-40 Centiloid) quantitation had lower reader agreement.

Discussion: A multicenter expert network achieved substantial agreement classifying amyloid PET scans. These scans provide a standard for reader training and reliability assurance in future studies.

Highlights: Calibration methods ensure reliable amyloid positron emission tomography (PET) visual reads across multiple raters. Substantial agreement is possible across readers using their preferred tools. Agreement is also substantial regardless of the amyloid PET tracer used. Scans with intermediate (10-40 Centiloid) quantitation have lower reader agreement. The calibration set will become a training tool for amyloid PET visual read studies.

Keywords: Amyloid positron emission tomography; inter‐rater reliability; intra‐rater reliability; visual reader calibration; visual reads.

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Conflict of interest statement

D.N.S.M. receives research support from NIH and serves on an Alzheimer's Association research council. R.L.J. has served as a paid consultant for GE Healthcare. D.R.J. has served as a consultant and/or on advisory boards for Novartis, Telix, and Cellectar. M.E.K. receives research support from NIH and Alzheimer's Association. J.E.M. receives research support from NIH, Eli Lilly/Avid Radiopharmaceuticals, GE Healthcare, Novartis, and Cytosite Biopharma. He has served as a consultant to Eli Lilly/AVID Radiopharmaceuticals, GE Healthcare, Telix, and Novartis, and he also received honoraria from Telix. I.M.N. receives research support from NIH. He has served as a consultant to Subtle Medical and on an advisory board for Eisai. V.L.V. receives research support from NIH and Aging Mind Foundation. He has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, ACE Barcelona, IXICO, and AC Immune. M.R.P has served as a paid scientific consultant for Avid Radiopharmaceuticals and Lantheus Medical Imaging and as a paid speaker for PETNET Solutions. She is the board chair of the American Board of Nuclear Medicine (ABNM). C.C.W. receives research support from the NIH and Alzheimer's Association. He has previously received honoraria from LCN, Onviv, Kinetix Group, and the American Academy of Neurology. W.A.K. receives research support from the NIH. He serves on external advisory committees for several ADRCs, including Kansas University, Boston University, and Icahn School of Medicine at Mount Sinai. He is an Associate Editor for Alzheimer's & Dementia: Translational Research & Clinical Interventions. E.C.M. receives research funding from NIH, Alzheimer's Association, Simon's Foundation, Archer Foundation, and Webb Family Foundation. She has served as a consultant to Eli Lilly, Roche, and Neurotrack. S.C.J. receives research support from NIH and has served as a consultant to Eli Lilly, AlzPath, and Enigma Biomedical. G.D.R. receives research support from NIH, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, Avid Radiopharmaceuticals, GE Healthcare, Genentech, and Life Molecular Imaging. He has served as a paid scientific consultant for Alector, Bristol Myers Squibb, C2N, Eli Lilly, Johnson & Johnson, Merck, Novo Nordisk, and Roche. He has served as a paid speaker for Medscape and Peerview. He is an Associate Editor for JAMA. All other authors report no conflicts of interest. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Amyloid PET scans examples and Centiloid distribution. A, Examples of amyloid PET scans for each radiotracer that span the Centiloid continuum. B, Centiloid distribution of amyloid PET scans by tracer. Red dotted lines represent the boundaries of the 10–40 Centiloid intermediate range. FBB, [¹⁸F]florbetaben; FBP, [¹⁸F]florbetapir; FFN, [¹⁸F]flutafuranol; PET, positron emission tomography; PIB, [¹¹C]Pittsburgh compound B.

**FIGURE 2**
Inter‐rater reliability. A, Bar plot showing overall and tracer‐specific inter‐rater agreement, quantified using Fleiss' Kappa (κ), for the 10 independent readers. Error bars indicate 95% CI. B, Heatmap displaying the agreement between reader pairs using Cohen's κ. C, Heatmap showing the percent agreement between reader pairs. CI, confidence interval; CL, Centiloids; FBB, [¹⁸F]florbetaben; FBP, [¹⁸F]florbetapir; FFN, [¹⁸F]flutafuranol; PIB, [¹¹C]Pittsburgh compound B.

**FIGURE 3**
Inter‐rater reliability and agreement across Centiloid (CL) ranges. A, Bar plot showing inter‐rater agreement, quantified using Fleiss' Kappa (κ), in high‐certainty (CL < 10 or > 40) and intermediate (10 ≤ CL ≤ 40) zones. Error bars indicate 95% confidence intervals (CI). B, Bar plot displaying percentage of scans with complete reader agreement within non‐elevated (CL < 10), elevated (CL > 40), and intermediate (10 ≤ CL ≤ 40) zones. C, Majority reader agreement (%) as a function of CL using a natural cubic spline model, with internal knots placed at 25th, 50th, and 75th percentiles (CL = 4.05, 21.31, and 50.38). Each point represents one unique scan and the solid blue line represents the fitted spline curve. The intermediate zone is highlighted with gray shading.

See this image and copyright information in PMC

References

1. Chapleau M, Iaccarino L, Soleimani‐Meigooni D, Rabinovici GD. The role of amyloid PET in imaging neurodegenerative disorders: a review. J Nucl Med Off Publ Soc Nucl Med. 2022;63:13S‐19S. doi: 10.2967/jnumed.121.263195 - DOI - PMC - PubMed
1. Jack CR, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement J Alzheimers Assoc. 2024;20:5143‐5169. doi: 10.1002/alz.13859 - DOI - PMC - PubMed
1. Rabinovici GD, Gatsonis C, Apgar C, Chaudhary K, Gareen I, Hanna L, et al. Association of amyloid positron emission tomography with subsequent change in clinical management among medicare beneficiaries with mild cognitive impairment or dementia. JAMA. 2019;321:1286‐1294. doi: 10.1001/jama.2019.2000 - DOI - PMC - PubMed
1. Cummings J, Apostolova L, Rabinovici GD, Atri A, Aisen P, Greenberg S, et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2023;10:362‐377. doi: 10.14283/jpad.2023.30 - DOI - PMC - PubMed
1. Rabinovici GD, Selkoe DJ, Schindler SE, Aisen P, Apostolova LG, Atri A, et al. Donanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2025:100150. doi: 10.1016/j.tjpad.2025.100150 - DOI - PMC - PubMed

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Calibration of multisite raters for prospective visual reads of amyloid PET scans

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Calibration of multisite raters for prospective visual reads of amyloid PET scans

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