. 2024 Sep;20(9):5833-5848.

doi: 10.1002/alz.13908. Epub 2024 Jul 23.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model

Antoine Leuzy^{1

2

3}, Lars Lau Raket^{1

4}, Victor L Villemagne^{5

6

7}, Gregory Klein⁸, Matteo Tonietto⁸, Emily Olafson⁹, Suzanne Baker¹⁰, Ziad S Saad¹¹, Santiago Bullich¹², Brian Lopresti¹³, Sandra Sanabria Bohorquez⁹, Mercè Boada^{14

15}, Tobey J Betthauser^{16

17

18}, Arnaud Charil¹⁹, Emily C Collins⁴, Jessica A Collins²⁰, Nicholas Cullen², Roger N Gunn^{21

22}, Makoto Higuchi²³, Eric Hostetler²⁴, R Matthew Hutchison²⁰, Leonardo Iaccarino⁴, Philip S Insel²⁵, Michael C Irizarry¹⁶, Clifford R Jack Jr²⁶, William J Jagust²⁷, Keith A Johnson^{28

29}, Sterling C Johnson^{16

17

18}, Yashmin Karten², Marta Marquié^{17

18}, Sulantha Mathotaarachchi³, Mark A Mintun⁴, Rik Ossenkoppele^{1

30}, Ioannis Pappas^{31

32}, Ronald C Petersen³³, Gil D Rabinovici^{34

35}, Pedro Rosa-Neto^{36

37}, Christopher G Schwarz²⁶, Ruben Smith^{1

38}, Andrew W Stephens¹², Alex Whittington²¹, Maria C Carrillo³⁹, Michael J Pontecorvo⁴, Samantha Budd Haeberlein³, Billy Dunn⁴⁰, Hartmuth C Kolb³, Sudhir Sivakumaran², Christopher C Rowe^{6

7

41}, Oskar Hansson^{1

42}, Vincent Doré^{7

43}

Affiliations

¹ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
² Critical Path for Alzheimer's Disease (CPAD) Consortium, Critical Path Institute, Tucson, Arizona, USA.
³ Enigma Biomedical Group, Knoxville, Tennessee, USA.
⁴ Eli Lilly and Company, Indianapolis, Indiana, USA.
⁵ Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁶ Florey Department of Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
⁷ Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, Australia.
⁸ F. Hoffmann-La Roche Ltd, Basel, Switzerland.
⁹ Clinical Imaging Group, Genentech, Inc., South San Francisco, California, USA.
¹⁰ Lawrence Berkeley National Laboratory, Berkeley, California, USA.
¹¹ Janssen Research & Development, Merryfield Row San Diego, California, USA.
¹² Life Molecular Imaging GmbH, Berlin, Germany.
¹³ Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
¹⁴ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
¹⁵ Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Av. de Monforte de Lemos, Madrid, Spain.
¹⁶ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁷ Department of Medicine Division of Geriatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁸ Department of Medical Physics, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁹ Eisai, Inc., Nutley, New Jersey, USA.
²⁰ Biogen, Cambridge, Massachusetts, USA.
²¹ Invicro, Hammersmith Hospital, London, UK.
²² Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK.
²³ Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Inage-ku, Chiba-shi, Chiba, Japan.
²⁴ Merck & Co., Inc, West Point, Pennsylvania, USA.
²⁵ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, California, USA.
²⁶ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁷ University of California Berkeley, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
²⁸ Harvard Medical School, Department of Radiology, Boston, Minnesota, USA.
²⁹ Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, Minnesota, USA.
³⁰ Amsterdam University Medical Center, Neuroscience Campus Amsterdam, Alzheimercenter, HZ Amsterdam, the Netherlands.
³¹ Department of Psychology, Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA.
³² Department of Neurology, VA Northern California Health Care System, Martinez, California, USA.
³³ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
³⁴ Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
³⁵ Department of Radiology & Biomedical Imaging, University of California, San Francisco, California, USA.
³⁶ Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Faculty of Medicine, The McGill University Research Centre for Studies in Aging, McGill University, Verdun, Quebec, Canada.
³⁷ Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
³⁸ Department of Neurology, Skåne University Hospital, Lund, Sweden.
³⁹ Alzheimer's Association, Chicago, Illinois, USA.
⁴⁰ Senior advisor to CPAD Consortium, Critical Path Institute, Tucson, Arizona, USA.
⁴¹ The Australian Dementia Network (ADNeT), The University of Melbourne, Parkville, Victoria, Australia.
⁴² Memory Clinic, Skåne University Hospital, Malmö, Sweden.
⁴³ Health and Biosecurity Flagship, The Australian eHealth Research Centre, CSIRO, Parkville, Victoria, Australia.

PMID: 39041435
PMCID: PMC11497758
DOI: 10.1002/alz.13908

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model

Antoine Leuzy et al. Alzheimers Dement. 2024 Sep.

. 2024 Sep;20(9):5833-5848.

doi: 10.1002/alz.13908. Epub 2024 Jul 23.

Authors

Affiliations

¹ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
² Critical Path for Alzheimer's Disease (CPAD) Consortium, Critical Path Institute, Tucson, Arizona, USA.
³ Enigma Biomedical Group, Knoxville, Tennessee, USA.
⁴ Eli Lilly and Company, Indianapolis, Indiana, USA.
⁵ Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁶ Florey Department of Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
⁷ Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, Australia.
⁸ F. Hoffmann-La Roche Ltd, Basel, Switzerland.
⁹ Clinical Imaging Group, Genentech, Inc., South San Francisco, California, USA.
¹⁰ Lawrence Berkeley National Laboratory, Berkeley, California, USA.
¹¹ Janssen Research & Development, Merryfield Row San Diego, California, USA.
¹² Life Molecular Imaging GmbH, Berlin, Germany.
¹³ Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
¹⁴ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
¹⁵ Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Av. de Monforte de Lemos, Madrid, Spain.
¹⁶ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁷ Department of Medicine Division of Geriatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁸ Department of Medical Physics, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA.
¹⁹ Eisai, Inc., Nutley, New Jersey, USA.
²⁰ Biogen, Cambridge, Massachusetts, USA.
²¹ Invicro, Hammersmith Hospital, London, UK.
²² Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK.
²³ Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Inage-ku, Chiba-shi, Chiba, Japan.
²⁴ Merck & Co., Inc, West Point, Pennsylvania, USA.
²⁵ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, California, USA.
²⁶ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁷ University of California Berkeley, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
²⁸ Harvard Medical School, Department of Radiology, Boston, Minnesota, USA.
²⁹ Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, Minnesota, USA.
³⁰ Amsterdam University Medical Center, Neuroscience Campus Amsterdam, Alzheimercenter, HZ Amsterdam, the Netherlands.
³¹ Department of Psychology, Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA.
³² Department of Neurology, VA Northern California Health Care System, Martinez, California, USA.
³³ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
³⁴ Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
³⁵ Department of Radiology & Biomedical Imaging, University of California, San Francisco, California, USA.
³⁶ Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Faculty of Medicine, The McGill University Research Centre for Studies in Aging, McGill University, Verdun, Quebec, Canada.
³⁷ Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
³⁸ Department of Neurology, Skåne University Hospital, Lund, Sweden.
³⁹ Alzheimer's Association, Chicago, Illinois, USA.
⁴⁰ Senior advisor to CPAD Consortium, Critical Path Institute, Tucson, Arizona, USA.
⁴¹ The Australian Dementia Network (ADNeT), The University of Melbourne, Parkville, Victoria, Australia.
⁴² Memory Clinic, Skåne University Hospital, Malmö, Sweden.
⁴³ Health and Biosecurity Flagship, The Australian eHealth Research Centre, CSIRO, Parkville, Victoria, Australia.

PMID: 39041435
PMCID: PMC11497758
DOI: 10.1002/alz.13908

Abstract

Introduction: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.

Methods: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale.

Results: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach.

Discussion: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification.

Highlights: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Keywords: Alzheimer's disease; CPAD; CenTauR; Centiloid; C‐Path; Imaging; PET; [18F]Flortaucipir; [18F]GTP1; [18F]MK‐6240; [18F]PI‐2620; [18F]RO948; head‐to‐head; standardization; tau.

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Conflict of interest statement

Antoine Leuzy, Nicholas C. Cullen, Yashmin Karten, and Sudhir Sivakuraman reported that their organization (Critical Path Institute) received research funding via membership fees paid by members of the Critical Path for Alzheimer's Disease (CPAD) Consortium outside the submitted work. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, FDA/HHS or the U.S. Government. Lars Lau Raket, Emily C. Collins, Leonardo Iaccarino, Michael J. Pontecorvo, and Mark A. Mintun are full‐time employees of Eli Lilly. Gregory Klein and Matteo Tonietto are full‐time employees of Hoffmann‐La Roche Ltd. Emily Olafson and Sandra Sanabria Bohorquez are full‐time employees of Genentech, Inc. Ziad Saad is a full‐time employees of Janssen. Antoine Leuzy, Samantha Budd Haeberlein and Hartmuch C. Kolb are consultants to Enigma Biomedical Group. Sulantha Mathotaarachchi is a full‐time employee of Enigma Biomedical Group (Enigma Biomedical Group). Roger Gunn and Alex Whittington are full‐time employees of Invicro. Maria C. Carillo is a full‐time employee of the Alzheimer's Association. Santiago Bullich and Andrew Stephen are full‐time employees of Life Molecular Imaging GmbH. Arnaud Charil and Michael C. Irizarry are full‐time employees of Eisai. Jessica A. Collins and R. Matthew Hutchison are full‐time employees of Biogen. Eric Hostetler is a full‐time employee of Merck & Co., Inc. Victor L. Villemagne has received research grants from NHMRC (GNT2001320), the Aging Mind Foundation (DAF2255207), and NIH 2P01AG025204‐16) and is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, Ace Barcelona, BRI Japan, and AC Immune. Makoto Higuchi has received research grants from JST (JPMJMS2024) and AMED (20dm0207072) and holds patents on florzolotau and related compounds (JP 5422782/EP 12 884742.3/US 11667628/CA 2894994/HK 1208672), and the license of the patent rights has been granted to APRINOIA Therapeutics. Gil D. Rabinovici has received research support from Avid Radiopharmaceuiticals, GE Healthcare, Life Molecular Imaging, Genentech. Consulting fees from Alector, Eli Lilly, Johnson & Johnson, Merck, and is the Associate Editor for JAMA Neurology. Ruben Smith has received a speaker fee from Roche. Oskar Hansson has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. Marta Marquié has received funding support from Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—Una manera de hacer Europa) grant PI19/00335, has received travel support to attend scientific meeting from F. Hoffmann‐La Roche Ltd, and has participated in the Spanish Scientific Advisory Board of Biomarkers of Araclon Biotech‐Grífols. Mercè Boada has received consultancy fees from Grifols, Araclon Biotech, Roche, Biogen, Eli Lilly, Merck, Zambon, and Novo‐Nordisk. Billy Dunn is a consultant for ArchVenture Partners, Cerveau Technologies, Epilepsy Foundation, F‐PRIME Capital, Loulou Foundation, and Michael J. Fox Foundation. He has served as president of the Virginia Neurological Society and is director of Prothena Inc. Keith Johnson is a consultant for Novartis and Merck. Sterling Johnson is a consultant for Enigma Biomedical Group and Alzpath. The other authors did not report any conflict of interest. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Overview of the CenTauR ROIs, the JPM and the linear regression approach. Universal and subregion regions of interest (ROIs) (left) along with an overview of both the joint propagation model (JPM) and the linear regression approaches (right). Using the JPM (top right), we assume that CenTauR (CTR) is common latent scale that has given rise to the observed data, and we do not assume a reference tracer. Using both anchor point (left) and head‐to‐head (right) data, maximum likelihood estimation is used to estimate the parameters that are most likely to generate the observed data. From these estimated parameters, equations that map standardized uptake value ratio (SUVR) values to CTRs can then be generated for a given tracer. Using the linear regression approach (bottom right; here assuming [¹⁸F]flortaucipir as the reference tracer), we first derive the equation to convert [¹⁸F]flortaucipir SUVR to (Equation 1) using anchor point values (left). Next, [¹⁸F]RO948 SUVR are converted to their equivalent in [¹⁸F]flortaucipir (i.e., Flortaucipir‐Calc) (Equation 2). Using Equation 1, these Flortaucipir–Calc values can then be converted to CTRs. [¹⁸F]Flortaucipir was used as the reference tracer as it is currently the most widely available and most widely studied tau tracer, and the only one validated against autopsy cases and approved by U.S. Food and Drug Administration.

**FIGURE 2**
CenTauR (CTR) values across regions of interest in anchor point and head‐to‐head cohorts. CTR values are shown for anchor point subjects on the left and for head‐to‐head subjects on the right for each ROI: universal (A, B), mesial temporal (C, D), meta temporal (E, F), temporoparietal (G, H), and frontal (I, J).

**FIGURE 3**
Associations between joint propagation model (JPM)‐based CenTauR (CTR) values across head‐to‐head cohorts and regions of interest (ROIs) (each row, left to right: universal, mesial temporal, meta temporal, temporoparietal, and frontal) for head‐to‐head cohorts. Top row, [¹⁸F]RO948 vs [¹⁸F]flortaucipir; second row, [¹⁸F]MK‐6240 vs [¹⁸F]flortaucipir; third row, [¹⁸F]GTP1 vs [¹⁸F]MK‐6240; fourth row, [¹⁸F]GTP1 vs [¹⁸F]PI‐2620; bottom row, [¹⁸F]RO948 vs [¹⁸F]PI‐2620.

**FIGURE 4**
Sensitivity analyses varying anchor point values using the joint propagation model (JPM). Comparison of tracer‐to‐tracer standardized uptake value ratio (SUVR) mapping equations from head‐to‐head cohorts are shown in solid red, with results from JPM based equations shown in solid blue. Dashed lines show sensitivity analyses using only [¹⁸F]flortaucipir anchor point data (green) and when varying [¹⁸F]MK‐6240 anchor point data by 30% (CenTauR: CTR‐0, purple; CTR‐100, orange). High agreement was observed between JPM results and head‐to‐head equations generated by linear regression in each of the five head‐to‐head cohorts. The biggest deviation was observed for [¹⁸F]PI‐2620 vs [¹⁸F]RO948, where head‐to‐head data was limited in its SUVR range. Across all three sensitivity analyses, there was very little impact on the estimated SUVR‐to‐SUVR equations. [¹⁸F]Flortaucipir was used as the reference tracer as it is currently the most widely available and most widely studied tau tracer, and the only one validated against autopsy cases and approved by U.S. Food and Drug Administration.

**FIGURE 5**
Mean square prediction error of the linear regression approach and the joint propagation model (JPM) on the CenTauR (CTR) scale and on the [¹⁸F]flortaucipir standardized uptake value ratio (SUVR) scale across 20 replications of five‐fold cross‐validation. Across 20 replications of five‐fold cross validation (totaling 100 evaluations), comparing the linear regression method with JPM on the CTR scale (left), the JPM consistently resulted in lower mean square prediction error (mean 45.0 vs. 76.8). This was primarily an effect of a slightly more compressed range of the CTR scale for the JPM compared to the linear regression method. When mapping results to [¹⁸F]flortaucipir SUVR values (right), similar results were observed in terms of mean square prediction error (mean JPM 0.00742, linear regression approach 0.00874). [¹⁸F]Flortaucipir was included in the sensitivity analyses as it is currently the most widely available and most widely studied tau tracer, and the only one validated against autopsy cases and approved by U.S. Food and Drug Administration.

See this image and copyright information in PMC

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Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model

Affiliations

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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LinkOut - more resources

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Medical

Research Materials

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