Volume 7, Issue 4 p. 474-485.e4
Perspective

Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease

Clifford R. Jack Jr.

Corresponding Author

Clifford R. Jack Jr.

Department of Radiology, Mayo Clinic, Rochester, MN, USA

Corresponding author. Tel.: 507-284-8548; Fax: 507-284-9778.

E-mail address: [email protected]

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Frederik Barkhof

Frederik Barkhof

Department of Radiology and Image Analysis Center, VU University Medical Center, Amsterdam, NL, USA

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Matt A. Bernstein

Matt A. Bernstein

Department of Radiology, Mayo Clinic, Rochester, MN, USA

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Marc Cantillon

Marc Cantillon

Coalition Against Major Diseases, Critical Path Institute, Rockville, MD, USA

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Patricia E. Cole

Patricia E. Cole

Imagepace, Cincinnati, OH, USA

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Charles DeCarli

Charles DeCarli

Department of Neurology and Center for Neuroscience, University of California–Davis, Sacramento, CA, USA

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Bruno Dubois

Bruno Dubois

Department of Neurology, Salpetriere Hospital, Pierre and Marie Curie University, Paris, France

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Simon Duchesne

Simon Duchesne

Departement de Radiologie, Centre de Recherche UniversitÉ Laval Robert-Giffard, Quebec, QC, Canada

Department of Radiology, UniversitÉ Laval, QuÉbec, QC, Canada

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Nick C. Fox

Nick C. Fox

Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom

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Giovanni B. Frisoni

Giovanni B. Frisoni

Laboratory of Epidemiology and Neuroimaging, IRCCS San Giovanni di Dio-FBF, Brescia, Italy

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Harald Hampel

Harald Hampel

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt, Germany

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Derek L.G. Hill

Derek L.G. Hill

Department of Medical Physics and Bioengineering, Centre for Medical Image Computing, University College, London, United Kingdom

IXICO Ltd, The London Bioscience Innovation Centre, London, United Kingdom

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Keith Johnson

Keith Johnson

Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Division of Molecular Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

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Jean-François Mangin

Jean-François Mangin

Neurospin, I2BM, CEA, Saclay, France

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Philip Scheltens

Philip Scheltens

Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, NL, USA

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Adam J. Schwarz

Adam J. Schwarz

Translational Medicine, Eli Lilly and Company, Indianapolis, IN, USA

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Reisa Sperling

Reisa Sperling

Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

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Joyce Suhy

Joyce Suhy

Division of Neurology, Synarc Inc., San Francisco, CA, USA

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Paul M. Thompson

Paul M. Thompson

Department of Neurology, Laboratory of Neuro Imaging, UCLA School of Medicine, Los Angeles, CA, USA

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Michael Weiner

Michael Weiner

Department of Veterans Affairs, Center for Imaging of Neurodegenerative Disease, VA Medical Center, San Francisco, CA, USA

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA

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Norman L. Foster

Norman L. Foster

Department of Neurology, Center for Alzheimer's Care, Imaging and Research, University of Utah, Salt Lake City, UT, USA

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First published: 01 July 2011
Citations: 142

Abstract

Background

The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization.

Methods and Results

The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers–Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark.

Conclusions

Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.