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International Panel Reports First Global Harmonized Protocol for Measuring Key Brain Region Tied to Memory

VANCOUVER, July 16, 2012 – An international panel of experts has developed the first global harmonized protocol for measuring a key region of the brain tied to memory, according to research reported today at the Alzheimer's Association International Conference® 2012 (AAIC® 2012) in Vancouver.

The harmonized protocol for measurement of the hippocampus, development of which was funded by the Alzheimer's Association®, will be presented to the broader Alzheimer's research community for review and input at AAIC 2012. The protocol will then be validated with data derived from healthy and diseased brain tissues, and compared for accuracy and consistency against protocols currently used in Alzheimer's research.

The hippocampus is a part of the brain important for memory. Changes in the size of the hippocampus measured by MRI may prove to be a key biomarker* for Alzheimer's disease. For example, measurements of hippocampal atrophy may be used to help select research subjects with greater likelihood of progression to Alzheimer's for participation in clinical trials.

"However, different methods of data gathering and analysis around the world lead to different size estimates, hampering comparison of studies and clinical use," said Maria Carrillo, PhD, Alzheimer's Association Senior Director of Medical and Scientific Relations. "Thus, there is an urgent need to define a global harmonized protocol for measurement of the hippocampus."

* A biomarker is something in the body that can be objectively measured as an indicator of normal biological processes, disease processes, or responses to therapy. For example, cholesterol levels are a biomarker for heart disease. A variety of imaging (amyloid PET, whole brain and hippocampal MRI) and fluid (amyloid and tau protein levels in blood and cerebrospinal fluid) biomarkers are under investigation in Alzheimer's disease.

"Biomarkers will be most useful for better diagnosis and earlier detection of Alzheimer's when they are administered, gathered and measured in the same way around the world," Carrillo said. "Because of the great importance of advancements in biomarkers to improving Alzheimer's diagnosis and speeding drug development, the Alzheimer's Association is spearheading several important efforts for global harmonization of Alzheimer's imaging and fluid biomarkers."

To prepare the harmonized protocol reported at AAIC 2012, neurologist Giovanni Frisoni, MD, of the National Alzheimer's Centre in Brescia, Italy and colleagues, first surveyed the 12 most used protocols for the manual segmentation of the hippocampus in the Alzheimer's literature. They divided the hippocampus into several blocks (segmentation units, or SUs) and measured how informative and reliable each block was in the measurement of Alzheimer's-related atrophy.

This data was given to a panel of 16 international experts in hippocampal segmentation who developed the first draft of the Harmonized Protocol. This draft protocol was provided to five independent international research centers who were asked to segment a sample of 40 brains using the methods and landmarks described in the Harmonized Protocol. These "benchmark" MRI images were used to improve the Harmonized Protocol – to reduce ambiguity, aid comprehension and improve compliance with the protocol, and provide reference descriptions and images to assist with future problem solving.

"The availability of a standard and shared protocol for hippocampal volumetry measured on magnetic resonance images provides researchers with an international standard of measurement that will help validate the new Alzheimer's diagnostic criteria and encourage their use in clinical settings, enable comparisons of the effect of disease modifying drugs, and represent the gold standard for automated segmentation algorithms," Frisoni said.

About AAIC®
The Alzheimer's Association International Conference® (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association®
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer's care, support and research. Our mission is to eliminate Alzheimer's through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit or call 800-272-3900.


O2-11-02  Monday, July 16 / Oral, 3:30-5 pm

Definition of Harmonized Protocol for Hippocampal Segmentation

Marina Boccardi1, Martina Bocchetta2, Liana Apostolova3, Josephine Barnes4, George Bartzokis5, Gabriele Corbetta2, Charles DeCarli6, Leyla DeToledo-Morrell7, Michael Firbank8, Rossana Ganzola2, Lotte Gerritsen9, Wouter Henneman10, Ronald Killiany11, Nikolai Malykhin12, Patrizio Pasqualetti13, Jens Pruessner14, Alberto Redolfi1, Nicolas Robitaille15, Hilkka Soininen16, Daniele Tolomeo2, Lei Wang17, Craig Watson18, Henrike Wolf19, Simon Duchesne15, Clifford Jack20, Giovanni Frisoni21 1IRCCS S.Giovanni di Dio - Fatebenefratelli, Brescia, Italy; 2IRCCS S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy; 3David Geffen School of Medicine, University of California, Los Angeles, California, United States; 4UCL Institute of Neurology, University College London, London, United Kingdom; 5David Geffen School of Medicine at UCLA, Los Angeles, California, United States; 6University of California at Davis, Sacramento, California, United States; 7Rush University, Chicago, Illinois, United States; 8Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle upon Tyne, United Kingdom; 9Karolinska Institute, Stockholm, Sweden; 10VU University Medical Center, Amsterdam, Netherlands; 11Boston University School of Medicine, Boston, Massachusetts, United States; 12Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada; 13Associazione Fatebenefratelli per la Ricerca, Rome, Italy; 14McGill Centre for Studies on Aging, Montreal, Quebec, Canada; 15Université Laval and Centre de Recherche Université Laval - Robert Giffard, Quebec, Quebec, Canada; 16University of Eastern Finland, Kuopio, Finland; 17Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; 18University Health Center, St. Antoine, Detroit, Michigan, United States; 19University of Zurich, Zurich, Switzerland; 20Mayo Clinic, Rochester, Minnesota, United States; 21IRCCS S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy
Presenting author e-mail:

Background: Heterogeneity of landmarks among protocols leads to different volume estimates, hampering comparison of studies and clinical use. There is an urgent need to define a harmonized protocol for manual hippocampal segmentation from magnetic resonance scans. Landmark differences among the 12 most common protocols were extracted, operationalized, and quantitatively investigated. The results were presented to the Delphi panel, consisting of seventeen researchers with substantial expertise in hippocampal segmentation, in order to reach an evidence-based consensus on segmentation landmarks.

Methods: The Delphi panel participated in iterative anonymous voting sessions where feedback from previous rounds was utilized to progressively facilitate panelists' convergence on agreement. Panelists were presented with segmentation alternatives, each associated with quantitative data relating: (i) reliability, (ii) impact on whole hippocampal volume, and (iii) correlation with AD-related atrophy. Panelists were asked to choose among alternatives and provide justification, comments and level of agreement with the proposed solution. Anonymous votes and comments, and voting statistics of each round were fed into the following Delphi round. Exact probability on binomial tests of panelists' preferences was computed.

Results: Sixteen panelists completed four Delphi rounds. Agreement was significant on (i) inclusion of alveus/fimbria (p=0.021); inclusion of the whole hippocampal tail (p=0.013); (iii) segmentation of the medial border of the body following visible morphology as the first choice (p=0.006) and following a horizontal line in the absence of morphological cues (p=0.021); inclusion of the minimum hippocampus (comprising head and body) (p=0.001); and inclusion of vestigial tissue in the segmentation of the tail (p=0.022) (Figure). Significant agreement was also achieved for exclusion of internal cerebrospinal fluid pools (p=0.004). Based on previous quantitative investigation, the hippocampus so defined covers 100% of hippocampal tissue, captures 100% of AD-related atrophy, and has good intra-rater (0.99) and inter-rater (0.94) reliability.

Conclusions: A Harmonized Protocol for Manual Segmentation has been agreed among an international panel of experts. The protocol will be validated with neuropathological data and its accuracy will be compared with protocols currently used in Alzheimer's disease research.


Alzheimer's Association
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