Scientists agree that Alzheimer’s disease ravages the hippocampus, making the volume of this small brain region a key marker for AD clinical trials. But as to precisely where the hippocampus starts and stops on a magnetic resonance image, researchers have little consensus. One tracing protocol can delineate a hippocampal volume more than twice as big as another method, said Giovanni Frisoni, of IRCCS Fatebenefratelli in Brescia, Italy, in a presentation at the Alzheimer’s Association International Conference, held 14-19 July 2012 in Vancouver, Canada. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) has standardized how radiologists should take the images. Now, another collaborative team is stepping in where ADNI left off. The collaboration for A Harmonized Protocol for Hippocampal Volumetry, which led a lively discussion at the meeting, is midway toward its goal of developing a hippocampal trace customized for Alzheimer’s. They have consulted experts to combine disparate methods into one grand, unified protocol they hope everyone will use, making it easy to compare data among different research groups.
“Eventually, in the literature, you will be able to compare apples to apples,” said Simon Duchesne of Université Laval in Québec City, Canada, one of the presenters at the 18 July discussion. Duchesne and principal investigators Frisoni and Clifford Jack, of the Mayo Clinic in Rochester, Minnesota, envision a system whereby wannabe hippocampal tracers the world over can study the protocol, hone their skills on training images, and pass a test to obtain certification. The international project is a joint effort between ADNI and the European Alzheimer’s Disease Consortium, and they are using ADNI images as test cases.
There is no shortage of interest in the new protocol. At the Vancouver meeting, in the sixth such discussion, attendance had quadrupled since the first, Frisoni told Alzforum. The talk grew spirited as researchers debated how best to validate the tracing method. “It is critically important to get standardized protocols,” Laurie Ryan, AD clinical trials coordinator at the National Institute on Aging in Bethesda, Maryland, told Alzforum. “Being able to compare across studies is invaluable.”
The challenge is that defining the precise edge where the hippocampus meets other brain tissue is far from straightforward. It is “painstaking” work, Frisoni noted, and the researchers found 40 different ways to do it in the scientific literature. The project leaders based their plan on the 12 most commonly used methods and consulted 16 expert panelists to define the hippocampus based on four main areas.
Researchers have defined the most informative hippocampal boundaries for AD, including a minimum hippocampus (red), tail (blue), subiculum (green), and alveus/fimbria (yellow). Image courtesy of Marina Boccardi, Brescia, Italy
The minimum hippocampus (red) is the undisputed hippocampal tissue; every protocol included this section. The tail segment (blue) includes everything behind the minimum hippocampus, which some tracing methods incorporated and others did not. The area called the subiculum (green), similarly, represents differences in how the top 12 protocols delineated the medial edge of the hippocampus. Finally, the researchers included white matter in the form of the alveus/fimbria (yellow), linking the hippocampus to other structures. This white matter is the not “hippocampus proper,” nor is it particularly informative for Alzheimer’s disease, noted project coordinator Marina Boccardi, who also works at the IRCCS in Brescia. However, excluding the white matter completely made it too difficult for tracers to define the hippocampal edge, so they settled on including just the part directly adjacent to the hippocampus.
The resulting hippocampal outline does not directly correspond to the brain’s anatomy. Instead, the researchers wanted to define the region that is most informative, and most reliable to trace, for studies of Alzheimer’s disease. Together, the four regions include all parts of the hippocampus affected by AD.
The current protocol runs 23 pages, with as many figures to illustrate the landmarks that define each region. Using those instructions, Boccardi’s team of five “master tracers” has outlined hippocampi with a correlation of 0.95 among them. This is an “almost perfect” match, Frisoni and Boccardi chorused in a discussion with Alzforum. Such accordance has never before been achieved with manual tracing, Frisoni said; a correlation of 0.8-0.9 is typically considered acceptable.
The next step, Boccardi said, is to validate the evolving protocol with more tracers. The protocol and images are also available to beta users who submit proposals to collaborate with the project. The team hopes to release the final version of the protocol in a year. Not only will the instructions help human tracers align their efforts, but also, researchers writing automated tracing algorithms can take advantage. Frisoni expects the protocol will be built into computerized tracing; this would be the project’s most important utility, he told Alzforum.
Scientists will be able to trace new images according to the standard, as well as go back and retrace old scans to match. With all tracers chiming in on the same tune, researchers should be better able to compare hippocampal volume across any set of drug trials, multiplying the data available to study the disease and medications’ effects.—Amber Dance.
- Boccardi M, Ganzola R, Bocchetta M, Pievani M, Redolfi A, Bartzokis G, Camicioli R, Csernansky JG, de Leon MJ, Detoledo-Morrell L, Killiany RJ, Lehéricy S, Pantel J, Pruessner JC, Soininen H, Watson C, Duchesne S, Jack CR, Frisoni GB. Survey of protocols for the manual segmentation of the hippocampus: preparatory steps towards a joint EADC-ADNI harmonized protocol. J Alzheimers Dis. 2011;26 Suppl 3:61-75. PubMed.
- Jack CR, Barkhof F, Bernstein MA, Cantillon M, Cole PE, Decarli C, Dubois B, Duchesne S, Fox NC, Frisoni GB, Hampel H, Hill DL, Johnson K, Mangin JF, Scheltens P, Schwarz AJ, Sperling R, Suhy J, Thompson PM, Weiner M, Foster NL. Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease. Alzheimers Dement. 2011 Jul;7(4):474-485.e4. PubMed.
- Frisoni GB, Jack CR. Harmonization of magnetic resonance-based manual hippocampal segmentation: a mandatory step for wide clinical use. Alzheimers Dement. 2011 Mar;7(2):171-4. PubMed.
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