Jul 17, 2011

Global Standardization of Biomarkers for Alzheimer's Disease (Two Studies)

The next step will be to create, test and verify a single protocol for MRI-based evaluation of Alzheimer's disease-related hippocampal shrinkage.

Alzheimer's Reading Room

Giovanni Frisoni
As the Alzheimer's field moves closer to new and earlier tests for the disease, innovative global research initiatives are taking the first important steps to standardize Alzheimer's biomarkers, as evidenced by two presentations made today at the Alzheimer's Association® International Conference 2011 (AAIC 2011) in Paris.

The first study takes a significant step forward in creating a standard international method for measuring the size of a key memory center in the brain (the hippocampus) – which often is one of the first brain areas affected by Alzheimer's.

The second study compared, for the first time, results of brain amyloid imaging and the impact of genetics and ethnicity on those results across countries on three different continents as part of a worldwide Alzheimer's disease imaging study.

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Towards a Harmonized Protocol for Measuring the Hippocampus

The earliest Alzheimer's related brain changes are usually seen in the hippocampus, the "control center" of memory-related activity in the brain.

In previous studies, MRI measurement of shrinkage of the hippocampus over time has shown value for diagnosis of Alzheimer's and tracking the progression of the disease. But harmonization (greater standardization) in assessing volume change is needed as researchers work to move hippocampal measurement from research centers into wider clinical use.

A variety of published protocols now exist for assessing hippocampal volume. These protocols differ because they rely on various techniques of "segmentation" - that is, assigning the electronic image voxels (volumetric pixels) to specific structures, such as the hippocampus, within the brain.

As a first phase of the standardization process, Giovanni Frisoni, MD, of San Giovanni di Dio Fatebenefratelli, Brescia, Italy, and colleagues surveyed the various available segmentation protocols to identify underlying reasons why they result in different volume estimates. This work was funded by the Alzheimer's Association.

"The next step will be to create, test and verify a single protocol for MRI-based evaluation of Alzheimer's disease-related hippocampal shrinkage," Frisoni said. "This initial quantification will help our international panel of experts define which key components should be included in an international harmonized protocol."

--Giovanni Frisoni, MD; et al. Estimating the Impact of Differences among Protocols for Manual Hippocampal Segmentation on Alzheimer's Disease-Related Atrophy: Preparatory Phase for a Harmonized Protocol. (Funders: Mike & Barbara Urbut, Stuart & Amy Savitz, Harriet K. Burnstein)

Alzheimer's Disease Neuroimaging Data from Three Countries

It has not been established whether the association between a well-established Alzheimer's risk gene – apolipoprotein E (APOE) ε4 – age, and amyloid deposition is consistent among ethnic groups.

Kenji Ishii, MD, of Tokyo Metropolitan Institute of Gerontology, and colleagues, used data from three multi-center studies of Alzheimer's that are using a harmonized protocol – the Alzheimer's Disease Neuroimaging Initiative (US-ADNI), Australian Imaging Biomarker and Lifestyle Flagship Study of Aging (AIBL), and Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) – to evaluate the influence of APOE ε4 and age on the accumulation of amyloid in the brain as measured by PET scan with 11C-Pittsburgh compound B (PiB). This is the first report of an international ADNI data analysis including these three different national populations, all three of which include people with Alzheimer's, MCI, and cognitively normal individuals.

The researchers found that:

  • The effect of age and APOE-ε4 on amyloid deposition in the Japanese population is similar to Caucasians, despite a lower ε4 allele frequency in the Japanese population.
  • In the cognitively normal people in the study, having a single copy of the APOE-ε4 gene is roughly equivalent to 12 additional years of age for PiB positivity.
  • Perhaps most importantly, for the Alzheimer's research field, the results suggest that the three multi-national ADNI data sets are feasible for combined analysis.

"This is one of the first demonstrations of the great value of open data sharing in the worldwide ADNI initiative," Ishii said. "Combined analysis enlarges and diversifies the study population and the data set. It increases the power of the results, decreases ethnicity effects and makes the findings more broadly applicable. This is very important as we identify and verify biomarker tests for Alzheimer's disease."

--Kenji Ishii, MD; et al. Age, APOE ε4, and Ethnic Effect on [C-11]PiB in Multi-national ADNI Studies - Direct Comparison of J-ADNI, US-ADNI and AIBL Data. Funders: New Energy and Industrial Technology Development Organization, Kanagawa, Japan; Ministry of Health Labor and Welfare, Tokyo, Japan)

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Original content Bob DeMarco, the Alzheimer's Reading Room