Global Standardization of Alzheimer's Biomarkers on the Way

Fran Lowry

July 18, 2011

July 18, 2011 (Paris, France) — Advancing global standardization of biomarkers for Alzheimer's disease (AD) and moving the field closer to harmonized protocols is the aim of 2 studies presented here at the Alzheimer's Association International Conference 2011 (AAIC 2011).

In the first study, Kenji Ishii, MD, from the Tokyo Metropolitan Institute of Gerontology in Japan, presented results showing that Alzheimer’s Disease Neuroimaging Initiative (ADNI) data obtained in 3 studies using a harmonized protocol in the United States, Australia, and Japan can be combined to determine whether the association between apolipoprotein E ε4 (APOE ε4) allele, age, and amyloid deposition are consistent among ethnic groups.

Dr. Kenji Ishii

Dr. Ishii and colleagues analyzed 3 multicenter studies — US-ADNI, the Australian Imaging Biomarker and Lifestyle Flagship Study of Aging, and the Japanese ADNI — to evaluate the influence of APOE ε4 and age on the accumulation of amyloid in the brain as measured by positron emission tomography with Pittsburgh compound B (PiB).

The researchers found that the effect of age and APOE ε4 on amyloid deposition in the Japanese population is similar to that in white persons, despite a lower ε4 allele frequency in the Japanese population.

They also found that among 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.

Importantly, Dr. Ishii and his team conclude, their results suggest that the 3 multinational 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," Dr. Ishii said in a statement. "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."

Standardized Hippocampal Measurement in 2012

In the second study, Giovanni Frisoni, MD, from San Giovanni di Dio Fatebenefratelli in Brescia, Italy, and colleagues surveyed existing protocols for measuring hippocampal volume to identify underlying wide variation in volume estimates.

Dr. Giovanni Frisoni

Dr. Frisoni and colleagues note that the earliest brain changes associated with AD are usually seen in the hippocampus. In previous studies, magnetic resonance imaging (MRI) measurement of shrinkage of the hippocampus over time has been valuable in diagnosis and for tracking disease progression.

The problem is that no 2 centers measure the hippocampus the same way or obtain the same results, Dr. Frisoni noted.

"When we try to measure the volume of the hippocampus, we do this by measuring the hippocampus in segments. If you do that in different places, you find dramatically different volumes. You find dramatically different results," he told reporters here at a press briefing.

"The exams will show a reduction of the size of the hippocampus, but that reduction will vary, so we don’t know how to measure what is normal and what is not," he added.

As a first step toward standardizing this measure, the investigators searched the literature for all the different ways of measuring the hippocampus and found 12 different methods.

They then gave this information to experts and asked them to come up with a single, standardized method of hippocampal measurement.

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

"This initial quantification will help our international panel of experts define which key components should be included in an international harmonized protocol."

Dr. Frisoni told reporters that the hope is that a final standardized test will be developed by September 2012.

Need for Worldwide Standardization

"We need to identify people in the earliest stages of Alzheimer's, even those without outward evidence of memory and thinking symptoms for treatment and prevention trials," Maria Carrillo, PhD, senior director of Medical and Scientific Relations at the Alzheimer's Association, said in a statement.

Dr. Maria Carrillo

"It is very important that the tests are accurate and effective, and that they are delivered and measured in the same way across the world so that measures are comparable."

Dr. Carrillo pointed out that methods for testing serum levels of cholesterol are the same in "Budapest, Bangalore, or Boston" and the results of the tests are comparable. This is not yet the case for AD, she noted.

"To ensure comparable results, the methods used for gathering and evaluating samples must be consistent," Dr. Carrillo said.

"One of the largest challenges is that when we make an important discovery in 1 country, or even at 1 center in 1 country, we are not always able to translate that across our borders and convince other researchers that the discovery is a good way to go. This is why bringing researchers together at meetings like this is so important," she added.

Dr. Ishii, Dr. Frisoni, and Dr. Carrillo have disclosed no relevant financial relationships.

Alzheimer's Association International Conference 2011 (AAIC 2011). Abstracts P1-378 & P1-299. Presented July 17, 2011.

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