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ADNI Researchers and Industry Partners Developing Proteomic Profiles to Track Alzheimer's Disease

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By Adam Bonislawski

Researchers working as part of the Alzheimer's Disease Neuroimaging Initiative are building proteomic profiles of plasma and cerebrospinal fluid in an effort to identify protein biomarkers useful in tracking and prognosing the progression of the disease.

Through the Foundation for the National Institutes of Health's Biomarkers Consortium, a group of biotechnology firms participating in the initiative have received plasma and CSF samples from ADNI participants and contributed funds for the processing of roughly 1,000 samples by biomarker discovery firm Rules-Based Medicine.

The first phase of the study will focus on building a proteomic profile for plasma both from patients exhibiting mild cognitive impairment and those with Alzheimer's disease, Neil Buckholtz, chief of dementias of aging at the National Institute on Aging, told ProteoMonitor. The next stage will involve proteomic analyses of CSF from the two groups, with researchers investigating subsets of proteins based on the results of the plasma analysis.

"We've just delivered the [plasma] data to ADNI," Sam Labrie, vice president of corporate development at Rules-Based Medicine, told ProteoMonitor. "We ran our DiscoveryMap platform, which is 189 quantitative immunoassays. We don't know yet what the results will be, but we're hopeful that there will be a plasma signature for Alzheimer's disease and also for mild cognitive impairment in the data."

ADNI is a research partnership supported primarily by the National Institute on Aging with 20 pharmaceutical companies providing private sector support through FNIH. It was launched in 2004 with $40 million in funding from NIH and an additional $20 million provided by private industry partners. In 2009 the initiative received $24 million in federal stimulus money under the American Recovery and Reinvestment Act that went to fund the ADNI-GO program, which seeks to recruit an additional 200 volunteers between the ages of 55 and 90 who may be transitioning between normal cognitive aging to an early stage of mild cognitive impairment – a condition that may progress to Alzheimer's.

The initiative comprises two primary approaches to mapping the progression of the disease — neuroimaging studies to track and define changes in the brain as individuals proceed from MCI to Alzheimer's and biomarker studies of plasma and CSF to track and define the same process. Since 2004 the roughly 500 participants in the study have been examined every six months, allowing researchers to look for longitudinal change in cognitive measures, structural imaging, and biomarker profiles.

ADNI-GO will expand the scope of the initiative to include 200 participants who may be transitioning from normal cognitive aging into an early stage of amnesiac mild cognitive impairment, allowing researchers to study the earliest points of the disease's progression.

The current proteomic profiling project with Rules-Based Medicine builds on previous biomarker studies under the initiative by scientists led by Les Shaw and John Trojanowski, researchers at the University of Pennsylvania School of Medicine and co-directors of the ADNI Biomarker Core.

Initial studies by the researchers determined that a pathological CSF biomarker signature of Alzheimer's could be defined by the combination of Abeta1-42 and total tau protein levels. Using the signature, researchers were able to predict roughly 90 percent of the time which patients would progress from MCI to Alzheimer's, Buckholtz said.

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This information could be particularly useful for the construction of drug trials, he said.

"They're trying to develop these measures to predict who will progress and who will not. This can be used in clinical trials to enrich the trials for MCI with those people who would be at highest risk of progressing, to basically give the drugs a better chance of showing an effect," he said.

Now researchers hope to be able to establish a similar signature in plasma, which, being easier to collect than CSF, is more applicable to routine clinical analysis.

"There have been some proteomic analyses in plasma before, but the results haven't always been replicable," Buckholtz said.

Researchers are also trying to establish the validity of using beta-amyloid levels in plasma as an MCI-Alzheimer's biomarker – an approach that has proven controversial in the past.

"In CSF it's very clear that as [Alzheimer's] progresses, levels of beta-amyloid decline. This has been shown in many studies and also in the ADNI studies," Buckholtz said. "The controversy has been whether beta-amyloid in plasma means anything. There have been very contradictory studies that have been done – some showing increases in plasma, some showing decreases, some showing no effect."

For this work ADNI researchers are using xMAP fluorescent bead immunoassays provided by Immunogen.

As data from the studies emerges, it will be made available on ADNI's open-access database, Buckholtz said.

"All of the data from ADNI go into the public database and basically anybody can request and almost everyone receives a password," he said. "Basically anybody can go into the database, get the data, analyze the data, and write papers. There are basically no restrictions. It's really quite a novel way of handling data."

This means no exclusivity in terms of samples or data for the initiative's private partners, but, Buckholtz noted, the initiative is providing information for future industry work.

"What they're doing is downloading the database and using it for developing clinical trials – for power calculations, for enrichment – that kind of thing," he said. "It's a bigger study than any of the companies could have mounted on their own."

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