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WUSTL Team Develops Blood-Based Test for Brain Amyloidosis

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NEW YORK (GenomeWeb) – Researchers at Washington University in St. Louis have developed a blood test for identifying patients with central nervous system amyloidosis.

Described in a study published today in Alzheimer's and Dementia, the test uses mass spec to measure the kinetics of different amyloid beta (Aβ) isoforms in plasma and could enable faster and cheaper screening of patients for Alzheimer's drug trials, said Randall Bateman, professor of neurology at WUSTL and senior author on the study.

Using immunoprecipitation combined with parallel-reaction monitoring mass spectrometry on a Thermo Fisher Scientific Orbitrap Fusion Tribrid instrument, the researchers measured in plasma the kinetics of three Aβ isoforms, Aβ38, Aβ40, and Aβ42. They found that in patients with brain amyloidosis, which is strongly linked to Alzheimer's disease, plasma Aβ42 showed faster turnover and lower concentrations than Aβ38 and Aβ40.

This matches the behavior of these three Aβ isoforms in patient cerebrospinal fluid, indicating that blood-based measurements could be effective for identifying patients with brain amyloidosis.

Looking at 41 patients, 23 without amyloidosis and 18 with, the researchers were able to distinguish between the two groups with an area under the receiver operating curve of .89. Bateman said that since then he and his colleagues have run the test in an additional 180 patients and achieved a similar level of performance.

He also noted that the test has yielded consistent results regardless of the severity of a patient's amyloidosis. "We have a range of people with different clinical stages from completely asymptomatic all the way through to mild and moderate dementia, and to date we haven't seen a pattern," he said, adding that he and his colleagues are currently looking at additional samples to further explore this question.

Bateman said that validation in additional, larger cohorts is needed to determine whether the test will be useful as a diagnostic for Alzheimer's disease. However, he said he thought its real near-term potential was as a tool for screening patients for Alzheimer's drug trials.

Brain amyloidosis is "necessary but not sufficient" for Alzheimer's disease, Bateman said. While amyloid plaques don't guarantee a person will develop the disease, "you can't have Alzheimer's unless you have amyloid plaques," he said. "And we know that people [with brain amyloidosis] are at much higher risk of developing Alzheimer's within the next five to seven years. It is a very significant risk factor."

That being the case, many drugs in development for Alzheimer's target these plaques. According to a recent analysis from ResearchersAgainstAlzheimer's, there are currently 23 Alzheimer's drugs in Phase II or Phase III clinical trials targeting brain amyloid plaques.

Alzheimer's drug development has a poor track record, however, with the last US Food and Drug Administration approval for an Alzheimer's therapy coming in 2003. With regard to amyloid-targeting drugs, one theory for the high failure rate is that researchers have traditionally tested these agents in patients whose disease is too far progressed for the drugs to make a difference.

This makes identification of patients with the early stages of amyloidosis a key challenge for putting together clinical trial cohorts. Imaging and CSF-based tests for screening asymptomatic patients exist, but they are expensive or invasive and difficult to do on the scale needed to recruit tens of thousands of patients for trials, Bateman said.

An assay like the one developed by the Wash U team "means that instead of having everyone have an MRI or PET scan or a spinal tap [to collect CSF], we can just do a simple blood test," he said. "We can screen people by the tens of thousands [using the blood test], and identify those people who are at risk of having amyloidosis and then confirm them with a PET scan or spinal tap."

Asymptomatic patients are often reluctant to undergo a brain scan or spinal tap in order to join a clinical trial, "but a blood test is simple enough that you can just do it at a regular doctor's office," Bateman said. "What that translates into is that we can accelerate trials by years, and that means that we can test many more drugs."

The Wash U assay uses the stable isotope labeling kinetics (SILK) platform developed by Bateman and his colleague David Holtzman, co-author on the paper. The SILK approach uses stable, non-radioactive isotope-labeled amino acids that the researchers introduce into human subjects and which allows them to track the synthesis and turnover of target proteins. In 2007, Bateman and Holtzman launched the company C2N Diagnostics to commercialize the technology, and C2N offers a number of SILK-based assays, including for measurement of Aβ isoforms in plasma.

Based on a high-resolution mass spec workflow using top-of-the line research instrumentation, the SILK assay is not as streamlined as most existing clinical mass spec workflows, and Bateman said that it remains "to be sorted out" whether the assay could be ported to, for instance, the sort of triple quadrupole instrument more commonly used for routine measurements in thousands of samples.

He said, though, that he believed the assay could be established in labs capable of running on the order of tens of thousands of samples. And, even using a high-res mass spec workflow, "the order of magnitude of complexity is quite different" compared to approaches that rely on imaging and CSF draws, he said. "Right now it takes weeks to months and tens of thousands of dollars to screen an individual, so this is a huge leap forward for us in terms of developing Alzheimer's treatment."

Bateman said he anticipated the test could be used for selecting patients for clinical trials as quickly as within a year.

"We're working right now on multiple efforts to see how quickly we can begin to screen people for clinical trials," he said. "We have high interest from groups that could benefit from this and know a lot about the disease."

Holtzman and C2N also published a recent study in Science Translational Medicine that found that plasma levels of the Alzheimer's biomarker tau reflect levels of the protein in the brain and could aid in diagnosis of the disease.

Bateman said this work was separate from the Aβ study but that combining the two measurements could lead to a blood-based test for Alzheimer's.

"You could identify amyloidosis without the tauopathy, with tauopathy, and that could help us say where people are and their relative risk of having clinical dementia in the next few years or five to ten years," he said. "You know amyloid plaques and tau tangles are intimately involved in [Alzheimer's], so it makes a lot of sense if you can to look for those things in an easily accessible compartment like blood."

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