Research Brief: Bead-Based Biomarkers Neatly Divide AD, FTLD

The total tau to amyloid-β42 ratio from cerebrospinal fluid reliably distinguishes Alzheimer’s disease from frontotemporal degeneration, according to a paper in the April 9 Archives of Neurology online. First author David Irwin and colleagues at the University of Pennsylvania in Philadelphia also showed they could translate results from the older enzyme-linked immunosorbent assays (ELISAs) to match data from their new method, Luminex xMAP technology.

“Can you differentiate AD from FTLD [frontotemporal lobar degeneration] in the memory clinic? This study profoundly suggests, yes, you can,” said author Les Shaw, citing “very compelling” differences between tau:Aβ ratios in the two conditions. The ratio tends to be lower in FTLD cerebrospinal fluid (CSF) than AD samples, the team reported previously (Grossman et al., 2005; Bian et al., 2008). In this study, using a cutoff ratio of 0.34, the researchers obtained a sensitivity of at least 90 percent and specificity of at least 91 percent, depending on the samples used. Doctors at the university are already applying the biomarker test, Shaw told ARF. While not diagnostic on its own, it could help distinguish ambiguous cases, said senior author Murray Grossman.

In addition to comparing AD with FTLD, the team compared ELISA versus xMAP immunoassays. While ELISAs remain the standard in many labs, the newer platform is catching on, Shaw said. “In our experience, it offers the possibility of improved precision and reproducibility,” he added. Like an ELISA, the xMAP assay, using reagents developed by Fujirebio/Innogenetics, relies on antibodies to capture antigens from biofluid samples. But whereas in an ELISA the antibodies line a plastic well, in xMAP studies, the antibodies are conjugated to microbeads. The beads are fluorescently color coded depending on the attached antibody. This allows researchers to mix up to a dozen different sets of beads in the same sample, Shaw estimated, then distinguish them by flow cytometry. The Luminex-based method is "a much better way to ascertain tau and amyloid levels," Grossman said.

In adopting the Luminex system, the researchers did not want to simply discard old ELISA data. Instead, they sought a way to reconcile the two. They compared 75 samples in both assays and worked out an equation to convert ELISA results to Luminex-like numbers. Crucially, Shaw noted, this conversion applies only to the study population analyzed by these UPenn labs in this set of experiments. If scientists wished to translate ELISA results from another group, they would have to perform a similar analysis and come up with their own equation. Thus, the research described here does not solve the ongoing challenge of standardizing biomarker results across many labs, Shaw said (see ARF related news story).

Irwin DJ, McMillan CT, Toledo JB, Arnold SE, Shaw LM, Wang LS, Van Deerlin V, Lee VM, Trojanowski JQ, Grossman M. Comparison of cerebrospinal fluid levels of tau and Aβ 1-42 in Alzheimer disease and frontotemporal degeneration using 2 analytical platforms. Arch Neurol. 2012 Apr 9. Abstract

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