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Wash U Study Shows VILIP-1 a Potential Biomarker for Predicting Alzheimer's Progression

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By Adam Bonislawski

Researchers from Washington University in St. Louis have demonstrated the potential utility of visinin-like protein-1 as a biomarker for predicting rates of cognitive decline in early-stage Alzheimer's patients.

Detailed in a study published this month in the journal Neurology, the group's findings suggest that VILIP-1 could prove a more effective prognostic marker for Alzheimer's disease than established protein markers Aβ42 and tau, Rawan Tarawneh, first author on the paper and currently an assistant professor of neurology at the University of Jordan, told ProteoMonitor.

The Wash U researchers are currently working with biotech firm Singulex on a commercial version of the VILIP-1 immunoassay used in the studies.

The researchers took baseline cerebrospinal fluid measurements of VILIP-1, tau, p-tau181, and Aβ42 in 60 patients with very mild or mild Alzheimer's and followed their progression for an average of 2.6 years, finding that individuals with high CSF levels of VILIP-1 declined much more rapidly than those with low levels.

High tau and p-tau levels also predicted more rapid cognitive decline in this cohort, but, the authors noted, their "results suggest trends for a potentially superior predictive performance for VILIP-1 to tau or Aβ42 over a two- to three-year follow-up period."

VILIP-1 "performed significantly better than Aβ42" as a prognostic marker, Tarawneh said. "When we compared it to tau, the difference was less, but still in favor of VILIP-1."

"These are only preliminary findings, though," she cautioned. "We'd still like to validate them in larger groups that we follow for longer periods of time and in patients from other centers. The main message is that this new marker can provide predictive value. How well it's going to compare to the other markers I think we can't say for sure at this point."

Like tau, VILIP-1 is a marker of neuronal damage – identified as such by Wash U researcher Jack Ladenson – also an author on the Neurology paper – in 2006. In a paper published last year in The Annals of Neurology, a team of Wash U researchers including Ladenson and Tarawneh demonstrated VILIP-1's utility as a marker for early detection of Alzheimer's as well as predicting future impairment in cognitively normal individuals.

As in the Neurology study, the authors found that VILIP-1 was comparable to tau as a diagnostic and prognostic marker for Alzheimer's. Their results also indicated that VILIP-1 plus the traditional Alzheimer's panel of Aβ42, tau, and p-tau was a stronger predictor of conversion to Alzheimer's from being cognitively normal than Aβ42, tau, and p-tau alone.

The assay that Ladenson's lab is developing with Singulex uses the company's Erenna single-molecule counting technology, which is designed for detection of low-abundance biomarkers. To date, Singulex has focused the majority of its commercial efforts on markers for cardiovascular disease, but it also offers commercial tests on the Erenna platform for Aβ40 and Aβ42.

Biotech firm Quanterix, whose Single Molecule Array, or SiMoA platform, competes with Singulex in the high-sensitivity detection space, is also working on assays for Alzheimer's biomarkers – Aβ42, tau, and p-tau, in particular (PM 4/15/2011).

In general, Alzheimer's biomarkers are a major area of protein biomarker research and are expected to represent a cumulative $9 billion market over the next ten years, according to a report commissioned last year by proteomics firm Proteome Sciences (PM 6/13/2011). In addition to their promise for diagnosis and predicting progression of the disease, early detection and progression biomarkers are seen as key to pharmaceutical research into drugs for the disease.

Hugo Vanderstichele, founder of Alzheimer's biomarker firm ADx Neurosciences, which launched in October 2011, told ProteoMonitor that the Wash U group's study was "nicely done," but said more validation work was needed to see where VILIP-1 might fit into Alzheimer's diagnosis and prognosis.

He suggested that addition of VILIP-1 to the traditional markers tau, p-tau, and Aβ42 could provide additional information useful for predicting disease progression and differential diagnoses. He noted, though, that more evidence would be needed to make the case for replacing tau with VILIP-1.

Prior to founding ADx, Vanderstichele worked as a principal developer at Innogenetics – now part of Fujirebio – where he helped develop commercial assays for CSF tau, p-tau, and Aβ42. The growing acceptance of these markers by the regulatory and pharmaceutical communities, he said, is one significant reason VILIP-1 is unlikely to replace tau as an Alzheimer's marker.

In particular, Vanderstichele noted, the European Medicines Agency last summer approved the use of tau and Aβ42 as CSF markers in Alzheimer's drug trials.

Given this, he said, "for pharma companies, switching from tau to VILIP-1 could have a major impact, because then they no longer have acceptance from the regulatory agencies. Right now there is almost a consensus in the [Alzheimer's research] world to use tau and Aβ42 to detect [Alzheimer's]. It has already been approved for pharma trials in Europe by the EMEA. So now if there is a switch from tau to VILIP, it is like starting all over again."

Before researchers would likely consider making such a switch, additional validation data conclusively demonstrating the added value of VILIP-1 compared to tau would be needed, Vanderstichele said.

Moving forward, Tarawneh said, the Wash U team plans to repeat the Neurology study over a longer follow-up period in a larger cohort that includes more patients with advanced Alzheimer's and patients from different centers. They also hope to investigate how VILIP-1 compares to tau, p-tau, and Aβ42 in predicting rates of brain atrophy as measured by MRI.

Additionally, the researchers would like to standardize the VILIP-1 assay "so that we could use it more in research and compare our results to results from other studies that might come out in the future," she said.

Cross-lab reproducibility has proven a challenge in Alzheimer's biomarker research, particularly with regard to Aβ42. Thus far, Tarawneh said, VILIP-1 appears to be comparatively easy to measure reproducibly. In particular, she said, it has proven relatively resistant to freeze-thaw cycles – which have been shown to alter Aβ42 levels in samples – and, unlike both Aβ42 and tau, VILIP-1 does not appear to adhere to polystyrene collection tubes.

In addition to their CSF work, the Wash U researchers are also investigating plasma VILIP-1 as an Alzheimer's biomarker. Plasma Alzheimer's markers are desirable because they could be assayed without having to perform a lumbar puncture – making them more useful for purposes like regular monitoring.

The researchers have found that Alzheimer's patients have higher plasma levels of VILIP-1 than controls, Tarawneh said, but, she added, "the difference wasn't as big as what we saw with CSF."

"It was statistically significant, but it wasn't impressive. We're not sure that it's a clinically meaningful difference." she said. "So it's something we would like to investigate further not only in terms of diagnosis, but prognostic ability as well."


Have topics you'd like to see covered in ProteoMonitor? Contact the editor at abonislawski [at] genomeweb [.] com.

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