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Quanterix, Gothenberg Researchers Show Potential Link Between Heart Attacks and Alzheimer's Marker


By Adam Bonislawski

Scientists from Quanterix and the University of Gothenberg have discovered evidence of a relationship between hypoxia and increased expression of the amyloid-beta1-42 peptide.

The work, which was presented this week at the American Academy of Neurology annual meeting, reinforces a hypothesis held by Alzheimer's researchers that the disease could be linked to cardiovascular conditions like atherosclerosis or cardiac arrest that cause a reduction in the supply of oxygen to the brain.

Abeta1-42 is a component of the amyloid plaques that are a hallmark of Alzheimer's. As such, it's considered one of the most promising biomarkers for the disease.

According to David Wilson, senior director of product development at Quanterix and lead author of the study, the relationship between hypoxia and increased expression of Abeta1-42 has been elucidated in animal models but hasn't been investigated in humans due to the difficulty of measuring the peptide in blood.

"Essentially what happens is there's a transcription factor called hypoxia-inducible factor 1, and what that does is stimulate production of the enzyme beta-secretase that acts upon an amyloid precursor protein known as APP," which then generates Abeta1-42, Wilson told ProteoMonitor. Under hypoxic stress, beta secretase is upregulated, resulting in an increase in the production of Abeta1-42.

Using Quanterix's Single Molecule Array protein-detection platform, the researchers were able to measure Abeta1-42 levels in the blood of 26 cardiac arrest patients, finding that levels of the peptide increased at levels ranging from 50 percent to 30-fold in the 72 hours following their heart attacks.

The SiMoA system, which uses arrays of femtoliter-sized reaction chambers to enable researchers to conduct immunoassays on a single-molecule level, has in past studies measured proteins like prostate specific antigen at sub-femtomolar levels. This sensitivity was key to the Abeta1-42 work, Wilson said, because the peptide typically exists in blood at levels too low to pick up with techniques like standard ELISAs or selected-reaction monitoring mass spec.

While Abeta1-42 is present in higher levels in cerebrospinal fluid, obtaining it requires a lumbar puncture, which, noted University of Gothenberg professor Kaj Blennow, is a much more involved procedure than taking blood.

"It's much more complicated to do a study like this in CSF," said Blennow, who co-authored the study. "It's difficult to take [serial] CSF samples they way you can with blood samples. And also from an ethical point of view, it's difficult to take a CSF sample one hour after you have a cardiac arrest and then to repeat that [every hour]."

In addition to observing increased Abeta1-42 levels in the cardiac arrest patients, the researchers were also able to show that the increase in the peptide was proportional to the amount of brain damage experienced by the subjects, indicating that the rise in Abeta1-42 was proportional to the amount of hypoxia each patient endured, Wilson said.

The study, he added, fit with previous research by other groups that demonstrated via imaging that atherosclerosis patients had elevated levels of the amyloid plaques characteristic of Alzheimer's.

"The suggestion was that atherosclerosis contributed to hypoxic conditions in the brain, which caused the accumulation of these amyloid plaques in the brain," he said. "So there was some evidence to suggest that this could be occurring in human brains, but nobody has ever done anything like this to show that you can measure that in blood."

Quanterix plans to continue Alzheimer's work in collaboration with Blennow's team, Wilson said. Next the researchers will use the SiMoA platform to measure the levels of protein biomarkers like Abeta1-42, tau and phosphorylated tau in blood samples from 100 Alzheimer's cases and controls. They also plan to test samples from patients who have suffered brain ischemia due to strokes and subarachnoid hemorrhages.

In February, Quanterix CEO David Okrongly told ProteoMonitor that the company was shifting its emphasis away from diagnostics development and toward building and selling the SiMoA platform itself with a goal of launching a research-use instrument in 2013 and a US Food and Drug Administration-approved version sometime after that (PM 02/25/2011).

According to Wilson, though, the company is still "aggressively pursuing" development of a neurology protein biomarker panel that "will include tau, phosphorylated tau, and Abeta1-42. The product will be "one of the key panels that we'll be offering with our life science research instrument," he said. "And then our strategy after that is to pursue the [in vitro diagnostic] market."

The company currently has completed versions of the tau and Abeta1-42 assays and is close to completing the phosphorylated tau assay, Wilson said, adding that it hopes to bring the panel to market sometime in 2012.

Neurology indications are particularly suited to the SiMoA platform, he suggested, because of the typical low abundance of brain proteins in blood.

"Right now there's very little in the way of blood tests to correlate what is going on in the central nervous system and the brain mainly because the biochemistry that's occurring in blood is at a very low level because the biochemistry that's occurring in the brain has to diffuse through the blood-brain barrier," he said. "So most of [the research] you see in the literature is the result of spinal taps and measurements of cerebrospinal fluid, and everybody hates doing that."

In February, the company announced it had entered into an agreement with Novartis to evaluate the SiMoA platform for diagnostic work related to a neuron-specific protein (GWDN 02/22/2011).

Alzheimer's is the obvious area of focus for the panel, with drug companies especially needing early detection and progression biomarkers to facilitate research into therapies for the disease.

The panel also has other potential uses, though, Blennow told ProteoMonitor. In particular, an assay measuring levels of tau in blood could be very useful for acute brain damage research and clinical work, he said.

"Tau is a neural-specific protein, so all tau in blood will come from the brain, and many CSF studies have shown that tau is a marker for the intensity or extent of neuronal damage due to both chronic diseases like Alzheimer's and also acute conditions like brain trauma," Blennow said.

"What is really needed in the clinic is a good and quick marker for brain damage," he said. "For instance, if a patient comes to the emergency ward with head trauma, if it were possible to take a blood sample and say either that there is evidence of brain damage and they have to stay for observation or that they are completely normal and can return home, that would be very valuable."

Such a test could also be useful for more basic research purposes, he added.

"There's a debate going on about what is happening in sports trauma – like with ice hockey players and American football players and boxers," he said. "If it would be possible to take a blood sample after a match, for example, and examine it, from a scientific standpoint that would be very interesting."

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

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