Amyloid Beta 1-42 Linked to Outcome After Cardiac Arrest

Susan Jeffrey

April 26, 2011

April 26, 2011 (Honolulu, Hawaii) — A new study using a sensitive assay technology shows a time-dependent rise in amyloid beta 1-42 (Aβ-42) in the blood of patients resuscitated after cardiac arrest.

A strong correlation was seen between the rise and fall of Aβ-42 in the hours after arrest and clinical outcomes, suggesting the elevated Aβ-42 level is derived from the brain of these patients. It also suggests this might be used as a marker of damage in the same way that troponins reflect cardiac damage after myocardial infarction.

"It can be a prognostic indicator of outcome over 6 months, but from a more basic research standpoint, it does provide evidence that hypoxic stress in the human brain triggers the amyloid cascade, and this could be important for Alzheimer's disease pathogenesis," said lead study author David H. Wilson, MD, from Quanterix Corporation, the company developing the assay.

Their findings were presented during the American Academy of Neurology 63rd Annual Meeting.

Hallmark of Alzheimer's

Aβ peptides are the proteolytic products from amyloid precursor protein (APP), and accumulation of these peptides in extracellular plaques are a hallmark of Alzheimer's disease, the study authors write.

Dr. David Wilson

Oxidative stress can increase the production of Aβ, potentially causing onset of vascular disease or Alzheimer's disease, they note. The theory is that hypoxic insult may trigger Aβ production by activating APP proteolysis, but Dr. Wilson said, "it's mostly a theory at this point."

Animal models have suggested that this is a mechanism that could be playing a role, but a direct link between hypoxic insult in the human brain and Aβ production has not been previously shown.

In this study, Dr. Wilson and colleagues used a new sensitive assay technology, Single Molecule Arrays (SiMoA, Quanterix Corp), to measure changes in serum Aβ-42 in 26 unconscious patients who had been resuscitated after a cardiac arrest.

All were 18 years or older, had a systolic blood pressure of 80 mm Hg or higher after return of spontaneous circulation, and a Glasgow Coma Scale score of 7 or higher at study entry.

Assessment of outcome was made at discharge from the intensive care unit and at 6 months using the Glasgow-Pittsburgh cerebral performance category (CPC) scale. A CPC score of 1 or 2 is considered a good outcome, with minimal to moderate cerebral disability, and 3 to 5 is a poor outcome, including severe disability, vegetative state, or death.

Time-Dependent Elevations

"We were surprised to see that the level of Aβ-42 definitely increased in these patients," Dr. Wilson said. "This is the first time that we've seen anything like that because other assay technologies are unable to measure Aβ at these low concentrations."

All patients showed significant time-dependent elevations in Aβ-42 after a lag of 10 or more hours from baseline, ranging from approximately 50% to more than 30-fold, with an average elevation of about 7-fold.

Aβ-42 profiles were highly predictive of overall cerebral impairment, the researchers found, suggesting the levels were related to the extent of brain hypoxia.

"There are only 26 patients that we looked at, so it's a little early right now to say that if we measure Aβ we're going to see a prognostic indication for every patient," Dr. Wilson concluded. "But it definitely shows you that we do have a correlation here, and it does provide strong evidence that hypoxic conditions in the brain contribute to the amyloid cascade for Alzheimer's disease."

It would also be of interest to examine the effect of mild chronic ischemia on Aβ-42 levels, they note. Dr. Wilson said they are now in the process of using this technology to measure tau, another protein thought to be important in the Alzheimer's disease process.

"We're actually testing samples right now for tau protein and we see similar types of things," he said.

The study was supported by Quanterix Corporation, Cambridge, Massachusetts. Dr. Wilson is an employee of the company. Disclosures for coauthors appear in the abstract.

American Academy of Neurology (AAN) 63rd Annual Meeting: Abstract P02.287. Presented April 12, 2011.


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