2011 AMERICAN ACADEMY OF NEUROLOGY ANNUAL MEETING, HONOLULU, HAWAII

D. Wilson1, E. Mortberg2, S. Rubertsson2, H. Zetterberg3, K. Blennow3, L. Song1, L. Chang1, G. Provuncher1, P. Patel1, E. Ferrell1, D. Fournier1, C. Kan1, T. Campbell1, A. Rivnak1, B. Pink1, K. Minnehan1, T. Piech1, D. Rissin1, D. Duffy1.1Quanterix Corporation, Cambridge, MA; 2Department of Surgical Sciences, Anaesthesia and Intensive Care, Uppsala University, Uppsala, Sweden; 3Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden.

Background: 

Amyloid beta (Aβ) peptides are proteolytic products from amyloid precursor protein (APP). Accumulation of Aβ in the form of extracellular plaques is a hallmark of Alzheimer’s disease (AD). Oxidative stress can increase the production of Aβ, which may potentiate AD onset and vascular dementia. It is believed hypoxic insults trigger Aβ production by activating APP proteolysis via a pathway involving β-secretase (BACE1) in which BACE1 is upregulated by the transcription factor hypoxia–inducible factor–1 (HIF–1). Animal models have helped elucidate this pathway, but a direct link between hypoxia and Aβ42 production in the human brain has not been established. We employed a new technology (Single Molecule Array, SiMoA) capable of ultrasensitive protein measurements to look for changes in serum Aβ42 in patients following cardiac arrest and resuscitation.

Methods: 

26 unconscious patients with cardiac arrest were resuscitated with restoration of spontaneous circulation (ROSC). Serial blood samples were collected within 6h after cardiac arrest, and continued at intervals from 1–108h. Inclusion criteria included age, systolic BP >80mmHg after ROSC, and a Glasgow Coma Scale ≤7. Serum aliquots were frozen until assay. Samples were measured in triplicate by SiMoA Aβ42 assay, which has a limit of detection of less than 0.04 pg/mL.

Results: 

Nearly all patients exhibited a significant time–dependent elevation of Aβ42. After a lag period of 10 or more hours, very clear Aβ42 elevations were observed in most cases. Elevations ranged from approximately 50% to over 30–fold, with most elevations in the range of 3–10–fold (average approximately 7–fold).

Conclusion: 

These data are the first to directly link hypoxic stress to Aβ elevation in humans. The kinetic profiles may be related to time–dependence of the HIF–1/BACE1 upregulation pathway leading to a hypoxia–induced amyloid cascade. The relevance of mild chronic ischemia with upregulation of the amyloid cascade in AD pathogenesis remains to be examined.