Beyond Amyloid Beta: A New Alzheimer Disease Biomarker?

An AAN Poster Brief

Bret Stetka, MD; Jacques Hugon, MD, PhD


March 25, 2013

Editor's Note:
This year's American Academy of Neurology Annual Meeting featured an Integrative Neuroscience Session looking at advances in, and the potential role of, biomarkers in Alzheimer disease (AD). Following the session, Medscape spoke with Jacques Hugon, MD, PhD, Professor of Neurology at Saint-Louis Lariboisière Fernand-Widal Hospital in Paris, France, about a biomarker with the potential to aid in AD diagnosis. It's not amyloid beta or tau.

Medscape: Dr. Hugon, what can you tell us about PKR?

Dr. Hugon: PKR is a kinase that has been shown to play a role in recognizing and signaling viral infection, but its activity has also been shown to be altered in several neurologic disorders in which it negatively modulates memory.[1] Once overactivated, PKR becomes a toxic kinase. As we have shown in our study,[2] PKR accumulates in the brain of patients with AD and can induce the death of neurons. We have seen that the PKR level in the cerebrospinal fluid (CSF) and the activity of PKR in the brain are highly elevated in patients with AD compared with non-AD patients. Our study showed that the mean level of PKR and phosphorylated PKR in the CSF was 300% higher in patients with AD. Sensitivity was 91.1% and the specificity was 94.3%.

In addition, patients with mild cognitive impairment already have high levels of total CSF PKR and phosphorylated PKR. So, the final story is that the level of PKR in those with high levels of the kinase can predict the degree of cognitive decline. Patients with high levels of PKR in the CSF have been followed for more than 2 years in our department, and we found a clear correlation between the levels of phosphorylated PKR and cognitive decline based on repeated mini-mental state exams. The patients with high CSF levels of PKR have had a more rapid cognitive decline.

Medscape: From your data it looks like PKR levels correlate with tau levels, What are the implications of this finding?

Dr. Hugon: Yes, they do correlate with tau levels. PKR can indirectly induce the phosphorylation of tau, so the two may be linked. PKR can also control the production of amyloid beta.

Medscape: Amyloid beta, tau, and phosphorylated tau increasingly are being tested as biomarkers of AD, particularly in research and academic settings. Could PKR ultimately be added to the list?

Dr. Hugon: Yes. This could definitely end up being a new biomarker. We performed CSF evaluations in my department rather frequently and now we have collected several hundreds of biomarker samples -- including PKR -- in patients with mild cognitive impairment and AD.

This procedure is a major part of our practice, especially in young patients. In addition, we are testing potential PKR antagonists in preclinical settings. We have shown earlier that blocking PKR can attenuate amyloid-beta-induced neuronal death in cell cultures. PKR is a possible new target to alter the course of the disease and to possibly restore memory deficits in affected patients.