Title: P4–433: The effect of acute administration of levetiracetam on cerebral perfusion in Alzheimer's disease as measured by arterial spin labeling MRI
Abstract: Both animal models of Alzheimer's disease (AD) and a study in mild cognitive impairment suggest that neuronal hyperexcitability, possibly epileptic in nature, occur in AD. We have previously shown that medial temporal lobe perfusion as measured by arterial spin labeling (ASL) MRI is increased in mild AD. To test whether this increase in perfusion might be due to neuronal hyperexcitability, we used the acute administration of levetiracetam (LEV), a medication that selectively blocks epileptic discharges, as a pharmacological probe. Patients with mild AD (n=10 enrolled, n=7 completed, 3 did not complete the protocol due to claustrophobia and excessive motion) underwent ASL MRI in three sessions held one week apart, performed in a double-blind manner and counterbalanced for order. At each session, a 32-lead EEG was recorded before, during, and after i.v. administration of placebo, levetiracetam 2.5mg/kg or levetiracetam 7.5mg/kg. Regional CBF was then measured with ASL MRI and cognitive performance on a battery of tests was performed. CBF was normalized to the whole brain mean and changes were expressed as percent change from placebo-baseline with analysis via paired t-tests. The acute administration of levetiracetam lead to significant decreases in perfusion bilaterally in the precuneus (mean +/- SEM: -5.3% +/- 1.5% in the left and -5.6% +/- 1.3% in the right, p < 0.05, uncorrected) and increases in perfusion in the amygdala/anterior temporal lobes (9.9% +/- 3.0% in the left and 10.3 +/- 3.4% in the right, p < 0.01, uncorrected). Cognitive testing showed little change at the low dose of LEV and a trend towards worse performance at the higher dose. The acute administration of i.v. levetiracetam lead to a pattern of relative decreased perfusion in posterior parietal regions and relative increased perfusion in anterior temporal lobe regions. The presence of significant changes in CBF after drug administration suggests that LEV is modifying neuronal activity. The relative CBF increase in anterior temporal lobe and decreases in posterior cingulate/precuneus regions could represent differential effects directly on hyperexcitability vs. indirect changes related to reduced inhibitory network activity.