A randomized controlled trial measuring changes in cerebral blood flow after levetiracetam in patients with Alzheimer’s disease

• Published in: Alzheimer's & dementia Vol. 16
• Main Authors: Musaeus, Christian Sandøe, Zhao, Li, Dai, Weiying, Breton, Jocelyn, Shafi, Mouhsin, Alsop, David C., Press, Daniel Z.
• Format: Journal Article
• Language: English
• Published: 01.12.2020
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.045476

Background Recent studies have shown that almost half of patients with Alzheimer’s disease demonstrate signs of epileptic activity as measured with EEG. Subclinical epileptic discharges can disrupt network activity, which is critical for long term memory. Therefore, suppressing epileptiform discharges may represent a novel therapeutic target for patients with Alzheimer’s disease. In the current randomized controlled trial, we recruited patients with mild Alzheimer’s disease and investigated the effect of a single administration of 2.5 mg/kg or 7.5 mg/kg of levetiracetam as compared with placebo on cerebral blood flow as measured with arterial spin‐labeling MRI (ASL‐MRI). Method We conducted a double‐blind, within‐subject crossover study in which nine participants with mild Alzheimer’s disease received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a randomized order across three sessions. Afterwards, participants underwent ASL‐MRI and performed a variety of neuropsychological cognitive tests. The regions with significant perfusion changes were analyzed with Statistical nonParametric Mapping (SnPM) toolbox. Result When comparing 2.5 mg/kg levetiracetam with placebo, we found significant (p<0.03 with family wise error corrected at a level of 0.05) increases in relative cerebral blood flow in a cluster involving both temporal lobes, including the hippocampus, with greater involvement on the left side. We found decreases in a cluster including the posterior cingulate cortex and precuneus. No clear changes were found following the higher dose. No significant differences in cognitive performance were found between the three groups, suggesting that the intervention neither worsened nor improved cognition. Conclusion In the current study, we found that in mild Alzheimer’s disease patients without any history of epilepsy a low dose of levetiracetam leads to changes in the cerebral blood flow in areas known to be affected early in the disease. One possible explanation could be that in mild AD, epileptic activity in the hippocampus leads to an excessive inhibition, and so relieving the inhibition with levetiracetam leads to an increased blood flow. These findings provide evidence of a potential beneficial effect of levetiracetam in patients with Alzheimer’s disease, but larger studies are needed, particularly with longer dosage schedules to determine whether there are any clinical improvements.