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PRECLINICAL ASSESSMENT OF DRUG TREATMENT OPTIONS FOR SLEEP-RELATED EPILEPTIC SPIKING IN ALZHEIMER'S DISEASE
Abstract
Aims
Epileptic spiking without motor manifestations can be found in 30-40% patients with early AD. This number may still be an underestimate as this spiking occurs almost exclusively during sleep and may limit to the deep temporal lobe. Further, AD patients with subclinical epileptiform
activity have about twice faster cognitive decline during a follow-up of 3-5 years (Vossel K Ann. Neurol. 2016; Horvath A EEG Clin Neurophys. 2021). Treating epileptic spiking during sleep may thus offer a way to slow down AD progression, but so far there is no published clinical study on the topic, calling for preclinical testing to guide the choice of optimal drug treatments.
Methods
Ten male APP/PS1 mice (3-5 months) were implanted with EEG screw electrodes and hippocampal triple wire electrodes to record local field potentials. Sleep was monitored by video-recording and neck EMG. We tested the standard AD-drugs donepezil and memantine as well as anti-epileptic drugs levetiracetam and lamotrigine recommended for AD patients with epilepsy. In addition, we administered the gamma-secretase inhibitor semagacestat to acutely reduce amyloid-beta levels and the anti-inflammatory tetracycline derivative minocycline to suppress neuroinflammation. The analysis focused on hippocampally generated giant spikes and cortical spike-wave dischanges and was done within-subject in reference to a repeated vehicle injection.
Results
Levetiracetam decreased while lamotrigine unexpectedly increased sleep-related giant spikes in APP/PS1 mice. Both reduced cortical spike-wave discharges, whereas memantine increased their prevalence. Other drugs had no significant effects.
Conclusions
Levetiracetam proved to be an effective treatment for sleep-related epileptic spiking while lamotrigine should be used with caution.