Abstract
Epileptic activity without visible convulsions is common in Alzheimer's disease (AD) and may contribute adversely to the disease progress and symptoms. Transgenic mice with amyloid plaque pathology also display epileptic seizures, but those are too infrequent to assess the effect of anti-epileptic treatments. Besides spontaneous seizures, these mice also display frequent epileptic spiking in epidural EEG recordings, and these have provided a means to test potential drug treatment to AD-related epilepsy. However, the origin of EEG spikes in transgenic AD model mice has remained elusive, which makes it difficult to relate electrophysiology with underlying pathology at the cellular and molecular level. Using multiple cortical and subcortical electrodes in freely moving APP/PS1 transgenic mice and their wild-type littermates, we identified several types of epileptic spikes among over 15 800 spikes visible with cortical screw electrodes based on their source localization. Cortical spikes associated with muscle twitches, cortico-hippocampal spikes, and spindle and fast-spindle associated spikes were present equally often in both APP/PS1 and wild-type mice, whereas pure cortical spikes were slightly more common in APP/PS1 mice. In contrast, spike-wave discharges, cortico-hippocampal spikes with after hyperpolarization and giant spikes were seen almost exclusively in APP/PS1 mice but only in a subset of them. Interestingly, different subtypes of spikes responded differently to anti-epileptic drugs ethosuximide and levetiracetam. From the translational point most relevant may be the giant spikes generated in the hippocampus that reached an amplitude up to ± 5 mV in the hippocampal channel. As in AD patients, they occurred exclusively during sleep. Further, we could demonstrate that a high number of giant spikes in APP/PS1 mice predicts seizures. These data show that by only adding a pair of hippocampal deep electrodes and EMG to routine cortical epidural screw electrodes and by taking into account underlying cortical oscillations, one can drastically refine the analysis of cortical spike data. This new approach provides a powerful tool to preclinical testing of potential new treatment options for AD related epilepsy.
Highlights
Accumulating evidence suggests that epilepsy is an integral part of the pathophysiology of Alzheimer’s disease (AD) [1]
We treated as separate category spikes associated with known spike-wave discharges [22], sleep spindles [21], or fast spindles, a novel type of spindle oscillation that we detected in this data set
(7) Cortico-hippocampal spikes with after hyperpolarization differed from type 2 spikes only in that the spike itself was followed by a slow baseline shift and suppression of fast activity, which in the hippocampal channels could last over 500 ms (Figure 7). [8] Giant spikes, as their name indicates, could have massive hippocampus spikes reaching an amplitude of ± 5 mV or 30 SD from the baseline
Summary
Accumulating evidence suggests that epilepsy is an integral part of the pathophysiology of Alzheimer’s disease (AD) [1]. A recent prospective EEG study found subclinical epileptiform activity in more than 40% of AD patients [3]. Their presence indicated significantly faster cognitive decline in 5-year follow-up. Subclinical epileptic discharges have been suggested to contribute to impaired memory and attention, and especially to cognitive fluctuation in AD patients [4]. There is an unmet need to find well-tolerated but effective treatment for these epileptic discharges. To this end, a fundamental question is whether AD-related epilepsy has a unique underlying mechanism requiring unconventional treatments
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