High Frequency Oscillations (>250Hz) Outnumber Interictal Spikes in Preclinical Studies of Alzheimer’s Disease

Abstract

Interictal spikes (IIS) and seizures are well-documented in Alzheimer’s disease (AD). IIS typically outnumber seizures, supporting their role as a prominent EEG biomarker in AD. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) also occur, but it is currently unknown how HFOs compare to IIS. Therefore, we asked whether the incidence of HFOs and IIS differed and if they are differentially affected by behavioral state.We used three mouse lines that simulate aspects of AD: Tg2576, presenilin 2 knockout, and Ts65Dn mice. We recorded and quantified HFOs and IIS in the hippocampus during wakefulness, slow-wave sleep, and rapid eye movement sleep.In all three mouse lines, HFOs were more frequent than IIS. High numbers of HFOs correlated with fewer IIS, suggesting for the first time possible competing dynamics among them in AD. Notably, HFOs occurred in more behavioral states than IIS.In summary, HFOs were the most abundant EEG abnormality when compared to IIS, and occurred in all behavioral states, suggesting they are a better biomarker than IIS. These findings pertained to three mouse lines, which is important because they simulate different aspects of AD. We also show that HFOs may inhibit IIS.SHORT SUMMARYInterictal spikes (IIS) and seizures are common in Alzheimer’s disease (AD). IIS are more frequent than seizures and occur during earlier disease stages. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) occur, but a comparison between IIS and HFOs is lacking. Here we used 3 mouse lines with AD features and local field potential recordings to quantify IIS and HFOs. We found that HFOs outnumbered IIS and that their total numbers were inversely correlated with IIS. HFOs occurred during more behavioral states than IIS. Therefore, HFOs were the most abundant EEG abnormality, and this was generalizable across 3 types of preclinical AD.