Abstracts

Rationale: Abnormal electrical activity in Alzheimer’s disease (AD) is well documented and it’s known to include seizures and interictal spikes (IIS). Abnormal electrical activity in AD is also known to negatively affect cognition as well as disease progression. Motivated by epilepsy studies, we expanded the recording bandwidth and sampling rate of conventional EEG and asked if high frequency oscillations (HFOs) in the 250-500Hz frequency range could also be detected in AD as they are in epilepsy.

Methods: Three mouse models of AD neuropathology were used. Tg2576 mice that overexpress a mutant form of the amyloid precursor protein (APP) with the Swedish mutation (n=6 mutant; n=4 controls). Presenilin 2 knock-out (PS2KO) mice that lack the catalytic subunit of an APP cleaving enzyme (n=4 mutant; n=4 controls), and Ts65Dn trisomic mice where the APP gene is triplicated (n=2 mutant; n=2 controls). Wideband (0.1-500 Hz) intra-hippocampal EEG was recorded at 2 kHz and hippocampal HFOs were detected using an automated approach previously validated in clinical research. We analyzed the number of HFOs during awake, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Spectral frequency and duration of AD HFOs were next compared with HFOs in the intra-hippocampal kainic acid (IHKA; n=6) and pilocarpine (PILO; n=4) model of temporal lobe epilepsy. In mouse models of AD, we also analyzed HFOs associated with IIS and seizures.      

Results: We report for the first time HFOs in the 250-500 Hz frequency range as a new EEG abnormality in AD. Hippocampal HFOs were recorded in all transgenic mice and were absent in controls (Tg2576, PS2KO; p< 0.001). In all AD models, HFOs were more frequent during SWS vs REM sleep (Tg2576, p< 0.01; PS2KO, p< 0.05) or awake state (Tg2576, p< 0.05; PS2KO, p< 0.01). Spectral frequency and duration of AD HFOs were indistinguishable from HFOs recorded in chronic epileptic mice (IHKA; p >0.05, PILO; p >0.05). When AD HFOs were associated with IIS they showed faster frequency (353±21 Hz vs. 325±1.8 Hz; p< 0.05) and shorter duration (9.0±1 ms vs. 14.7±1 ms; p< 0.01) compared to HFOs occurring independent of IIS.