Opposing interictal dynamics in Alzheimer's disease and epilepsy

Area of Science:

• Neuroscience
• Neurology
• Biomarkers

Background:

• Advanced electroencephalography (EEG) indicates frequent epileptiform activity in Alzheimer's disease (AD), yet its diagnostic utility is debated due to inconsistent observations.
• Previous explanations for absent epileptiform activity in AD focused on technical limitations like recording depth or duration.
• An alternative hypothesis suggests high-frequency oscillations (HFOs) might inhibit interictal spikes (IIS), the current clinical measure of hyperexcitability.

Purpose of the Study:

• To investigate the hypothesis that HFOs inhibit IIS in Alzheimer's disease (AD).
• To compare the relationship between HFOs and IIS in AD mouse models versus epilepsy mouse models.
• To explore the implications of these interactions for AD diagnostics and anti-seizure therapy stratification.

Main Methods:

• Recorded wideband (0.1-500 Hz) hippocampal local field potentials in AD (Tg2576, PS2-/-, Ts65Dn) and epilepsy (kainic acid, pilocarpine) mouse models.
• Analyzed HFOs (250-500 Hz fast ripples) and IIS rates across different behavioral states (wakefulness, sleep) and ages.
• Examined correlations and temporal relationships between HFOs and IIS rates in both AD and epilepsy models.

Main Results:

• HFOs occurred more frequently than IIS in both AD and epilepsy models across all conditions.
• A negative correlation between HFO and IIS rates was observed exclusively in AD models, contrasting with a positive correlation in epilepsy models.
• HFOs preceded IIS at significantly shorter intervals in epilepsy compared to AD.

Conclusions:

• A novel dissociation exists between EEG biomarkers in AD and epilepsy, with HFOs potentially inhibiting IIS in AD.
• This HFO-mediated inhibition could lead to underestimation of hyperexcitability in AD, complicating patient stratification for anti-seizure treatments.
• Wideband EEG/MEG recordings are crucial for AD research to capture undetected hyperexcitability and biomarker interactions.