Epileptic activity on foramen ovale electrodes is associated with sleep and tau pathology in Alzheimer's disease

Abstract

Both sleep alterations and epileptiform activity are associated with the accumulation of amyloid-β and tau pathology and are currently investigated for potential therapeutic interventions in Alzheimer's disease. However, a bidirectional intertwining relationship between sleep and neuronal hyperexcitability might modulate the effects of Alzheimer's disease pathology on the corresponding associations. To investigate this, we performed multiple day simultaneous foramen ovale (FO) plus scalp EEG and polysomnography recordings and acquired 18F-MK6240 tau PET-MR in three patients in the prodromal stage of Alzheimer's disease and in two patients with mild and moderate dementia due to Alzheimer's disease, respectively. As an eligibility criterion for the present study, subjects either had a history of a recent seizure (n = 2) or subclinical epileptiform activity (SEA) on a previous scalp EEG taken in a research context (n = 3). The 18F-MK6240 standard uptake value ratio (SUVR) and asymmetry index (AI) were calculated in a priori-defined volumes of interest. Linear mixed-effects models were used to study associations between interictal epileptiform discharges (IEDs), polysomnography parameters and 18F-MK6240 SUVR. Epileptiform activity was bilateral but asymmetrically present on FO electrodes in all patients and ≥95% of IEDs were not visible on scalp EEG. In one patient, two focal seizures were detected on FO electrodes, both without visual scalp EEG correlate. We observed lateralized periodic discharges, brief potentially ictal rhythmic discharges and lateralized rhythmic delta activity on FO electrodes in four patients. Unlike scalp EEG, intracranial electrodes showed a lateralization of epileptiform activity. Although the amount of IEDs on intracranial electrodes was not associated to the 18F-MK6240 SUVR binding in different volumes of interest, there was a congruent asymmetry of the 18F-MK6240 binding towards the most epileptic hemisphere for the mesial (P = 0.007) and lateral temporal cortex (P = 0.006). IEDs on intracranial electrodes were most abundant during slow wave sleep (SWS) (92/h) and non-REM sleep 2 (N2, 81/h), followed by non-REM sleep 1 (N1, 33/h) and least frequent during wakefulness (17/h) and REM sleep (9/h). The extent of IEDs during sleep was not reflected in the relative time in each sleep stage spent [REM% (P = 0.415), N1% (P = 0.668), N2% (P = 0.442), SWS% (P = 0.988)], and not associated with the arousal index (P = 0.317), apnoea-hypopnoea index (P = 0.846) or oxygen desaturation index (P = 0.746). Together, our observations suggest a multi-directional interaction between sleep, epileptiform activity and tau pathology in Alzheimer's disease.

Keywords: 18F-MK6240 tau-PET; epileptiform activity; mesial temporal lobe; neuronal hyperexcitability in Alzheimer’s disease; polysomnography; scalp-intracranial EEG.

Figure 1

Mesial temporal lobe seizures. Two unilateral nocturnal seizures were visible on the right foramen ovale electrode (FO R) in Patient 1. (A) The first seizure started during non-REM sleep 1 (N1) with paroxysmal fast activity on FO R (black star). Clinical arousal (dark shaded area) with transition to wakefulness (lighter shaded area). Ictal bradycardia (red arrow) was present. (B and C) Continuous ictal activity on FO R, evolving to more rhythmic spike-wave activity with bradycardia progressing to a cardiac pause of 5 s (pink arrow) with an abrupt end after 79 s (two black stars). The second seizure started during wakefulness, 8 s after the first seizure ended (blue star), with paroxysmal fast activity evolving to a rhythmic spike-wave pattern and ending after 58 s (two blue stars). The second seizure had no clinical correlate. Scalp EEG did not reveal epileptic activity. Each panel represents continuous EEG epochs of 60 s. Bipolar montage. Filters at 0.53–30.0 Hz. Sensitivity 30 µV for FO electrodes, 70 µV for scalp EEG.

Figure 2

Lateralized periodic discharges (LPDs) on foramen ovale electrodes. (A) In Patient 1, LPDs on the right foramen ovale electrode (FO R) consisted of spikes, which occurred at ±1 Hz. (B) In Patient 2, LPDs on FO R consisted of spikes and polyspikes, which occurred at a fluctuating frequency of 1–2 Hz, with no evidence of evolution. Each panel represents a 10-s epoch. Filters at 0.53–30.0 Hz. In Patient 1, a bipolar montage with a sensitivity of 30 µV is shown; in Patient 2, a reference montage with a sensitivity of 100 µV is shown.

Figure 3

Brief potentially ictal rhythmic discharges (BIRDs) and lateralized rhythmic delta activity (LRDA) on foramen ovale electrodes. (A) BIRDs on right foramen ovale electrode (FO R) in Patient 5: two episodes of ±11 Hz, sharply contoured, high amplitude waves, lasting 2.5 and 1 s, respectively. (B) LRDA on FO R in Patient 5. Each panel represents a 10-s epoch. Bipolar montage in A, reference montage in B. Sensitivity at 150 µV, filters at 0.53–30.0 Hz.

Figure 4

Interictal epileptiform discharges (IEDs) on scalp EEG and foramen ovale electrodes. (A) In Patient 2, IEDs can be seen on the right foramen ovale electrode (FO R) without scalp EEG correlate. One IED on scalp left (L, arrow) without corresponding IED on FO electrodes. (B) In Patient 3, IEDs are abundant on the left FO electrode (FO L) with only one visible correlate on scalp EEG (arrow). Each panel represents a 15-s epoch. Reference montage. Sensitivity at 100 µV for FO electrodes, 70 µV for scalp EEG. Filters at 0.53–30.0 Hz.

Figure 5

¹⁸F-MK6240 orthogonal PET images through the mesial temporal cortex, overlaid on MR. All patterns are consistent with Alzheimer’s disease. The ¹⁸F-MK6240 binding in the mesial and lateral temporal lobe shows a lateralization to the epileptogenic hemisphere: right-sided for Patients 1, 2, 4 and 5; left-sided for Patient 3. SUVR = standardized uptake value ratio.