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

Both sleep alterations and epileptiform activity are associated with the accumulation of amyloid-ß and tau pathology and are currently investigated for potential therapeutic interventions in Alzheimer's disease (AD). However, a bidirectional intertwining relation between sleep and neuronal hyperexcitability might modulate the effects of AD pathology on the corresponding associations. To investigate this, we performed multiple day simultaneous foramen ovale (FO) plus scalp EEG and polysomnography (PSG) recordings and acquired 18F-MK6240 tau PET-MR in three patients in the prodromal stage of AD and in two patients with mild and moderate dementia due to AD, 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 (VOIs). Linear mixed effects models were used to study associations between interictal epileptiform discharges (IEDs), PSG 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 VOIs, 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 N2 (81/h), followed by 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), apnea-hypopnea 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 AD.

Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-Tpeak c. Levofloxacin had little effect on J-Tpeak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-Tpeak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-Tpeak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined IKs and IKr inhibitory properties of moxifloxacin versus IKr suppression only of levofloxacin. The equipotent inhibition of IKs and IKr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in IKr and IKs balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs.

The Cardiovascular Effects of a Meal: J-Tpeak and Tpeak -Tend Assessment and Further Insights Into the Physiological Effects.

Meal intake leads to a significant and prolonged increase in cardiac output to supply the splanchnic vasculature. A meal is associated with sympathetic activation of the cardiovascular system, and food ingestion is correlated with an increase in heart rate, an increase in cardiac stroke volume, and QTc interval shortening for up to 7 hours. Given the complexity of the system, one or several of many mechanisms could explain this observation. The shortening of the QTc interval was correlated with a rise of C-peptide following food ingestion, but the mechanisms by which C-peptide may be involved in the modulation of cardiac repolarization are still unknown. This shortening of the myocardial action potential caused by the ingestion of food was further investigated in the present study by measuring the QRS, J-Tpeak , and Tpeak -Tend intervals in search of further clues to better understand the underlying mechanisms. A retrospective analysis was conducted based on data collected in a formal thorough QT/QTc study in which 32 subjects received a carbohydrate-rich "continental" breakfast, moxifloxacin without food, and moxifloxacin with food. We assessed the effect of food on T-wave morphology using validated algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Our findings demonstrate that a standardized meal significantly shortened J-Tpeak for 4 hours after a meal and to a much lesser extent and shorter duration (up to 1 hour) prolonged the Tpeak -Tend and QRS intervals. This suggests that the QTc shortening occurs mainly during phase 2 of the cardiac action potential. As there was no corresponding effect on Tpeak -Tend beyond the first hour, we conclude that a meal does not interfere with the outward correcting potassium channels but possibly with Ca2+ currents. An effect on mainly Ca2+ aligns well with our understanding of physiology whereby an increase in stroke volume, as observed after a meal, is associated with changes in Ca2+ cycling in and out of the sarcoplasmic reticulum during cardiac myocyte contraction.