Prevalence of epilepsy and sleep-wake disturbances in Alzheimer's disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease causing dementia and one of the leading causes of death. Currently, there is no curative therapy for AD. Epilepsy and sleep-wake disturbances are common co-morbid conditions in AD which are often present in an early stage of the disease. They not only cause more rapid deterioration of the disease by impairing memory and behaviour, but are also an increasing burden on the caregiver and often the reason to institutionalize the elderly. The prevalence and influence of these epilepsy and sleep-wake disorders in Alzheimer's disease is underestimated and is therefore an area where we can very much help patients and care providers. The most common seizure type in patients with AD are focal temporal lobe seizures and not generalized tonic-clonic seizures. The latter are non-convulsive seizures, characterized by autonomic disturbances (e.g. tachycardia, hyperventilation, sweating), psychic phenomena (e.g. anxiety, déjà vu, rising epigastric sensation), confusion and arousals during sleep. These seizures are easily overlooked by medical personnel or caregivers and often considered as episodes of confusion due to dementia. Those ictal and interictal epileptic discharges in AD are often not picked up by routine EEG studies. Long-term EEG monitoring is the best technique to diagnose interictal and (sub)clinical epileptic activity in elderly affected by AD. Sleep EEG recordings are more sensitive to detect epileptic spikes than awake recordings. Sleep-wake disturbances (e.g. reduced slow wave sleep, reduced REM sleep, prolonged REM latency, OSAS, …) are one of the most disruptive symptoms for patients and caretakers and may be one of the earliest symptoms in preclinical AD and Mild Cognitive Impairment. There is a bidirectional effect between AD pathology on sleep and vice-versa. In addition, there is a complex interaction between epilepsy and sleep-wake disorders whereby the sole manifestation of a focal temporal lobe seizure can be an arousal during sleep. The main seizure types in AD are probably aware and impaired awareness focal seizures of temporal lobe origin, occurring during sleep. The only manifestation of a focal temporal lobe attack could be an arousal from sleep. It is probable that a majority of these seizures goes unnoticed, and is not visible on scalp EEG, but can be captured with intracranial foramen ovale electrodes. The interictal spikes are most frequent during sleep. Co-morbidity of epilepsy and sleep-wake disturbances in AD have not been studied, so far, and will be the focus of our project. Based on this information, our hypotheses are as follows: - Epilepsy and sleep-wake disturbances are common and underestimated co-morbidities in AD, that these are present in an early stage of the disease, and that they can worsen AD; - Patients with increased severe sleep-wake disturbances will be more likely to have epileptic spikes and seizures, more specifically, we postulate that frequent nocturnal cortical arousals with autonomic features may be a manifestation of hippocampal/temporal lobe seizures, and that epilepsy will be more frequent in AD patients with sleep apnea with an apnea-hypopnea index ≥ 15; - Treatment of epilepsy and sleep-wake disturbances in AD may slow progression of AD; - Epilepsy is more common in patients with damage to the hippocampus, as evidenced with tau-PET; - A majority of patients with AD have silent hippocampal seizures and spikes which can be identified using foramen oval electrodes Our primary goal is to map the prevalence of epilepsy and sleep-wake disorders in patients with Alzheimer's disease by means of a case-control study using the most advanced technology. We will do a case-control study with 100 cases and 30 controls, where the project is systematically divided in ten different ‘work packages’ (WP). Firstly we will select and obtain our study population (WP1), who will receive an ambulant 24-hour EEG monitoring and polysomnography in combination with Sensor Dot (WP2). We will register the prevalence of interictal epileptic discharges and epileptic discharges (WP3) and sleep-wake disturbances (WP4) and register a possible interaction of those (WP5). Secondly we will look for features and patterns in the physiological data during the night that have a distinguishing character for AD population, in search for potential sleep biomarkers (WP6). In the next phase, fifteen selected patients with interictal epileptic activity on scalp EEG (see WP3) and/or frequent cortical arousals (see WP4), will receive long-term EEG monitoring with scalp and foramen oval electrodes/polysomnography to detect silent hippocampal seizures (see hypotheses). Those fifteen patients and ten control subjects will receive MR-tau-PET scanning to look for tau load and anatomic substrates of sleep-wake disturbances. In WP9, we will develop algorithms to quantify brain connectivity and apply these to model the dynamically interacting brain regions in different circumstances, discovering changes in network dynamics under different circumstances, such as sleep-wake disturbances, epileptic activity and different AD stages, or even in combinations of those. A usual relationship between sleep and epilepsy in the AD population will be explored. We expect to find an EEG biomarker for certain sleep-wake problem and/or epilepsy in AD. Finally, we are currently participating in an EIT-Health funded project “A multi-center study to examine clinical scenarios for long-term monitoring of epileptic seizures with a wearable biopotential technology (S63631)” and we aim to use this wearable biopotential technology in our current study. We will compare Sensor Dot data with the gold standard polysomnography EEG and study the feasibility of studying sleep-wake disturbances and epilepsy in patients with AD in the home setting using this multimodal wearable device.