Epileptiform Activity During REM Sleep in Alzheimer's Disease (EREMAD)

Centre de Recherches sur la Cognition Animale (CRCA - UMR5169 CNRS/UPS), Centre de Recherche Cerveau & Cognition (CerCo - UMR5549 CNRS/UPS), Toulouse NeuroImaging Center (ToNIC - UMR 1214 Inserm/UPS), Fondation Plan Alzheimer, IHNPS/FHU HoPeS

Recent clinical data showed that patients with Alzheimer Disease (AD) might present epilepsy at early stages of the disease (Cretin et al., 2016, Vossel et al., 2016). In mice models of Alzheimer disease, preclinical researchers observed an increase of epileptic events during Rapid Eye Movement (REM) sleep, which is very unusual. This study aims at testing if patients with AD present an exacerbation of epileptic events during REM sleep, which could constitute an early biomarker of the disease. Investigators will evaluate the incidence of epilepsy during each sleep stage in 40 patients with early or moderate forms of AD and in 40 healthy subjects. Investigators will also look for a link between epilepsy during sleep in AD participants and memory performances, brain damage (by using MRI scans) and in the case of patients, the phenotype of the Apolipoprotein E(ApoE) gene.

Preclinical researchers discovered that the Tg2576 mouse model of Alzheimer Disease (AD) presents epileptiform activity specifically during sleep, with a prominent increase during REM-sleep. This phenotype is specific to AD mice since REM-sleep usually prevents seizures and epileptiform activity in animal models of epilepsy. Preclinical research also evidenced that this epileptic phenotype occurs at very early age in Tg2576 mice, far before the onset of cognitive impairments. Thus, it was hypothesized that patients with AD might present subclinical epileptiform events during sleep with a potential worsening during REM-sleep. If so, it could be used as a specific and early biomarker of AD. Since sleep is involved in memory consolidation processes, preclinical researchers also hypothesized that epileptiform events during sleep might participate to cognitive dysfunction in AD patients. In order to test this hypothesis, a monocentric clinical study with a protocol consisting of three visits was designed aiming at evaluating seizures and subclinical epileptiform activity - and their consequences on memory - during sleep in 31 patients at early to moderate stages of AD and 31 matched healthy participants. During the first visit, a blood sample is collected of each patient for genetic testing of the ApoE gene before they undergo a high-resolution MRI scan. During the second visit (in the 60 days following the first one) participants first undergo a neuropsychological evaluation including visual, verbal and episodic memory tests before an overnight polysomnography. Following the overnight polysomnography, all subjects (patients and healthy participants) will be tested for the memories acquired the day before in order to evaluate sleep related memory consolidation. During the last visit, participants will fill out questionnaires aiming at evaluating pre-diagnostic lifestyle and they (and one family member if possible) will be interviewed about the presence of symptoms that might indicate an underlying epileptic syndrome for the participant. Healthy subjects will undergo the same procedures except for the blood test from which they will be exempted. This should allow to evidence sleep related epileptic events, to precise their incidence in AD patients as well as in healthy participants, and to correlate these events to anomalies in brain structure and functional resting state connectivity (MRI) and/or sleep disturbances and/or cognitive decline.

Overnight polysomnography with evaluation of each form of epileptiform activity during each vigilance state and memory scores at the overnight retention test

the proportion of participants from each group exhibiting a significant epileptiform activity (seizures and/or interictal spikes) during REM sleep. . Epileptiform activity will be defined as either at least one spike, or at least 4 paroxysmal activities.

Comparison of sleep characterization between the two groups: distribution of different sleep stages in time

Comparison of sleep characterization between the two groups: distribution of different sleep stages in percentage

The score on the questionnaire aiming at discovering potential symptoms of an underlying epileptic syndrome

Correlation between the frequency of epileptiform activity, the score on the epilepsy questionnaire and the index of micro-awakenings in the different sleep stages and: the results of the cognitive reserve inventory (CRIq)

Correlation between the frequency of epileptiform activity, the score on the epilepsy questionnaire and the index of micro-awakenings in the different sleep stages and: the speed of cognitive decline.

Correlation between the frequency of epileptiform activity, the score on the epilepsy questionnaire and the index of micro-awakenings in the different sleep stages and: the density of sleep spindles in the different sleep stages

Inclusion Criteria: For all participants: age from 50 to 90 years old affiliated to the French health care system For AD patients: meeting International Working Group (IWG)-2 criteria for diagnosis Mini-Mental State Examination (MMSE) ≥18 (Greco version) For healthy volunteers: MMSE>25 Dubois 5 words test ≥ 9 Exclusion Criteria: For all participants: Pregnancy people not able to give consent contraindication for MRI (metallic body parts, claustrophobia), aphasia, apraxia or agnosia neurological (other than AD) or any other serious disease (cancer, addiction, systemic disease) non treated sleep apnea major depression or anxiety for more than 3 months (Beck>10) or psychiatric disease documented epilepsy use of neuroleptics (more than one dose per day) use of antiepileptics use of benzodiazepines at a dose superior or equal to two intakes per day use of antidepressants restless leg syndrome treated by dopaminergic agonists. For AD patients: other causes of dementia non-degenerative neurological lesions white matter hypersignals acute cognitive deficits