Epileptiform Activity During REM Sleep in Alzheimer's Disease

Epileptiform Activity During REM Sleep in Alzheimer's Disease

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.

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