Epileptiform Activity During REM Sleep in Alzheimer's Disease

Alzheimer Disease, Early Onset Clinical Trial

— EREMAD  

Official title:

Epileptiform Activity During REM Sleep in Alzheimer's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03923569
• Other study ID #: RC31/18/0265
• Secondary ID: 2018-A02229-46
• Status: Recruiting
• Phase: N/A
• Start date: April 29, 2019
• Est. completion date: June 2023

Study information

• Verified date: July 2021
• Source: University Hospital, Toulouse
• Contact: Luc Valton, MD
• Phone: 05-61-77-94-88
• Email: valton.l[@]chu-toulouse.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 62
• Est. completion date: June 2023
• Est. primary completion date: June 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 50 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer Disease, Early Onset

Intervention

Diagnostic Test:
• Overnight polysomnography
Overnight polysomnography with evaluation of each form of epileptiform activity during each vigilance state and memory scores at the overnight retention test
• blood sample
blood sample for genetic testing of the Apolipoprotein E
• high-resolution MRI scan
Evaluation of anomalies in brain structure and functional resting state connectivity

Behavioral:
• neuropsychological evaluation
neuropsychological evaluation including episodic memory tests before an overnight polysomnography

Locations

Country	Name	City	State
France	Toulouse University Hospital	Toulouse	Occitanie

Sponsors (6)

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

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Epileptiform activity during REM sleep	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.	Day 2
Secondary	Number of epileptiform activity according to sleep-wake cycle	Number of epileptiform activity according to sleep-wake cycle in each group	Day 2
Secondary	Frequency of epileptiform activity according to sleep-wake cycle	Frequency of epileptiform activity according to sleep-wake cycle in each group	Day 2
Secondary	lateralization of epileptiform activity according to sleep-wake cycle	lateralization of epileptiform activity according to sleep-wake cycle in each group	Day 2
Secondary	localization of epileptiform activity according to sleep-wake cycle	localization of epileptiform activity according to sleep-wake cycle in each group	Day 2
Secondary	Comparison of sleep characterization between the two groups: total sleep time	total sleep time in hours and minutes	Day 2
Secondary	Comparison of sleep characterization between the two groups: number of sleep cycles	number of sleep cycles	Day 2
Secondary	Comparison of sleep characterization between the two groups: time spent awake during the night	time spent awake during the night	Day 2
Secondary	Comparison of sleep characterization between the two groups: index of micro-awakenings	index of micro-awakenings	Day 2
Secondary	Comparison of sleep characterization between the two groups: distribution of different sleep stages in time	distribution of different sleep stages in time	Day 2
Secondary	Comparison of sleep characterization between the two groups: distribution of different sleep stages in percentage	distribution of different sleep stages in percentage	Day 2
Secondary	Comparison of sleep characterization between the two groups: index of periodic movements	the index of periodic movements	Day 2
Secondary	Comparison of sleep characterization between the two groups: index of hypopnea	index of hypopnea (central and obstructive components)	Day 2
Secondary	Comparison of memory scores at the overnight retention test between the two groups	The memory scores are combined to compute a total score	Day 2
Secondary	symptoms of an underlying epileptic syndrome	The score on the questionnaire aiming at discovering potential symptoms of an underlying epileptic syndrome	Month 5
Secondary	sleep spindles in different sleep stages	The number and the density of sleep spindles in different sleep stages	day 2
Secondary	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 results of the cognitive reserve inventory (CRIq)	month 5
Secondary	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 speed of cognitive decline.	month 5
Secondary	density of sleep spindles in the different sleep stages	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	month 5