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

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.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease, Early Onset
• Intervention / Treatment: Diagnostic test: Overnight polysomnography; Diagnostic test: blood sample; Diagnostic test: high-resolution MRI scan; Behavioral: neuropsychological evaluation

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 62
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Luc Valton, MD; Phone Number: 33 05-61-77-94-88; Email: valton.l@chu-toulouse.fr
• Study Contact Backup: Name: Lionel Dahan, PHD; Phone Number: 33 06.43.18.23.16; Email: lionel.dahan@univ-tlse3.fr

Study Locations

• France
  • Occitanie
    • Toulouse, Occitanie, France, 31059
      • Recruiting
      • Toulouse University Hospital
      • Sub-Investigator: Claire Thalamas, MD
      • Sub-Investigator: Fabienne Calvas, MD
      • Contact: Brigitte POUZET; Phone Number: 33 5 61 77 91 25; Email: brigitte.pouzet@inserm.fr
      • Sub-Investigator: Jérémie PARIENTE, MD, PHD
      • Sub-Investigator: Rachel DEBS, MD
      • Sub-Investigator: Marie DENUELLE, MD
      • Sub-Investigator: Monique GALITZKY, MD
      • Principal Investigator: Luc VALTON, MD
      • Sub-Investigator: Florence RULQUIN, MD
      • Sub-Investigator: Helène CATALA, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Alzheimer's Disease patients group; This group contains the 31 (anticipated) participants with a diagnosis of Alzheimer's disease	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; Diagnostic test: blood sample; blood sample for genetic testing of the Apolipoprotein E; Diagnostic test: 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
Other: Healthy control group; This group contains the 31 (anticipated) age and sex -matched healthy controls	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; Diagnostic test: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of epileptiform activity according to sleep-wake cycle	Number of epileptiform activity according to sleep-wake cycle in each group	Day 2
Frequency of epileptiform activity according to sleep-wake cycle	Frequency of epileptiform activity according to sleep-wake cycle in each group	Day 2
lateralization of epileptiform activity according to sleep-wake cycle	lateralization of epileptiform activity according to sleep-wake cycle in each group	Day 2
localization of epileptiform activity according to sleep-wake cycle	localization of epileptiform activity according to sleep-wake cycle in each group	Day 2
Comparison of sleep characterization between the two groups: total sleep time	total sleep time in hours and minutes	Day 2
Comparison of sleep characterization between the two groups: number of sleep cycles	number of sleep cycles	Day 2
Comparison of sleep characterization between the two groups: time spent awake during the night	time spent awake during the night	Day 2
Comparison of sleep characterization between the two groups: index of micro-awakenings	index of micro-awakenings	Day 2
Comparison of sleep characterization between the two groups: distribution of different sleep stages in time	distribution of different sleep stages in time	Day 2
Comparison of sleep characterization between the two groups: distribution of different sleep stages in percentage	distribution of different sleep stages in percentage	Day 2
Comparison of sleep characterization between the two groups: index of periodic movements	the index of periodic movements	Day 2
Comparison of sleep characterization between the two groups: index of hypopnea	index of hypopnea (central and obstructive components)	Day 2
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
symptoms of an underlying epileptic syndrome	The score on the questionnaire aiming at discovering potential symptoms of an underlying epileptic syndrome	Month 5
sleep spindles in different sleep stages	The number and the density of sleep spindles in different sleep stages	day 2
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
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
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

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Collaborators: Fondation Plan Alzheimer; 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); IHNPS/FHU HoPeS
• Investigators: Study Director: Lionel Dahan, PHD, Centre de Recherches sur la Cognition Animale (CRCA), UMR CNRS 5169

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2019
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: March 29, 2019
• First Submitted That Met QC Criteria: April 19, 2019
• First Posted (Actual): April 22, 2019

Study Record Updates

• Last Update Posted (Actual): July 28, 2021
• Last Update Submitted That Met QC Criteria: July 20, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: MRI; Epilepsy; Alzheimer's disease; Memory consolidation; Rapid eye movement (REM) sleep
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: RC31/18/0265; 2018-A02229-46 (Other Identifier: ID RCB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No