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

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ClinicalTrials.gov Identifier: NCT03923569
Recruitment Status : Not yet recruiting
First Posted : April 22, 2019
Last Update Posted : April 22, 2019
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
University Hospital, Toulouse

Brief 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.

Condition or disease Intervention/treatment Phase
Alzheimer Disease, Early Onset Diagnostic Test: Overnight polysomnography Diagnostic Test: blood sample Diagnostic Test: high-resolution MRI scan Behavioral: neuropsychological evaluation Not Applicable

Detailed Description:

Preclinical researchers discovered that Tg2576 mouse model of Alzheimer Disease (AD) present 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 researchers also evidenced that this epileptic phenotype occurs at very early age in Tg2576 mice, far before the onset of cognitive impairments. Thus, preclinical researchers hypothesized that patients with AD might present subclinical epileptiform events during sleep which might worsen during REM-sleep. If so, it could be used as a specific and early biomarker of AD. Since sleep is involved in the consolidation of memory, preclinical researchers also hypothesized that epileptiform events during sleep might participate to cognitive dysfunction in AD patients.

In order to test this hypothesis, preclinical researchers designed a monocentric clinical study aiming at evaluating seizures and subclinical epileptiform activity during sleep in 40 patients at early to moderate stages of AD and 40 matched healthy participants. A blood sample will be collected of each patient for genetic testing of the Apolipoprotein E before they undergo a high-resolution MRI scan and a neuropsychological evaluation including episodic memory tests before an overnight polysomnography. Healthy subjects will undergo the same procedures except for the blood test from which they will be exempted. Then, all subjects (patients and healthy participants) will be tested for the memories acquired before the polysomnography in order to evaluate sleep related memory consolidation.

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 2 compared groups (Alzheimer's Disease patients vs controls)
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Epileptiform Activity During REM Sleep in Alzheimer's Disease
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Alzheimer's Disease patients group
This group contains the 40 (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

Healthy control group
This group contains the 40 (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




Primary Outcome Measures :
  1. Epileptiform activity during REM sleep [ Time Frame: Day 2 ]

    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.



Secondary Outcome Measures :
  1. Number of epileptiform activity according to sleep-wake cycle [ Time Frame: Day 2 ]
    Number of epileptiform activity according to sleep-wake cycle in each group

  2. Frequency of epileptiform activity according to sleep-wake cycle [ Time Frame: Day 2 ]
    Frequency of epileptiform activity according to sleep-wake cycle in each group

  3. lateralization of epileptiform activity according to sleep-wake cycle [ Time Frame: Day 2 ]
    lateralization of epileptiform activity according to sleep-wake cycle in each group

  4. localization of epileptiform activity according to sleep-wake cycle [ Time Frame: Day 2 ]
    localization of epileptiform activity according to sleep-wake cycle in each group

  5. Comparison of sleep characterization between the two groups: total sleep time [ Time Frame: Day 2 ]
    total sleep time in hours and minutes

  6. Comparison of sleep characterization between the two groups: number of sleep cycles [ Time Frame: Day 2 ]
    number of sleep cycles

  7. Comparison of sleep characterization between the two groups: time spent awake during the night [ Time Frame: Day 2 ]
    time spent awake during the night

  8. Comparison of sleep characterization between the two groups: index of micro-awakenings [ Time Frame: Day 2 ]
    index of micro-awakenings

  9. Comparison of sleep characterization between the two groups: distribution of different sleep stages in time [ Time Frame: Day 2 ]
    distribution of different sleep stages in time

  10. Comparison of sleep characterization between the two groups: distribution of different sleep stages in percentage [ Time Frame: Day 2 ]
    distribution of different sleep stages in percentage

  11. Comparison of sleep characterization between the two groups: index of periodic movements [ Time Frame: Day 2 ]
    the index of periodic movements

  12. Comparison of sleep characterization between the two groups: index of hypopnea [ Time Frame: Day 2 ]
    index of hypopnea (central and obstructive components)

  13. Comparison of memory scores at the overnight retention test between the two groups [ Time Frame: Day 2 ]
    The memory scores are combined to compute a total score



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

For all participants:

  • age from 50 to 75 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) ≥20 (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)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03923569


Contacts
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Contact: Luc Valton, MD 05-61-77-94-88 ext 33 valton.l@chu-toulouse.fr
Contact: Lionel Dahan, PHD 06.43.18.23.16 ext 33 lionel.dahan@univ-tlse3.fr

Locations
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France
Toulouse University Hospital Not yet recruiting
Toulouse, Occitanie, France, 31059
Contact: Brigitte POUZET    33 5 61 77 91 25    brigitte.pouzet@inserm.fr   
Sub-Investigator: Jérémie PARIENTE, MD, PHD         
Sub-Investigator: Claire THALAMAS, MD         
Sub-Investigator: Fabienne CALVAS, MD         
Sub-Investigator: Rachel DEBS, MD         
Sub-Investigator: Marie DENUELLE, MD         
Sub-Investigator: Monique GALITZKY, MD         
Principal Investigator: Luc VALTON, MD         
Sponsors and Collaborators
University Hospital, Toulouse
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
Investigators
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Study Director: Lionel Dahan, PHD Centre de Recherches sur la Cognition Animale (CRCA), UMR CNRS 5169

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Responsible Party: University Hospital, Toulouse
ClinicalTrials.gov Identifier: NCT03923569     History of Changes
Other Study ID Numbers: RC31/18/0265
2018-A02229-46 ( Other Identifier: ID RCB )
First Posted: April 22, 2019    Key Record Dates
Last Update Posted: April 22, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Toulouse:
Alzheimer's disease
Rapid eye movement (REM) sleep
Memory consolidation
Epilepsy
MRI

Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders