Biomarkers of Sleep-wake Cycle in Prodromal Alzheimer's Disease: Role in Cognitive Decline?

Study Overview
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Brief Summary
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Alzheimer's disease (AD) is characterised by a progressive loss of memory and cognitive function. In the early stages of AD, there is a progressive accumulation of molecules: β-amyloid peptides (Aβ) in the brain. There is a link between the accumulation of Aβ peptides and the deterioration of sleep, but current knowledge does not confirmed this link. The objective of this study is to define whether there is a link between cognitive decline and sleep disorders. If a correlation is found, this could allow earlier treatment of sleep disorders in the longer term in order to slow the development of AD.

Official Title
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Biomarkers of Sleep-wake Cycle in Prodromal Alzheimer's Disease: Role in Cognitive Decline?

Conditions
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Neuropathology

Intervention / Treatment
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* Procedure: Polysomnography
* Behavioral: Neuropsychological assessment
* Behavioral: Questionnaires on sleep and behavioural problems
* Procedure: Actimetry
* Diagnostic Test: Fractional diuresis
* Procedure: Internal temperature measurement
* Other: Biomarker assay


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of mild Alzheimer's disease with a Mini Mental State (MMS) between 21-30 The presence of a family carer to complete neuropsychological scales, questionnaires and sleep diaries Having a neurological assessment and/or follow-up requiring blood and cerebrospinal fluid (CSF) sampling with biomarkers for diagnostic purposes Patient who had a lumbar puncture less than one year ago or patient with a scheduled lumbar puncture as part of care Signed informed consent Able to carry out all visits and follow study procedures Affiliation to the French social security system Exclusion Criteria: Genetic form of alzheimer's disease Insufficient clinical and paraclinical information for the diagnosis of AD Anticholinesterase and/or memantine treatment or on stable doses for at least 3 months Use of antidepressants, anxiolytics, hypnotics, neuroleptics, 15 days before inclusion Patient living in a nursing home Illiteracy or inability to perform psycho-behavioural tests Major physical or neurosensory problems that may interfere with the tests Initial contraindication to diagnostic lumbar puncture (LP) (spinal surgery, skin infection, haemostasis abnormality, intracranial hypertension, severe coagulation disorders, curative anticoagulant therapy, severe liver failure) Refusal to perform a diagnostic lumbar puncture Contraindication to the use of E-Celsius: people weighing less than 40 kg, with intestinal disorders, with known swallowing disorders Patient deprived of liberty, by judicial or administrative decision; Major protected by law; Patient in a period of relative exclusion from another protocol or for whom the maximum annual compensation of €4500 has been reached; Refusal to participate in the protocol.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>Alzheimer | Procedure: Polysomnography<br>* Polysomnography will be performed for 24 hours at inclusion and 24 months<br>Behavioral: Neuropsychological assessment<br>* A full neuropsychological assessment will be performed at inclusion, 12 and 24 months<br>Behavioral: Questionnaires on sleep and behavioural problems<br>* Questionnaires on sleep and behavioural problems<br>Procedure: Actimetry<br>* Measurement of actimetrics for 14 days at inclusion and at 24 months<br>Diagnostic Test: Fractional diuresis<br>* Split diuresis from 7pm-7am, 7am-12am and 12pm-19pm during polysomnography at inclusion inclusion and 24 months to measure melatonin concentration<br>Procedure: Internal temperature measurement<br>* eCelsius capsule to measure internal temperature at inclusion and 24 months<br>Other: Biomarker assay<br>* Determination of the biomarkers Aβ42, Aβ40, Tau and P-Tau in blood and in the cerebrospinal fluid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Free and Cued Selective Reminding Test (FCSRT) scale score | The FCSRT test evaluates memory, the score obtained is between 0 and 48, higher score mean a better outcome | From inclusion to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Free and Cued Selective Reminding Test (FCSRT) scale score | The FCSRT test evaluates memory, the score obtained is between 0 and 48, higher score mean a better outcome | From inclusion to 12 months | 
| Cognitive decline in ADCS-PACC composite score | The ADCS-PACC composite score is used to assess cognitive decline | At inclusion and at 24 months | 
| Cognitive decline in the Alzheimer's Disease Cooperative Study- Preclinical Alzheimer Cognitive Composite (ADCS-PACC) composite score | The ADCS-PACC composite score is used to assess cognitive decline | At inclusion and at 12 months | 
| Concentration of proteins involved in Alzheimer disease | Determination of Aβ42, Aβ40, Tau and P-Tau proteins in serum and cerebrospinal fluid | At inclusion and at 24 months | 
| Concentration of orexinA/hypocretin | Determination in serum and cerebrospinal fluid | At inclusion and at 24 months | 
| Changes in sleep duration | Average sleep duration (in hours and minutes) over a 14-day period from inclusion to M24 measured by actimetry | At inclusion and at 24 months | 
| Sleep time at stage 1-2 during polysomnography | Time spent in stage 1-2 sleep measured in hours and minutes during polysomnography | At inclusion and at 24 months | 
| Sleep time at stage 3 during polysomnography | Time spent in stage 3 sleep measured in hours and minutes during polysomnography | At inclusion and at 24 months | 
| Time spent in Rapid eye movement (REM) sleep during polysomnography | Time spent in stage 3 sleep measured in hours and minutes during polysomnography | At inclusion and at 24 months | 
| Apnea Hypopnea Index | The Apnea-Hypopnea Index is calculated from the number of apneas and hypopneas per hour of sleep (AHI = number of apneas + number of hypopneas / number of hours of sleep) during polysomnography | At inclusion and at 24 months | 
| Nocturnal oxygen saturation (SaO2) | The nocturnal SaO2 is an average of SaO2 values taken during the night. The value is expressed as a percentage and is measured during polysomnography | At inclusion and at 24 months | 
| Urinary melatonin concentration | Fractional diuresis | At inclusion and at 24 months | 
| Internal temperature | The internal temperature will be measured with an e-Celsius capsule during polysomnography | At inclusion and at 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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biomarkers, cognitive composite score, sleep, cognitive decline