Melatonin in Alzheimer's Disease: Effect on Disease Progression and Epileptiform Activity. (MADE)

This is a long-term, prospective, observational study to investigate and compare the levels and rhythm of melatonin in patients with AD dementia, mild cognitive impairment due to AD and healthy volunteers. The investigators would like to validate the use of salivary and urine melatonin measurements as an alternative for blood/CSF melatonin. Furthermore, the investigators would like to assess the effects of melatonin levels on cognition by correlating the levels and changes on cognitive tasks over a two year time frame. The investigators will also investigate whether these effects could be due to its anticonvulsive properties.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Diagnostic test: MEG+hdEEG+MRI

Detailed Description

Melatonin production gets disrupted in AD, as shown in post-mortem pineal glands and CSF of AD patients. CSF melatonin levels are known to significantly drop in patients with Alzheimer's dementia. It is known that CSF melatonin levels are much higher than blood melatonin levels, due to melatonin secretion from the pineal recess directly into the third ventricle. It has never been investigated whether blood melatonin accurately correlates with CSF melatonin in AD, nor whether saliva or urine melatonin levels accurately reflect blood/CSF melatonin in the AD continuum. The investigators want to validate the use of blood, saliva and urine melatonin levels as alternative for CSF melatonin in the AD continuum to pave the way for further use of less invasive collection techniques (blood, saliva, urine instead of CSF) and to possibly study circadian rhythm in a less disrupting, in home environment (saliva, urine).

Furhtermore, melatonin exerts several potential anti-AD properties, including anti-inflammatory, anti-oxidant, tilting APP processing towards the non-amyloidogenic pathway, exerting positive effects on sleep and so on. In vivo studies furthermore point to anticonvulsive and antiepileptic effects of melatonin in a whole range of rodent models. Some evidence exists for a role of melatonin in prevention of epileptic seizures in humans.

The investigators want to investigate influence of melatonin on changes in cognition in a longitudinal way, and investigate influence on (sub)clinical epileptiform activity.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sebastiaan Engelborghs, MD, PHD; Phone Number: 02 477 64 10; Email: sebastiaan.engelborghs@uzbrussel.be
• Study Contact Backup: Name: Amber Nous, MD; Phone Number: 0479477937; Email: amber.nous@uzbrussel.be

Study Locations

• Belgium
  • Jette
    • Brussels, Jette, Belgium, 1090
      • Recruiting
      • Universitair Ziekenhuis Brussel
      • Contact: Amber Nous, MD; Phone Number: +322 474 94 38; Email: amber.nous@uzbrussel.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Dementia due to AD, according to National Institute on Aging-Alzheimer's Association (NIA-AA) criteria
2. MCI due to AD, according to NIA-AA criteria
3. Healthy controls: Age- and gender matched healthy controls

Exclusion Criteria:

Patients (AD dementia, MCI)

• Age < 18 years old
• Pregnancy
• Expected death due to illness within 2 years
• Pacemaker or other ferrromagnetic material that is not MRI compatible
• Other neurodegenerative or cerebrovascular disease
• Pattern compatible with NPH (clinically, imaging)
• Epilepsy
• Multiple sclerosis or other demyelinating disease
• Depression, psychosis or other mental disease
• Use of anti-epileptic drugs
• Alcohol or substance abuse
• Korsakoff syndrome
• Symptomatic liver disease
• Uncontrolled thyroid disorders
• Untreated HIV or syphilis
• Clinically significant vitamin B12 deficiency
• Severe systemic medical illness (eg end-stage cardiac disease, …)
• Use of melatonin, agomelatine, or other sleep medications
• Night worker
• REM sleep behavior disorder, OSAS

Healthy controls

• Age < 18 years old
• Pregnancy
• Pacemaker or other ferromagnetic material that is not MRI compatible
• Mild cognitive impairment or dementia of any cause
• Epilepsy
• Multiple sclerosis or other demyelinating disease
• Depression, psychosis or other mental disease
• Use of anti-epileptic drugs
• Alcohol or substance abuse
• Symptomatic liver disease
• Uncontrolled thyroid disorders
• Untreated HIV or syphilis
• Clinically significant vitamin B12 deficiency
• Severe systemic medical illness (eg end-stage cardiac disease, …)
• Use of melatonin, agomelatine, or other sleep medications
• Night worker
• REM sleep behavior disorder, OSAS

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
Experimental: Patients with dementia or mild cognitive impairment due to AD; Dementia or MCI due to AD according to NIA-AA research criteria.	Diagnostic test: MEG+hdEEG+MRI; We will perform several tests: Neuropsychological testing to evaluate evolution of cognition during our study.; Lumbar puncture, blood sampling, saliva and urine collection to assess melatonin levels at several timepoints within these biological fluids.; MEG+hdEEG and MRI (to project MEG information) ; LTM-EEG to detect epileptiform activity in patients and healthy controls; Other Names: Blood sampling; Lumbar puncture; Long-term EEG monitoring; Saliva collection; Urine collection; Neuropsychological examination
Active Comparator: Healthy volunteers; Age-and-gender matched healthy controls.	Diagnostic test: MEG+hdEEG+MRI; We will perform several tests: Neuropsychological testing to evaluate evolution of cognition during our study.; Lumbar puncture, blood sampling, saliva and urine collection to assess melatonin levels at several timepoints within these biological fluids.; MEG+hdEEG and MRI (to project MEG information) ; LTM-EEG to detect epileptiform activity in patients and healthy controls; Other Names: Blood sampling; Lumbar puncture; Long-term EEG monitoring; Saliva collection; Urine collection; Neuropsychological examination

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CSF and blood melatonin levels in patients with AD dementia, MCI due to AD and healthy volunteers	Comparison of CSF and blood melatonin levels between patients with MCI and dementia due to AD and healthy volunteers.	24 hours
Blood, saliva and urine melatonin correlations	Correlation between blood melatonin and urinary and salivary melatonin in the AD continuum	24 hours
Melatonin influence on cognition	Correlations between melatonin levels and cognitive performance over a 2 year time frame. This will be assessed by use of neuropsychological testing including MMSE, MoCA, RBANS, VAT, ...	2 years
Melatonin influence on epileptiform activity	Correlations between melatonin levels and (subclinical) epileptiform activity. Over a time frame of 8 weeks patients will undergo neuropsychological testing (with MMSE, MoCA, RBANS, VAT...), LTM-EEG monitoring (during 24 hours), MEG + hdEEG.	8 weeks

Collaborators and Investigators

• Sponsor: Universitair Ziekenhuis Brussel

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2020
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: August 13, 2020
• First Submitted That Met QC Criteria: August 18, 2020
• First Posted (Actual): August 21, 2020

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Disease Attributes; Neurodegenerative Diseases; Dementia; Tauopathies; Disease Progression; Alzheimer Disease
• Other Study ID Numbers: UZB-NEU-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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