Epilepsy in Alzheimer's Disease: Effect on Disease Progression (EADP)

This is a long-term, prospective, interventional study to investigate the role and prevalence of subclinical epileptiform activity in the hippocampus in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). The investigators would like to investigate whether subclinical epileptiform activity in the hippocampus is more prevalent in patients with MCI, compared to healthy controls and to evaluate its effects on cognitive decline. Evolution of cognitive decline will be assessed over a time period of two years.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease; Mild Cognitive Impairment
• Intervention / Treatment: Procedure: Lumbar puncture

Detailed Description

Epilepsy is a known comorbidity of Alzheimer's disease. In the past, it was considered to be a late complication of AD. Recent literature suggest seizures to be prevalent much earlier in the time course of the disease. Systematic reviews suggest the occurrence of at least one seizure in 10-22% of AD cases and of epilepsy in 5 out of 100 AD cases. One important factor leading to the underdiagnosis of epilepsy in AD, is the fact that it is difficult to diagnose epilepsy in patients with AD because of an overlap in symptomatology (e.g. speech arrest, staring, confusion, …) A recent pilot study showed that even subclinical epileptiform discharges, without overt epilepsy, were more frequent (42%) in patients with dementia due to AD than in healthy controls (10%). These subclinical epileptic discharges were diagnosed with prolonged electroencephalogram (EEG)-monitoring and magnetoencephalogram (MEG)-registration.

There is overlap in AD and epilepsy pathogenesis. In both diseases, activation of microglia, astrogliosis, neuroinflammation and hippocampal neuronal loss has been described. Studies in mice have shown that hippocampal hyperexcitability is an early electrophysiological impairment in AD, and, that this might be a consequence of soluble Amyloid bèta oligomers. Another study in mice, expressing human Amyloid Precursor Protein (APP), showed hippocampal synchronized large amplitude potentials to be present before onset of spontaneous seizures, memory impairments or Amyloid bèta plaques. Low levels of soluble forms of Amyloid bèta might have increased excitability. Increased neuronal activity per se increases both Amyloid bèta and Tau secretion. This means that recurrent epileptic activity in AD might establish a vicious cycle.

Since hippocampal hyperactivity might be an early electrophysiological impairment in AD according to rodent studies, even before memory impairment exist, the investigators thought it to be useful to track subclinical, hippocampal epileptic activity by use of magnetoencephalogram - high density electroencephalogram (MEG-EEG) in patients with MCI due to AD (aka a stage of predementia) and compare this prevalence to healthy controls. The investigators would also like to track evolution to AD in patients with MCI and subclinical epileptiform activity versus those without.

This could support further investigations, with monitoring of the effect of several antiepileptic drugs in patients with MCI due to AD.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sebastiaan Engelborghs, MD, PHD; Phone Number: +32 476 37 24; Email: sebastiaan.engelborghs@uzbrussel.be
• Study Contact Backup: Name: Amber Nous, MD; Phone Number: +32 474 94 38; Email: amber.nous@uzbrussel.be

Study Locations

• Belgium
  • Jette
    • Brussels, Jette, Belgium, 1090
      • Recruiting
      • UZ Brussel
      • Contact: Amber Nous, MD; Phone Number: 0479477937; Email: amber.nous@live.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Patients

Inclusion Criteria:

• Cognitive concern reflecting a change in cognition reported by patient or informant or clinician
• Objective evidence of impairment in one or more cognitive domains, typically including memory.
• Preservation of independence in functional abilities
• Not demented

Exclusion Criteria:

• Age < 18 years old
• Pregnancy
• Expected death due to illness within 2 years
• Pacemaker or other ferromagnetic material that is not MRI compatible
• Other neurodegenerative or cerebrovascular disease
• Pattern compatible with Normal Pressure Hydrocephalus (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, …)

Healthy volunteers Inclusion criteria Age- and gender matched healthy controls

Exclusion criteria

• 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, …)

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: Patients with Mild Cognitive Impairment (MCI) due to AD; Neuropsychological investigation, lumbar puncture, long term-EEG monitoring and/or MEG-EEG, magnetic resonance imaging (MRI), blood sample with deep genetic profiling and Apolipoprotein E (APOE) determination.	Procedure: Lumbar puncture; Lumbar puncture for AD biomarker fluid analysis
Other: Healthy volunteers; Neuropsychological investigation, lumbar puncture, long term-EEG monitoring and/or MEG-EEG, MRI, blood sample with deep genetic profiling and APOE determination.	Procedure: Lumbar puncture; Lumbar puncture for AD biomarker fluid analysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence, expressed as percentage, of subclinical epileptiform activity in MCI due to AD patients, compared to healthy controls.	Comparison of prevalence of subclinical epileptiform activity (measured by LTM-EEG and MEG)	Patients will have their investigations at inlcusion within a time frame of 8 weeks. Healthy Volunteers will have their investigations at inclusion within a time frame of 4 weeks.
Odds ratio for conversion to clinical AD when comparing MCI patients with and without subclinical signs of epilepsy at the baseline evaluation.	Odds ratio of conversion (measured by neuropsychological examination).	Patients will have their investigations at inlcusion (time frame: 8 weeks), after 1 year (time frame: 4 weeks) and after 2 years (time frame: 4 weeks).

Collaborators and Investigators

• Sponsor: Universitair Ziekenhuis Brussel

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2020
• Primary Completion (Anticipated): September 30, 2023
• Study Completion (Anticipated): September 30, 2023

Study Registration Dates

• First Submitted: October 15, 2019
• First Submitted That Met QC Criteria: October 17, 2019
• First Posted (Actual): October 18, 2019

Study Record Updates

• Last Update Posted (Estimate): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 10, 2023
• Last Verified: May 1, 2023

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; Cognition Disorders; Epilepsy; Disease Progression; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: UZB-NEU-001

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
• product manufactured in and exported from the U.S.: No