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Completed

NCT Number: NCT05984446

Targeting Default Mode Network Dysfunction in Persons At Risk of Alzheimer's Disease with Non-invasive Techniques

Default mode network (DMN) dysfunction is a well-established feature of Alzheimer's Disease (AD) and is already present in preclinical stages and in subjects at risk for AD, thus offering a potential target for early intervention. Non-invasive stimulation techniques are candidate approaches to modulate network dysfunction, however interventions specifically targeting subjects at risk for AD are lacking. This project will test a non-invasive intervention to modulate the DMN in cognitively healthy older adults carrying the main genetic risk factor for AD, the APOE e4 allele. The proposal will non-invasively stimulate the DMN in at risk subjects and will assess the neuronal-cognitive effect of this approach with multimodal neuroimaging and neurophysiological techniques.

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Key information

Conditions

Alzheimer Disease Brain Diseases Central Nervous System Diseases Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies

Age range

60 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

IRCCS Centro San Giovanni di Dio Fatebenefratelli

Brescia, 25125, Italy

About this study

Sixty-four participants will be enrolled (n=32 APOE e4 carriers, 32 non-carriers as reference group) and will undergo rTMS stimulation, TMS with concurrent electroencephalography (TMS-EEG), multimodal imaging (resting-state and task functional MRI, and diffusion tensor imaging) and cognitive assessment at baseline, after the intervention (week 1) and after 2 months. Participants will be randomized to 2 groups: active DMN stimulation (real-rTMS) or placebo (sham-rTMS). Each subject will undergo a rs-fMRI scan before the intervention to derive individualized DMN stimulation targets. rTMS will be applied over the left inferior parietal lobule node of the DMN.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age: 60 years and older
  • MMSE score > 24

Exclusion criteria

  • Pathological scores in at least two standardized cognitive tests
  • Participation in other interventional studies
  • Known carriers of an autosomal dominant genetic mutation associated to AD
  • Neurological, psychiatric or medical conditions not compatible with the study

Exclusion criteria

for MRI and rTMS:

  • metal implants, pace-makers, prosthetic heart valves
  • claustrophobia
  • history of epilepsy
  • pregnancy

Treatment and study plan

real-rTMS

Device

Each subject will undergo 4 rTMS sessions using a 70-mm figure-eight coil (20Hz for 25 minutes). Target localization will be performed with a stereotaxic neuronavigation system.

Sham-rTMS

Device

The sham condition will match the real-rTMS protocol, but a sham coil will be used.

Primary outcomes

  1. Change in DMN connectivity on rs-fMRI following real-rTMS compared to sham-rTMS in APOE4 carriers

    Time frame: Baseline, post rTMS (1 week)

    Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity.

  2. Change in DMN connectivity on TMS-EEG following real-rTMS compared to sham-rTMS in APOE4 carriers

    Time frame: Baseline, post rTMS (1 week)

    Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical excitability and connectivity. The response in the natural frequency of the target area will index cortical excitability. Effective connectivity will be measured through amplitude and latency of TEPs.

Secondary outcomes

  1. Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers

    Time frame: Baseline, post rTMS (1 week)

    Memory is assessed on task fMRI using a face-name associative paradigm

Other outcomes

  1. Change in DMN connectivity on rs-fMRI following real-rTMS in APOE4 carriers compared to non-carriers

    Time frame: Baseline, post rTMS (1 week)

    Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity.

  2. Change in DMN connectivity on TMS-EEG following real-rTMS in APOE4 carriers compared to non-carriers

    Time frame: Baseline, post rTMS (1 week)

    Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical excitability and connectivity. The response in the natural frequency of the target area will index cortical excitability. Effective connectivity will be measured through amplitude and latency of TEPs.

  3. Change in task-fMRI associative memory performance following real-rTMS in APOE4 carriers compared to non-carriers

    Time frame: Baseline, post rTMS (1 week)

    Memory is assessed on task fMRI using a face-name associative paradigm

  4. Change in cognition following real-rTMS in APOE4 carriers compared to non-carriers

    Time frame: Baseline, post rTMS (1 week)

    Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.

  5. Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers

    Time frame: Baseline, post rTMS (1 week)

    Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.

  6. Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers

    Time frame: Baseline, post rTMS (2 months)

    Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.

Sponsors and collaborators

Lead sponsor

IRCCS Centro San Giovanni di Dio Fatebenefratelli

Other

Registry information

Acronym: NEST4AD

Important dates

Study start
2019
Primary completion
2024
Study completion
2024
First posted
Aug 9, 2023
Registry last updated
Jan 16, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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