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

NCT05984446 | Completed

• 1 other identifier: GR-2018-12368250
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alzheimer Disease

Keywords

Alzheimer's disease; Default mode network; APOE; rTMS; connectivity

Outcome Measures

Primary Outcomes (2)

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

  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.

  Baseline, post rTMS (1 week)

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

  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.

  Baseline, post rTMS (1 week)

Secondary Outcomes (1)

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

  Baseline, post rTMS (1 week)

Other Outcomes (6)

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

  Baseline, post rTMS (1 week)

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

  Baseline, post rTMS (1 week)

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

  Baseline, post rTMS (1 week)

Study Arms (2)

real-rTMS

EXPERIMENTAL

4 daily 25-minutes high-frequency rTMS sessions over one week

Device: real-rTMS

sham-rTMS

SHAM COMPARATOR

4 daily 25-minutes sham-rTMS sessions over one week

Device: sham-rTMS

Interventions

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.

real-rTMS

sham-rTMS DEVICE

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

sham-rTMS

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• IRCCS Centro San Giovanni di Dio Fatebenefratelli: lead

Study Sites (1)

IRCCS Centro San Giovanni di Dio Fatebenefratelli

Brescia, Brescia, 25125, Italy

Location

Related Publications (2)

• Pievani M, Mega A, Quattrini G, Guidali G, Ferrari C, Cattaneo A, D'Aprile I, Mascaro L, Gasparotti R, Corbo D, Brignani D, Bortoletto M. Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease with Transcranial Magnetic Stimulation (NEST4AD): Rationale and Study Design. J Alzheimers Dis. 2021;83(4):1877-1889. doi: 10.3233/JAD-210659.

  PMID: 34459405 BACKGROUND

• Bagattini C, Brignani D, Bonni S, Quattrini G, Gasparotti R, Pievani M. Functional Imaging to Guide Network-Based TMS Treatments: Toward a Tailored Medicine Approach in Alzheimer's Disease. Front Neurosci. 2021 Jul 5;15:687493. doi: 10.3389/fnins.2021.687493. eCollection 2021.

  PMID: 34290585 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Michela Pievani

  IRCCS Centro San Giovanni di Dio Fatebenefratelli

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head, Lab Alzheimer's Neuroimaging & Epidemiology

Study Record Dates

• First Submitted: August 2, 2023
• First Posted: August 9, 2023
• Study Start: December 5, 2019
• Primary Completion: July 30, 2024
• Study Completion: December 4, 2024
• Last Updated: January 16, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)