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

Alzheimer Disease Clinical Trial

— NEST4AD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05984446
• Other study ID #: GR-2018-12368250
• Status: Recruiting
• Phase: N/A
• Start date: December 5, 2019
• Est. completion date: December 4, 2024

Study information

• Verified date: September 2023
• Source: IRCCS Centro San Giovanni di Dio Fatebenefratelli
• Contact: Michela Pievani
• Phone: +39 030 3501311
• Email: mpievani[@]fatebenefratelli.eu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 64
• Est. completion date: December 4, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

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

Locations

Country	Name	City	State
Italy	IRCCS Centro San Giovanni di Dio Fatebenefratelli	Brescia

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS Centro San Giovanni di Dio Fatebenefratelli

Country where clinical trial is conducted

Italy, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in DMN connectivity on rs-fMRI following real-rTMS in APOE4 carriers compared to non-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)
Other	Change in DMN connectivity on TMS-EEG following real-rTMS in APOE4 carriers compared to non-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)
Other	Change in task-fMRI associative memory performance following real-rTMS in APOE4 carriers compared to non-carriers	Memory is assessed on task fMRI using a face-name associative paradigm	Baseline, post rTMS (1 week)
Other	Change in cognition following real-rTMS in APOE4 carriers compared to non-carriers	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.	Baseline, post rTMS (1 week)
Other	Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers	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.	Baseline, post rTMS (1 week)
Other	Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers	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.	Baseline, post rTMS (2 months)
Primary	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)
Primary	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	Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers	Memory is assessed on task fMRI using a face-name associative paradigm	Baseline, post rTMS (1 week)