Alzheimer DiseaseNEST4ADNCT05984446
Targeting Default Mode Network Dysfunction in Persons At Risk of Alzheimer's Disease with Non-invasive Techniques
A study testing real-rTMS in people with Alzheimer Disease, run by IRCCS Centro San Giovanni di Dio Fatebenefratelli at 1 site in Italy.
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. Read more about this study
- Who is it for?
- Ages 60 years and olderHealthy volunteers can take part
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- real-rTMS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 86 participants
- Where
- 1 siteItaly
- Study dates
- 5 Dec 2019to 4 Dec 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age: 60 years and older
- MMSE score > 24
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Italy1 site
IRCCS Centro San Giovanni di Dio Fatebenefratelli
Brescia, Brescia, 25125
About this study
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.
Read the detailed 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.
- Conditions
- Alzheimer Disease
- Being tested
- real-rTMS, sham-rTMS
- Keywords
- Alzheimer's disease, Default mode network, APOE, rTMS, connectivity
- Medical subject headings
- Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
real-rTMSDevice
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-rTMSDevice
The sham condition will match the real-rTMS protocol, but a sham coil will be used.
| Study group | Role | What they receive |
|---|---|---|
| real-rTMS | Experimental | 4 daily 25-minutes high-frequency rTMS sessions over one week Receives: Device: real-rTMS |
| sham-rTMS | Sham comparator | 4 daily 25-minutes sham-rTMS sessions over one week Receives: Device: sham-rTMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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
Memory is assessed on task fMRI using a face-name associative paradigm
Measured: Baseline, post rTMS (1 week)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Aug 2023
- Study start5 Dec 2019
- Primary completion30 Jul 2024
- Study completion4 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 86 participants (actual)
Sponsor and investigators
- Lead sponsor
- IRCCS Centro San Giovanni di Dio Fatebenefratelli
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Michela Pievani, IRCCS Centro San Giovanni di Dio Fatebenefratelli
- Investigators
- Michela Pievani, Principal investigator, IRCCS Centro San Giovanni di Dio Fatebenefratelli
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05984446
- Sponsor's protocol ID
- GR-2018-12368250
- Acronym
- NEST4AD
- Status last verified
- Jan 2025
- First submitted
- 2 Aug 2023
- Last updated
- 16 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 34459405Bagattini 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.
PubMed 34290585
Study at a glance
From the registry record, last updated by the sponsor on 16 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeting Default Mode Network Dysfunction in Persons At Risk of Alzheimer's Disease with Non-invasive Techniques
- ClinicalTrials.gov ID
- NCT05984446
- Acronym / sponsor ID
- NEST4AD / GR-2018-12368250
- Conditions
- Alzheimer Disease
- Keywords
- Alzheimer's disease, Default mode network, APOE, rTMS, connectivity
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 86 participants (actual)
- Lead sponsor
- IRCCS Centro San Giovanni di Dio FatebenefratelliUniversity, hospital or other
- Study start
- 5 Dec 2019 (actual)
- Primary completion
- 30 Jul 2024 (actual)
- Study completion
- 4 Dec 2024 (actual)
- First posted
- 9 Aug 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| real-rTMS | Experimental | Device: real-rTMS4 daily 25-minutes high-frequency rTMS sessions over one week |
| sham-rTMS | Sham comparator | Device: sham-rTMS4 daily 25-minutes sham-rTMS sessions over one week |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Age: 60 years and older
- MMSE score > 24
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| real-rTMSEach 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. | Device | real-rTMS |
| sham-rTMSThe sham condition will match the real-rTMS protocol, but a sham coil will be used. | Device | sham-rTMS |
Primary outcome
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.
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.
1 secondary outcome
Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers
Time frame: Baseline, post rTMS (1 week)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jan 2025.
- Background: PubMed 34459405Pievani 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.
- Background: PubMed 34290585Bagattini 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michela Pievani principal investigator
IRCCS Centro San Giovanni di Dio Fatebenefratelli
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing real-rTMS in people with Alzheimer Disease, run by IRCCS Centro San Giovanni di Dio Fatebenefratelli at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in DMN connectivity on rs-fMRI following real-rTMS compared to sham-rTMS in APOE4 carriers (time frame: Baseline, post rTMS (1 week)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05984446, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jan 2025.