Clinical trial NCT05984446: Targeting Default Mode Network Dysfunction in Persons At Risk of Alzheimer's Disease with Non-invasive Techniques
Official title: Targeting Default Mode Network Dysfunction in Persons At Risk of Alzheimer's Disease with Non-invasive Techniques
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alzheimer Disease
Keywords: Alzheimer's disease
Default mode network
APOE
rTMS
connectivity
Lead sponsor: IRCCS Centro San Giovanni di Dio Fatebenefratelli
Sponsor class: OTHER
First posted: 2023-08-09
Enrollment: 86
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in DMN connectivity on rs-fMRI following real-rTMS compared to sham-rTMS in APOE4 carriers
timeFrame: Baseline, post rTMS (1 week)
measure: Change in DMN connectivity on TMS-EEG following real-rTMS compared to sham-rTMS in APOE4 carriers
timeFrame: Baseline, post rTMS (1 week)
Secondary outcomes:
measure: Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers
timeFrame: Baseline, post rTMS (1 week)
Other outcomes:
measure: Change in DMN connectivity on rs-fMRI following real-rTMS in APOE4 carriers compared to non-carriers
timeFrame: Baseline, post rTMS (1 week)
measure: Change in DMN connectivity on TMS-EEG following real-rTMS in APOE4 carriers compared to non-carriers
timeFrame: Baseline, post rTMS (1 week)
measure: Change in task-fMRI associative memory performance following real-rTMS in APOE4 carriers compared to non-carriers
timeFrame: Baseline, post rTMS (1 week)
measure: Change in cognition following real-rTMS in APOE4 carriers compared to non-carriers
timeFrame: Baseline, post rTMS (1 week)
measure: Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers
timeFrame: Baseline, post rTMS (1 week)
measure: Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers
timeFrame: Baseline, post rTMS (2 months)
Locations:
city: Brescia
country: Italy
facility: IRCCS Centro San Giovanni di Dio Fatebenefratelli
Study officials:
affiliation: IRCCS Centro San Giovanni di Dio Fatebenefratelli
name: Michela Pievani
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.