Alzheimer Disease
Conditions
Keywords
Alzheimer's disease, Default mode network, APOE, rTMS, connectivity
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.
Interventions
DEVICEreal-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.
DEVICEsham-rTMS
The sham condition will match the real-rTMS protocol, but a sham coil will be used.
Sponsors
IRCCS Centro San Giovanni di Dio Fatebenefratelli
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in DMN connectivity on rs-fMRI following real-rTMS compared to sham-rTMS in APOE4 carriers | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers | Baseline, post rTMS (1 week) | Memory is assessed on task fMRI using a face-name associative paradigm |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in cognition following real-rTMS in APOE4 carriers compared to non-carriers | 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. |
| Change in DMN connectivity on rs-fMRI following real-rTMS in APOE4 carriers compared to non-carriers | 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 cognition following real-rTMS compared to sham-rTMS in APOE4 carriers | 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. |
| Change in DMN connectivity on TMS-EEG following real-rTMS in APOE4 carriers compared to non-carriers | 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. |
| Change in task-fMRI associative memory performance following real-rTMS in APOE4 carriers compared to non-carriers | Baseline, post rTMS (1 week) | Memory is assessed on task fMRI using a face-name associative paradigm |
Countries
Italy
Outcome results
None listed