Deep Brain Stimulation for Alzheimer's

Study Overview
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Brief Summary
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This project will investigate the potential of Deep Brain Stimulation to improve cognitive abilities and counteract the effects of Alzheimer's disease. Deep Brain Stimulation electrodes targeting the Nucleus Basalis of Meynert (NB) will be implanted bilaterally in a cohort of patients. NB is the sole source of acetylcholine to the neocortex. Such stimulation may not only treat the cognitive symptoms but may have disease-modifying effects. Drawing from animal experiments in non-human primates that showed success of this approach, intermittent stimulation will be delivered at 60 pulses per second for 20 seconds of each minute for one hour per day. The study team will recruit patients, shortly after first being diagnosed with Alzheimer's disease. The study design will test the safety and efficacy of stimulation, potential benefits in cognitive function assessed with a battery of neurocognitive tests, cholinergic neurotransmission evaluated with Positron Emission Tomography, and ability to reverse Alzheimer's biomarkers, including beta amyloid and tau in the cerebrospinal fluid. Successful completion of this project will lead to a potential new intervention for the cognitive impairments of Alzheimer's disease.

Official Title
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Cholinergic Deep Brain Stimulation for Alzheimer's Disease

Conditions
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Alzheimer Disease, Early Onset, Dementia, Alzheimer Disease

Intervention / Treatment
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* Procedure: Device Implantation- Boston Scientific, VERCISE GENUS™ system
* Device: DBS Stimulation - Boston Scientific, VERCISE GENUS™ system


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Probable, early-stage AD, as defined by NIA-AA 2018 criteria, including amnestic Mild Cognitive Impairment (MCI) Clinical Dementia Rating (CDR) global score of 0.5-1.0 with a memory box score of at least 0.5 MMSE ³ 23 Stable cognitive enhancer medication equivalent to 10 mg/day donepezil or less for at least 60 days Stable other medications (e.g., psychotropics) Valid informed consent if female, subjects who are post-menopausal or surgically sterile or willing to use birth control methods for the duration of the study an available caregiver willing to participate subject is living at home and likely to remain at home for the study duration. Exclusion Criteria: Active or unstable psychiatric illness Inability to tolerate general anesthesia. Another concurrent CNS condition or clinical co-morbidity interfering with the study (ie, stroke, Parkinson's disease, Lewy-Body dementia or other form of dementia, other evidence of significant structural brain pathology). Current major psychiatric disorder such as schizophrenia, bipolar disorder or major depressive disorder based on psychiatric consult at screening visit Verbal IQ<85 Contraindication regarding anesthesia, stereotactic operation, MRI (e.g. claustrophobia, or implants), or PET (e.g. insulin dependent diabetes) procedures Inability to undergo PET or MRI imaging Active alcohol or substance abuse as defined by DSM5 Is unable or unwilling to comply with protocol follow-up requirements Is actively enrolled in another concurrent clinical trial. Terminal illness associated with expected survival of <12 months

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Following the implantation of the device, patients will be assigned to one of two groups in a double-blinded fashion and will either receive intermittent NB stimulation or sham for twelve months. Patients in the sham group will subsequently receive 12 months of intermittent NB stimulation as well. During the sham stimulation period, the patients will not receive stimulation. They will participate in weekly check-ins with the study coordinator to assess concerns and safety, as well as be reminded to wirelessly recharge their implanted device. Cross-group comparisons of progression on dementia ratings scales will be the primary endpoint, evaluated with the Clinical Dementia Rating-Sum of Boxes.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Deep Brain Stimulation<br>Patients who are implanted and receive intermittent stimulation daily for the first 12 months | Procedure: Device Implantation- Boston Scientific, VERCISE GENUS™ system<br>* Participants will be implanted with DBS leads bilaterally, targeting the Nucleus Basalis of Meynert. The study team will record Local Field Potentials with and without stimulation, intraoperatively. These results will help the team determine at the end of the study whether LFP desynchronization (decrease in 5-15 Hz power), or other physiological signature, can be used to predict the location that provides the most effective intervention. Finally, the team will also ascertain the safety of the procedure and NB stimulation itself.<br>Device: DBS Stimulation - Boston Scientific, VERCISE GENUS™ system<br>* Daily intermittent stimulation (60 Hz x 20s/min)<br>|
| Sham Comparator: Non-Deep Brain stimulation<br>Patients who are implanted but do not receive intermittent stimulation daily for 12 months, but receive it after this period for the duration of the study | Procedure: Device Implantation- Boston Scientific, VERCISE GENUS™ system<br>* Participants will be implanted with DBS leads bilaterally, targeting the Nucleus Basalis of Meynert. The study team will record Local Field Potentials with and without stimulation, intraoperatively. These results will help the team determine at the end of the study whether LFP desynchronization (decrease in 5-15 Hz power), or other physiological signature, can be used to predict the location that provides the most effective intervention. Finally, the team will also ascertain the safety of the procedure and NB stimulation itself.<br>Device: DBS Stimulation - Boston Scientific, VERCISE GENUS™ system<br>* Daily intermittent stimulation (60 Hz x 20s/min)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Dementia Rating score change | The primary outcome indicating success will be an increase in the mean score of the Clinical Dementia Rating -Sum of Boxes of the sham group relative to its baseline that is equal or greater than the increase in the mean score of the NB stimulation group (relative to its own baseline) by 1 point or more | 12 - 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stimulation, Nucleus Basalis, Alzheimer, Memory