Fornix and NbM as Targets of Stimulation In Alzheimer's Disease

Study Overview
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Brief Summary
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The primary goal of this study is to evaluate the efficacy and safety of the DBS to the fornix/NbM among patients who are diagnosed as AD according to a series of evaluations including cerebrospinal fluid (CSF) biomarkers and molecular imaging examinations; The secondary goal is to compare the efficacy among the two treatment groups of different targets.

Official Title
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A Randomized Controlled Study of 12 Months to Evaluate the Safety and Efficacy of Deep Brain Stimulation(DBS) to the Fornix & Meynert Nucleus(NbM) in Patients With Mild to Moderate Alzheimer's Disease(AD)

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Device: DBS of the fornix, power on
* Device: DBS of the NbM, power on
* Device: DBS of the fornix, power off
* Device: DBS of the NbM, power off


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with informed consent; 45-75 years of age; At least 6 years of education; AD according to the National Institute on Aging and the Alzheimer's Association (NIA-AA) guidelines (McKhann et al., 2011); Clinical Dementia Rating Scale (CDR): 1.0-2.0; Positive findings with amyloid PET imaging; Stable prescription of donepezil (5mg, qd) for at least 3 months, and without any intentions to modify the dosage during the observation period. Exclusion Criteria: Fazekas scale>2; Neuropsychiatric inventory (NPI) total score ≥10, or any subdomain≥4； Modified Hachinski ischemic score>4； Young Mania Rating Scale>11(Young, Biggs, Ziegler, & Meyer, 1978); Any suicidal tendencies in recent 2 years; Cornell Scale for Depression and Dementia>10; Familial AD; Abnormal brain structural magnetic resonance imaging (MRI) scan, including hydrocephalus, stroke, structural lesions, etc. that would potentially confound the outcome; Surgical history of the central nervous system; Severe cardiovascular/pulmonary disorders.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DBS of the fornix, power on<br> | Device: DBS of the fornix, power on<br>* DBS of bilateral columns of the fornix is performed, with the power of the device on since the 1st month after the implantation. Observations will start at the time when the device is turning on . DBS system includes: Pins G102 Implantable Neurostimulator; Pins L301 DBS Electrode； Pins E202 DBS extension lead<br>|
| Experimental: DBS of the NbM, power on<br> | Device: DBS of the NbM, power on<br>* DBS of bilateral NbMs is performed, with the power of the device on since the 1st month after the implantation. Observations will start at the time when the device is turning on . DBS system includes: Pins G102 Implantable Neurostimulator; Pins L301 DBS Electrode； Pins E202 DBS extension lead<br>|
| Sham Comparator: DBS of the fornix, power off<br> | Device: DBS of the fornix, power off<br>* DBS of bilateral columns of the fornix is performed, the power of the device is going to keep off during the first 7 months after the implantation. Observations will start after 1 month of the implantation. DBS system includes: Pins G102 Implantable Neurostimulator; Pins L301 DBS Electrode； Pins E202 DBS extension lead<br>|
| Sham Comparator: DBS of the NbM, power off<br> | Device: DBS of the NbM, power off<br>* DBS of bilateral NbMs is performed, the power of the device is going to keep off during the first 7 months after the implantation. Observations will start after 1 month of the implantation. DBS system includes: Pins G102 Implantable Neurostimulator; Pins L301 DBS Electrode； Pins E202 DBS extension lead<br>|
| No Intervention: Control group<br>The patients are going to prescribe stable dosage of donepezil during observation period without surgical interference. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive outcome | Cognitive function measured by Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog, 13-items version). ADAS-cog 13 scale range: 0-80; (Higher value represents a worse outcome) | 12 months (from 1 month to 13 month after implantation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuroplasticity outcome | Protection of hippocampal volume revealed by magnetic resonance imaging (MRI). | 12 months (from 1 month to 13 month after implantation) | 
| Neuroplasticity outcome | Improved cerebral metabolic level revealed by FDG positron emission tomography(PET) imaging. | 12 months (from 1 month to 13 month after implantation) | 
| Cognitive outcome | Improvement of cognitive function evaluated by Clinical Dementia Rating Scale sum of the boxes (CDR-SB). CDR-SB scale range: 0-18; (0 represents normal cognition, the higher the score, the worse the cognitive function). | 12 months (from 1 month to 13 month after implantation) | 
| Functional outcome | Improvement of life quality according to Activities of Daily Living (ADL) scale. ADL scale range: 20-80 (20 represents normal life ability, the higher the score, the worse the life ability). | 12 months (from 1 month to 13 month after implantation) | 
| Safety outcome | Device/therapy related side effects or complications such as mortality an morbidity. | 12 months (from 1 month to 13 month after implantation) |