Ultrasonic Neuromodulation for Treatment of Cognitive Impairment

Study Overview
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Brief Summary
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This study will evaluate a new form of non-invasive deep brain therapy for individuals with Alzheimer's disease. Low-intensity transcranial focused ultrasound stimulation will first be delivered using a range of stimulation parameters during psychophysical and physiological monitoring. A well-tolerated stimulation protocol will be selected for subsequent testing in a blinded randomized sham-controlled cross-over trial. The trial will evaluate brain target engagement using magnetic resonance imaging, PET imaging, and numerical scales of cognitive performance.

Official Title
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Deep Brain Therapy With Low-intensity Ultrasound for Treatment of Cognitive Impairment

Conditions
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Alzheimer Disease, Dementia, Cognitive Impairment

Intervention / Treatment
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* Device: Diadem prototype


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mild cognitive impairment or mild dementia due to Alzheimer's disase (AD) with confirmed AD biomarkers (Amyloid PET or CSF) Age 65-80 MOCA > 18 Exclusion Criteria: Evidence of cerebral amyloid angiopathy or stroke within 1 year Clinical symptoms or findings suggestive of alternative diagnosis or co-pathology Inability to complete MRI Suicidal ideation

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active stimulation<br>Low-intensity transcranial focused ultrasound stimulation of deep brain targets affected by Alzheimer's disease. | Device: Diadem prototype<br>* The device delivers low-intensity ultrasonic waves into specific brain targets.<br>|
| Sham Comparator: Sham stimulation<br>Sham stimulation that applies the device in the same way as verum but only delivers auditory sounds correspoding to the ultrasonic pulses. | Device: Diadem prototype<br>* The device delivers low-intensity ultrasonic waves into specific brain targets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montreal Cognitive Assessment Test for Dementia (MoCA) | The MoCA is a 30-point test to detect cognitive impairment. Scores range from 0 (poor) and 30 (perfect). | Up to 3 months following study initiation | 
| Hamilton Depression Rating Scale (HDRS-17) | This 17-item questionnaire rates the severity of depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. The scores range from 0 (no symptoms) to 52 (worst possible). | Up to 3 months following study initiation | 
| Amyloid PET | PET (positron emission tomography) combined with fluorine-18 labelled radiotracers provide brain scans that are interpreted as either amyloid-beta positive or negative. | Up to 3 months following study initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hopkins Verbal Learning Test-Revised (HVLT-R) | HVLT-R is a verbal memory test with 12 words learned over three trials, with the correct words summed for the Total Recall score (range = 0 (worst) - 36 (best)). The Delayed Recall score is the number of correct words recalled after a 20 - 25-minute delay (range = 0 (worst) - 12 (best)). | Up to 3 months following study initiation | 
| Digit Span Memory Test | A standard test for working memory. In this test, a list of random numbers or letters is presented on a computer screen at the rate of one per second. The test begins with three numbers, increasing until the person commits errors. The average digit span for normal adults without error is seven plus or minus two. The higher the number, the more patent the working memory. | Up to 3 months following study initiation | 
| Trail Making Test, Part A and B | The test probes visual scanning and working memory. The task is to connect a set of 25 dots as quickly as possible while maintaining accuracy. The faster the completion of Part A and Part B, the better. | Up to 3 months following study initiation |