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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01AG073480-01 | U.S. NIH Grant/Contract | View source | |
| IRB#21-000995 | Other Identifier | UCLA |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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The goal of this study is to investigate whether Low Intensity Focused Ultrasound Pulsation (LIFUP) targeting a part of the brain involved in memory will have an affect on brain activity and whether it may improve memory in people with Mild Cognitive Impairment and Mild Alzheimer's Disease.
The main questions the study seeks to answer are:
Participants in this study will complete MRIs and memory testing, and receive Low Intensity Focused Ultrasound to a part of their brain involved in memory (the entorhinal cortex).
This is a proof of concept trial of Low Intensity Focused Ultrasound Pulsation (LIFUP) targeting the entorhinal cortex in patients with amnestic MCI and Mild Alzheimer's Disease. Participation in the study will entail one Zoom intake session, three in-person sessions and three remote Zoom follow-up sessions over the course of about five weeks. The in-person sessions will take about 5 hours for the first and 3 hours for the following two. The Zoom intake session will take 1-2 hours, and the Zoom follow-up sessions will take about 2 hours each. Participants will be asked to complete questionnaires and tests of learning and memory, have their blood drawn, undergo painless ultrasound stimulation to a part of their brain related to memory, and complete MRI scans of their brain. LIFUP will be administered inside of the MRI scanner, so that we can measure changes in brain activity in real-time.
At the start of the study, you will be randomly assigned to one of four different groups that determines the amount of LIFUP stimulation you will receive. You have an equal chance of being assigned to each group. Participants in one of the three active stimulation groups will receive either 1 dose, 2 doses, or 3 doses of LIFUP at their second in-person session, and will receive the same dose again at their third in-person session. Participants in the placebo group will receive no LIFUP stimulation at either MRI/LIFUP session (in-person visits 2 and 3). However, if at the end of our study, the treatment has been shown to be effective, and you were a placebo subject, we will offer you a free session using the most effective dose.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LIFUP Dose Group 1 | Active Comparator | Administration of low intensity focused ultrasound (LIFUP) dose level 1 to the entorhinal cortex. |
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| LIFUP Dose Group 2 | Active Comparator | Administration of low intensity focused ultrasound (LIFUP) dose level 2 to the entorhinal cortex. |
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| LIFUP Dose Group 3 | Active Comparator | Administration of low intensity focused ultrasound (LIFUP) dose level 3 to the entorhinal cortex. |
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| Sham LIFUP | Sham Comparator | No administration of LIFUP. The device will be affixed to the user's head but not turned on. Additionally, if at the end of the study, the treatment has been shown to be effective, placebo subjects will be offered a free session using the optimally effective dose, if they consented to being contacted for this purpose. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Low-Intensity Focused Ultrasound Pulsation (LIFUP) | Device | Low intensity focused ultrasound pulsation will be administered to the left entorhinal cortex at 650kHz, ispta.3 720mW/cm, pulse repetition frequency 100Hz, duty cycle 50%, duration 30s with 30s spacing between sonications, 6 sonications per dose (participants receive 0, 1, 2 or 3 doses depending on group assignment) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Perfusion Arterial Spin Labeling (ASL) fMRI Signal throughout Brain | Perfusion ASL fMRI data will be collected before and after sonication. Analyses will assess the statistical relationship between ASL signal throughout the brain pre and post sonication. | 40 minutes |
| Changes in BOLD-related functional connectivity from baseline in fMRI brain scan to 40 minutes. | Primary outcomes for proof of mechanism that may be depicted in the fMRI scans may include changes in BOLD-related functional connectivity increases within the DMN including regions functionally connected to the target. BOLD data will be collected before, during, and following LIFUP sonication. Analyses will assess any changes in BOLD signal in the brain following sonication. | 40 minutes |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Brief Visual Memory Test Scores | Potential LIFUP-related changes in memory will be assessed via neuropsychological assessments including the Brief Visual Memory Tests (BVMT). Scores range from 0 to 12 and reflect recent, long-term learning, with higher scores indicating better learning. | 48 hours |
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Inclusion Criteria
Exclusion Criteria
GENERAL
MRI-Related:
Medical:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Natalie Rotstein | Contact | (310) 794-0077 | tfus@mednet.ucla.edu | |
| Sabrina Halavi | Contact | (310) 794-0077 | tfus@mednet.ucla.edu |
| Name | Affiliation | Role |
|---|---|---|
| Susan Y Bookheimer, PhD | UCLA Psychiatry & Biobehavioral Sciences | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCLA Semel Institute for Neuroscience and Behavior | Recruiting | Los Angeles | California | 90024 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24060532 | Background | Hescham S, Lim LW, Jahanshahi A, Blokland A, Temel Y. Deep brain stimulation in dementia-related disorders. Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 2):2666-75. doi: 10.1016/j.neubiorev.2013.09.002. Epub 2013 Sep 20. | |
| 25873429 | Background | Lin WT, Chen RC, Lu WW, Liu SH, Yang FY. Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model. Sci Rep. 2015 Apr 15;5:9671. doi: 10.1038/srep09671. |
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Subjects are randomly assigned to one of four treatment dosage conditions: 0, 1, 2 or 3 treatments at each MRI-LIFUP session. After 2 weeks, a second dose is administered with the same dosage level for each subject. Memory assessment occurs once at baseline and remotely after each treatment at the onset of the optimal time window (48 hours) for LIFUP-induced change based on prior data. Finally, after 2 weeks, memory is again assessed. Alternate forms are used for the primary outcome measures to avoid practice effects.
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Participants and the participants' caregivers will be blinded to arm assignment. Additionally, the person administering memory testing will be blinded to assignment.
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| Change in Verbal Learning Test Scores |
Potential LIFUP-related changes in memory will be assessed via the Rey Auditory Verbal Learning Test (RAVLT) neuropsychological assessment. The RAVLT involves providing participants with 15 unrelated words and asking them to recall the word list. There are 5 trials designed to determine short-term memory and then a 20 minute delay to assess long-term memory. The total words correct in both the short- and long-term trials are used as outcome measures. |
| 48 hours |
| Post-hoc biomarker analysis of APOE-4 status as a predictor of tFUS efficacy | Biomarker post hoc analysis will determine the degree to which blood based biomarkers predict the level of effectiveness of tFUS. Samples are collected before LIFUP is administered. | Baseline (pre-LIFUP) |
| Post-hoc biomarker analysis of plasma AB42/40 ratio as a predictor of tFUS efficacy | Biomarker post hoc analysis will determine the degree to which blood based biomarkers predict the level of effectiveness of tFUS. Samples are collected before LIFUP is administered. An Aβ42/40 ratio <0.160 suggests a higher-than-normal risk of having of AD and is warranted to support a diagnosis of AD (West et al 2021). | Baseline (pre-LIFUP) |
| Post-hoc biomarker analysis of plasma ptau as a predictor of tFUS efficacy | Biomarker post hoc analysis will determine the degree to which blood based biomarkers predict the level of effectiveness of tFUS. Samples are collected before LIFUP is administered. | Baseline (pre-LIFUP) |
| 25222068 | Background | Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I, Hynynen K. Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology. 2014 Dec;273(3):736-45. doi: 10.1148/radiol.14140245. Epub 2014 Sep 15. |
| 21777872 | Background | Bystritsky A, Korb AS, Douglas PK, Cohen MS, Melega WP, Mulgaonkar AP, DeSalles A, Min BK, Yoo SS. A review of low-intensity focused ultrasound pulsation. Brain Stimul. 2011 Jul;4(3):125-36. doi: 10.1016/j.brs.2011.03.007. Epub 2011 Apr 1. |
| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| D019965 | Neurocognitive Disorders |
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D001523 | Mental Disorders |
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
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