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: 1. Can LIFUP increase brain activity in the targeted area? 2. Can LIFUP improve memory in people with MCI and mild AD? 3. Can LIFUP improve connectivity of memory networks in the brain? 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
144
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)
UCLA Semel Institute for Neuroscience and Behavior
Los Angeles, California, United States
RECRUITINGChange 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.
Time frame: 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.
Time frame: 40 minutes
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.
Time frame: 48 hours
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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: Baseline (pre-LIFUP)
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