Low Intensity Focused Ultrasound for Mild Cognitive Impairment and Mild Alzheimer's Disease (LIFUP-MCIAD)

• ClinicalTrials.gov Identifier: NCT05417555
• Recruitment Status: Recruiting
• First Posted: June 14, 2022
• Last Update Posted: March 20, 2024
• Sponsor: University of California, Los Angeles
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Taylor Kuhn, University of California, Los Angeles

Tracking Information

• First Submitted Date: June 1, 2022
• First Posted Date: June 14, 2022
• Last Update Posted Date: March 20, 2024
• Actual Study Start Date: September 1, 2022
• Estimated Primary Completion Date: July 31, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 8, 2022)

• Change in Perfusion Arterial Spin Labeling (ASL) fMRI Signal throughout Brain [ Time Frame: 40 minutes ]
  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.
• Changes in BOLD-related functional connectivity from baseline in fMRI brain scan to 40 minutes. [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 18, 2024)

• Change in Brief Visual Memory Test Scores [ Time Frame: 48 hours ]
  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.
• Change in Verbal Learning Test Scores [ Time Frame: 48 hours ]
  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.
• Post-hoc biomarker analysis of APOE-4 status as a predictor of tFUS efficacy [ Time Frame: Baseline (pre-LIFUP) ]
  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.
• Post-hoc biomarker analysis of plasma AB42/40 ratio as a predictor of tFUS efficacy [ Time Frame: Baseline (pre-LIFUP) ]
  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).
• Post-hoc biomarker analysis of plasma ptau as a predictor of tFUS efficacy [ Time Frame: Baseline (pre-LIFUP) ]
  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.

Original Secondary Outcome Measures (submitted: June 8, 2022)

• Change in Brief Visual Memory Test Scores [ Time Frame: 48 hours ]
  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.
• Change in Verbal Learning Test Scores [ Time Frame: 48 hours ]
  Potential LIFUP-related changes in memory will be assessed via the Rey 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 30 minute delay to assess long-term memory. The total words correct in both the short- and long-term trials are used as outcome measures.
• Post-hoc biomarker analysis of APOE-4 status as a predictor of tFUS efficacy [ Time Frame: 4 years ]
  Biomarker post hoc analysis will determine the degree to which blood based biomarkers predict the level of effectiveness of tFUS. Analyses conducted post-data collection phase of the entire study, up to four years after study visit.
• Post-hoc biomarker analysis of plasma AB42/40 ratio as a predictor of tFUS efficacy [ Time Frame: 4 years ]
  Biomarker post hoc analysis will determine the degree to which blood based biomarkers predict the level of effectiveness of tFUS. Analyses conducted post-data collection phase of the entire study, up to four years after study visit. 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).
• Post-hoc biomarker analysis of plasma ptau as a predictor of tFUS efficacy [ Time Frame: 4 years ]
  Biomarker post hoc analysis will determine the degree to which blood based biomarkers predict the level of effectiveness of tFUS. Analyses conducted post-data collection phase of the entire study, up to four years after study visit.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Low Intensity Focused Ultrasound for Mild Cognitive Impairment and Mild Alzheimer's Disease
• Official Title: Modulation of Hippocampal Circuitry and Memory Function With Focused Ultrasound in Amnestic MCI

Brief Summary

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).

Detailed Description

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
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.

Masking: Double (Participant, Outcomes Assessor)
Masking Description:

Participants and the participants' caregivers will be blinded to arm assignment. Additionally, the person administering memory testing will be blinded to assignment.

Primary Purpose: Treatment

Condition

• Mild Cognitive Impairment
• Amnestic Mild Cognitive Disorder
• Deep Brain Stimulation
• Mild Alzheimer's Disease

Intervention

Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)

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)

Other Names:

• transcranial focused ultrasound
• tFUS
• LIFUP
• low intensity focused ultrasound

Study Arms

• Active Comparator: LIFUP Dose Group 1
  Administration of low intensity focused ultrasound (LIFUP) dose level 1 to the entorhinal cortex.
  Intervention: Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)
• Active Comparator: LIFUP Dose Group 2
  Administration of low intensity focused ultrasound (LIFUP) dose level 2 to the entorhinal cortex.
  Intervention: Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)
• Active Comparator: LIFUP Dose Group 3
  Administration of low intensity focused ultrasound (LIFUP) dose level 3 to the entorhinal cortex.
  Intervention: Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)
• Sham Comparator: Sham LIFUP

  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.

  Intervention: Device: Low-Intensity Focused Ultrasound Pulsation (LIFUP)

Publications *

• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 8, 2022): 144
• Original Actual Enrollment: Same as current
• Estimated Study Completion Date: July 31, 2026
• Estimated Primary Completion Date: July 31, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

• Amnestic MCI or Mild Alzheimer's diagnosis
• Age 50-90
• English-speaking
• Right-handed
• Ability to provide informed consent
• Normal or corrected-to-normal hearing and vision

Exclusion Criteria

GENERAL

• Participation in another clinical trial
• Active use of immunotherapeutic medications for cognition (Aduhelm)
• Moderate to Severe Alzheimer's
• Inability to provide informed consent

MRI-Related:

• Weight exceeding 275 pounds
• Pregnancy, suspicion of pregnancy, or attempting to become pregnant
• Claustrophobia
• Difficulties during previous MRIs
• Top permanent retainer (bottom only is okay), 5 or more non-removable gold-teeth, metal braces, top spacers, and/or palate expanders
• Any of the following implants: Cardiac Pacemaker, Aneurysm clips, Cochlear implants, Defibrillator, Electrodes or wires, Magnetically-activated device, Spinal cord stimulator, Infusion or insulin pumps, Implanted drug infusion device, Deep brain stimulation device
• Non-removable hairpieces, hairpiece extensions, and/or piercings
• Facial tattoos or permanent makeup
• Metal implants that are MR-incompatible, or where participant is unable to provide sufficient information to determine MR compatibility
• Previous injury by metallic foreign body (e.g., bullet, BB, shrapnel) where the object entered the body and participant lacks doctor's confirmation that it was fully removed

Medical:

• Diagnosis of one or more of the following neurological disorders: Parkinson's disease, Lou Gehrig's disease (ALS), Multiple sclerosis, Cerebral Palsy
• Diagnosis of one or more of the following genetic disorders: Cystic Fibrosis, Sickle Cell Disease
• Diagnosis of one or more of the following psychiatric disorders: Bipolar, Psychosis
• Psychiatric illness that has not been controlled for at least one year (if controlled >1 year, with or without medication, they are not exclusionary)
• Severe lung, liver, heart, and/or kidney disease/s (e.g., heart failure, liver failure, and etc...)
• Diagnosis of thyroid disorder or change of thyroid medication dose within the last year
• Cancer treatment/s with chemotherapy and/or radiation to head and neck, or stage 4 (metastatic) cancer
• Autoimmune disorder or viral infection such as HIV, COVID 19, or hepatitis C that has caused current problems with cognition/memory
• History of substance abuse in the past year
• History of stroke (Transient ischemic attack / mini-stroke not exclusionary if symptoms lasted <1 week)
• History of 2 or more seizures or diagnosis of epilepsy, unless the seizures occurred prior to age 5 alongside a fever.
• History of brain tumor, brain aneurysm, brain hemorrhage, or subdural hematoma (transient ischemic attack not exclusionary)
• Head injury that resulted in loss of consciousness lasting >30 minutes, cognitive issues lasting >18 months, and/or brain abnormalities visible in CT or MRI scan
• Uncontrolled high blood pressure or diabetes
• Heart attack within the last year

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Bianca H Dang; ‭(310) 794-0077‬; tfus@mednet.ucla.edu

Contact: Natalie M Rotstein; ‭(310) 794-0077‬; tfus@mednet.ucla.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05417555
• Other Study ID Numbers: IRB#21-000995; 1R01AG073480-01 ( U.S. NIH Grant/Contract ); IRB#21-000995 ( Other Identifier: UCLA )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Taylor Kuhn, University of California, Los Angeles
• Original Responsible Party: Same as current
• Current Study Sponsor: University of California, Los Angeles
• Original Study Sponsor: Same as current
• Collaborators: National Institute on Aging (NIA)

Investigators

• Principal Investigator: Susan Y Bookheimer, PhD; UCLA Psychiatry & Biobehavioral Sciences
• Principal Investigator: Taylor P Kuhn, PhD; UCLA Psychiatry & Biobehavioral Sciences

• PRS Account: University of California, Los Angeles
• Verification Date: March 2024