Low Intensity Focused Ultrasound for Mild Cognitive Impairment and Mild Alzheimer's Disease

Официальное название

Modulation of Hippocampal Circuitry and Memory Function With Focused Ultrasound in Amnestic MCI

Обзор

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).

Подробное описание

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.

Вмешательства

• Устройство 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)

Первичные конечные точки

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

Вторичные конечные точки (5)

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

Критерии участия

Критерии включения

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

Критерии исключения

GENERAL

• Participation in another clinical trial
• Active use of immunotherapeutic medications for cognition (Aduhelm, Leqembi, Kisunla)
• 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 two months (if controlled >2 months, 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 3 months
• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• UCLA Semel Institute for Neuroscience and Behavior — Los Angeles

Публикации

• 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. PMID 24060532
• 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. PMID 25873429
• 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. PMID 25222068
• 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. PMID 21777872

Идентификаторы

NCT: NCT05417555 · IRB#21-000995 · 1R01AG073480-01 · IRB#21-000995

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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