Overview
This study is a proof of concept/proof of mechanism study addressing the hypothesis that Low Intensity Focused Ultrasound Pulsation (LIFUP) targeting the entorhinal cortex can
(A) successfully target and increase activity in the entorhinal cortex and functionally connected brain regions (B) improve connectivity of memory networks (C) improve memory for information (D) have a dose-dependent effect on memory and brain activity.
A secondary objective is to determine the relationship between blood-based AD biomarkers and LIFUP treatment outcomes, and the relationship between magnitude of HC volume decline and LIFUP treatment outcomes.
Description
- PRÉCIS --- This is a proof of concept/proof of mechanism trial of Low Intensity Focused
Ultrasound Pulsation (LIFUP) targeting the entorhinal cortex in patients with amnestic
MCI. The study will integrate behavioral and multimodal neuroimaging to assess the
utility, dose and duration of LIFUP to a) increase neural activity in deep neural
structures and 2) to enhance memory function in patients with amnestic MCI. The
intervention will randomly assign subjects to one of four dose conditions (0, 1, 2, or 3
doses). Each dose consists of six 30-second sonications, alternating with 30-second OFF
blocks for a total of 6 minutes. Each participant will have two LIFUP sessions with the
same condition, spaced 2 weeks apart. Sessions occur within the MRI scanner with
pre-sonication ASL and rsfMRI, simultaneous rsfMRI, and post-sonication ASL. Verbal and
visuospatial memory will be assessed at baseline, 48 hours after each session via Zoom,
and two weeks after the last in-person session.
- Objectives --- Imaging markers of target modulation: Use fMRI collected simultaneously with LIFUP to assess modulation of neural activity in the hippocampal region and DMN, and ASL pre- and post- LIFUP to assess direct up-regulation of ErC perfusion
Measure LIFUP changes in functional connectivity (change from grant based on reviews: the investigators initially also included cortical thickness changes; current research methods now use CT as a predictor)
Determine whether LIFUP-induced changes in ErC perfusion and ErC/DMN FC will be associated with improved learning and memory
Determine the relationship between AD risk and LIFUP-induced changes: LIFUP-induced functional changes will be associated with blood-based biomarker status (AB42/40 and Ptau217)
---Design and Outcomes --- This is an intervention assessing the effects of focused ultrasound on memory, cerebral blood flow, and functional connectivity in memory circuits in patients with MCI. Patients will be assigned to one of 4 dose groups: 0, 1, 2, or 3 doses at each LIFUP session. At an initial baseline in-person session, subjects will receive structural MRI, a premorbid intelligence test and memory pre-testing. At the second in-person visit, the subjects will undergo a blood draw, pre- and simultaneous resting-state functional MRI and LIFUP sonication, as well as pre- and post-LIFUP ASL to measure blood flow changes. Memory will be assessed remotely 48 hours after the treatment. An identical in-person MRI-LIFUP session and follow-up session will occur 2 weeks later, and a final memory evaluation will occur remotely 2 weeks after the last in-person session. Those administrating memory assessments and analyzing data will be blind to dosage group. The study design section presents a diagram and more detailed description of procedures.
--- Interventions and Duration --- At each of the two MRI-LIFUP sessions, subjects will receive 0, 1, 2, or 3 doses of LIFUP, with each dose consisting of six 30-second sonication blocks.
Eligibility
Inclusion Criteria
- Amnestic MCI diagnosis
- Age 50-90
- English-speaking
- Right-handed
- Ability to provide informed consent via UBACC (Jeste et.al., 2007) procedure
- Normal or corrected-to-normal hearing or vision
Exclusion Criteria
GENERAL
Participation in another clinical trial
Active use of prescribed medications to improve cognition and/or memory, e.g.,
cholinesterase inhibitors, memantine, or Aduhelm
MRI Incompatibility
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:
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
Cardiac pacemaker
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 (one of the following conditions):
The metallic foreign body wasn't fully removed
Participant lacks a doctor's confirmation that the metallic foreign body was fully removed
Diagnosis of one or more of the following neurological disorders:
Alzheimer's disease
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
Psychosis
Dementia
Mental illness other than anxiety or depression
GAD and depression if they have not been controlled for at least one year (if controlled >1
year, with or without medication, they are not exclusionary)
Other Medical
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
Stage 4 (metastatic) cancer
Treatment/s for:
Hepatitis
HIV
Rheumatoid arthritis
Lupus
Any autoimmune disorder
Treatment/s to prevent transplant rejection
History of substance abuse
Including alcohol, but not nicotine or caffeine
History of stroke
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)
History of concussion or similar head injury if any of the following were present:
Head injury requiring hospitalization
Head injury succeeded by loss of consciousness for more than 30 minutes
Head injury succeeded by amnesia, confusion, and/or loss of orientation lasting longer than
24 hours
CT scan that revealed brain abnormalities
2 or more of the following symptoms if they lasted for longer than 3 months after head
injury
Headache
Dizziness
Hypersomnia or insomnia
Phono- or photophobia
Trouble with attention, memory, or staying on task
Decline in school performance
Depression and/or anxiety
Panic attacks
PTSD
Uncontrolled high blood pressure or diabetes
Heart attack within the last year
Daily use of prescribed migraine medication