Focused Ultrasound for Early Alzheimer's Disease

(LIFUP-MCIAD Trial)

Overseen By Sabrina Halavi

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, Los Angeles

Must not be taking: Immunotherapeutics

Disqualifiers: Moderate Alzheimer's, Parkinson's, Bipolar, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 5 weeks

144 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether Low Intensity Focused Ultrasound Pulsation (LIFUP) can aid individuals with memory problems related to early Alzheimer's. The researchers aim to determine if this ultrasound technique can enhance memory and brain activity in those with mild cognitive impairment (MCI) or mild Alzheimer's. Participants will undergo MRIs, memory tests, and receive LIFUP targeting the brain's memory area. Individuals diagnosed with amnestic MCI or mild Alzheimer's may be suitable for this study. As an unphased trial, this study offers participants the chance to contribute to groundbreaking research that could lead to new treatments for memory issues.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are actively using certain medications for cognition like Aduhelm, Leqembi, or Kisunla.

What prior data suggests that Low-Intensity Focused Ultrasound Pulsation (LIFUP) is safe for use in people with Mild Cognitive Impairment and Mild Alzheimer's Disease?

Research shows that Low-Intensity Focused Ultrasound Pulsation (LIFUP) is generally safe and well-tolerated. Studies have found that LIFUP has a strong safety record, supporting its use in clinical trials. One study on a similar method, low-intensity transcranial focused ultrasound, reported no serious side effects and even suggested it might help brain function.

Overall, these findings indicate that LIFUP is safe for people in research settings, with no major negative events reported so far. Participants in these studies have usually not experienced significant negative effects, making LIFUP a promising option for further research in treating early Alzheimer's disease. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using Low-Intensity Focused Ultrasound Pulsation (LIFUP) for early Alzheimer's disease because it offers a novel, non-invasive approach to targeting the brain. Unlike current treatments like cholinesterase inhibitors and memantine, which work to enhance neurotransmitter function, LIFUP aims to stimulate the entorhinal cortex directly, potentially improving cognitive function by promoting brain plasticity and clearing harmful proteins. This innovative method could provide a new avenue for treatment with fewer side effects than traditional medications, sparking hope for more effective management of Alzheimer's symptoms.

What evidence suggests that Low-Intensity Focused Ultrasound Pulsation (LIFUP) might be an effective treatment for early Alzheimer's Disease?

Research has shown that Low-Intensity Focused Ultrasound Pulsation (LIFUP) could aid in treating Alzheimer's. Studies have found that it can temporarily open the blood-brain barrier, a protective layer around the brain, possibly facilitating medication delivery to the brain. In trials, LIFUP showed promise in enhancing memory and brain connections in individuals with mild memory issues. Early results also suggested that LIFUP can boost brain activity in specific areas. This trial will test different dose levels of LIFUP to evaluate its effectiveness. Overall, these findings offer hope that LIFUP might improve memory in Alzheimer's patients. ^{1 6 7 8 9}

Who Is on the Research Team?

Susan Y Bookheimer, PhD

Principal Investigator

UCLA Psychiatry & Biobehavioral Sciences

Taylor P Kuhn, PhD

Principal Investigator

UCLA Psychiatry & Biobehavioral Sciences

Are You a Good Fit for This Trial?

This trial is for English-speaking, right-handed individuals aged 50-90 with amnestic MCI who can consent and have normal or corrected vision/hearing. Excluded are those with MR-incompatible metal implants, certain genetic disorders, psychiatric conditions other than controlled anxiety/depression, severe organ diseases, recent cancer treatments to the head/neck area, autoimmune disorder treatments, substance abuse history (excluding nicotine/caffeine), significant head injuries or neurological disorders.

Inclusion Criteria

English-speaking

Right-handed

I am between 50 and 90 years old.

Exclusion Criteria

My high blood pressure or diabetes is not under control.

I have had a brain tumor, aneurysm, hemorrhage, or subdural hematoma.

My thyroid medication dose has not changed in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (virtual)

Treatment

Participants receive Low Intensity Focused Ultrasound Pulsation (LIFUP) targeting the entorhinal cortex, with MRIs and memory testing

5 weeks

3 visits (in-person), 3 visits (virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

3 visits (virtual)

Open-label extension (optional)

Placebo participants may receive a free session using the most effective dose if the treatment is shown to be effective

What Are the Treatments Tested in This Trial?

Interventions

• Low-Intensity Focused Ultrasound Pulsation (LIFUP)

Trial Overview The study tests if Low-Intensity Focused Ultrasound Pulsation (LIFUP) targeting the entorhinal cortex can activate brain regions connected to memory and improve memory function in a dose-dependent manner. It also examines how blood-based AD biomarkers and hippocampal volume changes relate to LIFUP outcomes.

How Is the Trial Designed?

Group I: LIFUP Dose Group 3 Active Control 1 Intervention

Administration of low intensity focused ultrasound (LIFUP) dose level 3 to the entorhinal cortex.

Group II: LIFUP Dose Group 1 Active Control 1 Intervention

Administration of low intensity focused ultrasound (LIFUP) dose level 1 to the entorhinal cortex.

Group III: LIFUP Dose Group 2 Active Control 1 Intervention

Administration of low intensity focused ultrasound (LIFUP) dose level 2 to the entorhinal cortex.

Group IV: Sham LIFUP Placebo Group 1 Intervention

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.

Low-Intensity Focused Ultrasound Pulsation (LIFUP) is already approved in United States for the following indications:

Approved in United States as Low-Intensity Focused Ultrasound for:

• Investigational for Mild Cognitive Impairment and Mild Alzheimer's Disease

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

In a study involving 22 patients with Alzheimer's disease and Parkinson's disease, focused ultrasound treatment showed promising results, with 62.5% of patients experiencing improved cognitive scores and 87% showing stable or improved motor skills after 8 weekly sessions.

No adverse events were reported during the treatment, indicating that focused transcranial Doppler ultrasound is a safe intervention for enhancing cognitive and motor functions in neurodegenerative conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focused transcranial ultrasound for treatment of neurodegenerative dementia. Nicodemus, NE., Becerra, S., Kuhn, TP., et al.[2022]

Low intensity focused ultrasound (LiFUS) can effectively disrupt the blood-brain barrier (BBB) in a dose-dependent manner, with increased tracer uptake in the brain observed when using higher microbubble and cavitation doses.

The timing of tracer administration is crucial; the highest accumulation of small solutes occurs when administered just before LiFUS, but significant uptake is also seen up to 6 hours post-treatment, indicating a biphasic response in BBB permeability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of passive permeability after low intensity focused ultrasound mediated blood-brain barrier disruption in a preclinical model. Arsiwala, TA., Sprowls, SA., Blethen, KE., et al.[2023]

Focused ultrasound (FUS) safely opened the blood-brain barrier (BBB) in eight participants with Alzheimer's disease, with no serious adverse effects reported, indicating its potential as a therapeutic approach.

Post-treatment imaging showed that BBB opening led to significant changes in brain fluid dynamics, suggesting a new pathway for fluid movement in the brain, which could have implications for future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound-mediated blood-brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer's disease. Mehta, RI., Carpenter, JS., Mehta, RI., et al.[2023]

In a pilot study involving four patients with Alzheimer's disease, low-intensity transcranial focused ultrasound (tFUS) was found to increase cerebral glucose metabolism in specific brain regions, indicating potential therapeutic effects.

Patients showed mild improvements in cognitive functions, such as memory and executive function, after the tFUS treatment, and no adverse events were reported, suggesting that this method may be safe for use in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer's disease. Jeong, H., Im, JJ., Park, JS., et al.[2021]

MRI-guided low-intensity focused ultrasound (FUS) safely opened the blood-brain barrier in 10 participants with mild Alzheimer's disease, with no serious adverse events reported during the 6-12 month follow-up period.

The treatment resulted in a 14% reduction in β-amyloid plaque in targeted brain regions, and cognitive assessments showed no significant worsening, indicating that FUS may not negatively impact disease progression while potentially allowing for therapeutic delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: long-term safety, imaging, and cognitive outcomes. Rezai, AR., Ranjan, M., Haut, MW., et al.[2023]

Focused ultrasound (FUS) combined with microbubbles has been shown to safely open the blood-brain barrier in animal studies, allowing therapeutic agents to enter the brain and potentially improve cognitive function in Alzheimer's disease.

Human studies indicate that repeated FUS treatments are well tolerated with minimal side effects, and they may enhance brain blood flow and neural function, which is associated with cognitive improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Applications of Focused Ultrasound (FUS) in Alzheimer's Disease Treatment: A Systematic Review on Both Animal and Human Studies. Liu, X., Naomi, SSM., Sharon, WL., et al.[2021]

The novel low-intensity pulsed ultrasound (LIPUS) therapy for Alzheimer's disease was found to be safe in a small roll-in trial with 5 participants, showing no adverse effects.

In a randomized controlled trial with 22 participants, LIPUS therapy showed a trend towards suppressing cognitive decline, with 50% of participants in the LIPUS group showing no worsening of cognitive scores compared to 0% in the placebo group, suggesting potential efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pilot Study of Whole-Brain Low-Intensity Pulsed Ultrasound Therapy for Early Stage of Alzheimer's Disease (LIPUS-AD): A Randomized, Double-Blind, Placebo-Controlled Trial. Shimokawa, H., Shindo, T., Ishiki, A., et al.[2022]

In a phase I safety trial involving five patients with early to moderate Alzheimer's disease, focused ultrasound successfully and safely opened the blood-brain barrier without causing serious adverse events or worsening cognitive function over three months.

Although the procedure was safe, exploratory analysis showed no significant changes in beta-amyloid levels post-treatment, indicating that while the method is feasible, further research is needed to assess its efficacy in reducing Alzheimer's pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. Lipsman, N., Meng, Y., Bethune, AJ., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05997030

Low-Intensity Focused Ultrasound (LIFU) Neuromodulation This study is a prospective, single-center, single-arm early feasibility study, to establish safety and tolerability of LIFU for neuromodulation in patients ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11333319/

Focused ultrasound therapy for Alzheimer's disease Focused ultrasound shows promise as a non-invasive technique for disrupting the blood–brain barrier, potentially enhancing drug delivery directly to the brain.

3. fusfoundation.org fusfoundation.org/posts/alzheimers-disease-focused-ultrasound-neuromodulation-clinical-trial-completed-in-korea/

Alzheimer's Disease Results from an Alzheimer's clinical trial testing low-intensity focused ultrasound (LIFU) neuromodulation have now been published.

4. rsna.org rsna.org/media/press/i/2131

Focused Ultrasound May Open Door to Alzheimer's ... Low-intensity focused ultrasound can open the blood-brain barrier and allow for targeted drug and stem-cell delivery. Researchers targeted ...

5. clinicaltrial.be clinicaltrial.be/en/details/428?per_page=100&only_recruiting=0&only_eligible=0&only_active=0

Low Intensity Focused Ultrasound for Mild Cognitive Impai... 1. Change in Brief Visual Memory Test Scores · 2. Change in Verbal Learning Test Scores · 3. Post-hoc biomarker analysis of APOE-4 status as a ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8446491/

A pilot clinical study of low-intensity transcranial focused ... These results suggest that hippocampal sonication with low-intensity tFUS may have beneficial effects on cerebral glucose metabolism and cognitive function in ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1094715924006627

A Comprehensive Review of Low-Intensity Focused ... Regardless, given LIFU has revealed a strong safety profile, research is rapidly moving beyond basic mechanistic studies to clinical trials to assess its impact ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6289486/

Focused ultrasound and Alzheimer's disease A systematic ... The study evaluated the efficacy and safety of LIPUS throughout the brain in mice with 2 types of dementia: vascular dementia and Alzheimer's dementia. In both ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT05417555?cond=Alzheimer%20Disease&term=focused%20ultrasound&aggFilters=status:not%20rec&rank=2

Low Intensity Focused Ultrasound for Mild Cognitive ... 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 ...