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

Trial Summary

What is the purpose of this trial?

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).

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 data supports the effectiveness of the treatment Low-Intensity Focused Ultrasound Pulsation (LIFUP) for early Alzheimer's disease?

Research shows that focused ultrasound can safely open the blood-brain barrier in Alzheimer's patients, which may help reduce harmful proteins linked to the disease. Animal studies suggest this method can improve memory and cognitive function, and early human studies indicate it is well-tolerated with potential cognitive benefits. ^{1 2 3 4 5}

Is focused ultrasound safe for treating Alzheimer's disease?

Focused ultrasound, including low-intensity versions, has been tested in humans with Alzheimer's disease and is generally considered safe. Studies show it can open the blood-brain barrier without causing serious side effects, and repeated treatments are well tolerated with few adverse events. ^{1 3 4 6 7}

How is the Low-Intensity Focused Ultrasound Pulsation (LIFUP) treatment different from other treatments for Alzheimer's disease?

LIFUP is unique because it uses focused ultrasound to temporarily open the blood-brain barrier, allowing potential therapeutic agents to enter the brain more effectively. This non-invasive approach is still in early research stages but shows promise in safely targeting Alzheimer's disease pathology without significant side effects. ^{1 2 3 5 8}

Research Team

Susan Y Bookheimer, PhD

Principal Investigator

UCLA Psychiatry & Biobehavioral Sciences

Taylor P Kuhn, PhD

Principal Investigator

UCLA Psychiatry & Biobehavioral Sciences

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Focused transcranial ultrasound for treatment of neurodegenerative dementia. [2022]

3. United States 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. [2021]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer's disease. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Ultrasound-mediated blood-brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer's disease. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: long-term safety, imaging, and cognitive outcomes. [2023]

7. Japan 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Characterization of passive permeability after low intensity focused ultrasound mediated blood-brain barrier disruption in a preclinical model. [2023]