ExAblate BBB Disruption for Alzheimer's Disease

Recruiting at14 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: InSightec

Must be taking: Alzheimer's medications

Disqualifiers: Cardiac disease, Depression, Seizure, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing a device that uses ultrasound waves to temporarily open the brain's protective barrier in patients with Alzheimer's Disease. The goal is to see if this can help medications reach the brain better. Focused ultrasound with microbubbles has been studied recently and shows promise for opening the brain's protective barrier in Alzheimer's disease treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on Alzheimer's medication, you must have been taking it for at least 2 months and at a stable dose for at least 3 months.

What safety data exists for ExAblate Neuro 4000 in humans?

The ExAblate Neuro 4000 system, used for focused ultrasound treatments, has been shown to safely open the blood-brain barrier in Alzheimer's patients without severe adverse effects. Studies report no significant worsening in cognitive decline and no persistent blood-brain barrier dysfunction, indicating a favorable safety profile. ^{1 2 3 4 5}

How is the ExAblate Model 4000 Type 2.0 System treatment different from other Alzheimer's treatments?

The ExAblate Model 4000 Type 2.0 System is unique because it uses focused ultrasound to temporarily disrupt the blood-brain barrier, potentially allowing for better delivery of therapeutic agents to the brain, which is a novel approach compared to traditional Alzheimer's treatments that do not target the blood-brain barrier in this way. ^{6 7 8 9 10}

Research Team

Eligibility Criteria

This trial is for people aged 50-85 with probable Alzheimer's Disease who can walk and report sensations during the procedure. They must have been on stable Alzheimer's medication for at least 3 months if applicable. Exclusions include significant heart disease, MRI contraindications, bleeding disorders, severe liver or kidney issues, untreated sleep apnea, seizure history, current participation in other trials, chronic lung problems, HIV positive status or certain genetic risk factors.

Inclusion Criteria

I am between 50 and 85 years old.

I have been diagnosed with probable Alzheimer's Disease.

You can tell the doctor how you are feeling during the procedure.

Exclusion Criteria

Any contraindications to MRI scanning

I cannot have a lumbar puncture due to health reasons.

My kidney function is severely impaired.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo three serial ExAblate BBB disruption procedures

Varies

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• ExAblate Model 4000 Type 2.0 System (Ultrasound Therapy)

Trial Overview The study tests the safety and effectiveness of the ExAblate Model 4000 Type 2.0 System to temporarily disrupt the blood-brain barrier in patients with Alzheimer's Disease. This disruption could potentially allow better delivery of treatments to the brain.

Participant Groups

Group I: Blood Brain Barrier (BBB) Disruption Experimental Treatment 1 Intervention

ExAblate Model 4000 Type 2.0 System

ExAblate Model 4000 Type 2.0 System is already approved in Canada for the following indications:

Approved in Canada as ExAblate Model 4000 Type 2.0 System for:

• Essential Tremor
• Parkinson's Disease
• Alzheimer's Disease (clinical trials)

Who Is Running the Clinical Trial?

InSightec

Lead Sponsor

Trials

92

Recruited

3,800+

Dr. Maurice R. Ferré

InSightec

Chief Executive Officer

MD

Dr. Arjun Desai

InSightec

Chief Medical Officer

MD

Findings from Research

Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) was safely used to temporarily increase blood-brain barrier (BBB) permeability in nine older participants with Alzheimer's disease, without causing serious adverse events or worsening cognitive decline over six months.

While MRgFUS showed some reduction in amyloid levels in specific brain regions, it did not lead to significant changes in Alzheimer's disease biomarkers in the cerebrospinal fluid or blood, indicating that while the technique is safe, its efficacy in altering disease pathology needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound. Meng, Y., Goubran, M., Rabin, JS., 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]

In the ongoing phase 1b PRIME study involving patients with prodromal or mild Alzheimer's disease, aducanumab treatment led to significant reductions in amyloid PET SUVR, indicating a decrease in amyloid plaque burden over time and with higher doses.

The choice of reference regions for calculating SUVR significantly influenced effect sizes, with subcortical white matter and the pons yielding the largest effect sizes, while using the anterior cingulate cortex as a target ROI provided better results than a composite cortex approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Reference and Target Region Selection on Amyloid PET SUV Ratios in the Phase 1b PRIME Study of Aducanumab. Chiao, P., Bedell, BJ., Avants, B., et al.[2019]

The ExAblate Neuro 4000 system uses Magnetic Resonance guided Focused UltraSound (MRgFUS) to precisely target and thermally ablate specific brain tissues, showing promise particularly in treating conditions like Essential Tremor.

Current clinical applications demonstrate that MRgFUS is both safe and effective, but ongoing advancements in technology are needed to enhance its efficacy and expand its use for various neurological diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Device profile of exAblate Neuro 4000, the leading system for brain magnetic resonance guided focused ultrasound technology: an overview of its safety and efficacy in the treatment of medically refractory essential tremor. Jameel, A., Bain, P., Nandi, D., et al.[2021]

The ExAblate device, approved for treating movement disorders like tremor-dominant Parkinson's disease, shows minimal cognitive decline in patients post-treatment, particularly in areas like verbal fluency and inhibition.

Current research on the neurocognitive effects of MRgFUS in Parkinson's disease is limited, with only two studies using comprehensive evaluations, highlighting the need for more rigorous assessments to understand cognitive risks associated with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic resonance-guided focused ultrasound for Parkinson's disease since ExAblate, 2016-2019: a systematic review. Lennon, JC., Hassan, I.[2022]

The study suggests that highly connected 'hub' regions in the brain are particularly vulnerable to Alzheimer's disease due to their excessive neuronal activity, which leads to increased amyloid-β deposition.

Using a computational model, the research found that this excessive activity can cause structural and functional changes in the brain, indicating that targeting neuronal activity may be a potential strategy for early detection and intervention in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity dependent degeneration explains hub vulnerability in Alzheimer's disease. de Haan, W., Mott, K., van Straaten, EC., et al.[2022]

The study utilized a computational platform called The Virtual Brain (TVB) to create personalized virtual brain models for patients with mild cognitive impairment and Alzheimer's disease, linking amyloid beta levels to neural hyperexcitability and altered brain dynamics.

Simulations successfully replicated known EEG alterations in Alzheimer's patients, showing that higher amyloid beta loads lead to slower brain wave frequencies, and suggested that NMDA receptor antagonism from memantine could potentially reverse these changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease. Stefanovski, L., Triebkorn, P., Spiegler, A., et al.[2023]

In a study of 16 aged subjects with varying levels of Alzheimer's disease pathology, changes in the GABA(B) receptor R1 protein (GBR1) were observed, indicating its potential role in the vulnerability of hippocampal neurons as the disease progresses.

In early stages of Alzheimer's, increased GBR1 expression may help protect neurons, but in advanced stages, particularly in the CA1 region, reduced GBR1 levels are linked to neuronal loss, suggesting that these changes could disrupt the balance of neurotransmitters and contribute to cognitive dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in hippocampal GABABR1 subunit expression in Alzheimer's patients: association with Braak staging. Iwakiri, M., Mizukami, K., Ikonomovic, MD., et al.[2023]

In a study using the J20 transgenic mouse model of familial Alzheimer's disease, researchers found that early amyloid beta (Aβ) buildup leads to significant impairments in the medial entorhinal cortex (MEC) grid cell network, affecting spatial coding.

These impairments in grid cells occurred early in the disease process, coinciding with reduced spatial memory performance, highlighting the critical role of Aβ in disrupting neural circuits essential for navigation and memory.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disruption of the grid cell network in a mouse model of early Alzheimer's disease. Ying, J., Keinath, AT., Lavoie, R., et al.[2022]

Alzheimer's disease leads to significant disruption of cortical circuitry, particularly affecting memory-related systems, which results in severe cognitive dysfunction and behavioral disturbances.

The early and selective degeneration of specific cortical circuits, such as those connecting the hippocampus and the cholinergic system, is likely responsible for the pronounced memory loss in Alzheimer's patients, highlighting the need for early diagnosis and targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormalities of neural circuitry in Alzheimer's disease: hippocampus and cortical cholinergic innervation. Geula, C.[2019]

References

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

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound. [2023]

2. 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]

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

Impact of Reference and Target Region Selection on Amyloid PET SUV Ratios in the Phase 1b PRIME Study of Aducanumab. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Device profile of exAblate Neuro 4000, the leading system for brain magnetic resonance guided focused ultrasound technology: an overview of its safety and efficacy in the treatment of medically refractory essential tremor. [2021]

5. Italy pubmed.ncbi.nlm.nih.gov

Magnetic resonance-guided focused ultrasound for Parkinson's disease since ExAblate, 2016-2019: a systematic review. [2022]

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

Activity dependent degeneration explains hub vulnerability in Alzheimer's disease. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Changes in hippocampal GABABR1 subunit expression in Alzheimer's patients: association with Braak staging. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Disruption of the grid cell network in a mouse model of early Alzheimer's disease. [2022]

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

Abnormalities of neural circuitry in Alzheimer's disease: hippocampus and cortical cholinergic innervation. [2019]