Neuronavigation-guided FUS-induced BBB Opening in Alzheimer's Disease Patients and Its Effects on Brain Amyloid and Tau

NCT ID: NCT06600880

Last Updated: 2025-05-11

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-08-31
• Study Completion Date: 2027-12-31

Brief Summary

The primary purpose of this phase 1b study is to further assess the safety and reversibility of focused ultrasound induced blood-brain barrier opening (FUS-BBBO) in participants with Alzheimer´s Disease (AD) using a single-element transducer with neuronavigation guidance. Preliminary results from our phase 1a study demonstrate that our neuronavigation-guided FUS system was capable of safely and transiently open the BBB in participants with AD. The information collected in this new study may be used to design future clinical trials to ultimately provide a viable alternative for treatment of AD in a safe and noninvasive manner.

Our secondary objective includes the assessment of the therapeutic efficacy of FUS-BBBO in reducing amyloid beta and neurofibrillary tangles, the main hallmark pathologies of AD, using PET tracers. Based on our preclinical studies in AD transgenic mouse models, FUS-BBBO alone was able to reduce both the amyloid beta and tau protein load, resulting in improvements in behavioral tasks assessing memory. Therefore, in this new study, the effect of FUS-BBBO on the amyloid beta and tau protein load in patients with AD will be assessed through the use of PET tracers.

Detailed Description

Regarding the primary purpose of this study, the human module for the neuronavigator was implemented in our phase 1a trial, and initial feasibility and safety in a small cohort of AD patients had been tested, with a fast procedural time that required no anesthesia.

Regarding the secondary objective, both amyloid beta and tau protein load in the brain will be assessed at baseline (before FUS-BBBO treatment), and 3-weeks and 3-months after FUS-BBBO treatment, to assess any short-term or long-term changes, respectively.

Conditions

Alzheimer Disease, Early Onset

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DEVICE_FEASIBILITY
• Blinding Strategy: NONE

Study Groups

Focused ultrasound treatment

Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with microbubbles.

Group Type: EXPERIMENTAL

Neuronavigation-guided single-element focused ultrasound transducer

Intervention Type: DEVICE

Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system.

Lumason

Intervention Type: DRUG

New packages of Lumason microbubbles will be shipped from Bracco Diagnostics Inc. and will be used in conjunction with the ultrasound transducer to temporarily open the BBB. Lumason microbubbles will be freshly activated before treatment sonication and will be drawn using a 10-ml syringe to reach the desired dosage of 0.1mL/kg right before the intravenous injection.

Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents

Intervention Type: OTHER

A high-resolution MRI (with and without gadolinium (Dotarem) contrast agent) will be acquired prior to BBB opening on the GE SIGNATM Premier (3T) (same scanner as in the NHP study) for pre-treatment planning and screening purposes. Then, a second MRI (with and without gadolinium) will be acquired and read by a Board-Certified Radiologist immediately after the treatment sonication in order to assess the BBB opening and safety. Finally, a final follow-up MRI (with and without gadolinium) will be conducted 3 days (±1 day) after the treatment to confirm BBB closing and/or safety. This will be read by a Board-Certified Radiologist as well.

All MRI procedures will be performed at the CUIMC/Neurological Institute of New York.

Positron Emission Tomography (PET)

Intervention Type: RADIATION

A first PET/CT scan with Amyvid (18F-Florbetapir) and MK-6240 (F18-Florquinitau) tracers will be performed on the SIEMENS Biograph 64 to assess the baseline amyloid plaque load and tau load before the treatment, respectively. Finally, two follow-up PET/CT scans will be conducted 3 weeks (±1 week) and 3 months (±2 weeks) post-treatment to assess amyloid plaque load (using Amyvid) and tau load (using MK-6240).

Amyvid

Intervention Type: DRUG

Amyloid PET tracer Amyvid (18F- Florbetapir) will be stored in their original container with proper radiation shielding at 25 °C and only handled by properly trained personnel in the handling and administration of radioactive materials, which requires employing proper radiation protection procedures.

MK-6240

Intervention Type: DRUG

\[18F\]MK-6240 will be synthesized, purified, and formulated at the local radiochemistry synthesis laboratory and will be administered as a sterile, pyrogen-free solution by IV injection. The radiotracer \[18F\]MK-6240 is supplied in a sterile, ready-to-use solution, direct from the Columbia University PET Center. It is supplied for a targeted calibration time, the precise volume to be administered at a given time can be calculated based on the decay of F-18. Only personnel properly trained in the handling and administration of radioactive materials should handle \[18F\]MK-6240. Usual radiation protection procedures should be used for handling radiotracers, including shielding (lead or tungsten containers/shields), and personal protective equipment including gloves. There are no specific procedures required for the handling of \[18F\]MK-6240. The expiry of \[18F\]MK-6240 is eight hours from the time at End of Synthesis (EOS).

Dotarem

Intervention Type: DRUG

FDA-approved medication. Dotarem will be handled in accordance with the CUMC Research Pharmacy procedures and NYP policy P168, Version 4. Dotarem will be used according to its labeling. 0.2 ml/kg.

Blood draw

Intervention Type: DIAGNOSTIC_TEST

Blood samples will be collected through an intravenous catheter or a finger prick during screening, on the day of the FUS treatment and the follow up examinations (week 3 and month 3). These samples will be processed to assess any blood content changes induced by the focused ultrasound treatment.

UR5e

Intervention Type: DEVICE

Universal Robots robotic arm used for the accurate positioning of the neuronavigation-guided single-element focused ultrasound transducer with respect to the patient's head.

Urine test

Intervention Type: DIAGNOSTIC_TEST

Urine test required following the MRI and PET Centers policy used clinically for pregnancy screening

Interventions

Neuronavigation-guided single-element focused ultrasound transducer

Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system.

Intervention Type: DEVICE

Lumason

New packages of Lumason microbubbles will be shipped from Bracco Diagnostics Inc. and will be used in conjunction with the ultrasound transducer to temporarily open the BBB. Lumason microbubbles will be freshly activated before treatment sonication and will be drawn using a 10-ml syringe to reach the desired dosage of 0.1mL/kg right before the intravenous injection.

Intervention Type: DRUG

Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents

A high-resolution MRI (with and without gadolinium (Dotarem) contrast agent) will be acquired prior to BBB opening on the GE SIGNATM Premier (3T) (same scanner as in the NHP study) for pre-treatment planning and screening purposes. Then, a second MRI (with and without gadolinium) will be acquired and read by a Board-Certified Radiologist immediately after the treatment sonication in order to assess the BBB opening and safety. Finally, a final follow-up MRI (with and without gadolinium) will be conducted 3 days (±1 day) after the treatment to confirm BBB closing and/or safety. This will be read by a Board-Certified Radiologist as well.

All MRI procedures will be performed at the CUIMC/Neurological Institute of New York.

Intervention Type: OTHER

Positron Emission Tomography (PET)

A first PET/CT scan with Amyvid (18F-Florbetapir) and MK-6240 (F18-Florquinitau) tracers will be performed on the SIEMENS Biograph 64 to assess the baseline amyloid plaque load and tau load before the treatment, respectively. Finally, two follow-up PET/CT scans will be conducted 3 weeks (±1 week) and 3 months (±2 weeks) post-treatment to assess amyloid plaque load (using Amyvid) and tau load (using MK-6240).

Intervention Type: RADIATION

Amyvid

Amyloid PET tracer Amyvid (18F- Florbetapir) will be stored in their original container with proper radiation shielding at 25 °C and only handled by properly trained personnel in the handling and administration of radioactive materials, which requires employing proper radiation protection procedures.

Intervention Type: DRUG

MK-6240

\[18F\]MK-6240 will be synthesized, purified, and formulated at the local radiochemistry synthesis laboratory and will be administered as a sterile, pyrogen-free solution by IV injection. The radiotracer \[18F\]MK-6240 is supplied in a sterile, ready-to-use solution, direct from the Columbia University PET Center. It is supplied for a targeted calibration time, the precise volume to be administered at a given time can be calculated based on the decay of F-18. Only personnel properly trained in the handling and administration of radioactive materials should handle \[18F\]MK-6240. Usual radiation protection procedures should be used for handling radiotracers, including shielding (lead or tungsten containers/shields), and personal protective equipment including gloves. There are no specific procedures required for the handling of \[18F\]MK-6240. The expiry of \[18F\]MK-6240 is eight hours from the time at End of Synthesis (EOS).

Intervention Type: DRUG

Dotarem

FDA-approved medication. Dotarem will be handled in accordance with the CUMC Research Pharmacy procedures and NYP policy P168, Version 4. Dotarem will be used according to its labeling. 0.2 ml/kg.

Intervention Type: DRUG

Blood draw

Blood samples will be collected through an intravenous catheter or a finger prick during screening, on the day of the FUS treatment and the follow up examinations (week 3 and month 3). These samples will be processed to assess any blood content changes induced by the focused ultrasound treatment.

Intervention Type: DIAGNOSTIC_TEST

UR5e

Universal Robots robotic arm used for the accurate positioning of the neuronavigation-guided single-element focused ultrasound transducer with respect to the patient's head.

Intervention Type: DEVICE

Urine test

Urine test required following the MRI and PET Centers policy used clinically for pregnancy screening

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

18F-Florbetapir

Eligibility Criteria

Inclusion Criteria

• Age greater than 50 years old.
• Diagnosis of MCI or AD. All following criteria must be met:
• MMSE score between 12 and 26.
• Modified Hachinski Ischemia Scale (MHIS) score of <= 4
• Short form Geriatric Depression Scale (GDS) score of <= 6.
• PET scan confirming amyloid plaque load using Amyvid (18F-Florbetapir).
• PET scan confirming tau positivity in the frontal lobe using MK-6240 (F18-Florquinitau).
• Ability to provide informed consent.

Exclusion Criteria

• Prior administration of any amyloid-reducing agent such as aducanumab or lecanemab.
• Contraindication for MRI.
• Contra-indication history or hypersensitivity to MRI contrast agents (e.g., Dotarem) or microbubbles (e.g., Definity, Lumason), including polyethylene glycol (PEG) allergy.
• Prior brain surgery, including deep brain stimulation.
• Metallic implants.
• Abnormal coagulation profile (significant abnormality in PT, PTT, or platelets).
• Anticoagulant therapy.
• History of seizure disorder.
• Brain atrophy to a degree that would interfere with ultrasound delivery.
• Inability to comply with the procedures of the protocol, including follow-up scans.
• Women with capacity to bear children or lactating.
• Impaired renal function with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 provided by a standard blood test 2-4 weeks prior to the ultrasound treatment.
• Active infection/inflammation.
• Acute or chronic hemorrhages, i.e. > 4 lobar microbleeds, or an area of siderosis or macrohemorrhages.
• Tumors or space-occupying lesions of significance.
• Any uncontrolled medical disorder that might interfere with the ability to safely perform the study.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Grace McIlvain, PhD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Columbia University Irving Medical Center

New York, New York, United States

Countries

United States

Central Contacts

Sergio Jimenez Gambin, PhD

Role: CONTACT

sj3044@columbia.edu

9295455655 ext. 1

Facility Contacts

Sergio Jimenez Gambin, PhD

Role: primary

sj3044@columbia.edu

929-545-5655 ext. 1

Other Identifiers

AAAV4854

Identifier Type: -

Identifier Source: org_study_id