Back to results

Non-invasive Blood-brain Barrier Opening in Alzheimer's Disease Patients Using Focused Ultrasound

Primary Purpose

Alzheimer Disease

Status

Active

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Neuronavigation-guided single-element focused ultrasound transducer

Definity

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

Positron Emission Tomography (PET)

Amyvid

About this trial

This is an interventional device feasibility trial for Alzheimer Disease focused on measuring focused ultrasound, blood-brain barrier opening, non-invasive therapy

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

50 years of age or older.
Diagnosis of early Alzheimer's disease (AD) or mild cognitive impairment (MCI) at minimum. All following criteria must be met:
- Probable MCI or AD consistent with criteria outlined in (McKhann et al 2011, Petersen et al 2018).
- Mini Mental State Examination (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).
Ability to provide informed consent.

Exclusion Criteria:

Contraindication for Magnetic Resonance Imaging (MRI).
Contra-indication history or hypersensitivity to MRI contrast agents (e.g., Dotarem) or microbubbles (e.g., Definity).
Prior brain surgery, including deep brain stimulation.
Metallic implants.
Moderate or severe uncontrolled hypertension (systolic blood pressure > 140 mmHg).
Abnormal coagulation profile, e.g. hemophilia A or B.
Coagulopathy or under anticoagulant therapy.
History of stroke or cardiovascular disease.
Active/detectable gingivitis, herpes simplex, hepatitis, tuberculosis, and minor skin or respiratory infections.
History of seizure disorder.
History of asthma or allergies to food or medication with significant symptoms in past 3 years.
Severe brain atrophy.
Inability to comply with the procedures of the protocol, including follow-up MRI scans.
Pregnancy or lactation.
Impaired renal function with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 provided by a standard blood test at maximum 2 weeks prior to the ultrasound treatment.
Active infection/inflammation.
Acute or chronic hemorrhages, i.e. > 4 lobar microbleeds, and no siderosis or macrohemorrhages.
Tumors or space occupying lesions.
Meningeal enhancements.
Intracranial hypotension.

Sites / Locations

Columbia University Irving Medical Center/NYPH

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Focused ultrasound treatment

Arm Description

Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg).

Outcomes

Primary Outcome Measures

Total Number of Individuals with Successful Opening of the BBB

The total number of individuals with successful opening of the BBB will be assessed. Blood-brain barrier opening volume will be measured in mm^3 through contrast-enhanced T1-weighted MRI on the day of the focused ultrasound treatment and 3 days after treatment, to confirm blood-brain barrier restoration.

Total number of Safety Events Related to Opening of BBB

The total number of safety events related to opening of the BBB as assessed by T2 and susceptibility-weighted (SWI) MRI. Safety will be established by the presence and the total area of hyper-intense or hypo-intense areas in the T2 and SWI scans.

Secondary Outcome Measures

Percent Change in Amyloid PET Signal Intensity

Amyloid plaques will be assessed through PET imaging before and after the focused ultrasound treatment. The standardized uptake value ratio images (SUVr) will be compared before and after the FUS treatment, to investigate if there is a change in the uptake of 18F-Florbetapir within the treated area.

Change in Mini-Mental State Examination (MMSE) Score

The MMSE is a 30-point questionnaire that is used to measure cognitive impairment. MMSE scores range from 0 (worst outcome)-30 (better outcome). Cognitive function will be assessed before and after the focused ultrasound treatment to determine a the change in MMSE.

Full Information

NCT ID

NCT04118764

First Posted

October 1, 2019

Last Updated

February 6, 2023

Sponsor

Elisa Konofagou

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT04118764

Brief Title

Non-invasive Blood-brain Barrier Opening in Alzheimer's Disease Patients Using Focused Ultrasound

Official Title

Neuronavigation-guided Focused Ultrasound-induced Blood-brain Barrier Opening in Alzheimer's Disease Patients

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 6, 2020 (Actual)

Primary Completion Date

September 2023 (Anticipated)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Elisa Konofagou

Collaborators

National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to test a new technique that may, in the future, help deliver medications to the brain of people with Alzheimer's disease. Participants in this study will undergo a focused ultrasound treatment to the brain, along with Magnetic Resonance Imagine (MRI) and Positron Emission Tomography (PET) scans.

Detailed Description

Central nervous system disorders are currently being symptomatically treated since the molecular events provoking their onset have not been yet identified. Drug delivery techniques have to overcome the almost impermeable blood-brain barrier (BBB) and can be grouped into two main categories: (i) invasive and targeted, and (ii) non-invasive and non-targeted methods. However, the technological advances of the past decades revealed the immense potential of focused ultrasound (FUS) in transcranial applications. In contrast to other techniques, FUS-mediated BBB opening is both non-invasive and targeted. The localized energy delivery coupled with the circulation of intravenously administered microbubbles initiates biological effects confined only to the vessel walls and contained only in the targeted region within the brain. The purpose of the study is to assess the safety and feasibility of focused ultrasound-induced blood-brain barrier opening in Alzheimer's disease patients, using a single-element transducer with neuronavigation guidance. The investigators will also test whether treatment with focused ultrasound alone alters the amyloid protein levels in the treated brain areas and its potential effects on the cognitive function of Alzheimer's patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer Disease

Keywords

focused ultrasound, blood-brain barrier opening, non-invasive therapy

7. Study Design

Primary Purpose

Device Feasibility

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Focused ultrasound treatment

Arm Type

Experimental

Arm Description

Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg).

Intervention Type

Device

Intervention Name(s)

Neuronavigation-guided single-element focused ultrasound transducer

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Definity

Other Intervention Name(s)

Perflutren Lipid Microsphere

Intervention Description

Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier.

Intervention Type

Other

Intervention Name(s)

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

Intervention Description

MRI scans will be completed at baseline and immediately after the focused ultrasound treatment to confirm BBB opening and safety. A follow-up MRI will be performed three days after treatment to confirm BBB closure, only in the case of successful BBB opening.

Intervention Type

Other

Intervention Name(s)

Positron Emission Tomography (PET)

Intervention Description

A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load.

Intervention Type

Other

Intervention Name(s)

Amyvid

Other Intervention Name(s)

18F-Florbetapir

Intervention Description

To be used during the PET scan to determine uptake of Amyvid within the treated area.

Primary Outcome Measure Information:

Title

Total Number of Individuals with Successful Opening of the BBB

Description

Time Frame

Baseline through 3 days post-treatment

Title

Total number of Safety Events Related to Opening of BBB

Description

Time Frame

Baseline through 3 days post-treatment

Secondary Outcome Measure Information:

Title

Percent Change in Amyloid PET Signal Intensity

Description

Time Frame

Screening through 3 days post-treatment

Title

Change in Mini-Mental State Examination (MMSE) Score

Description

Time Frame

Screening through 3 months post-treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 50 years of age or older. Diagnosis of early Alzheimer's disease (AD) or mild cognitive impairment (MCI) at minimum. All following criteria must be met: Probable MCI or AD consistent with criteria outlined in (McKhann et al 2011, Petersen et al 2018). Mini Mental State Examination (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). Ability to provide informed consent. Exclusion Criteria: Contraindication for Magnetic Resonance Imaging (MRI). Contra-indication history or hypersensitivity to MRI contrast agents (e.g., Dotarem) or microbubbles (e.g., Definity). Prior brain surgery, including deep brain stimulation. Metallic implants. Moderate or severe uncontrolled hypertension (systolic blood pressure > 140 mmHg). Abnormal coagulation profile, e.g. hemophilia A or B. Coagulopathy or under anticoagulant therapy. History of stroke or cardiovascular disease. Active/detectable gingivitis, herpes simplex, hepatitis, tuberculosis, and minor skin or respiratory infections. History of seizure disorder. History of asthma or allergies to food or medication with significant symptoms in past 3 years. Severe brain atrophy. Inability to comply with the procedures of the protocol, including follow-up MRI scans. Pregnancy or lactation. Impaired renal function with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 provided by a standard blood test at maximum 2 weeks prior to the ultrasound treatment. Active infection/inflammation. Acute or chronic hemorrhages, i.e. > 4 lobar microbleeds, and no siderosis or macrohemorrhages. Tumors or space occupying lesions. Meningeal enhancements. Intracranial hypotension.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Elisa Konofagou, PhD

Organizational Affiliation

Columbia University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Columbia University Irving Medical Center/NYPH

City

New York

State/Province

New York

ZIP/Postal Code

11021

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

No individual participant data (IPD) will be shared with other researchers.

Citations:

PubMed Identifier

29789530

Citation

Wu SY, Aurup C, Sanchez CS, Grondin J, Zheng W, Kamimura H, Ferrera VP, Konofagou EE. Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping. Sci Rep. 2018 May 22;8(1):7978. doi: 10.1038/s41598-018-25904-9.

Results Reference

background

PubMed Identifier

31668690

Citation

Pouliopoulos AN, Wu SY, Burgess MT, Karakatsani ME, Kamimura HAS, Konofagou EE. A Clinical System for Non-invasive Blood-Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer. Ultrasound Med Biol. 2020 Jan;46(1):73-89. doi: 10.1016/j.ultrasmedbio.2019.09.010. Epub 2019 Oct 25.

Results Reference

background

PubMed Identifier

34815790

Citation

Mathew AS, Gorick CM, Price RJ. Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption. Theranostics. 2021 Oct 11;11(20):9847-9858. doi: 10.7150/thno.65064. eCollection 2021.

Results Reference

derived

Links:

URL

https://ueil.bme.columbia.edu/

Description

Ultrasound Elasticity Imaging Laboratory - Columbia University

Learn more about this trial

Non-invasive Blood-brain Barrier Opening in Alzheimer's Disease Patients Using Focused Ultrasound

We'll reach out to this number within 24 hrs