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

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

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Device: Neuronavigation-guided single-element focused ultrasound transducer; Drug: Definity; Other: Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents; Other: Positron Emission Tomography (PET); Other: Amyvid

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 11021
      • Columbia University Irving Medical Center/NYPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Device Feasibility
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Device: 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.; Drug: Definity; Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier.; Other Names: Perflutren Lipid Microsphere; Other: Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents; 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.; Other: Positron Emission Tomography (PET); A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load.; Other: Amyvid; To be used during the PET scan to determine uptake of Amyvid within the treated area.; Other Names: 18F-Florbetapir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline through 3 days post-treatment
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.	Baseline through 3 days post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Screening through 3 weeks post-treatment
Change in Mini-Mental State Examination (MMSE) Score	The MMSE is a questionnaire that is used to measure cognitive impairment. The total score range is 0 to 30, with a higher score indicating a better outcome. Cognitive function will be assessed before and after the focused ultrasound treatment to determine the change in MMSE.	Screening through 3 months post-treatment

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Elisa Konofagou, PhD, Columbia University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• Ultrasound Elasticity Imaging Laboratory - Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2020
• Primary Completion (Actual): July 11, 2022
• Study Completion (Actual): September 28, 2022

Study Registration Dates

• First Submitted: October 1, 2019
• First Submitted That Met QC Criteria: October 4, 2019
• First Posted (Actual): October 8, 2019

Study Record Updates

• Last Update Posted (Actual): August 26, 2024
• Last Update Submitted That Met QC Criteria: July 31, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: focused ultrasound; blood-brain barrier opening; non-invasive therapy
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: AAAS5163; R01AG038961 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No individual participant data (IPD) will be shared with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes