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

• ClinicalTrials.gov Identifier: NCT04118764
• Recruitment Status: Recruiting
• First Posted: October 8, 2019
• Last Update Posted: October 29, 2021
• Sponsor: Elisa Konofagou
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Elisa Konofagou, Columbia University

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease	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	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Device Feasibility
• Official Title: Neuronavigation-guided Focused Ultrasound-induced Blood-brain Barrier Opening in Alzheimer's Disease Patients
• Actual Study Start Date: October 1, 2020
• Estimated Primary Completion Date: July 2022
• Estimated Study Completion Date: July 2022

Arms and Interventions

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 Name: 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 Name: 18F-Florbetapir

Outcome Measures

Primary Outcome Measures :

1. Total Number of Individuals with Successful Opening of the BBB [ Time Frame: Baseline through 3 days post-treatment ]
   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.
2. Total number of Safety Events Related to Opening of BBB [ Time Frame: Baseline through 3 days post-treatment ]
   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 :

1. Percent Change in Amyloid PET Signal Intensity [ Time Frame: Screening through 3 days post-treatment ]
   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.
2. Change in Mini-Mental State Examination (MMSE) Score [ Time Frame: Screening through 3 months post-treatment ]
   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.

Eligibility Criteria

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

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.

Contacts and Locations

Contacts

Contact: Elisa Konofagou, PhD; (212) 342-1612; ek2191@columbia.edu

Contact: Katherine Liu, MS; (212) 342-1612; kl2779@columbia.edu

Locations

United States, New York

Columbia University Irving Medical Center/NYPH; Recruiting

New York, New York, United States, 11021

Contact: Elisa Konofagou, PhD 212-342-1612 ek2191@columbia.edu

Contact: Katherine Liu, MS (212) 342-1612 kl2779@columbia.edu

Principal Investigator: Elisa Konofagou, PhD

Sub-Investigator: Lawrence S. Honig, MD, PhD

Sponsors and Collaborators

Elisa Konofagou

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Elisa Konofagou, PhD; Columbia University

More Information

Additional Information:

Ultrasound Elasticity Imaging Laboratory - Columbia University 

Publications:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Elisa Konofagou, Robert and Margaret Hariri Professor in Biomedical Engineering and Radiology, Columbia University
• ClinicalTrials.gov Identifier: NCT04118764
• Other Study ID Numbers: AAAS5163; R01AG038961 ( U.S. NIH Grant/Contract )
• First Posted: October 8, 2019
• Last Update Posted: October 29, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

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

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Keywords provided by Elisa Konofagou, Columbia University:

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

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders