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

Columbia University

Status: Completed

Conditions: Alzheimer Disease

Treatments: Other: Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents; Device: Neuronavigation-guided single-element focused ultrasound transducer; Other: Positron Emission Tomography (PET); Other: Amyvid; Drug: Definity

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT04118764

AAAS5163

R01AG038961 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 6 patients

Sex: All

Ages: 50+ years old

Volunteers: No 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.

Trial design

Primary purpose: Device Feasibility

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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6 participants in 1 patient group

Focused ultrasound treatment

Experimental group

Description:

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

Treatment:

Drug: Definity

Other: Amyvid

Other: Positron Emission Tomography (PET)

Device: Neuronavigation-guided single-element focused ultrasound transducer

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