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

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

6 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-08-06

Study Completion Date

2022-09-28

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Alzheimer Disease

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

DEVICE_FEASIBILITY

Blinding Strategy

NONE

Study Groups

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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).

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.

Definity

Intervention Type DRUG

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

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

Intervention Type OTHER

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.

Positron Emission Tomography (PET)

Intervention Type OTHER

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

Amyvid

Intervention Type OTHER

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

Interventions

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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

Definity

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

Intervention Type DRUG

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.

Intervention Type OTHER

Positron Emission Tomography (PET)

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

Intervention Type OTHER

Amyvid

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

Intervention Type OTHER

Other Intervention Names

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Perflutren Lipid Microsphere 18F-Florbetapir

Eligibility Criteria

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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.

Minimum Eligible Age

50 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No