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

Not Applicable

Completed

Interventions: 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

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.

Recruitment & Eligibility

Inclusion Criteria

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.

Arm && Interventions

Group	Intervention	Description
Focused ultrasound treatment	Neuronavigation-guided single-element focused ultrasound transducer	Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg).
Focused ultrasound treatment	Definity	Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg).
Focused ultrasound treatment	Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents	Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg).
Focused ultrasound treatment	Positron Emission Tomography (PET)	Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg).
Focused ultrasound treatment	Amyvid	Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg).

Primary Outcome Measures

Name	Time	Method
Total Number of Safety Events Related to Opening of BBB	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.
Total Number of Individuals With Successful Opening of the BBB	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.

Secondary Outcome Measures

Name	Time	Method
Change in Mini-Mental State Examination (MMSE) Score	Screening through 3 months post-treatment	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.
Percent Change in Amyloid PET Signal Intensity	Screening through 3 weeks 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.

Locations (1): Columbia University Irving Medical Center/NYPH
🇺🇸
New York, New York, United States