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

Study Overview
=================
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.

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

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


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Device Feasibility
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Focused ultrasound treatment<br>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<br>* Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system.<br>Drug: Definity<br>* Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier.<br>* Other names: Perflutren Lipid Microsphere;Other: Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents<br>* 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.<br>Other: Positron Emission Tomography (PET)<br>* A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load.<br>Other: Amyvid<br>* To be used during the PET scan to determine uptake of Amyvid within the treated area.<br>* 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 days post-treatment | 
| Change in Mini-Mental State Examination (MMSE) Score | 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. | Screening through 3 months post-treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
focused ultrasound, blood-brain barrier opening, non-invasive therapy