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

Inclusion Criteria:

• 50 years of age or older.

• Diagnosis of early Alzheimer's disease (AD) or mild cognitive impairment (MCI) atminimum. 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 minorskin or respiratory infections.

• History of seizure disorder.

• History of asthma or allergies to food or medication with significant symptoms inpast 3 years.

• Severe brain atrophy.

• Inability to comply with the procedures of the protocol, including follow-up MRIscans.

• Pregnancy or lactation.

• Impaired renal function with estimated glomerular filtration rate (eGFR) <30mL/min/1.73m2 provided by a standard blood test at maximum 2 weeks prior to theultrasound treatment.

• Active infection/inflammation.

• Acute or chronic hemorrhages, i.e. > 4 lobar microbleeds, and no siderosis ormacrohemorrhages.

• Tumors or space occupying lesions.

• Meningeal enhancements.

• Intracranial hypotension.